Clinical trial NCT04632992
Conditions: Advanced Unresectable or Metastatic Solid Malignancy
Sponsor: Genentech, Inc.
Start date: 2021-01-13; Completion date: 2024-02-27
Enrollment: 252 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase II, multicenter, non-randomized, open-label, multi-arm study designed to evaluate the safety and efficacy of targeted therapies as single agents or in rational, specified combinations in participants with advanced unresectable or metastatic solid tumors determined to harbor specific biomarkers.

Patients will be enrolled based on local testing performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently accredited diagnostic laboratory. The multi-arm structure of the MyTACTIC study allows patients with solid tumors to be treated with a drug or drug regimen tailored to their biomarker identified at screening.

Detailed description:

Arms: arm 1: Participants in this treatment arm must have a positive tumor biomarker result for ROS1 gene fusion. arm 2: Participants in this treatment arm must have a positive tumor biomarker result for PI3KCA activating mutation. arm 3: Participants in this treatment arm must have a positive tumor biomarker result for ALK rearrangement tumors. arm 4: Participants in this treatment arm must have a positive tumor biomarker result for either AKT1/2/3 activating mutation or PTEN loss/loss of function. arm 5: Participants in this treatment arm must have a positive tumor biomarker result for either tumor mutational burden (TMB) high or microsatellite instability (MSI) high/deficient mismatch repair (dMMR). arm 6: Participants in this treatment arm must have a positive tumor biomarker result for human epidermal growth factor receptor 2 (HER2) mutations or amplification without known TMB high or MSI high/dMMR. arm 7: Participants in this treatment arm must have a positive tumor biomarker result for HER2 mutation or amplification without known TMB high or MSI high/dMMR. arm 8: Participants in this treatment arm must have a positive tumor biomarker result for HER2 mutation or amplification without known TMB high or MSI high/dMMR. arm 9: Participants in this treatment arm must have a positive tumor biomarker result for HER2 mutation or amplification without known TMB high or MSI high/dMMR. arm 10: Participants in this treatment arm must have positive tumor biomarker results for HER2 mutation or amplification and TMB high or MSI high/dMMR. arm 11: Participants in this treatment arm must have a positive tumor biomarker result for PI3KCA activating mutation. arm 12: Participants in this treatment arm must have a positive tumor biomarker result for either AKT1/2/3 activating mutation or PTEN loss/loss of function. arm 13: Participants in this treatment arm must have a positive tumor biomarker results for PI3KCA activating mutations and either AKT1/2/3 activating mutation or PTEN loss/loss of function. arm 14: Participants in this treatment arm must have a positive tumor biomarker result for either TMB high or MSI high/dMMR. arm 15: Participants in this treatment arm must have a positive tumor biomarker result for RET fusion.
Interventions: intervention 1: Entrectinib intervention 2: Inavolisib intervention 3: Alectinib intervention 4: Ipatasertib intervention 5: Atezolizumab intervention 6: Trastuzumab Emtansine intervention 7: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf intervention 8: Tucatinib intervention 9: Investigator's Choice of Chemotherapy intervention 10: Paclitaxel intervention 11: Tiragolumab intervention 12: Pralsetinib
Intervention descriptions: intervention 1: Entrectinib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 600 milligrams (mg) per day once a day (QD) until disease progression, intolerable toxicity, or consent withdrawal. intervention 2: Inavolisib will be self-administered by participants orally at home (except on clinic days) at the same time each day, on a starting dose of 9 mg/day QD until disease progression, intolerable toxicity, or consent withdrawal. intervention 3: Alectinib will be self-administered by participants orally at home (except on clinic days), at the same times each day, on a starting dose of 600 mg twice a day (BID) until disease progression, intolerable toxicity, or consent withdrawal. intervention 4: Ipatasertib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 400 mg QD until disease progression, intolerable toxicity, or consent withdrawal. intervention 5: Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg for participants on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit). intervention 6: Trastuzumab emtansine will be administered at 3.6 mg per kilogram (kg) of body weight by IV infusion every 21 days (unless dose reduction and/or dose delays are required) until disease progression or unacceptable toxicity. intervention 7: PH FDC SC will be administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab once every 3 weeks. intervention 8: Tucatinib 300 mg will be administered orally BID continuously starting from Cycle 1 Day 1 onwards. intervention 9: Chemotherapy will consist of docetaxel, paclitaxel, or capecitabine, as determined by the investigator, and will be administered per the respective package insert and institutional guidelines. intervention 10: The dose of paclitaxel is 80 mg/m2 administered by IV infusion on Days 1, 8, and 15 of each 28-day cycle. The paclitaxel infusion will be delivered over at least 60 minutes for each dose per institutional guidelines and administered after the oral dose of ipatasertib. intervention 11: Following the administration of atezolizumab and an observation period, participants will receive 600 mg tiragolumab at a fixed dose administered by IV infusion on Day 1 of each 21-day cycle. intervention 12: Pralsetinib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 400 mg/day (four 100-mg capsules per day) once a day (QD) until disease progression, intolerable toxicity, or consent withdrawal.

Protocol documents:
Prot_000.pdf: 
Official Title: 
NCT Number: 
Document Date: 
MyTACTIC: An Open-Label Phase II Study Evaluating Targeted 
Therapies in Patients Who Have Advanced Solid Tumors With 
Genomic Alterations or Protein Expression Patterns Predictive of 
Response
NCT04632992
Protocol Amendment Version 6: 28-February-2023


CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
MyTACTIC Study—Genentech, Inc. 
Protocol ML42439, Version 6 
TITLE: 
MYTACTIC:  AN OPEN-LABEL PHASE II STUDY 
EVALUATING TARGETED THERAPIES IN PATIENTS 
WHO HAVE ADVANCED SOLID TUMORS WITH 
GENOMIC ALTERATIONS OR PROTEIN EXPRESSION 
PATTERNS PREDICTIVE OF RESPONSE  
PROTOCOL NUMBER: 
ML42439 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
152738 
NCT NUMBER: 
NCT04632992 
TEST PRODUCT: 
Entrectinib (RO7102122), Trastuzumab emtansine 
(RO5304020), Pertuzumab Trastuzumab Fixed Dose 
Combination Subcutaneous (PH FDC SC, RO7198574), 
Inavolisib (GDC-0077; RO7113755), Alectinib 
(RO5424802), Ipatasertib (RO5532961), Atezolizumab 
(RO5541267), Tucatinib, Pralsetinib (RO7499790), 
Tiragolumab (RO7092284)   
SPONSOR: 
Genentech, Inc. 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document 


MyTACTIC Study—Genentech, Inc. 
2/Protocol ML42439, Version 6 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
6 
See electronic date stamp on the final page of this document. 
5 
20 January 2022 
4 
19 July 2021 
3 
22 February 2021 
2 
10 November 2020 
1 
8 October 2020 


MyTACTIC Study—Genentech, Inc. 
3/Protocol ML42439, Version 6 
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE
Protocol ML42439 has been amended primarily to update safety information and to 
remove survival follow-up.  Changes to the protocol and a rationale for each change are 
outlined below:
General Updates
 
The study objective has shifted to look for short-term treatment response; therefore
overall survival (OS) will no longer be analyzed and has been removed as a 
secondary endpoint (Sections 2.1.1, 5.3.5.8, and 6.4.2).  Furthermore, it has been 
determined that the 1-year follow-up will not provide meaningful additional OS data 
considering the small sample size within each treatment group; therefore, follow-up 
visits/phone calls after the end of treatment (EOT) visit have been removed from the 
Schedule of Activities (SOA; SOA for each study arm). Additional language
regarding survival follow-up has been updated to reflect these changes (Sections 
3.1.1, 3.2, 4.6.1, 4.6.2; Section 4.6.3 was removed).  Death will be reported as a 
safety endpoint.
 
Due to the signal seeking nature of the study, tumor assessment images will
no longer be submitted to an independent review facility.  This language has been 
removed from the protocol (Sections 4.5.6 and 9.5).
 
The disease control rate definition has been updated to “the proportion of 
patients whose best response is confirmed complete response (CR), confirmed
partial response (PR), or a response of CR, PR, stable disease, or non-CR/non-pro-
gressive disease for a minimum of 98 days for 28-day cycle arms or 70 days for 21-
day cycle arms after the first treatment date” to align with the statistical analysis plan 
(Sections 2.1.2 and 6.4.2).
 
To align with previous updates, language regarding rescreening for a different 
treatment arm after disease progression has been removed (Section 3.1.1).  This is
no longer allowed.
 
The email address for withdrawal from the Research Biosample Repository after site
closure has been corrected (Section 4.5.8.6).
 
Personal identifiable information (i.e., name) for the Medical Monitor has been
removed from the protocol (title page).  Sites are provided the Medical Monitor’s 
name separately and can contact the Medical Monitor via the Emergency Medical 
Call Center Help Desk (Section 5.4.1).
 
A description of the technical and organizational security measures taken to protect
personal data has been added to align with Clinical Trials Regulation requirements 
(Section 8.4).
 
Language was added to reflect that quality tolerance limits for monitoring
patient safety and data integrity were established prior to study enrollment (Section
9.3).
 
The URL for the Roche Global Policy on Sharing of Clinical Study Information has
been updated (Section 9.6).


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4/Protocol ML42439, Version 6 
 
Definitions of hepatotoxicity grades have been updated throughout to reflect the 
National Cancer Institute Common Terminology Criteria for Adverse Events, version
5 (NCI CTCAE v5; Sections D.5.2.2.5, F.5.2.4.2, J.5.2.4.2, I.5.2.2.5, and I.5.2.3).
     It has been clarified that hematology/complete blood count (CBC) and chemistry tests
for the EOT visit do not need to be repeated if done within 7 days prior to treatment 
discontinuation, unless clinically indicated (SOA for all study arms, except Arm C).
 
It has been clarified that the blood sample at disease progression may be drawn
within 7 days after disease progression (SOA for all study arms).
 
Language has been clarified to indicate that the end of treatment visit must be done
within 28 days after last study dose (SOA for all study arms).
Arm A: Entrectinib
     Note: because no patients were enrolled in this arm and the enrollment period is
 over, no updates were made to this treatment arm during this amendment
(Appendix 10).
 
Arms D, K, L, M: Ipatasertib-specific Changes  
 
 
To account for ipatasertib’s impact on glucose metabolism, instructions for taking 
ipatasertib have been updated to indicate it should be taken at least 2 hours after 
the last meal of the day, and patients should refrain from eating overnight (Sections
D.4.2.2, K.4.2.2, L.4.2.2, and M.4.2.2).
 
Management guidelines for dyslipidemia were added (Section D.5.2.2.9).
 
Dermatologic toxicity guidelines for Arms K and L have been clarified (Sections
K.5.2.2.3 and L.5.2.2.3).
 
Arms E, F, J, K, L, N: Atezolizumab-specific Changes  
 
 
The adverse event management guidelines have been updated to align with the
Atezolizumab Investigator’s Brochure, Version 19, as well as Addendum 1  and 
Addendum 2 to the Atezolizumab Investigator’s Brochure, Version 19 (throughout 
sections and associated subsections of Sections E.5.2, F.5.2, J .5.2, K.5.2, L.5.2, and 
N.5.2).  Adverse event management guidelines for overlapping toxicities were also 
updated accordingly (Sections F.5.2.4.1, J.5.2.4.1, K.5.2.2.3, and L.5.2.2.3).
 
The list of identified risks for atezolizumab has been revised to include myelitis,
facial paresis, and pericardial disorders. Additionally, hemophagocytic 
lymphohistiocytosis has been updated from a potential risk to an identified risk asso-
ciated with atezolizumab, and language has been revised accordingly (Sections 
E.5.1.1, F.5.1.2, J.5.1.2, K.5.1.2,  L.5.1.2, and N.5.1.1).
 
The list of adverse events of special interest has been revised to include myelitis
and facial paresis (Sections E.5.3, F.5.3, J.5.3, K.5.3, L.5.3, and N.5.3).
 
Appendix 8 has been revised to indicate that caution should be used when
considering atezolizumab for patients who have previously experienced a pericardial 
disorder while receiving another immunostimulatory anti-cancer agent.


MyTACTIC Study—Genentech, Inc. 
5/Protocol ML42439, Version 6 
 
Appendix 8 has been revised to include autoimmune myelitis. 
 
Arm N: Tiragolumab-specific Changes  
 
 
The required timing for thyroid function testing has been corrected and aligned to
every 4 cycles (e.g. Cycles 1, 5, 9, 13, etc.)  (Section N.6).
     To align with the Tiragolumab Investigator's Brochure, Version 7, the potential risks 
for tiragolumab have been updated to include lymphopenia and embryofetal
toxicity (Section N.5.1.2).  Additionally, immune-mediated hepatitis has been updated 
to an identified risk associated with tiragolumab (Section N.5.1.2).
 
The dose modifications and treatment interruption sections have been moved to
Section N.5.2.2 to align with combination treatment guidance for atezolizumab plus 
tiragolumab.
 
Infusion-related reactions and cytokine-release syndrome management have been 
separated to align with the tiragolumab plus atezolizumab adverse event manage-
ment guidelines (Sections N.5.2.2.7 and N.5.2.2.8).
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


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4/Protocol ML42439, Version 5 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................. 13 
PROTOCOL SYNOPSIS .................................................................................... 14 
1. 
BACKGROUND ............................................................................ 60 
1.1 
Background and Rationale For Molecularly-Targeted 
Therapies ................................................................................. 64 
1.1.1 
Arm A:  Entrectinib Treatment for Tumors with ROS1 Gene 
Fusions .................................................................................... 64 
1.1.2 
Arm B:  Inavolisib (GDC-0077) Treatment for Tumors with 
PI3Kalpha (PIK3CA) Activating Mutations ............................... 65 
1.1.3 
Arm C:  Alectinib Treatment for Tumors with ALK Gene 
Fusion ...................................................................................... 66 
1.1.4 
Arm D:  Ipatasertib Treatment for Tumors with AKT Gene 
Activating Mutations or PTEN Loss or Loss of Function .......... 68 
1.1.5 
Arm E:  Atezolizumab plus Chemotherapy for Tumors with 
Tumor Mutational Burden10/Microsatellite Instability High 
/Deficient Mismatch Repair ...................................................... 69 
1.1.6 
HER2 Targeted Therapy for HER2-Positive Tumors ............... 71 
1.1.6.1 
Arm F:  Trastuzumab Emtansine plus Atezolizumab for 
HER2-Positive Tumors (without knownTMB-H/MSI-
H/dMMR) ................................................................................. 72 
1.1.6.2 
Arms G & H:  PH FDC SC with or without Chemotherapy 
for HER2-Positive Tumors ....................................................... 73 
1.1.6.3 
Arm I:  Trastuzumab Emtansine plus Tucatinib for HER2-
Positive Tumors ....................................................................... 74 
1.1.6.4 
Arm J: Trastuzumab Emtansine plus Atezolizumab for 
HER2-Positive and TMB-H/MSI-H/dMMR Tumors .................. 75 
1.1.7 
Arms K and L: Ipatasertib Plus Atezolizumab for PI3K 
Activating Mutations or AKT Activating Mutation and/or 
PTEN Loss/Loss of Function ................................................... 77 
1.1.8 
Arm M: Ipatasertib Plus Paclitaxel for Co-mutations in the 
PI3K/AKT Pathway .................................................................. 78 
1.1.9 
Arm N: Tiragolumab Plus Atezolizumab for TMB-
H/MSI-H/dMMR Tumors .......................................................... 79 
1.1.10 
Arm O: Pralsetinib for RET fusion positive Tumors .................. 81 
1.1.10.1 
RET-altered Thyroid Cancer .................................................... 81 


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1.1.10.2 
Other RET-driven Cancers ...................................................... 81 
1.1.10.3 
Pralsetinib Activity .................................................................... 82 
1.2 
Study Rationale ....................................................................... 83 
1.3 
Risk/benefit Assessment ......................................................... 84 
1.3.1 
Risk/Benefit Assessment during COVID-19 ............................. 85 
1.3.1.1 
All Treatment Arms .................................................................. 85 
1.3.1.2 
Immunotherapy Treatment Arms (Arms containing 
Atezolizumab:  E, F, J, K, L & N) ............................................. 85 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 87 
2.1 
Efficacy .................................................................................... 87 
2.1.1 
Primary Efficacy Objective ....................................................... 87 
2.1.2 
Secondary Efficacy Objective .................................................. 87 
2.1.3 
Exploratory Efficacy Objectives ............................................... 87 
2.2 
Safety Objective ....................................................................... 88 
2.3 
Biomarkers Objective ............................................................... 88 
3. 
STUDY DESIGN ........................................................................... 88 
3.1 
Description of the Study ........................................................... 88 
3.1.1 
Overview of Study Design........................................................ 88 
3.1.2 
Dosing of Study Treatment beyond Disease Progression ....... 91 
3.1.3 
Number of Patients .................................................................. 91 
3.2 
End of Study and Length of Study ........................................... 91 
3.3 
Rationale for Study Design ...................................................... 92 
3.3.1 
Rationale for Biomarker Assessments ..................................... 92 
4. 
MATERIALS AND METHODS ...................................................... 93 
4.1 
Patients .................................................................................... 93 
4.1.1 
Inclusion Criteria ...................................................................... 93 
4.1.2 
Exclusion Criteria ..................................................................... 95 
4.2 
Method of Treatment Assignment ............................................ 97 
4.2.1 
Treatment Assignment ............................................................. 97 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 97 
4.3.1 
Study Treatment Formulation and Packaging .......................... 97 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 97 


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4.3.3 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 97 
4.3.4 
Continued Access to Study Treatments ................................... 98 
4.4 
Concomitant Therapy Prohibited Food, and Additional 
Restrictions .............................................................................. 99 
4.5 
Study Assessments ................................................................. 99 
4.5.1 
Informed Consent Forms and Screening Log .......................... 99 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ....................................... 100 
4.5.3 
Physical Examinations ........................................................... 100 
4.5.4 
Vital Signs .............................................................................. 100 
4.5.5 
ECOG Performance status .................................................... 101 
4.5.6 
Tumor and Response Evaluations ......................................... 101 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples .......... 102 
4.5.8 
Optional Samples for Research Biosample Repository ......... 104 
4.5.8.1 
Overview of the Research Biosample Repository .................. 104 
4.5.8.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................. 104 
4.5.8.3 
Sample Collection .................................................................. 105 
4.5.8.4 
Confidentiality ........................................................................ 105 
4.5.8.5 
Consent to Participate in the Research Biosample 
Repository.............................................................................. 106 
4.5.8.6 
Withdrawal from the Research Biosample Repository ........... 106 
4.5.8.7 
Monitoring and Oversight ....................................................... 107 
4.6 
Treatment, Patient, Study, Arm and Site Discontinuation ...... 107 
4.6.1 
Study Treatment Discontinuation ........................................... 107 
4.6.2 
Patient Discontinuation from the Study .................................. 107 
4.6.3 
Study Discontinuation ............................................................ 108 
4.6.4 
Study Arm Discontinuation..................................................... 108 
4.6.5 
Site Discontinuation ............................................................... 108 
5. 
ASSESSMENT OF SAFETY ....................................................... 109 
5.1 
Safety Plan ............................................................................ 109 
5.2 
Safety Parameters and Definitions ........................................ 109 
5.2.1 
Adverse Events ...................................................................... 109 


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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 110 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 110 
5.2.4 
Selected Adverse Events ....................................................... 111 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 111 
5.3.1 
Adverse Event Reporting Period ............................................ 111 
5.3.2 
Eliciting Adverse Event Information ....................................... 112 
5.3.3 
Assessment of Severity of Adverse Events ........................... 112 
5.3.4 
Assessment of Causality of Adverse Events.......................... 112 
5.3.5 
Procedures for Recording Adverse Events ............................ 113 
5.3.5.1 
Infusion-Related Reactions or Injection-Site Reactions 
(When applicable) .................................................................. 113 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................. 114 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 114 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 115 
5.3.5.5 
Abnormal Laboratory Values ................................................. 115 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 116 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 116 
5.3.5.8 
Deaths ................................................................................... 116 
5.3.5.9 
Preexisting Medical Conditions .............................................. 117 
5.3.5.10 
Lack of Efficacy or Worsening of Cancer ............................... 117 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 117 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 118 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 120 
5.4.1 
Emergency Medical Contacts ................................................ 121 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 121 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 121 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 121 
5.4.3 
Reporting Requirements for Pregnancies .............................. 122 
5.4.3.1 
Pregnancies in Female Patients ............................................ 122 


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5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 122 
5.4.3.3 
Abortions................................................................................ 123 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 123 
5.4.4 
Reporting Requirements for Special Situations and 
Non-Serious Adverse Events Associated with a Special 
Situation ................................................................................. 124 
5.5 
Follow-Up of Patients after Adverse Events........................... 124 
5.5.1 
Investigator Follow-Up ........................................................... 124 
5.5.2 
Sponsor Follow-Up ................................................................ 124 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 124 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 125 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 126 
6.1 
Determination of Sample Size ............................................... 126 
6.2 
Summaries of Conduct of Study ............................................ 126 
6.3 
Summaries of Demographic and Baseline Characteristics .... 126 
6.4 
Efficacy Analyses ................................................................... 127 
6.4.1 
Primary Efficacy Endpoint ...................................................... 127 
6.4.2 
Secondary Efficacy Endpoints ............................................... 127 
6.5 
Exploratory Efficacy ............................................................... 128 
6.5.1 
Exploratory Efficacy Objectives ............................................. 128 
6.6 
Safety Analyses ..................................................................... 128 
6.7 
Biomarker Analyses ............................................................... 128 
6.8 
Non-binding Futility Analyses ................................................. 129 
6.9 
Optional Interim Analyses ...................................................... 129 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 129 
7.1 
Data Quality Assurance ......................................................... 129 
7.2 
Electronic Case Report Forms ............................................... 129 
7.3 
Source Data Documentation .................................................. 130 
7.4 
Use of Computerized Systems .............................................. 130 
7.5 
Retention of Records ............................................................. 131 
8. 
ETHICAL CONSIDERATIONS .................................................... 131 


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8.1 
Compliance with Laws and Regulations ................................ 131 
8.2 
Informed Consent .................................................................. 131 
8.3 
Institutional Review Board or Ethics Committee .................... 132 
8.4 
Confidentiality ........................................................................ 133 
8.5 
Financial Disclosure ............................................................... 134 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 134 
9.1 
Study Documentation ............................................................ 134 
9.2 
Protocol Deviations ................................................................ 134 
9.3 
Management of Study Quality .............................................. 134 
9.4 
Site Inspections ..................................................................... 135 
9.5 
Administrative Structure ......................................................... 135 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 135 
9.7 
Protocol Amendments ........................................................... 136 
10. 
REFERENCES............................................................................ 137 
LIST OF TABLES 
Table 1 
Biomarker-specific Study Treatments ......................................... 62 
Table 2 
Estimated Pan-tumor Prevalence of Specified Biomarkers ......... 83 
Table 3 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 112 
Table 4 
Causal Attribution Guidance ..................................................... 113 
Table 5 
Pregnancy Reporting Period after the Last Dose of Study 
Drug .......................................................................................... 122 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 90 
 
LIST OF APPENDICES 
Appendix 1 
MyTACTIC Biomarker Overview ............................................... 148 
Appendix 2 
Contraception and Pregnancy Requirements ........................... 155 
Appendix 3 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 157 
Appendix 4 
Response Assessment in Neuro-Oncology (RANO) Criteria .... 166 
Appendix 5 
Performance Status Scales ....................................................... 169 
Appendix 6 
Anaphylaxis Precautions ........................................................... 170 


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Appendix 7 
Moderate and Strong CYP450 Inhibitors, Inducers and 
Enzyme- and Transporter-Specific Substrates .......................... 171 
Appendix 8 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 174 
Appendix 9 
NYHA Functional Classification System for Heart Failure and 
LVSD NCI CTCAE V5.0 Grading .............................................. 175 
Appendix 10 Arm A: Entrectinib in Patients with ROS1 Fusion-Positive 
Tumors ...................................................................................... 176 
Appendix 11 Arm B:  Inavolisib (GDC-0077) in Patients with PI3K 
(PIK3CA) Activating MutationPositive Tumors ........................ 192 
Appendix 12 Arm C:  Alectinib in Patients with ALK Gene Fusion-Positive 
Tumors ...................................................................................... 214 
Appendix 13 Arm D:  Ipatasertib in Patients with PTEN Loss/ 
Loss-of-Function or AKT Activating Mutation-Positive 
Tumors ...................................................................................... 230 
Appendix 14 Arm E:  Atezolizumab plus Chemotherapy in Patients with 
TMB-H/MSI-H/dMMR-Positive Tumors ..................................... 256 
Appendix 15 Arm F:  Trastuzumab Emtansine Plus Atezolizumab in 
Patients with ERBB2 Gene Amplification- or Mutation-
Positive Tumors ........................................................................ 303 
Appendix 16 Arm G:  PH FDC SC in Patients with ERBB2 Gene 
Amplification- or Mutation-Positive Tumors ............................... 331 
Appendix 17 Arm H:  PH FDC SC Plus Chemotherapy In Patients With 
ERBB2 Amplification- or Mutation-Positive Tumors .................. 347 
Appendix 18 Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients 
with ERBB2 Amplification- or Mutation-Positive Tumors ........... 366 
Appendix 19 Arm J:  Trastuzumab Emtansine Plus Atezolizumab in 
Patients with ERBB2 Amplification Or Mutation Plus TMB-
H/MSI-H/dMMR-Positive Tumors .............................................. 389 
Appendix 20 Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K 
(PIK3CA) Activating Mutation-Positive Tumors ......................... 417 
Appendix 21 Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN 
Loss/ Loss-of-Function or AKT Mutation-Positive Tumors ........ 455 
Appendix 22 Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-
mutations in PI3K (PIK3CA) Activating Mutations and PTEN 
Loss/ Loss-of-Function or AKT Activating Mutation-Positive 
Tumors ...................................................................................... 493 
Appendix 23 Arm N:  Atezolizumab plus Tiragolumab in Patients with 
TMB-H/MSI-H/dMMR-Positive Tumors ..................................... 526 
Appendix 24 Arm O: Pralsetinib in Patients with RET Fusion-Positive 
Tumors ...................................................................................... 580 


 
MyTACTIC Study—Genentech, Inc. 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
MYTACTIC:  AN OPEN-LABEL PHASE II STUDY 
EVALUATING TARGETED THERAPIES IN PATIENTS 
WHO HAVE ADVANCED SOLID TUMORS WITH 
GENOMIC ALTERATIONS OR PROTEIN EXPRESSION 
PATTERNS PREDICTIVE OF RESPONSE 
PROTOCOL NUMBER: 
ML42439 
VERSION NUMBER: 
6 
Eudract Number: 
Not Applicable 
IND NUMBER: 
152738 
NCT NUMBER: 
NCT04632992 
TEST PRODUCT: 
Entrectinib (RO7102122), Trastuzumab emtansine 
(RO5304020); Pertuzumab Trastuzumab Fixed Dose 
Combination Subcutaneous (PH FDC SC, RO7198574); 
Inavolisib (GDC-0077; RO7113755), Alectinib 
(RO5424802), Ipatasertib (RO5532961), Atezolizumab 
(RO5541267); Tucatinib, Pralsetinib (RO7499790), 
Tiragolumab (RO7092284)  
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy 
of the signed form to the CRO. 
 


 
MyTACTIC Study—Genentech, Inc. 
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PROTOCOL SYNOPSIS 
TITLE: 
MYTACTIC:  AN OPEN-LABEL PHASE II STUDY 
EVALUATING TARGETED THERAPIES IN PATIENTS WHO 
HAVE ADVANCED SOLID TUMORS WITH GENOMIC 
ALTERATIONS OR PROTEIN EXPRESSION PATTERNS 
PREDICTIVE OF RESPONSE 
PROTOCOL 
NUMBER: 
ML42439 
VERSION NUMBER: 
6 
Eudract Number: 
Not Applicable 
IND NUMBER: 
152738 
NCT NUMBER: 
NCT04632992 
TEST PRODUCT: 
Entrectinib (RO7102122), Trastuzumab emtansine 
(RO5304020), Pertuzumab Trastuzumab Fixed Dose 
Combination Subcutaneous (PH FDC SC, RO7198574), 
Inavolisib (GDC-0077; RO7113755), Alectinib (RO5424802), 
Ipatasertib (RO5532961), Atezolizumab (RO5541267), 
Tucatinib, Pralsetinib (RO7499790), Tiragolumab (RO7092284)  
PHASE: 
Phase II 
INDICATION: 
Solid tumors 
SPONSOR: 
Genentech, Inc. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of multiple therapies that are selected based on 
potential predictive biomarkers identified in patients with solid tumors.  
EFFICACY 
PRIMARY EFFICACY OBJECTIVE  
The primary objective for this study is to evaluate the efficacy of various treatments and/or 
combinations of treatments in eligible patients with advanced unresectable or metastatic solid 
tumors, on the basis of the following endpoint: 
 
The primary endpoint for each arm of this study will be confirmed ORR (cORR) as 
assessed by the investigator and according to response evaluation criteria in solid tumors 
version 1.1 (RECIST v1.1), or Response Assessment in Neuro-Oncology [RANO] Criteria 
for primary CNS tumors.  The cORR is defined as the proportion of patients whose 
confirmed best response is a complete response (CR) or partial response (PR) for those 
with measurable disease and CR for those with non-measurable disease.  
 


 
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SECONDARY EFFICACY OBJECTIVE  
The secondary efficacy objectives for this study are to evaluate the efficacy of each targeted 
treatment on the basis of the following endpoints: 
 
Progression-Free Survival (PFS) defined as the time from start of treatment to the first 
occurrence of disease progression or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1.  
 
Duration of objective response (DOR), defined as the time from the first occurrence of a 
documented objective response to disease progression or death from any cause 
(whichever occurs first), as determined by the investigator according to RECIST v1.1. 
 
PFS rate at 3 months during treatment and every 3 months thereafter for at least up to 1 
year, defined as the proportion of patients who have not experienced disease progression 
or death from any cause as determined by the investigator, according to RECIST v1.1.   
 
Disease control rate (DCR), defined as the proportion of patients whose best response is 
confirmed CR, confirmed partial response (PR), or a response of CR, PR, stable disease 
(SD), or non-CR/non-progressive disease (PD) for a minimum of 98 days for 28-day 
cycle arms or 70 days for 21-day cycle arms after the first treatment date.   
 
EXPLORATORY EFFICACY OBJECTIVE  
Exploratory efficacy objectives are to evaluate efficacy based following the following: 
 
Analysis of primary and secondary efficacy endpoints when subgrouped by basket, tumor 
site of origin, and/or self-reported race and ethnicity.  
 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety and tolerability of the study 
medications for the tumor types studied based on the following endpoints:  
 
Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 
(NCI CTCAE [v5.0]) 
 
Change from baseline in targeted clinical laboratory test results 
 
BIOMARKERS OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are early surrogates of efficacy or relapse, are associated with a more severe disease state 
(i.e., prognostic biomarkers), are associated wit h acquired resistance to study drug(s), or can 
increase the knowledge and understanding of disease biology and drug safety, on the basis of 
the following endpoint: 
 
The association of baseline and changes in circulating tumor DNA (ctDNA) levels with 
response and progression to therapy. 
 
Determination of baseline and changes in expression or levels of biomarkers in the tumor 
tissue or blood that may be associated with response or resistance to therapy. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
OVERVIEW OF STUDY DESIGN 
MyTACTIC is a Phase II, multicenter, non-randomized, open-label, multi-arm study designed 
to evaluate the safety and efficacy of targeted therapies as single agents or in rational, 
specified combinations in patients with advanced unresectable or metastatic solid tumors 
determined to harbor specific biomarkers.  Patients will be enrolled based on local testing 
performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently 
accredited diagnostic laboratory.  For all patients whose positive biomarker result is from an 
assay other than a tissue-based assay conducted by Foundation Medicine, Inc. (FMI), central 
testing of pre-treatment tissue (preferably from the most recent block) and blood is required 
after enrollment.  Pre-treatment tissue will be submitted within 21 days after enrollment to a 


 
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Sponsor-approved laboratory for central testing; this testing will not impact the study 
participation of enrolled patients.   
The multi-arm structure of the MyTACTIC study allows patients with solid tumors to be treated 
with a drug or drug regimen tailored to their biomarker identified at screening.  Each study 
treatment arm may have separate endpoints, screening, and treatment requirements, defined 
in the respective appendix.  Futility analyses will be employed on all treatment arms to limit 
enrollment where evidence of very limited or lack of efficacy is observed. 
During the study, the following biomarker samples will be collected: 
Tumor tissue  
 
For patients with a positive biomarker result from an assay other than a tissue-based 
assay conducted by FMI, pre-treatment tissue samples (archival or recent resection or 
biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If 
both archival and recent tissue is available, the recent tissue should be preferentially 
submitted.  
Blood samples 
 
Mandatory blood samples will be collected at screening, 8 weeks after first treatment, and 
at disease progression (within 7 days after progression) for analyses including ctDNA 
 
These samples will be used to evaluate predictive and/or prognostic biomarkers, including but 
not limited to biomarkers related to driver oncogene signaling, response to study treatment, 
tumor pathogenesis, and mechanisms of resistance. 
Treatment will be assigned by the treating investigator on the basis of relevant specified 
biomarkers, and will continue until radiographic disease progression (per RECIST v1.1; 
Response Assessment in Neuro-Oncology (RANO) Criteria for primary CNS tumors, or loss of 
clinical benefit for specific treatment arms, upon Medical Monitor consultation; unacceptable 
toxicity; patient or physician decision to discontinue; or death, whichever occurs first.  If a 
patient discontinues treatment prior to disease progression (because of adverse event or other 
reason), tumor assessments will continue as specified in the treatment-specific appendix until 
disease progression, death, withdrawal of consent, or arm/study closure by the Sponsor, 
whichever occurs first.   
Patients who do not meet the criteria for participation in this study (screen failure) or the 
timeline for the screening window may qualify for re-screening at the investigator's discretion.  
Patients must re-sign the consent form prior to rescreening.  The investigator will record 
reasons for screen failure in the screening log.   
 
NUMBER OF PATIENTS 
Approximately 260 patients are anticipated to be enrolled at approximately 60 sites.  Each arm 
will be limited to approximately 25 patients, with the exception of Arms M and O, which will  be 
limited to approximately 10 patients. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following general inclusion criteria to be eligible to enroll in any 
treatment arm:   
 
Signed treatment-specific Informed Consent Form 
 
Positive biomarker results from a CLIA-certified or equivalently accredited diagnostic 
laboratory and availability of a full report of the testing results.  This may be from a tissue 
or blood sample.  
 
For patients with a positive biomarker result from an assay other than a tissue-based 
assay conducted by FMI:  Sufficient archival tissue or a recent pretreatment tissue sample 
must be available for central testing (i.e. at least 11 slides or equivalent block) unless 
approved by Medical Monitor.  If both archival and recent tissues are available, the recent 
tissue should be preferentially submitted.   
 
Age  18 years at time of signing Informed Consent Form 


 
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17/Protocol ML42439, Version 6 
 
Participation in a clinical trial is an appropriate treatment option, in the opinion of the 
investigator 
 
Ability to comply with the study protocol 
 
Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic 
solid malignancy 
 
Evaluable or measurable disease (i.e., at least one target or non-target lesion per RECIST 
V1.1 or one measurable or non-measurable lesion per RANO criteria for patients with 
primary CNS tumors)  
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 02 
 
Life expectancy  8 weeks 
 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment: 
– 
ANC per arm-specific eligibility criteria 
– 
Platelet count  100  109/L (100,000/L) without transfusion  
– 
Hemoglobin  90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
AST, ALT, and alkaline phosphatase (ALP)  3  upper limit of normal (ULN), with the 
following exceptions: 
Patients with documented liver involvement:  AST and ALT  5  ULN 
Patients with documented liver or bone involvement:  ALP  5  ULN 
– 
Total bilirubin  1.5  ULN with the following exception: 
Patients with known Gilbert disease:  total bilirubin  3  ULN 
– 
Serum creatinine  1.5 mg/dL or Glomerular filtration rate  50 mL/min/1.73 m2 as 
calculated through use of the Chronic Kidney Disease Epidemiology Collaboration 
equation 
Glomerular filtration rate (GFR) estimation:  GFR141  min(Scr/κ, 
1)α  max(Scr/κ, 1)-1.209  0.993Age  1.018 [if female]   1.159 [if black] where:  
Scr is serum creatinine in mg/dL,  
κ is 0.7 for females and 0.9 for males,  
α is -0.329 for females and -0.411 for males,  
min indicates the minimum of Scr/κ or 1, and  
max indicates the maximum of Scr/κ or 1 
– 
Albumin  25 g/L (2.5 g/dL) 
 
Agrees to take measures to prevent pregnancy in the patient or partner 
 
In addition to the general inclusion criteria above, in order to be enrolled in a treatment arm 
of the study, patients must meet all of the treatment-specific inclusion criteria for the 
respective arm as detailed in the treatment-specific appendix.  
Note:  The requirements for enrollment into a specific arm may be more stringent.   
 
Exclusion Criteria 
Patients who meet any of the following criteria will be ineligible and excluded from study entry 
in any arm: 
 
Current participation or enrollment in another therapeutic clinical trial 
 
Eligible for an approved indication included in the local prescribing information for the 
applicable study treatment   
 
Symptomatic or actively progressing CNS metastases 
Asymptomatic patients with treated or untreated CNS metastases are eligible, provided 
that all of the following criteria are met: 


 
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18/Protocol ML42439, Version 6 
– No ongoing requirement for corticosteroids as therapy for CNS metastases, unless 
noted otherwise in the arm-specific appendix 
– No evidence of interim progression between the completion of CNS-directed therapy 
and screening radiographic study 
– No history of intracranial hemorrhage or spinal cord hemorrhage 
– Evaluable disease must be present outside the CNS 
 
History of leptomeningeal disease, unless noted otherwise in the arm-specific appendix  
 
Wide field radiotherapy within 14 days prior to start of study treatment 
 
Stereotactic radiosurgery within 7 days prior to start of study treatment 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infections, or any active infection that, in the 
opinion of the investigator, could impact patient safety 
– 
In the setting of a pandemic or epidemic, screening for active infections should be 
considered according to local or institutional guidelines or those of applicable 
professional societies (e.g., American Society of Clinical Oncology [ASCO] or 
European Society for Medical Oncology [ESMO]). 
 
Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to Cycle 
1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1; 
recovery of treatment-related toxicity consistent with other eligibility criteria 
– 
Androgen blockage may be continued for male patients with prostate cancer 
 
Patients known to be positive for HIV are excluded if they meet any of the following 
criteria: 
– 
CD4+ T-cell count of  350 cells/L 
– 
Detectable HIV viral load 
– 
History of an opportunistic infection within the past 12 months 
– 
On stable antiretroviral therapy for  4 weeks 
 
Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with 
the following exceptions:  
– 
Patients who are HCV Ab positive but HCV RNA negative due to prior treatment or 
natural resolution are eligible  
– 
Patients with untreated HCV may be enrolled if the HCV is stable, the patient is not at 
risk for hepatic decompensation, and the intended treatment is not expected to 
exacerbate the HCV infection  
– 
Patients on concurrent HCV treatment may be enrolled if they have HCV below the 
limit of quantification  
 
Patients known to have active hepatitis B (chronic or acute; defined as having a positive 
hepatitis B surface antigen [HBsAg] test) 
– 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible only if they are negative for HBV DNA 
 
History of or concurrent serious medical condition or abnormality in clinical laboratory tests 
that, precludes the patient's safe participation in and completion of the study or confounds 
the ability to interpret data from the study (e.g., clinically significant cardiovascular, 
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures) 
– 
Patients with well-controlled comorbid disease on a stable treatment regimen for 
4 weeks prior to screening are eligible for the study. 


 
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19/Protocol ML42439, Version 6 
 
History of malignancy other than disease under study within 3 years prior to screening, 
with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-
year OS rate  90%), such as adequately treated carcinoma in situ of the cervix, 
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or 
Stage I uterine cancer 
 
Incomplete recovery from any surgery prior to the start of study treatment that would 
interfere with the determination of safety or efficacy of study treatment 
 
Major surgical procedure, other than for diagnosis, or significant traumatic injury within 
4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical 
procedure during the study 
 
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months 
prior to enrollment, unstable arrhythmias, or unstable angina 
 
Pregnant or breastfeeding, or intending to become pregnant during the study 
 
In addition to the general exclusion criteria above, in order to be enrolled in a treatment 
arm of the study, patients must meet all of the treatment-specific exclusion criteria for the 
respective arm as detailed in the treatment-specific appendix.   
Note:  The requirements for enrollment into a specific arm may be more stringent 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV), occurs or 
the date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  LPLV is expected to occur 
approximately 1 year after the last patient is enrolled. 
LENGTH OF STUDY 
LPLV is expected to occur approximately 1 year after the last patient is enrolled.


 
 
 
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INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCTS (INVESTIGATIONAL DRUGS) 
Biomarker alteration 
Study Treatment 
ROS1 gene fusion  
Arm A: Entrectinib 
PIK3CA activating mutation 
Arm B: Inavolisib (GDC-0077) 
Arm K: Ipatasertib + atezolizumab 
ALK gene fusion 
Arm C: Alectinib 
AKT activating mutations and/or PTEN 
loss/loss of function 
Arm D: Ipatasertib 
Arm L: Ipatasertib + atezolizumab 
Co-mutation in PI3KCA activating mutation 
and AKT activating mutation or PI3KCA 
activating mutation and PTEN loss/loss of 
function 
Arm M: Ipatasertib + paclitaxel  
TMB  10/MSI-H/dMMR 
Arm E: Atezolizumab + chemotherapya  
Arm N: Atezolizumab + tiragolumab 
ERBB2 gene mutation or amplification 
without known TMB  10/MSI-H/dMMR 
Arm F: Trastuzumab emtansine + 
atezolizumab 
Arm G: PH FDC SC 
Arm H: PH FDC SC + chemotherapy a 
Arm I: Trastuzumab emtansine + tucatinib 
ERBB2 gene amplification or mutation and 
TMB 10/MSI-H/dMMR  
Arm J: Trastuzumab emtansine + 
atezolizumb   
RET gene fusion  
Arm O: Pralsetinib 
chemochemotherapy; dMMRdeficient mismatch repair; HER2human epidermal growth 
factor receptor 2; IVintravenous; PH FDC SCfixed dose combination of trastuzumab and 
pertuzumab administered subcutaneously; MSI-Hmicrosatellite instability high; 
PI3Kphosphatidylinositol 3-kinase; SCsubcutaneous; TMBtumor mutational burden. 
a 
Investigator’s choice of docetaxel, paclitaxel, or capecitabine. 
 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary endpoint for this study will be cORR as assessed by the investigator and 
according to the corresponding assessment criteria (RECIST v1.1 or RANO).  The cORR is 
defined as the proportion of patients whose confirmed best response is a CR or PR for those 


 
 
 
MyTACTIC Study—Genentech, Inc. 
21/Protocol ML42439, Version 6 
with measurable disease and CR for those with non-measurable disease.  Confidence 
intervals at both 70% and 95% nominal levels will be reported using the Clopper-Pearson 
method.  The primary efficacy endpoint will be computed for all treatment arms.  If a patient 
receives at least one dose of study treatment and discontinues the study for any reason before 
confirmed response can be assessed, the patient will be considered a non-responder (not PR 
and not CR) and will be added to the denominator of the computation of cORR.   
DETERMINATION OF SAMPLE SIZE   
The focus for this study will be estimation since the study is composed of many single arms 
specific to a targeted therapy.  Estimation of the primary endpoint will be 95% confidence 
intervals using the Clopper-Pearson method.  As such, the maximum margin of error for 
sample sizes 25, 50, and 75 are 20.7%, 14.5%, and 11.8%, respectively.  On a per arm basis, 
if the lower bound of the confidence interval is larger than a benchmark specific to that arm, 
then we will consider the given treatment as a significant improvement over the benchmark.   
INTERIM ANALYSES 
Non-binding Futility Analyses  
For some arms, limited data are available regarding the efficacy and safety of the treatment 
across the eligible tumor population(s).  Therefore, data from the first 12 efficacy-evaluable 
patients in a given arm will be used to conduct non-binding interim tumor agnostic futility 
analyses.  Futility analyses for some arms may be conducted with the integration of data from 
other ongoing studies (see the Statistical Analysis Plan [SAP] for details).  These analyses 
may be used to identify whether a treatment may be ineffective in a tumor agnostic population 
due to limited or lack of efficacy, and further accrual into such an arm may be stopped.  
Enrollment will not be stopped while awaiting results of the tumor agnostic futility analysis.  To 
perform the analysis we will use Bayesian gating with arm-specific gating criteria and non-
informative prior where futility will be declared if there is a posterior probability of greater than 
60% that the true cORR is less than an arm-specific unacceptable level. 
Optional Interim Analyses 
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct 
additional interim efficacy analyses.  The decision to conduct an optional interim analysis and 
the timing of the analysis will be documented in the Sponsor's trial master file prior to the 
conduct of the interim analysis.  The interim analysis will be performed and interpreted by 
Sponsor study team personnel. 
 
 
 
ARM A:  ENTRECTINIB IN PATIENTS WITH ROS1 FUSION-POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm A:  entrectinib treatment, patients must have met and continue to meet 
all general eligibility criteria, in addition to the arm-specific criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm A: entrectinib 
treatment: 
 
ROS1 gene fusion positivity, except patients with non-small cell lung cancer (NSCLC), as 
determined by a Clinical Laboratory Improvement Amendments (CLIA) or equivalently 
certified next-generation sequencing (NGS) assay (tissue or blood) 
Gene fusion positivity is defined as a 3’ ROS1 fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain.  
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Ability to swallow entrectinib intact, without chewing, crushing, or opening the 
capsules/tablets 


 
 
 
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 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 5 weeks after the last dose of 
entrectinib; and agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
 1% per year during the treatment period and for at least 3 months after the last dose of 
entrectinib, and agreement to refrain from donating sperm during this same period. 
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm 
A: entrectinib treatment: 
 
ROS1 fusion-positive NSCLC 
 
Prior treatment with crizotinib 
 
Whole-brain radiotherapy and/or stereotactic radiosurgery for CNS disease within 14 days 
prior to the start of entrectinib treatment. 
 
Symptomatic or uncontrolled CNS involvement 
– 
Patients with CNS involvement, including leptomeningeal carcinomatosis or prior brain 
metastases, which are either asymptomatic or previously treated and controlled, are 
allowed.   
– 
Patients requiring corticosteroids must be at stable or decreasing doses for at least 
2 weeks prior to the start of entrectinib treatment. 
 
Requirement for enzyme inducing anti-epileptic drugs (EIAEDs) or use within 14 days or 
5 half lives (whichever is longer) prior to the start of entrectinib treatment 
– 
The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme 
inducing anti-epileptic drugs (non-EIAEDs).  
– 
If patients require an anti-epileptic medication, a cytochrome (CYP) 3A4 non-EIAED 
can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or 
lacosamide.  Moderate inducers of CYP450, such as dexamethasone or other 
glucocorticoids, may be used at the discretion of the investigator.   
 
History of non-pharmacologically induced prolonged corrected QT (QTc) interval 
(e.g., repeated demonstration of a QTc interval  450 ms from ECGs performed at least 
24 hours apart) 
 
History of recent (within the past 3 months) symptomatic congestive heart failure or ejection 
fraction  50% observed during screening for the study 
 
History of additional risk factors for torsade de pointes (e.g., family history of long QT 
syndrome) 
 
Grade  2 peripheral neuropathy  
 
Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut 
syndrome) or other malabsorption syndromes that would reasonably affect drug absorption 
 
Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase 
inhibitorinduced pneumonitis  
Note:  Radiation-induced lung disorders are not included in this exclusion criterion. 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Entrectinib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose of 600 mg/day (three 200-mg capsules per day) once a 
day (QD) until disease progression, intolerable toxicity or consent withdrawal.  Modification may 
be needed in cases of coadministration with moderate or strong CYP3A4 inducers.  For more 
specific dosing instructions, refer to the pharmacy manual. 


 
 
 
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ARM B:  INAVOLISIB (GDC-0077) IN PATIENTS WITH PIK3CA ACTIVATING MUTATION-
POSITIVE TUMORS 
Target Population 
To be enrolled in Arm B:  inavolisib (GDC-0077) treatment, patients must have met and 
continue to meet all general eligibility criteria, in addition to arm-specific criteria below.  
 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm B:  inavolisib 
(GDC-0077) treatment: 
 
PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
PIK3CA mutation positivity is defined by the presence of at least one nucleotide variant 
listed below: 
– H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V 
– Other activating mutations with Medical Monitor approval 
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Fasting glucose  126 mg/dL and glycosylated hemoglobin (HbA1c)  5.7%  
 
Willingness and ability to swallow GDC-0077 intact, without chewing, or crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 60 days after the last dose of 
inavolisib (GDC-0077); and agreement to refrain from donating eggs during this same 
period.  For all other women, documentation must be present in medical history confirming 
that patient is not of childbearing potential.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of  1% 
per year during the treatment period and for at least 120 days after the last dose of 
inavolisib (GDC-0077), and agreement to refrain from donating sperm during this same 
period.   
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm B:  
inavolisib (GDC-0077) treatment: 
 
Primary CNS tumors 
 
Type 2 diabetes requiring antihyperglycemic medication or any history of type 1 diabetes 
Patients with elevated fasting glucose at baseline (fasting glucose  126 mg/dL 
[ 7.0 mmol/L]) or HbA1c  5.7% will be excluded from the study 
 
Malabsorption syndrome or other condition that would interfere with enteral absorption 
 
Uncontrolled pleural effusion or ascites requiring recurrent drainage procedures twice 
monthly or more frequently  
Indwelling pleural or abdominal catheters are allowed provided the patient has 
adequately recovered from the procedure, is hemodynamically stable and 
symptomatically improved  


 
 
 
MyTACTIC Study—Genentech, Inc. 
24/Protocol ML42439, Version 6 
 
Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in 
the opinion of the investigator and/or study ophthalmologist, would require medical or 
surgical intervention during the study period to prevent or treat vision loss that might result 
from that condition 
 
Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, 
scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-
associated uveitis in either eye 
 
Patients requiring any daily supplemental oxygen 
 
History of or active inflammatory disease (e.g., Crohn’s disease or ulcerative colitis) or any 
active bowel inflammation (including diverticulitis)  
Patients currently receiving immunosuppressants (e.g., sulfasalazines) are considered 
to have active disease and are, therefore, ineligible. 
 
Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab 
therapy 
Bisphosphonate and denosumab therapy for bone metastases or 
osteopenia/osteoporosis is allowed. 
 
Clinically significant and active history of liver disease, including severe liver impairment 
(ChildPugh score B/C), current alcohol abuse, or cirrhosis  
 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula (QTcF) 
  470 ms demonstrated by at least two ECGs  30 minutes apart, or family history of 
sudden unexplained death or long QT syndrome 
 
Current treatment with medications that are well known to prolong the QT interval  
 
Allergy or hypersensitivity to components of the inavolisib (GDC-0077) formulation 
 
Any symptomatic active lung disease, including pneumonitis 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Inavolisib (GDC-0077) will be self-administered by patients orally at home (except on clinic 
days) at the same time each day, on a starting dose of 9 mg/day (one 9-mg tablet per day) once 
a day (QD) until disease progression, intolerable toxicity or consent withdrawal.  For more 
specific dosing instructions, refer to the pharmacy manual. 
 
 
 
ARM C:  ALECTINIB IN PATIENTS WITH ALK REARRANGEMENT-POSITIVE TUMORS  
 
TARGET POPULATION 
To be enrolled in Arm C:  alectinib treatment, patients must have met and continue to meet all 
general eligibility criteria, in addition to the arm-specific criteria below. 
 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm C: alectinib 
treatment: 
 
ALK gene fusion positivity, in indications other than non-small cell lung cancer (NSCLC), as 
determined by a Clinical Laboratory Improvement Amendments (CLIA) or equivalently 
certified next generation sequencing (NGS) assay (tissue or blood) 
Gene fusion positivity is defined as a 3’ ALK fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain.  
 
ANC  1000/L within 14 days prior to initiation of study treatment 


 
 
 
MyTACTIC Study—Genentech, Inc. 
25/Protocol ML42439, Version 6 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 90 days after the last dose of 
alectinib; and agreement to refrain from donating eggs during this same period.   
 
For males with female partners of childbearing potential:  Agreement to remain abstinent 
(refrain from heterosexual intercourse) or use a condom plus an additional contraception 
method that together result in a failure rate of  1% per year during the treatment period 
and for at least 90 days after the last dose of alectinib, and agreement to refrain from 
donating sperm during this same period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm C: 
alectinib treatment: 
 
ALK-positive NSCLC 
 
Inability to swallow pills 
 
Any gastrointestinal disorder that may affect absorption of oral medications, such as 
refractory vomiting, malabsorption syndrome, external biliary shunt, or significant bowel 
resection that would preclude absorption of alectinib 
 
Detection of the following ALK point mutations:  I1171N/S, G1202R 
 
Symptomatic or uncontrolled CNS involvement 
– 
Patients with CNS involvement, including leptomeningeal carcinomatosis or prior brain 
metastases, which are either asymptomatic or previously treated and controlled, are 
allowed.   
– 
Patients requiring corticosteroids must be at stable or decreasing doses for at least 
2 weeks prior to the start of alectinib treatment. 
 
Liver disease, characterized by any of the following: 
– 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other 
conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices 
– 
Active autoimmune, alcoholic, or other types of acute hepatitis 
 
History of organ transplant 
 
Symptomatic bradycardia 
 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
This includes, but is not limited to, patients with galactose intolerance, a congenital 
lactase deficiency, or glucose-galactose malabsorption. 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Alectinib will be self-administered by patients orally at home (except on clinic days), at the same 
times each day, on a starting dose of 600 mg (four 150-mg capsules) twice a day (BID) until 
disease progression, intolerable toxicity or consent withdrawal.  For more specific dosing 
instructions, refer to the pharmacy manual. 
 
 
 
ARM D:  IPATASERTIB IN PATIENTS WITH PTEN LOSS-OF-FUNCTION OR AKT1/2/3 
MUTANT-POSITIVE SOLID TUMORS  
TARGET POPULATION 
To be enrolled in Arm D:  ipatisertib treatment, patients must have met and continue to meet all 
general eligibility criteria, in addition to the arm-specific criteria below. 


 
 
 
MyTACTIC Study—Genentech, Inc. 
26/Protocol ML42439, Version 6 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm D:  ipatasertib 
treatment: 
 
AKT1/2/3 mutant positivity or PTEN loss of function, as determined by a Clinical Laboratory 
Improvement Amendments (CLIA) or equivalently certified next-generation sequencing 
(NGS) assay (tissue or blood) 
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as listed 
below: 
– AKT1:  E17K; L52R; Q79K 
– AKT2:  E17K 
– AKT3:  E17K; L51R; Q78K 
 
PTEN loss of function is defined as PTEN dominant negative missense mutations or 
deleterious in-frame and missense mutations affecting protein function 
Other applicable mutations are eligible with Medical Monitor approval 
or PTEN protein loss as determined by a CLIA or equivalently certified 
immunohistochemistry assay  
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c)  7.5% 
 
Ability to swallow ipatasertib without chewing or crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib; and agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of  1% 
per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib, and agreement to refrain from donating sperm during this same period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm D: 
ipatasertib treatment: 
 
Triple negative adenocarcinoma of the breast (TNBC) 
TNBC tumors are defined as HER2 negative, estrogen receptor (ER) negative, and 
progesterone receptor (PgR) negative: 
– ER or PgR negativity is defined as 1% of tumor cell nuclei immunoreactive to the 
respective hormonal receptor 
– HER2 negativity is assessed by IHC and/or in situ hybridization according to 2018 
American Society of Clinical Oncology/College of American Pathologists 
(ASCO/CAP) guidelines  
 
History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction 
(LVEF)  50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF)  480 milliseconds  


 
 
 
MyTACTIC Study—Genentech, Inc. 
27/Protocol ML42439, Version 6 
 
History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion (including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of  10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease.  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to 
initiation of study treatment are eligible for enrollment.  
 
Grade  2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia  
 
History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis)  
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A inducers 
within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study 
treatment 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) until disease progression, intolerable toxicity or consent withdrawal.  For more specific 
dosing instructions, refer to the pharmacy manual. 
 
 
ARM E:  ATEZOLIZUMAB PLUS CHEMOTHERAPY IN PATIENTS WITH TMB-H/ 
MSI-H/DMMR-POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm E:  atezolizumab plus chemotherapy treatment, patients must have met 
and continue to meet all general eligibility criteria, in addition to the arm-specific criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm E:  atezolizumab 
plus chemotherapy treatment: 
 
Documentation of one of the following biomarkers, as determined by a Clinical Laboratory 
Improvement Amendments (CLIA) or equivalently certified assay (tissue or blood): 
– 
Tumor mutational burden-high (TMB-H), defined as  10 mutations per megabase, as 
determined by a tissue-based NGS assay 
– 
Microsatellite instability high (MSI-H) 
– 
Deficient mismatch repair (dMMR) 
 
ANC  1500/L within 14 days prior to initiation of study treatment 
 
Lymphocyte count  500/L 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 5 months after the last dose of 
atezolizumab or 6 months after the last dose of chemotherapy, whichever is later; and 
agreement to refrain from donating eggs during this same period. 


 
 
 
MyTACTIC Study—Genentech, Inc. 
28/Protocol ML42439, Version 6 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of  1% 
per year during the treatment period and for 3 months after the last dose of chemotherapy 
and agreement to refrain from donating sperm during this same period. 
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm E:  
atezolizumab plus chemotherapy treatment: 
 
Primary CNS tumors with any of the following characteristics: 
– 
History of intracranial hemorrhage or spinal cord hemorrhage  
– 
Neurosurgical resection or brain biopsy to the primary brain tumor within 28 days of 
Cycle 1, Day 1 
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium 
 12 mg/dL, or corrected calcium  upper linit of normal  [ULN]) 
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
Patients with a history of HCV infection but who are negative for HCV RNA by PCR 
will be considered non-infected with HCV. 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid replacement hormone are eligible for the study 
– 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen 
are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
o 
Rash must cover  10% of body surface area 
o 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 
12 months 


 
 
 
MyTACTIC Study—Genentech, Inc. 
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 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intraveneous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study   
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
antiPD-1, and antiPD-L1 therapeutic antibodies  
Patients who have had prior anti-cytotoxic Tlymphocyte-associated protein 4 
(CTLA-4) treatment may be enrolled, provided the following requirements are met: 
– Last dose of anti-CTLA-4 at least 6 weeks prior to enrollment 
– No history of severe immune-related adverse events from the anti-CTLA-4 (National 
Cancer Institute Common Terminology Criteria for Research Adverse Events 
version 5.0 [NCI CTCAE v5.0] Grade 3 and 4)  
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study treatment, 
with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study 
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation  
 
TEST PRODUCTS (INVESTIGATIONAL DRUGS) 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients on 
Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical 
benefit in consultation with the Medical Monitor).  
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags. 
 
Docetaxel, paclitaxel, or capecitabine will be administered per package insert and institutional 
guidelines, including considerations for premedication, supportive medications, infusion times, 
infusion frequency, and total cycle count. 
 
 
 


 
 
 
MyTACTIC Study—Genentech, Inc. 
30/Protocol ML42439, Version 6 
ARM F:  TRASTUZUMAB EMTANSINE PLUS ATEZOLIZUMAB IN PATIENTS WITH ERBB2 
AMPLIFICATION OR MUTATION-POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm F:  trastuzumab emtansine plus atezolizumab treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm F:  trastuzumab 
emtansine plus atezolizumab treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below: 
– Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; 
C311R/S; E321G; C334S 
– Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C 
– Transmembrane domain:  S653C; V659E; G660D; R678Q 
– GFR domain IV:  P551L; R552S 
– Receptor L:  S418T; A440T 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of  6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio  2.0 and average HER2 
copy number/cell  4.0 signals/cell  
 
ANC  1200/L within 14 days prior to initiation of study treatment 
 
For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or 5 months after the last dose of atezolizuamb, whichever is 
longer; and agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of  1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine and agreement to refrain from donating sperm during this same 
period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm F: 
trastuzumab emtansine plus atezolizumab treatment: 
 
Breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS assay, 
microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) status 
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
History of exposure to the following cumulative doses of anthracyclines as specified below: 
– 
Doxorubicin  500 mg/m2 


 
 
 
MyTACTIC Study—Genentech, Inc. 
31/Protocol ML42439, Version 6 
– 
Liposomal doxorubicin  500 mg/m2 
– 
Epirubicin  720 mg/m2 
– 
Mitoxantrone  120 mg/m2 
– 
Idarubicin  90 mg/m2 
If another anthracycline or more than one anthracycline has been used, the cumulative 
dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
 
Patients who received prior trastuzumab, DS-8201, or other human epidermal growth factor 
receptor 2 (HER2)-targeting agents are eligible 
 
History of severe hypersensitivity to components of the trastuzumab emtansine formulation 
 
Cardiopulmonary dysfunction as defined by any of the following: 
– 
Uncontrolled hypertension (systolic  150 mmHg and/or diastolic  100 mmHg) 
– 
Inadequate left ventricular ejection fraction at baseline,  50% by echocardiogram 
(ECHO) or multiple-gated acquisition (MUGA) 
– 
History of symptomatic congestive heart failure Grade  3 per National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0)  
– 
History of decrease in left ventricular ejection function to  40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of enrollment 
– 
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy  
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade  2) relating to left ventricular ejection fraction (LVEF), 
cardiac arrhythmia, or cardiac ischemia  
– 
Serious cardiac arrhythmia not controlled by adequate medication 
 
Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, or sclerosis cholangitis  
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium  upper limite of normal [ULN]) 
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
– 
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV 
 
Grade  3 peripheral neuropathy, as defined by National Cancer Institute Common 
Terminology Criteria for Research Adverse Events version 5.0 [NCI CTCAE v5.0] 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid replacement hormone are eligible for the study 
– 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen 
are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
o 
Rash must cover  10% of body surface area 


 
 
 
MyTACTIC Study—Genentech, Inc. 
32/Protocol ML42439, Version 6 
o 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 
12 months 
 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated  14 days prior to 
Cycle 1, Day 1.  The patient must have recovered from any resulting acute toxicity (to 
Grade  1) prior to study treatment initiation 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment 
 
Symptomatic pleural effusion, pericardial effusion, or ascites.  History of idiopathic 
pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan.  Patients with a 
history of radiation pneumonitis in the radiation field (fibrosis) are eligible.  
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab 
 
Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor-alpha (TNF-α) agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study treatment, 
with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
 


 
 
 
MyTACTIC Study—Genentech, Inc. 
33/Protocol ML42439, Version 6 
TEST PRODUCTS (INVESTIGATIONAL DRUGS) 
Atezolizumab will be administered first followed by trastuzumab emtansine.  Atezolizumab will 
be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle until 
unacceptable toxicity or progressive disease (or loss of clinical benefit with Medical Monitor 
consultation).  Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.  The 
size of the infusion bag for each dose is listed below and will accommodate fluid restrictions 
needed for smaller patients. 
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 21 days 
(unless dose reduction and/or dose delays are required) until disease progression or 
unacceptable toxicity.  The dose of trastuzumab emtansine will be administered on the basis of 
the patient’s baseline weight.  Weight will be measured at each visit and dose must be 
re-adjusted for weight changes  10% compared to the previous visit or baseline.  The 
investigator may choose to recalculate the dose at every cycle using actual weight at that time, 
according to their local practice.   
 
 
 
ARM G:  PH FDC SC IN PATIENTS WITH ERBB2 AMPLIFICATION OR MUTATION-
POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm G:  fixed dose combination of trastuzumab and pertuzumab administered 
subcutaneously (PH FDC SC) treatment, patients must have met and continue to meet all 
general eligibility criteria, in addition to the arm-specific criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm G:  PH FDC SC 
treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below: 
– Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; 
C311R/S; E321G; C334S 
– Kinase domain: T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C 
– Transmembrane domain:  S653C; V659E; G660D; R678Q 
– GFR domain IV:  P551L; R552S 
– Receptor L:  S418T; A440T 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of  6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio  2.0 and average HER2 
copy number/cell  4.0 signals/cell  
 
Intact skin at planned site of subcutaneous (SC) injections (thigh) 
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Baseline and most recent (within 3 months) left ventricular ejection fraction (LVEF)  50% 
measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)  


 
 
 
MyTACTIC Study—Genentech, Inc. 
34/Protocol ML42439, Version 6 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 7 months after the last dose of 
PH FDC SC; and agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
 1% per year during the treatment period and for at least 7 months after the last dose of 
PH FDC SC, and agreement to refrain from donating sperm during this same period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm G: 
PH FDC SC treatment:  
 
Breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS assay, 
microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) status 
 
History of National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0 (NCI CTCAE v5.0) Grade  3 symptomatic congestive heart failure (CHF)  
 
In addition to the core exclusion criterion for significant cardiovascular disease, patients will 
be excluded if they have any of the following:  
– 
High-risk arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at rest, 
significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz type II] or 
third-degree AV-block) not controlled by adequate medication 
– 
Evidence of transmural infarction on ECG 
– 
Evidence of myocardial infarction within 12 months prior to enrollment, cerebrovascular 
accident within 3 months prior to enrollment 
– 
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg) 
– 
Angina pectoris requiring anti-angina medication 
– 
Clinically significant valvular heart disease 
 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left 
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., 
hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained 
death or long QT syndrome 
 
Known active liver disease, for example, autoimmune hepatic disorders, or sclerosing 
cholangitis 
 
Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
 
Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins 
 
Previously experienced severe injection related reactions with pertuzumab plus 
trastuzumab IV and/or PH FDC SC 
 
Current chronic daily treatment with corticosteroids (dose  10 mg methylprednisolone or 
equivalent excluding inhaled steroids) 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
PH FDC SC is given as a fixed dose (i.e. non-weight based) by SC injection.  Two doses of 
PH FDC SC may be administered in the study:  a 15 mL loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab and a 10 mL maintenance dose consisting of 600 mg 
pertuzumab and 600 mg trastuzumab.  Patients who have had  6 weeks since a prior dose of 


 
 
 
MyTACTIC Study—Genentech, Inc. 
35/Protocol ML42439, Version 6 
Perjeta and Herceptin intravenous (IV) or PH FDC subcutaneous (SC) at study entry, or have 
had  6 weeks since their last study treatment during the study treatment periods, must receive 
a loading dose before continuing with maintenance doses for subsequent administrations.  
 
 
 
ARM H:  PH FDC SC PLUS CHEMOTHERAPY IN PATIENTS WITH ERBB2 AMPLIFICATION 
OR MUTATION-POSITIVE TUMORS-POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm H:  fixed dose combination of trastuzumab and pertuzumab administered 
subcutaneously (PH FDC SC) plus chemotherapy treatment, patients must have met and 
continue to meet all general eligibility criteria, in addition to the arm-specific criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm H:  PH FDC SC 
plus chemotherapy treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below: 
– Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; 
C311R/S; E321G; C334S 
– Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C 
– Transmembrane domain:  S653C; V659E; G660D; R678Q 
– GFR domain IV:  P551L; R552S 
– Receptor L:  S418T; A440T 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of  6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio  2.0 and average HER2 
copy number/cell  4.0 signals/cell  
 
Intact skin at planned site of subcutaneous (SC) injections (thigh) 
 
ANC  1500/L within 14 days prior to initiation of study treatment 
 
Baseline and most recent (witin 3 months) left ventricular ejection fraction (LVEF)  50% 
measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)  
 
For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 7 months after the last dose of PH 
FDC SC or 6 months after the last dose of chemotherapy, whichever is later; and 
agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of  1% 
per year during the treatment period and for at least 7 months after the last dose of PH FDC 
SC or for 3 months after the last dose of chemotherapy, whichever is longer, and 
agreement to refrain from donating sperm during this same period.   
 


 
 
 
MyTACTIC Study—Genentech, Inc. 
36/Protocol ML42439, Version 6 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm H: 
PH FDC SC plus chemotherapy treatment:  
 
Breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS assay, 
microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) status 
 
History of National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 5.0 (NCI CTCAE v5.0) Grade  3 symptomatic congestive heart failure (CHF)  
 
In addition to the core exclusion criterion for significant cardiovascular disease, patients will 
be excluded if they have any of the following:  
– 
High-risk arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at rest, 
significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz type II] or 
third-degree AV-block) not controlled by adequate medication 
– 
Evidence of transmural infarction on ECG 
– 
Evidence of myocardial infarction within 12 months prior to enrollment, cerebrovascular 
accident within 3 months prior to enrollment 
– 
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg) 
– 
Angina pectoris requiring anti-angina medication 
– 
Clinically significant valvular heart disease 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left 
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., 
hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained 
death or long QT syndrome 
 
Known active liver disease, for example, autoimmune hepatic disorders, or sclerosing 
cholangitis 
 
Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
 
Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins 
 
Previously experienced severe injection related reactions with pertuzumab plus 
trastuzumab IV and/or PH FDC SC 
 
Current chronic daily treatment with corticosteroids (dose  10 mg methylprednisolone or 
equivalent excluding inhaled steroids) 
 
TEST PRODUCTS (INVESTIGATIONAL DRUGS) 
PH FDC SC is given as a fixed dose (i.e. non-weight based) by SC injection.  Two doses of 
PH FDC SC may be administered in the study:  a 15 mL loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab and a 10 mL maintenance dose consisting of 600 mg 
pertuzumab and 600 mg trastuzumab.  Patients who have had  6 weeks since a prior dose of 
Perjeta and Herceptin intravenous (IV) or PH FDC SC at study entry, or have had  6 weeks 
since their last study treatment during the study treatment periods, must receive a loading dose 
before continuing with maintenance doses for subsequent administrations.  
Docetaxel, paclitaxel, or capecitabine will be administered per package insert and institutional 
guidelines, including considerations for premedication, supportive medications, infusion times, 
infusion frequency, and total cycle count. 
 
 
 


 
 
 
MyTACTIC Study—Genentech, Inc. 
37/Protocol ML42439, Version 6 
ARM I:  TRASTUZUMAB EMTANSINE PLUS TUCATINIB IN PATIENTS WITH ERBB2 
AMPLIFICATION OR MUTATION-POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm I:  trastuzumab emtansine plus tucatinib treatment, patients must have 
met and continue to meet all general eligibility criteria, in addition to the arm-specific criteria 
below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm I:  trastuzumab 
emtansine plus tucatinib treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below: 
– Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; 
C311R/S; E321G; C334S 
– Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C 
– Transmembrane domain:  S653C; V659E; G660D; R678Q 
– GFR domain IV:  P551L; R552S 
– Receptor L:  S418T; A440T 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of  6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio  2.0 and average HER2 
copy number/cell  4.0 signals/cell  
 
ANC  1200/L within 14 days prior to initiation of study treatment 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or at least 1 week after last administration of tucatinib, whichever is 
longer; and agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of  1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or at least 1 week after last dose of tucatinib, whichever is longer 
and agreement to refrain from donating sperm during this same period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm I:  
trastuzumab emtansine plus tucatinib treatment: 
 
Breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS assay, 
microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) status 
 
History of exposure to the following cumulative doses of anthracyclines as specified below: 
– 
Doxorubicin  500 mg/m2 
– 
Liposomal doxorubicin  500 mg/m2 


 
 
 
MyTACTIC Study—Genentech, Inc. 
38/Protocol ML42439, Version 6 
– 
Epirubicin  720 mg/m2 
– 
Mitoxantrone  120 mg/m2 
– 
Idarubicin  90 mg/m2 
If another anthracycline or more than one anthracycline has been used, the cumulative 
dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
 
Patients who received prior trastuzumab, DS-8201, or other human epidermal growth factor 
receptor 2 (HER2)-targeting agents are eligible 
 
History of severe hypersensitivity to components of the trastuzumab emtansine or tucatinib 
formulations 
 
Cardiopulmonary dysfunction as defined by any of the following: 
– 
Uncontrolled hypertension (systolic  150 mmHg and/or diastolic  100 mmHg) 
– 
Inadequate left ventricular ejection fraction at baseline,  50% by echocardiogram 
(ECHO) or multiple-gated acquisition (MUGA) 
– 
History of symptomatic congestive heart failure Grade  3 per National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0)  
– 
History of decrease in left ventricular ejection function to  40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of enrollment 
– 
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy  
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade  2) relating to left ventricular ejection fraction (LVEF), 
cardiac arrhythmia, or cardiac ischemia  
– 
Serious cardiac arrhythmia not controlled by adequate medication 
 
Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, sclerosis cholangitis  
 
Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, 
or have used a strong CYP3A4 or CYP2C8 inducer within 5 day prior to start of treatment 
 
Grade  3 peripheral neuropathy, as defined by NCI CTCAE v5.0 
 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 21 days 
(unless dose reduction and/or dose delays are required) until disease progression or 
unacceptable toxicity.  The dose of trastuzumab emtansine will be administered on the basis of 
the patient’s baseline weight.  Weight will be measured at each visit and dose must be 
re-adjusted for weight changes  10% compared to the previous visit or baseline.  The 
investigator may choose to recalculate the dose at every cycle using actual weight at that time, 
according to their local practice.   
Tucatinib drug product may be supplied as both a coated yellow oval-shaped tablet in a 150 mg 
dosage strength and a coated yellow round convex tablet in a 50 mg dosage strength.  The 
tablets are manufactured from a drug product intermediate amorphous dispersion of tucatinib in 
polyvinylpyrrolidone-vinyl acetate copolymer, which is then combined with the pharmaceutical 
excipients (microcrystalline cellulose, sodium chloride, potassium chloride, sodium bicarbonate, 
silicon dioxide, crospovidone, and magnesium stearate), and compressed into tablets. 
 
 
 


 
 
 
MyTACTIC Study—Genentech, Inc. 
39/Protocol ML42439, Version 6 
ARM J:  TRASTUZUMAB EMTANSINE PLUS ATEZOLIZUMAB IN PATIENTS WITH ERBB2-
AMLIFICATION OR MUTATAION AND TMB-H/MSI-H/DMMR TUMORS 
TARGET POPULATION 
To be enrolled in Arm J:  trastuzumab emtansine plus atezolizumab treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm J:  trastuzumab 
emtansine plus atezolizumab treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below: 
– Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; 
C311R/S; E321G; C334S 
– Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C 
– Transmembrane domain:  S653C; V659E; G660D; R678Q 
– GFR domain IV:  P551L; R552S 
– Receptor L:  S418T; A440T 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of  6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio  2.0 and average HER2 
copy number/cell  4.0 signals/cell  
 
Documentation of one of the following biomarkers, as determined by a CLIA or equivalently 
certified assay (tissue or blood): 
– 
Tumor mutational burden high (TMB-H) high, defined as  10 mutations per megabase, 
as determined by a tissue-based NGS assay 
– 
Microsatellite instability high (MSI-H)  
– 
Deficient mismatch repair (dMMR)  
 
ANC  1200/L within 14 days prior to initiation of study treatment 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or 5 months after the last dose of atezolizuamb, whichever is 
longer; and agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of  1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine and agreement to refrain from donating sperm during this same 
period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm J:  
trastuzumab emtansine plus atezolizumab treatment: 


 
 
 
MyTACTIC Study—Genentech, Inc. 
40/Protocol ML42439, Version 6 
 
Breast cancer  
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
History of exposure to the following cumulative doses of anthracyclines as specified below: 
– 
Doxorubicin  500 mg/m2 
– 
Liposomal doxorubicin  500 mg/m2 
– 
Epirubicin  720 mg/m2 
– 
Mitoxantrone  120 mg/m2 
– 
Idarubicin  90 mg/m2 
If another anthracycline or more than one anthracycline has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
 
Patients who received prior trastuzumab, DS-8201, or other human epidermal growth factor 
receptor 2 (HER2)-targeting agents are eligible 
 
History of severe hypersensitivity to components of the trastuzumab emtansine formulation 
 
Cardiopulmonary dysfunction as defined by any of the following: 
– 
Uncontrolled hypertension (systolic  150 mmHg and/or diastolic  100 mmHg) 
– 
Inadequate left ventricular ejection fraction (LVEF) at baseline,  50% by 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
– 
History of symptomatic congestive heart failure Grade  3 per National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) or 
Class  II New York Heart Association 
– 
History of decrease in left ventricular ejection function to  40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of enrollment 
– 
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy  
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade  2) relating to LVEF, cardiac arrhythmia, or cardiac 
ischemia  
– 
Serious cardiac arrhythmia not controlled by adequate medication 
 
Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, sclerosis cholangitis  
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12  mg/dL, or corrected calcium  upper limite of normal [ULN]) 
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
– 
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV 
 
Grade  3 peripheral neuropathy, as defined by NCI CTCAE v5.0 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid replacement hormone are eligible for the study 
– 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen 
are eligible for the study 


 
 
 
MyTACTIC Study—Genentech, Inc. 
41/Protocol ML42439, Version 6 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
o 
Rash must cover  10% of body surface area 
o 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 
12 months 
 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated  14 days prior to 
Cycle 1, Day 1.  The patient must have recovered from any resulting acute toxicity (to 
Grade  1) prior to study treatment initiation. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
 
Symptomatic pleural effusion, pericardial effusion, or ascites.  History of idiopathic 
pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan.  Patients with a 
history of radiation pneumonitis in the radiation field (fibrosis) are eligible.  
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab 
 
Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of 
need for systemic immunosuppressive medication during study treatment, with the following 
exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study 


 
 
 
MyTACTIC Study—Genentech, Inc. 
42/Protocol ML42439, Version 6 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Atezolizumab will be administered first followed by trastuzumab emtansine.  Atezolizumab will 
be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle until 
unacceptable toxicity or progressive disease (or loss of clinical benefit with Medical Monitor 
consultation).  Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.  The 
size of the infusion bag for each dose is listed below and will accommodate fluid restrictions 
needed for smaller patients. 
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 21 days 
(unless dose reduction and/or dose delays are required) until disease progression or 
unacceptable toxicity.  The dose of trastuzumab emtansine will be administered on the basis of 
the patient’s baseline weight.  Weight will be measured at each visit and dose must be 
re-adjusted for weight changes  10% compared to the previous visit or baseline.  The 
investigator may choose to recalculate the dose at every cycle using actual weight at that time, 
according to their local practice. 
 
 
ARM K:  IPATASERTIB PLUS ATEZOLIZUMAB IN PATIENTS WITH PIK3CA ACTIVATING 
MUTATION POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm K: ipatasertib in combination with atezolizumab treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm K: ipatasertib in 
combination with atezolizumab treatment: 
 
PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
PIK3CA mutation positivity is defined by the presence of at least one nucleotide 
variant listed below: 
– H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V 
– Kinase domain:  T733I; L755P/S; I767M; L768S; D769H/N/Y; Y772_A775dup; 
A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); L755P/S/_T759del; 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C 
Other activating mutations with Medical Monitor approval 
 
No available acceptable treatment for malignancy that is expected to provide clinical benefit 
 
ANC  1000/l within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c) 7.5% 
 
Ability to swallow ipatasertib intact, without chewing or crushing the tablets 


 
 
 
MyTACTIC Study—Genentech, Inc. 
43/Protocol ML42439, Version 6 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib and 5 months after the last dose of atezolizumab; and agreement to refrain from 
donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib, and agreement to refrain from donating sperm during this same period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm K: 
ipatasertib plus atezolizumab treatment: 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Use of an indwelling catheter (e.g., PleurX®) is allowed. 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not presently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium  12 
mg/dL, or corrected serum calcium  ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
– Rash must cover  10% of body surface area 
– Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
– No occurrence of acute exacerbations of the underlying condition requiring psoralen 
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 


 
 
 
MyTACTIC Study—Genentech, Inc. 
44/Protocol ML42439, Version 6 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study   
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab 
 
Prior treatment with anti-PD-1 or anti PD-L1 therapeutics unless approved by Medical 
Monitor 
– Up to approximately 12 such patients may be enrolled 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study treatment, 
with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study 
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
 
Prior treatment with ipatasertib or other Akt inhibitors 
 
History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction 
(LVEF)  50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF)  480 milliseconds  
 
History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion (including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of  10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease.  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to 
initiation of study treatment are eligible for enrollment.  
Diabetic patients with fasting total serum glucose  8.3 mmol/L (150 mg/dL) and/or 
HbA1C  7.5 are not eligible for enrollment. 
 
History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis)  


 
 
 
MyTACTIC Study—Genentech, Inc. 
45/Protocol ML42439, Version 6 
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A inducers 
within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study 
treatment  
 
Uncontrolled pleural effusion, pericardial effusion, or ascites 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) until disease progression, intolerable toxicity or consent withdrawal.  For more specific 
dosing instructions, refer to the pharmacy manual.   
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients on Day 
1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical 
benefit upon Medical Monitor consultation). 
 
 
 
ARM L: IPATASERTIB PLUS ATEZOLIZUMAB IN PATIENTS WITH PTEN LOSS/ LOSS OF 
FUNCTION OR AKT ACTIVATING MUTATIONPOSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm L: ipatasertib in combination with atezolizumab treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm L: ipatasertib in 
combination with atezolizumab treatment: 
 
AKT1/2/3 mutant positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as listed 
below: 
– AKT1:  E17K; L52R; Q79K 
– AKT2:  E17K 
– AKT3:  E17K; L51R; Q78K 
or PTEN protein loss of function or protein loss as determined by a CLIA or equivalently 
certified tissue-based NGS, in situ hybridization (ISH), or immunohistochemistry (IHC) 
assay  
 
No available acceptable treatment for malignancy that is expected to provide clinical benefit 
 
ANC  1000/l within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c) 7.5% 
 
Ability to swallow ipatasertib intact, without chewing or crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib and 5 months after the last dose of atezolizumab; and agreement to refrain from 
donating eggs during this same period.   


 
 
 
MyTACTIC Study—Genentech, Inc. 
46/Protocol ML42439, Version 6 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib, and agreement to refrain from donating sperm during this same period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm L: 
ipatasertib plus atezolizumab treatment: 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Use of an indwelling catheter (e.g., PleurX®) is allowed. 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to enrollment.  
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not presently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium  12 
mg/dL, or corrected serum calcium  ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
– Rash must cover  10% of body surface area 
– Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
– No occurrence of acute exacerbations of the underlying condition requiring psoralen 
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study   
 
Prior allogeneic stem cell or solid organ transplantation 


 
 
 
MyTACTIC Study—Genentech, Inc. 
47/Protocol ML42439, Version 6 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab 
 
Prior treatment with anti-PD-1 or anti PD-L1 therapeutics unless approved by Medical 
Monitor 
– 
Up to approximately 12 such patients may be enrolled 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study treatment, 
with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study 
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
 
Prior treatment with ipatasertib or other Akt inhibitors 
 
History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction 
(LVEF)  50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF)  480 milliseconds  
 
History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion (including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of  10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease.  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to initiation 
of study treatment are eligible for enrollment.  
Diabetic patients with fasting total serum glucose  8.3 mmol/L (150 mg/dL) and/or HbA1C 
 7.5 are not eligible for enrollment. 
 
History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis)  
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 


 
 
 
MyTACTIC Study—Genentech, Inc. 
48/Protocol ML42439, Version 6 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A inducers 
within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study 
treatment  
 
Uncontrolled pleural effusion, pericardial effusion, or ascites 
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) until disease progression, intolerable toxicity or consent withdrawal.  For more specific 
dosing instructions, refer to the pharmacy manual.   
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients on Day 
1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical 
benefit with Medical Monitor consultation). 
 
ARM M: IPATASERTIB PLUS PACLITAXEL IN PATIENTS WITH CO-MUTATIONS IN 
PIK3CA ACTIVATING MUTATIONS AND PTEN LOSS/ LOSS-OF-FUNCTION OR AKT 
ACTIVATING MUTATION-POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm M: ipatasertib in combination with paclitaxel treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm M: ipatasertib in 
combination with paclitaxel treatment: 
 
A co-mutation of either PIK3CA activating mutation and AKT activating mutation or a 
PIK3CA activating mutation and PTEN loss or loss of function based on the following 
biomarkers: 
– 
PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
PIK3CA mutation positivity is defined by the presence of at least one nucleotide variant 
listed below: 
o 
H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V 
o 
Other activating mutations with Medical Monitor approval 
– 
AKT1/2/3 mutant positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood) 
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as listed 
below: 
o 
AKT1:  E17K; L52R; Q79K 
o 
AKT2:  E17K 
o 
AKT3:  E17K; L51R; Q78K 
or PTEN protein loss of function or protein loss as determined by a CLIA or 
equivalently certified tissue-based NGS, in situ hybridization (ISH), or 
immunohistochemistry (IHC) assay  
 
ANC  1500/l within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c)  7.5% 
 
Ability to swallow ipatasertib intact, without chewing or crushing the tablets 


 
 
 
MyTACTIC Study—Genentech, Inc. 
49/Protocol ML42439, Version 6 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib and 6 months after the last dose of paclitaxel, whichever occurs later, and 
agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib, and 3 months after the last dose of paclitaxel, whichever occurs later and 
agreement to refrain from donating sperm during this same period.   
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm M: 
ipatasertib in combination with paclitaxel treatment: 
 
History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction 
(LVEF) 50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF) 480 milliseconds  
 
History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion (including complete left bundle branch block, second- or third degree heart block, or 
evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease 
 
Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 
peripheral neuropathy  
 
Uncontrolled pleural effusion, pericardial effusion, or ascites 
Patients with indwelling catheters (e.g., PleurX) are allowed.  
 
Uncontrolled tumor-related pain 
– 
Patients requiring pain medication must be on a stable regimen at study entry 
– 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated  14 days prior to 
Cycle 1, Day 1.  The patient must have recovered from any resulting acute toxicity (to 
Grade  1) prior to study treatment initiation 
– 
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment 
 
Uncontrolled hypercalcemia ( 1.5 mmol/L ionized calcium,  12 mg/dL calcium, or 
corrected serum calcium  ULN) or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to initiation of 
study treatment are eligible for enrollment.  
 
Grade  2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia  


 
 
 
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 
History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis)  
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A inducers 
within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study 
treatment  
 
Prior treatment with an Akt inhibitor 
 
Note that prior PI3K or mTOR inhibitors are allowed. 
 
Known hypersensitivity or contraindication to any component of the study treatments, 
including the paclitaxel excipient macrogolglycerol ricinoleate  
 
Grade  2 peripheral neuropathy 
 
Prior treatment with paclitaxel treatment  
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) on days 1 through 21 of 28-day cycles until disease progression, intolerable toxicity or 
consent withdrawal.  For more specific dosing instructions, refer to the pharmacy manual.   
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
and 15 of each 28-day cycle. The paclitaxel infusion will be delivered over at least 60 minutes 
for each dose per institutional guidelines and administered after the oral dose of ipatasertib. 
 
 
ARM N: ATEZOLIZUMAB PLUS TIRAGOLUMAB IN PATIENTS WITH TMB-H/MSI-H/DMMR-
POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm N: atezolizumab plus tiragolumab treatment, patients must have met and 
continue to meet all general eligibility criteria, in addition to the arm-specific criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm N: atezolizumab 
plus tiragolumab treatment: 
 
Documentation of one of the following biomarkers, as determined by a CLIA or equivalently 
certified assay (tissue or blood): 
– 
Tumor mutational burden high (TMB-H) high, defined as  10 mutations per megabase, 
as determined by a tissue-based NGS assay 
– 
Microsatellite instability high (MSI-H)  
– 
Deficient mismatch repair (dMMR)  
 
ANC  1200/L within 14 days prior to initiation of study treatment 
 
Lymphocyte count  500/L 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 02 
 
For patients not receiving therapeutic anticoagulation:  INR and aPTT  1.5  ULN 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 90 days after the final dose of 
tiragolumab or 5 months after the last dose of atezolizumab, whichever is later; and 
agreement to refrain from donating eggs during this same period.   


 
 
 
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 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom during the treatment period and for 90 days after the last dose of tiragolumab and 
agreement to refrain from donating sperm during this same period.    
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm N: 
atezolizumab plus tiragolumab treatment: 
 
Primary CNS tumors with any of the following characteristics: 
– 
History of intracranial hemorrhage or spinal cord hemorrhage  
– 
Neurosurgical resection or brain biopsy to the primary brain tumor within 28 days of 
Cycle 1, Day 1 
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to enrollment.  
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, calcium  12 
mg/dL, or corrected calcium  upper limit of normal [ULN]) 
 
Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with 
the following exception (note that this is more stringent than the core criterion):  
Patients who are HCV Ab positive but HCV RNA negative due to prior treatment or 
natural resolution are eligible  
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV. 
 
Positive EBV viral capsid antigen IgM test at screening  
An EBV polymerase chain reaction (PCR) test should be performed as clinically 
indicated to screen for acute infection or suspected chronic active infection.  Patients 
with a positive EBV PCR test are excluded. 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on thyroid  
replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
– Rash must cover  10% of body surface area 


 
 
 
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– Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
– No occurrence of acute exacerbations of the underlying condition requiring psoralen 
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 
12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study   
 
Prior allogeneic stem cell or solid organ transplantation 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to initiation of 
study treatment, during study treatment, for 90 days after the final dose of tiragolumab, and 
for 5 months after the final dose of atezolizumab. 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti-TIGIT, anti-LAG3, antiPD-1, and antiPD-L1 therapeutic antibodies 
Patients who have had prior anti-CTLA-4 treatment may be enrolled, provided the 
following requirements are met: 
– Last dose of anti-CTLA-4 at least 6 weeks prior to enrollment 
– No history of severe immune-related adverse events from the anti-CTLA-4 (National 
Cancer Institute Common Terminology Criteria for Research Adverse Events [NCI 
CTCAE] Grade 3 and 4)  
 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study treatment, 
with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor 
consultation 
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study 
– 
Any prior Grade   3 immune-mediated adverse event or any unresolved Grade  1 
immune-mediated adverse event while receiving any previous immunotherapy agent 
other than immune checkpoint blockade agents  
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab or tiragolumab formulation 
 


 
 
 
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TEST PRODUCT (INVESTIGATIONAL DRUG) 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit with 
Medical Monitor consultation). Atezolizumab should be administered prior to tiragolumab on 
days when both are administered.  
Following the administration of atezolizumab and an observation period, patients will receive 
600 mg tiragolumab at a fixed dose administered by IV infusion on Day 1 of each 21-day cycle.  
The tiragolumab dose is fixed and is not dependent on body weight. 
 
 
ARM O: PRALSETINIB IN PATIENTS WITH RET FUSION-POSITIVE TUMORS 
TARGET POPULATION 
To be enrolled in Arm O: pralsetinib treatment, patients must have met and continue to meet all 
general eligibility criteria, in addition to the arm-specific criteria below. 
ADDITIONAL INCLUSION CRITERIA 
Patients must meet the following additional inclusion criteria for entry into Arm O: pralsetinib 
treatment: 
 
RET fusion positivity, except patients with non-small cell lung cancer (NSCLC) or thyroid 
cancers, as determined by a Clinical Laboratory Improvement Amendments (CLIA) or 
equivalently certified next-generation sequencing (NGS) assay (tissue or blood) 
Gene fusion positivity is defined as a 3’ RET fusion with a protein coding 5’ gene fusion 
partner, which are predicted to be in frame with an intact kinase domain. 
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Ability to swallow pralsetinib intact, without chewing, crushing, or opening the 
capsules/tablets 
 
For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 14 days after the last dose of 
pralsetinib; and agreement to refrain from donating eggs during this same period.   
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
 1% per year during the treatment period and for at least 7 days after the last dose of 
pralsetinib, and agreement to refrain from donating sperm during this same period.    
 
ADDITIONAL EXCLUSION CRITERIA 
Patients who meet any of the following additional criteria will be excluded from entry into Arm O: 
pralsetinib treatment: 
 
RET fusion-positive NSCLC 
 
RET fusion-positive thyroid cancer 
 
Patient’s tumor has any additional known primary driver alterations other than RET, such as 
targetable mutations of EGFR, ALK, ROS1, MET, KRAS or BRAF. 
 
Known history of hypersensitivity to pralsetinib or any of its excipients 
 
Prior treatment with RET inhibitors (approved or investigational) 
 
Note: Other prior anti-cancer therapy is allowed 
 
Screening QT interval corrected using Fridericia's formula (QTcF)  480 milliseconds, 
history of prolonged QT syndrome or torsades de pointes, and/or familial history of 
prolonged QT syndrome 
 
History of pneumonitis during the prior 12 months 
 
Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic 
steroids   10 mg/day of prednisone (or equivalent)  


 
 
 
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 
Active, uncontrolled infection (viral, bacterial, or fungal) 
– 
Participants with controlled infections who are stable on treatment may be eligible if the 
benefitrisk assessment is justified  
 
Clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation 
pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention) 
 
Neutrophil growth factor support within 14 days of the first dose of study drug 
 
Treatment with a prohibited medication or herbal remedy that cannot be discontinued at 
least 14 days before the start of study drug administration.   
 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Pralsetinib will be self-administered by patients orally at home, at the same time each day, on a 
starting dose of 400 mg/day (four 100 mg capsules per day) once a day (QD) until disease 
progression, intolerable toxicity, or consent withdrawal.  For more specific dosing instructions, 
refer to the pharmacy manual. 
 
 


 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
Ab 
antibody 
ACE 
angiotensin-converting enzyme 
ACTH 
adrenocorticotropic hormone 
ADC 
antibody-drug conjugate 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
AML 
acute myeloid leukemia 
ARDS 
Acute respiratory distress syndrome 
ARR 
Administration-related reaction 
ASCO 
American Society of Clinical Oncology 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AV 
atrioventricular 
BAL 
bronchoalveolar lavage 
BID 
twice a day 
BiPAP 
bi-level positive airway pressure 
CAR 
chimeric antigen receptor 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CLL 
chronic lymphocytic leukemia 
CO2 
carbon dioxide 
COPD 
chronic obstructive pulmonary disease 
cORR 
confirmed ORR 
COVID-19 
coronavirus disease 2019 
CPAP 
continuous positive airway pressure 
CPK 
creatine phosphokinase 
CR 
complete response 
CRF 
Case Report Form 
CRO 
contract research organization 
CRS 
cytokine-release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 


 
 
 
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Abbreviation 
Definition 
CTLA-4 
cytotoxic Tlymphocyte-associated protein 4 
CYP 
cytochrome 
DCR 
Disease control rate 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
dMMR 
deficient mismatch repair 
DOR 
duration of objective response 
DPP4 
dipeptidyl peptidase 4 
DTC 
differentiated thyroid cancer 
EBV 
epstein-barr virus 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECMO 
extracorporeal membrane oxygenation 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EIAED 
enzyme inducing anti-epileptic drugs 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
ER+ 
estrogen receptor positive 
ESMO 
European Society for Medical Oncology 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
FLAIR 
fluid-attenuated inversion recovery 
FISH 
fluorescence in situ hybridization 
FMI 
Foundation Medicine, Inc. 
FNA 
Fine needle aspiration 
FSP 
Functional Service Provider 
G-CSF 
granulocyte colony-stimulating factor 
GDFN 
glial cell line-derived neurotrophic factors 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GFR 
Glomerular filtration rate 
GFR 
GDNF family receptors- 
GI 
gastrointestinal 
HbA1c 
hemoglobin A1c 
HBcAb 
hepatitis B core antibody 


 
 
 
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Abbreviation 
Definition 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HER2- 
human epidermal growth factor receptor 2 negative 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HR+ 
hormone receptor positive 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
ICU 
intensive care unit 
IFN 
interferon 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IL 
interleukin 
IMP 
investigational medicinal product 
IMT 
inflammatory myofibroblastic tumors 
IND 
Investigational New Drug (application) 
IR 
incomplete response 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IV 
intravenous 
IxRS 
Interactive Voice Response System 
LDAC 
low-dose cytarabine 
LFT 
liver function test 
LOF 
loss-of-function 
LPLV 
last patient, last visit 
LVEF 
left ventricular ejection fraction  
LVSD 
left ventricular systolic dysfunction 
MAb 
monoclonal antibody 
MASC 
mammary analogue secretory carcinoma 
MAP 
mitogen-activated protein 
MAS 
macrophage activation syndrome 
MKI 
multikinase inhibitors 
MRI 
magnetic resonance imaging 


 
 
 
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Abbreviation 
Definition 
MSI-H 
microsatellite instability high 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multiple-gated acquisition 
NCCN 
National Cancer Comprehensive Network 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NK 
natural killer 
NRH 
nodular regenerative hyperplasia 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1 
PE 
polyethylene 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFT  
pulmonary function tests 
P-gp 
P-glycoprotein 
PH FDC SC 
fixed dose combination of pertuzumab and trastuzumab 
administered subcutaneously 
PI3K 
phosphatidylinositol 3-kinase 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit 
alpha 
PIP2 
phosphatidylinositol-4,5-bisphosphate 
PIP3 
phosphatidylinositol-3,4,5-triphosphate 
PK 
pharmacokinetic 
PO  
by mouth 
PPE 
palmar-plantar erythrodysesthesia 
PR 
partial response 
PTEN 
phosphatase and tensin homolog 
QD 
once a day 
QTc 
corrected Q-T interval 
QTcF 
QT interval corrected using Fridericia’s formula 


 
 
 
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Abbreviation 
Definition 
RAI 
radioactive iodine 
RANO 
Response Assessment in Neuro-Oncology 
RBR 
Research Biosample Repository 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RET 
Rearranged during Transfection 
S6RP 
S6 ribosomal protein 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SD 
stable disease 
SGLT2 
sodium-glucose transport protein 2 
SLL 
small lymphocytic lymphoma 
SLS 
sodium lauryl sulfate 
SMCC 
succinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate 
STAT 
statim (immediately) 
T3 
triiodothyronine 
T4 
thyroxine 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
TLS 
tumor lysis syndrome 
TMB 
tumor mutational burden 
TMB-H 
tumor mutational burden-high 
TNBC 
triple negative adenocarcinoma of the breast 
TNF- 
tumor necrosis factor-alpha 
TPS 
tumor proportion score 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
U.S. 
United States 
VAD 
ventricular assist device 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
WT 
wild type 
 


 
 
 
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1. 
BACKGROUND 
Oncology is rapidly evolving into a more personalized healthcare approach.  Improved 
understanding of the role of cancer biomarkers, further development of 
molecular-targeted therapies, and the standardization of appropriate targeted treatment 
into treatment guidelines have shifted clinical practice to utilize genomic information as 
an integral component of clinical decision-making (Kris et al. 2014; Barlesi et al. 2016).  
Therapies that specifically target actionable oncogenic drivers have become the 
cornerstone of precision oncology.  
Currently, targeted agents are approved for use in specific cancer types (as defined by 
primary site), or a subset of that population harboring the specific molecular alteration.  
Usually, targeted agents have been approved in the cancer types that most frequently 
carry the specific molecular target.  However, it is now clear that molecular alterations 
can be found in cancers from other primary sites, although often at low incidence levels.  
The potential therapeutic importance of these abnormalities is not clear, although 
anecdotal reports have documented activity with the investigational use of appropriate 
targeted therapy (Cappuzzo et al. 2006; Masago et al. 2009; LoRusso et al. 2011; 
Masago et al. 2011; Kelly et al. 2012; Minor et al. 2012).  With the relative rarity of these 
alterations (usually  5%) in any specific cancer type, it is difficult to identify sufficient 
patients for clinical trials.  
With these recent advancements, numerous platforms have been developed to survey 
the cancer cell genome and detect critical molecular alterations.  With increased 
molecular profiling, gene alterations for which a targeted agent exists, or are associated 
with improved efficacy of cancer immunotherapies, are being identified more frequently 
in tumor types for which these agents are currently not approved.  These findings 
present a new opportunity to test the efficacy of available targeted agents and 
immunotherapies. 
In addition, there have been recent drug approvals in pan-tumor indications paving the 
way for registration for molecular alterations in multiple tumor types. 
For example, entrectinib (Rozlytrek) was approved in the United States based on the 
results in 51 adult patients across three clinical trials.  A pooled analysis of 3 Phase I-II 
studies investigating patients with locally-advanced or metastatic ROS1 fusion-positive 
non-small-cell lung cancer demonstrated that treatment with entrectinib induced a 
durable and clinically meaningful response.  Among the efficacy-evaluable patients, 77% 
had an objective response, with a median duration of response of 24.6 months (95% CI 
11.4-34.8) (Drilon et al. 2020).  The same analysis investigated patients with metastatic 
or locally advanced solid tumors harboring a fusion in the NTRK gene (NTRK1, NTRK2, 
or NTRK3), comprising of 10 different tumor types and 19 different histologies.  Similarly, 
treatment with entrectinib demonstrated a durable and clinically meaningful response, 
showing Entrectinib to be a viable treatment option for patients with NTRK 


 
 
 
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fusion-positive solid tumors.  An objective response was observed in 57% of the 
evaluable patients (95%CI 43.2-70.8), with 4 complete responses and 27 partial 
responses.  The median duration of response was 10 months (95% CI 7.1 to NE), 
(Doebele et al. 2019).  
Tumor mutational burden has been associated with treatment outcomes with cytotoxic 
Tlymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1) 
inhibitors.  Pembrolizumab (Keytruda) was granted accelerated approval by the FDA for 
the treatment of adult and pediatric patients with unresectable or metastatic tumor 
mutational burden-high (TMB-H) solid tumors, defined as 10 mutations/megabase 
(mut/Mb).  The Phase II basket study of pembrolizumab monotherapy in this patient 
population demonstrated that TMB-H was associated with higher response rates in a 
number of different unresectable or metastatic tumor types, suggesting that tumor 
mutational burden (TMB) may predict efficacy of pembrolizumab treatment.  
In addition to testing targeted therapies in a pan-tumor setting, this study aims to expand 
study access to patients that are traditionally underrepresented in clinical trials.  
Classical registrational clinical trials often underrepresent patients of color, with data 
indicating that 88% of genetic sequencing/association studies have been done in 
individuals of European decent.  In addition, industry study design standards may 
unintentionally prevent diverse patients from being enrolled, as most studies include 
certain inclusion/exclusion criteria that tend to exclude people of specific ethnicities.  
This study will focus on inclusion of underrepresented, understudied patients with 
broader entry criteria and with an emphasis on recruiting patients of color to ensure this 
study reflects the US population more accurately.  
Specific biomarkers of interest for this protocol and their respective targeted therapies 
are outlined in Table 1.  Background and rationale for the biomarkers and the associated 
targeted therapies, are provided in the sections below. 


 
 
 
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Table 1 
Biomarker-specific Study Treatments  
Biomarker alteration 
Study Treatment 
Appendix 
ROS1 gene fusion  
Arm A: Entrectinib 
Appendix 10 
PIK3CA activating mutation 
Arm B: Inavolisib (GDC-0077) 
Appendix 11 
Arm K: Ipatasertib + atezolizumab 
Appendix 20 
ALK gene fusion 
Arm C: Alectinib 
Appendix 12 
AKT activating mutations and/or PTEN loss/loss of 
function 
Arm D: Ipatasertib 
Appendix 13 
Arm L: Ipatasertib + atezolizumab 
Appendix 21 
Co-mutation in PI3KCA activating mutation and AKT 
activating mutation or PI3KCA activating mutation and 
PTEN loss/loss of function 
Arm M: Ipatasertib + paclitaxel  
Appendix 22 
TMB  10/MSI-H/dMMR 
Arm E: Atezolizumab + chemotherapya  
Appendix 14 
Arm N: Atezolizumab + tiragolumab 
Appendix 23  
ERBB2 gene mutation or amplification 
without known TMB  10/MSI-H/dMMR 
Arm F: Trastuzumab emtansine + atezolizumab 
Appendix 15 
Arm G: PH FDC SC 
Appendix 16 
Arm H: PH FDC SC + chemotherapy a 
Appendix 17 
Arm I: Trastuzumab emtansine + tucatinib 
Appendix 18 


 
 
 
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Biomarker alteration 
Study Treatment 
Appendix 
ERBB2 gene amplification or mutation and 
TMB 10/MSI-H/dMMR  
Arm J: Trastuzumab emtansine + atezolizumb   
Appendix 19 
RET gene fusion  
Arm O: Pralsetinib 
Appendix 24 
dMMRdeficient mismatch repair; PH FDC SCfixed dose combination of trastuzumab and pertuzumab administered subcutaneously; MSI-
Hmicrosatellite instability high; PI3Kphosphatidylinositol 3-kinase; RETRearranged during Transfection; TMBtumor mutational burden. 
a Investigator’s choice of docetaxel, paclitaxel, or capecitabine. 


 
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1.1 
BACKGROUND AND RATIONALE FOR 
MOLECULARLY-TARGETED THERAPIES 
Cancer treatment is evolving toward a more personalized approach where the 
intersection of genomics, pathology, and classical imaging methods lead to 
individualized cancer care.  As novel genomic alterations and other biomarkers are 
identified, research evolves and leads to customized targeted treatments.  A clinical trial 
matching therapy choice to tumor biomarkers has the potential to yield valuable clinical 
information and provide meaningful treatment options for patients.  
1.1.1 
Arm A:  Entrectinib Treatment for Tumors with ROS1 Gene 
Fusions 
ROS1 belongs to the insulin-receptor superfamily.  Upon activation, it plays a role in 
relaying cell signals from the extracellular environment to the nucleus thereby promoting 
cell proliferation and cell survival.  ROS1 gene rearrangements create fusion proteins 
with constitutively active kinase domains that then activate downstream cell signaling 
pathways.  These pathways include Ras/ERK for cellular proliferation and the JAK-STAT 
and phosphoinositide 3-kinase (PI3K)/AKT pathways, which regulate cell survival (anti-
apoptosis) and proliferation.  ROS1 fusion proteins may also activate the mammalian 
target of rapamycin (mTOR) pathway, which is critical for the regulation of protein 
translation.  Cancers that have these pathways activated tend to be more aggressive, 
with invasion and metastasis leading to poor survival for patients (Davies and Doebele 
2013). 
ROS1 fusion partners have been identified in patients with non-small cell lung cancer 
(NSCLC), and ROS1 gene rearrangements have also been detected in other tumor 
types including glioblastoma multiforme, cholangiocarcinoma, ovarian cancer, gastric 
adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, 
and epithelioid hemangioendothelioma (Davies et al. 2012; Davies and Doebele 2013; 
Lee et al. 2013; Shaw et al. 2013).  The prevalence of ROS1 gene fusions across solid 
tumors excluding NSCLC is ~0.05% (Hartmaier et al. 2017; Foundation Medicine 2019). 
Several small-molecule inhibitors have been developed to treat tumors harboring ROS1 
oncogenic fusion kinases (e.g., the ROS1 inhibitors crizotinib and entrectinib, which 
have demonstrated targeted activity against lung cancers harboring ROS1 gene 
rearrangements). 
Crizotinib (Xalkori, Pfizer) was approved in the United States on the basis of results of a 
single-arm study of 50 patients (Shaw et al. 2014).  The majority of patients had received 
some prior therapy for the treatment of NSCLC, although 14% were reported to be 
treatment naïve.  Almost all patients had ROS1 fusions identified using a fluorescence in 
situ hybridization (FISH) assay from a tissue sample.  The objective response rate 
(ORR) in this study was 72% (95% CI: 58%, 84%), with 3 complete responses and 
33 partial responses.  The median duration of response (DOR) was 17.6 months (95% 


 
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CI: 14.5, not reached), and the median progression-free survival (PFS) was 19.2 months 
(95% CI: 14.4 months, not reached) (Shaw et al. 2014).  
Entrectinib (Rozlytrek) was approved for ROS1-postive NSCLC in the United States 
based on the results in 53 adult patients across three clinical trials.  Entrectinib is a 
potent inhibitor of the ROS1 tyrosine kinase with an IC50 of 0.2 nM (see Entrectinib 
Investigator's Brochure).  In ROS1 fusion-positive NSCLC, patients treated with 
entrectinib had clinically meaningful and durable systemic responses.  The majority of 
patients had received prior therapy for the treatment of their disease.  The ORR was 
77.4% (95% CI: 63.8, 87.7) with a median DOR of 24.6 months (95% CI: 11.4, 34.8).  
Patients with CNS metastases at baseline had an intracranial ORR of 55.0%, with 
4 patients having a complete response (20.0%), and a median intracranial DOR of 
12.6 months (Drilon et al. 2020). 
Entrectinib has demonstrated clinical activity across multiple tumor types including 
colorectal, NSCLC, pancreatic, thyroid, breast, sarcoma, cholangiocarcinoma, mammary 
analogue secretory carcinoma (MASC), neuroendocrine tumors, and gynecological 
etiology in NTRK gene fusion-positive cancers (Demetri et al. 2018).  Entrectinib was 
also approved in the United States for adults and pediatric patients 12 years of age and 
older who have solid tumors that harbor a NTRK gene fusion, based on the results 
across three clinical trials.  As entrectinib is a potent inhibitor of both NTRK and ROS1 
tyrosine kinase domains, it is hypothesized that therapeutic effects may be observed in 
patients who harbor ROS1 gene fusions, regardless of tumor type.  Given that multiple 
tumor responses have been observed among different tumor types that harbor NTRK 
gene fusions, and the ability for entrectinib to cross the blood-brain barrier, entrectinib 
potentially presents a favorable option for patients whose tumors harbor ROS1 gene 
fusions outside of NSCLC. 
1.1.2 
Arm B:  Inavolisib (GDC-0077) Treatment for Tumors with 
PI3Kalpha (PIK3CA) Activating Mutations  
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that upon activation by growth 
factor receptors and integrins regulates cell proliferation, survival, and migration.  PI3K 
catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to 
generate phosphatidylinositol-3,4,5-triphosphate (PIP3), a second messenger involved in 
the phosphorylation of AKT and other components in the AKT/mTOR pathway (Cantley 
2002; Guertin and Sabatini 2007).  PI3K and its downstream effectors, AKT and mTOR, 
are major nodes in the PI3K/AKT/mTOR signaling pathway and are critical for cell-cycle 
modulation, cell growth, metabolism, motility, and survival (Cantrell 2001; Hanahan and 
Weinberg 2011; Vanhaesebroeck et al. 2012).  
Dysregulation of the PI3K/AKT/mTOR signaling pathway through multiple different 
mechanisms has been described in solid tumor malignancies, including activating and 
transforming mutations, as well as amplification, of PIK3CA – the gene that encodes the 
p110 alpha subunit of PI3K (Gustin et al. 2008; Yuan and Cantley 2008; Courtney et al. 


 
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2010).  Activating mutations in the PIK3CA gene occur primarily in exons 9 and 20 
(“hotspot” regions) that encode the helical and kinase domains of the alpha isoform of 
the PI3K protein (Bachman et al. 2004; Samuels et al. 2004).  It is estimated that such 
activating mutations occur in ~11% of solid tumors (Roche, data on file).  
Inavolisib (GDC-0077) is a potent selective inhibitor of the Class I PI3K alpha isoform, 
with  300-fold less potent biochemical inhibition for other Class I PI3Ks, including the 
beta, delta, and gamma isoforms, and increased activity in tumor cells bearing mutated 
PIK3CA over wild type (WT) PIK3CA cells.  Inavolisib (GDC-0077)  exerts its activity by 
binding to the ATP binding site of PI3K, thereby inhibiting the phosphorylation of 
membrane-bound PIP2 to PIP3.  Inhibiting the phosphorylation of PIP2 to PIP3 decreases 
downstream activation of AKT and S6, resulting in decreased cellular proliferation, 
metabolism, and angiogenesis.  Nonclinical studies demonstrate that inavolisib (GDC-
0077) also induces specific degradation of mutated p110 alpha, inhibits proliferation and 
induces apoptosis of PIK3CA-mutation positive breast cancer cell lines, inhibits tumor 
growth in human breast xenograft models harboring PIK3CA mutations, and reduces 
downstream PI3K-pathway markers, including pAKT, pPRAS40, and pS6. 
PI3K inhibition is an attractive target for clinical drug development because of the 
frequency of mutations observed across multiple tumor types in the PI3K-AKT-mTOR 
pathway (Massacesi 2016).  Clinical trials, including SOLAR-1 (Phase III, alpelisib) and 
SANDPIPER (Phase III, taselisib), have demonstrated the anti-tumor activity of PI3K 
inhibitors in tumor types including estrogen receptor positive (ER+) breast cancers 
harboring PIK3CA mutations.  More recently, a Phase I/Ib study of inavolisib (Study 
GO39374) has shown preliminary, encouraging safety and anti-tumor activity in 
PIK3CAmutation-positive, hormone receptor positive (HR+)/human epidermal growth 
factor receptor 2 negative (HER2–) metastatic breast cancer.  
With increasing evidence for the utility of PI3K inhibitors in tumors that harbor one or 
more PIK3CA mutations, further research of this drug class that includes patients whose 
tumors have one or more PIK3CA mutations is warranted. 
1.1.3 
Arm C:  Alectinib Treatment for Tumors with ALK Gene Fusion 
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in 
some cancers due to gene alterations, including chromosomal rearrangements.  Many 
different ALK fusion partners have been identified in a variety of tumor types including 
but not limited to lung cancer, Spitz tumors, inflammatory myofibroblastic tumors (IMT), 
thyroid cancer, digestive tract cancer, ovarian cancer, and renal cell carcinoma (Cao et 
al. 2019).  The formation of ALK fusion proteins results in activation and dysregulation of 
the gene’s expression and signaling, which can contribute to increased cell proliferation 
and survival in tumors expressing these genes.  ALK gene alterations are generally in a 
mutually exclusive relationship with mutations in EGFR or KRAS (Soda et al. 2007; 
Inamura et al. 2008, 2009; Wong et al. 2009), although EGFR mutations may develop as 


 
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a resistance mechanism after treatment with crizotinib, an inhibitor of ROS1 activation 
(Doebele et al. 2012).   
While the ALK fusions have been observed in many tumor types, the prevalence of 
these translocations is approximately 5% in NSCLC versus only ~0.1%0.2% in 
non-NSCLC solid tumors (Hartmaier et al. 2017; Ross et al. 2017; Foundation Medicine 
2019).  Consequently, ALK inhibitor development has been largely limited to NSCLC.   
Crizotinib, was the first ALK inhibitor approved for ALK-positive NSCLC demonstrating 
improvement in PFS and ORR over chemotherapy; however, no difference in overall 
survival (OS) was noted between the two groups (Shaw et al. 2013, Solomon et al. 
2014).   
Next-generation ALK inhibitors were designed to overcome two major limitations of 
crizotinib treatment: the development of resistance because of secondary 
(e.g., gatekeeper) mutations (predominantly in ALK or occasionally in other genes, such 
as EGFR, cKIT, or KRAS) (Katayama et al. 2011; Doebele et al. 2012; Kim et al. 2013) 
and CNS relapse (crizotinib has poor control of brain metastases compared to other 
sites).  Thus next-generation ALK inhibitors may offer patients a better chance of 
prolonged remission and minimize the development of CNS metastases and the 
attendant comorbidity.  
Alectinib (Alecensa) is a small-molecule, highly selective, and potent oral 
next-generation ALK inhibitor with a benzo[b]carbazole scaffold.  In enzyme inhibition 
assays performed in vitro, this compound has been shown to selectively inhibit ALK and 
RET.  The compound also shows high anti-tumor activity both in vitro and in vivo against 
tumor cell lines with some type of somatic ALK gene mutation, including NSCLC and 
anaplastic large cell lymphoma lines harboring an ALK translocation and a 
neuroblastoma line harboring an amplified ALK gene.  Alectinib shows good exposure in 
the brain, demonstrated in rodents, and is not a substrate of efflux transporters in the 
blood-brain barrier, such as P-gp, and therefore is able to distribute into and be retained 
within the CNS.   
While ALK fusions are rare in tumors other than non-squamous NSCLC, in vivo studies 
and clinical case reports suggest that ALK inhibition could be an interesting treatment 
approach for such patients.  Cases of clinical responses have also been reported with 
alectinib treatment in patients with various solid tumors including papillary renal cell 
carcinoma (Pal et al. 2018), metastatic inflammatory myofibroblastic tumors (Honda et 
al. 2019; Saiki et al. 2017), pancreatic ductal adenocarcinoma, squamous cell carcinoma 
(Huang et al. 2018; Mayesaya et al. 2017), and large cell neuroendocrine carcinoma 
(Shimizu et al. 2019).  This promising clinical activity in non-NSCLC tumors supports 
further investigation in this population in which ALK oncogenic fusions are particularly 
rare. 


 
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1.1.4 
Arm D:  Ipatasertib Treatment for Tumors with AKT Gene 
Activating Mutations or PTEN Loss or Loss of Function 
AKT is one of the most frequently activated protein kinases in human cancers, and plays 
a critical role in tumor growth, proliferation, metabolism, survival, and resistance to 
therapy (Bellacosa et al. 1995; Manning and Cantley 2007; Jiang and Liu 2008; 
Tokunaga et al. 2008; Robey and Hay 2009).  AKT is encoded by three closely related 
gene isoforms in the mammalian genome, AKT1, AKT2 and AKT3.  AKT is the central 
node of the PI3K/AKT/mTOR pathway, and is negatively regulated by the tumor 
suppressor PTEN, a phospholipid phosphatase that negatively regulates the activity of 
PI3K.  Most commonly found alterations in solid and liquid tumors include the loss of 
PTEN, activating and transforming mutations in the p110 subunit of PI3K, deregulation 
of receptor tyrosine kinase signaling, and oncogenic Ras mutations.  Alterations in AKT 
itself, including overexpression and amplification of individual AKT isoforms, as well as 
an E17K mutation in the PH domain of AKT1 that results in PI3K-independent 
membrane recruitment of AKT1, have been identified in a subset of human cancers 
(reviewed in Bellacosa et al. 2005; Brugge et al. 2007; Tokunaga et al. 2008).  All of 
these mechanisms of pathway activation ultimately funnel through AKT as the central 
node that drives cell survival, growth, proliferation, angiogenesis, metabolism, and 
migration (Manning and Cantley 2007).  The prevalence of AKT1/2/3 gene activating 
mutations or genomic alterations resulting in PTEN loss or loss of function has not been 
fully characterized, but may occur in ~13% of solid tumors (Roche, data on file). 
Ipatasertib is a potent, highly selective small-molecule inhibitor of all three isoforms of 
the serine/threonine kinase AKT.  Ipatasertib binds to the activated conformation of AKT 
and is ATP competitive.  Ipatasertib binding inhibits the kinase activity of AKT and 
suppresses the phosphorylation of its direct substrates, including PRAS40, and 
additional downstream targets, such as S6 ribosomal protein (S6RP), resulting in G1 
arrest and/or apoptosis in human cancer cells (Lin et al. 2012).  In clinical tumor 
samples, robust AKT pathway inhibition by ipatasertib can be achieved at clinically 
relevant doses (Yan et al. 2013). 
In nonclinical models with high levels of phosphorylated AKT or PI3K/AKT pathway 
activity (i.e., PIK3CA mutation, PTEN alterations), sensitivity to ipatasertib has been 
observed across different tumor models (Lin et al. 2013).  
Study PAM4743g was an open-label, Phase I, dose-escalation study designed to assess 
the safety, tolerability, and pharmacokinetics (PK) of ipatasertib as a single agent in 
patients with refractory solid tumors (Saura et al. 2018).  Fifty-two patients across 
multiple tumor types, including metastatic breast cancer, castration-resistant prostate 
cancer, colorectal cancer, chondrosarcoma, and ovarian cancer, were enrolled into 
respective tumor-specific cohorts regardless of mutation status.  Across all dosing 
cohorts, 16 of 47 (34%) of patients had a best overall response of stable disease (SD) or 
incomplete response (IR).  The anti-tumor activity of single-agent ipatasertib in a patient 


 
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population whose tumors are AKT mutation positive or exhibit PTEN loss or loss of 
function is currently unknown. 
Additionally, in a Phase II randomized, placebo-controlled study, ipatasertib plus 
paclitaxel as first-line therapy demonstrated improved PFS in patients with locally 
advanced or metastatic triple negative adenocarcinoma of the breast (TNBC) compared 
to paclitaxel alone (Kim et al. 2017).  In the ipatasertib group, median PFS was 6.2 
months (95% CI 3.89) versus 4.9 months (95% CI 3.65.4) with placebo (hazard ratio 
[HR] 0.6, 95% CI 0.370.98; p=0.037).  In a subset of the study population, patients with 
PTEN-low tumors by immunohistochemistry [IHC] had a median PFS of 6.2 months 
(95% CI 3.69.1) with ipatasertib versus 3.7 months (95% CI), median PFS was 6.2 
months (95% CI 3.69.1) with ipatasertib versus 3.7 months with placebo (HR 0.59, 95% 
CI 0.261.32; p=0.18).  These promising results support further investigation in patients 
with tumors harboring activating AKT1/2/3 gene activating mutations or genomic 
alterations resulating in PTEN loss or loss of function alterations. 
Based on the scientific rationale that PI3K/AKT/mTOR blockade reduces survival signals 
and acceptable safety profile observed to date, treating patients with solid tumors that 
harbor such alterations with ipatasertib warrants further investigation. 
1.1.5 
Arm E:  Atezolizumab plus Chemotherapy for Tumors with 
Tumor Mutational Burden10/Microsatellite Instability High 
/Deficient Mismatch Repair 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies (Hodi et al. 
2010; Kantoff et al. 2010; Chen et al. 2012).   
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, programmed cell death protein 1 (PD-1) and B7-1.  PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, and expression is 
sustained in states of chronic stimulation (Blank et al. 2005; Keir et al. 2008).  B7-1 is a 
molecule expressed on antigen-presenting cells and activated T cells.  Binding of PD-L1 
to PD-1 and B7-1 inhibits T-cell proliferation and activation, cytokine production, and 
cytolytic activity, leading to the functional inactivation or exhaustion of T cells (Butte et al. 
2007; Yang et al. 2011).  Therefore, interruption of the PD-L1 pathway represents an 
attractive strategy for restoring tumor-specific T-cell immunity. 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 


 
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and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells.  
In recent years, PD-L1/PD-1 inhibitors have demonstrated clinical efficacy in patients 
with advanced malignancies who have failed standard of care therapy and agents have 
shown activity across a broad range of tumor types.  For example, in patients treated 
with atezolizumab, objective responses have been across a broad range of tumor types, 
including urothelial carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head 
and neck cancer, gastric cancer, breast cancer, and sarcoma (see Atezolizumab 
Investigator’s Brochure for detailed efficacy results).  Additionally, pembrolizumab has 
been approved in a tumor-agnostic setting based on mismatch repair deficiency (dMMR) 
or microsatellite instability high (MSI-H) as well as TMB  10 mutations per megabase.  
A growing body of evidence points to higher TMB and MSI-H/dMMR being correlated 
with better clinical outcomes with checkpoint inhibitor therapies.  The higher mutational 
burden in these tumors likely produces an array of immunogenic neoantigens that 
renders greater sensitivity to the effects of the immune system (Schumacher and 
Schreiber 2015).  Evidence in a variety of cancer types suggests that patients with a 
high burden of somatic mutations derive significant clinical benefit from anti-PD1/PD-L1 
therapy.  Multiple clinical studies have reported that high TMB is associated with 
response to several immunotherapeutic agents, including anti- CTLA-4 in melanoma 
(Snyder et al. 2014; Johnson et al. 2016), antiPD-L1 therapy in bladder cancer 
(Rosenberg et al. 2016), and antiPD-1 therapy in lung and colorectal cancers (Le et al. 
2015; Rizvi et al. 2015; Fehrenbacher et al. 2016).  In a Phase II signal-seeking study, 
patients with advanced solid tumors who had progressed on or were intolerant to 
standard therapy, were treated with pembrolizumab.  The ORR was 30.3% in patients 
with tissue TMB elevated tumors compared with 6.7% in patients with non-high TMB 
(Marabelle et al. 2019).   
Combining immunotherapy with chemotherapy has been demonstrated to have a 
synergistic effect and enhance antitumor immunity and improve outcomes beyond those 
achieved with each therapy alone.  It is thought that tumor cell killing by cytotoxic 
chemotherapy may expose the immune system to increased levels of tumor antigens, 
and unblocking tumor-specific T-cell immunity in this setting by inhibiting PD-L1/PD-1 
signaling may result in synergistic activity.  AntiPD-L1/PD-1 therapies have been 
approved in the United States across a broad range of indications including in 
combination with taxane or fluorpyrimidine chemotherapies.  Given the promising activity 
of checkpoint inhibition in MSI-H/dMMR and TMB-H tumors and the synergistic effects 
and acceptable safety profile observed in combination with chemotherapy, further study 
of atezolizumab in combination with docetaxel, paclitaxel, or capecitabine is warranted in 
a tumor-agnostic setting.   


 
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1.1.6 
HER2 Targeted Therapy for HER2-Positive Tumors  
The ERBB2 gene, which encodes HER2, a member of the erbB family of receptor 
tyrosine kinases, has been described as a key proto-oncogene in solid tumors (Slamon 
et al. 1989; Slamon et al. 1987).  Approximately 6% of all solid tumor samples tested at 
Foundation Medicine have demonstrated amplification or activating alterations in HER2 
(Foundation Medicine database, Q1 2020).  Until recently, development of HER2-
targeted therapies has been focused in HER2-overexpessing tumors, with approved 
indications in breast and gastric cancers.  More recently, there has been interest in the 
potential oncogenic effect of HER2 somatic mutations and targeting of HER2-mutation 
positive tumors (Bose et al. 2013; Cousin et al. 2018; Li et al. 2015).   
HER2 activating mutations including insertions/deletions and point mutations in the 
kinase, transmembrane, and extracellular domains occur across solid tumors and have 
been identified as oncogenic drivers (Connell & Doherty 2017; Cousin et al. 2018; 
Wen et al. 2015).  HER2 mutations occur at a prevalence of 1.48% in solid tumors 
(Hartmaier et al. 2017; Foundation Medicine 2019), and the majority of tumors do not 
have co-occurring HER2 mutations and HER2 amplification.  HER2 mutations occur in 
as many as 10% of bladder cancers and at meaningful frequencies in more common 
tumors including lung, breast, gastric and colorectal cancers, among many others.   
Nonclinical studies have demonstrated activity of HER2-targeted therapies in HER2 
mutation-positive solid tumors including of neratinib, afatinib, dacomitinib, and 
trastuzumab in HER2 mutation-positive lung and breast cancer cell lines (Engelman et 
al. 2007; Greulich et al. 2012; Lee et al. 2006; Li et al. 2008; Shimamura et al. 2006; 
Wang et al. 2006).  Nonclinical models have shown the inhibitory effects of single-agent 
trastuzumab on HER2 mutation-positive lung cancer cell lines (Greulich et al. 2012; 
Wang et al. 2006) and clinical series of patients with HER2 mutation-positive lung cancer 
have reported high response rates from trastuzumab-based therapy (Cappuzzo et al. 
2006; Mazieres et al. 2013).  
In the clinical setting, responses have been seen in patients with HER2 mutation-positive 
solid tumors who were treated with HER2-targeting therapies including epidermal growth 
factor receptor (EGFR)-targeted tyrosine kinase inhibitors (summarized in Connell and 
Doherty 2017) and trastuzumab emtansine (Li et al. 2018).  An ORR of 44% was 
observed in patients with HER2 mutation-positive lung cancers treated with trastuzumab 
emtansine (Li et al 2018).  
Activating HER2 mutations have demonstrated increased tumorgenicity, invasiveness 
and survival compared with non-HER2 amplified cells (Wang et al. 2006; Bose et al. 
2013).  HER2 amplification and activating mutations occur across tumor types and 
nonclinical and clinical evidence suggests that tumors that harbor these alterations may 
be vulnerable to HER2-targeted therapy.  This evidence, combined with the relatively 
low prevalence of HER2 alterations outside of breast, supports further assessment of the 
efficacy of HER2-targeted therapies in a tumor-agnostic fashion. 


 
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1.1.6.1 
Arm F:  Trastuzumab Emtansine plus Atezolizumab for 
HER2-Positive Tumors (without knownTMB-H/MSI-H/dMMR)  
Trastuzumab emtansine (known as ado-trastuzumab emtansine in the United States) is 
a novel antibody-drug conjugate (ADC), specifically designed for the treatment of 
HER2-positive cancer.  It is composed of the following components:  trastuzumab, a 
humanized antibody directed against the extracellular region of HER2; DM1, an 
anti-microtubule agent derived from maytansine; and succinimidyl 4[-Nmaleimidomethyl] 
cyclohexane-1-carboxylate (SMCC), a thioether linker molecule used to conjugate DM1 
to trastuzumab.  Trastuzumab emtansine binds to HER2 with an affinity similar to that of 
unconjugated trastuzumab.  It is hypothesized that after binding to HER2, trastuzumab 
emtansine undergoes receptor-mediated internalization, resulting in intracellular release 
of DM1 and subsequent cell death.  DM1 is an inhibitor of tubulin polymerization; it binds 
to tubulin competitively with vinca- alkaloids.  It is thought that trastuzumab emtansine 
provides a dual mechanism of action providing both HER2 targeted inhibition from the 
trastuzumab component along with chemotherapy from DM1. 
Trastuzumab Emtansine (T-DM1) therapeutic activity may be accentuated by enhancing 
anti-tumor immunity.  Recently, it was shown that the precursor of DM1, ansamitocin P3 
may potentiate antitumor immunity by inducing maturation of dendritic cells, facilitating 
antigen uptake and the migration of tumor-resident dendritic cells to tumor-draining 
lymph nodes (Martin et al. 2014; Müller et al. 2014).  A HER2-positive murine model has 
suggested therapeutic efficacy was dependent on T-DM1 induced infiltration by effector 
T-cells.  After T-DM1 treatment, tumors became more T-cell–inflamed with an increase 
in γδT-cells that may cooperate with cancer immunotherapy, natural killer (NK)-cells and 
expansion of CD45+ cells.  In addition, paired samples from 28 HER2-positive breast 
cancer patients treated with T-DM1 prior to surgery demonstrated increases in 
tumor-infiltrating T-cells after treatment (Müller et al. 2015). 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells.  
Evidence suggests that treatment with atezolizumab plus an anti-HER2 therapy could 
have greater anti-cancer activity than either agent alone.  Nonclinical studies have 
shown that trastuzumab inhibition of HER2-positive tumors could upregulate PD-L1, 
suggesting that trastuzumab and anti-PD-L1 therapy could be more effective against 
HER2-positive tumors than trastuzumab alone (Chaganty et al 2018). 


 
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Superior effectiveness of treatment with T-DM1 plus atezolizumab is also suggested by 
data from clinical studies.  In the KATE2 trial, T-DM1 plus atezolizumab was compared 
to T-DM1 alone in the treatment of HER2+ metastatic breast cancer previously treated 
with trastuzumab and a taxane.  In the final safety and clinical activity analysis, overall 
survival was numerically greater in the T-DM1 plus atezolizumab arm over the T-DM1 
only arm (stratified HR0.74; 95% CI: 0.42–1.30) (Emens et al. 2019).  This suggests 
that T-DM1 plus atezolizumab alone could have greater anti-tumor activity than T-DM1 
alone.  Furthermore, in KATE2, the safety profile of the combination was consistent with 
the known safety profile of each drug, suggesting tolerability for the combination (see 
treatment-specific appendix for more on risks and adverse event management of the 
treatment combination). 
The presence of TMB-H and/or MSI-H/dMMR status is known to enhance the activity of 
anti-PD-L1/PD-1 targeting agents, but the impact of these biomarkers on the 
combination of T-DM1 plus atezolizumab is not yet well characterized.  However, the 
body of available data suggests that there may be therapeutic benefit to the addition of 
atezolizumab to T-DM1, even in the absence of TMB-H and/or MSI-H/dMMR status.  
With these considerations, and taking into account the acceptable safety profile 
demonstrated in the KATE2 trial, further study of the combination in a tumor-agnostic 
setting is warranted. 
1.1.6.2 
Arms G & H:  PH FDC SC with or without Chemotherapy for 
HER2-Positive Tumors 
The fixed dose combination of pertuzumab and trastuzumab administered 
subcutaneously (PH FDC SC) represents a combination of both anti-HER2 monoclonal 
antibodies along with hyaluronidase in a single drug product and is approved in the 
United States for the treatment of HER2 positive early stage and metastatic breast 
cancer in combination with chemotherapy.  
Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 and, 
thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family 
members, including EGFR, HER3, and HER4.  As a result, pertuzumab inhibits 
ligand-initiated intracellular signaling through two major signaling pathways, 
mitogen-activated protein (MAP) kinase and PI3K.  Inhibition of these signaling 
pathways can result in cell growth arrest and apoptosis, respectively.  
Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to 
inhibit the ligand-independent, HER2 mediated cell proliferation and PI3K signaling 
pathway in human tumor cells that overexpress HER2.  
Both pertuzumab and trastuzumab-mediated antibody-dependent cell-mediated 
cytotoxicity (ADCC) have been shown to be preferentially exerted on HER2 
overexpressing cancer cells compared with cancer cells that do not overexpress HER2.  


 
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Clinically, dual HER2 inhibition with both pertuzumab and trastuzumab has 
demonstrated superiority over regimens containing trastuzumab alone.  
Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing 
hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous 
tissue.  In the doses administered, hyaluronidase in PH FDC SC acts transiently and 
locally. 
The safety profile for HER2 inhibition in combination with docetaxel, paclitaxel, or 
capecitabine chemotherapy is known to be acceptable.  Trastuzumab and pertuzumab 
are approved for use in combination with either docetaxel or paclitaxel in HER2 positive 
early stage and metastatic breast cancer and trastuzumab is further approved in 
combination with a regimen containing capecitabine in HER2 positive metastatic gastric 
cancer.  
As noted above, HER2 amplification and activating mutations occur across tumor types 
and nonclinical and clinical evidence suggests that tumors that harbor these alterations 
may be vulnerable to HER2-targeted therapy.  The wealth of efficacy and safety data 
supporting HER2 inhibition with or without chemotherapy, along with the relatively low 
prevalence of HER2 alterations outside of breast, supports further assessment of the 
efficacy of dual HER2-targeted therapies with or without docetaxel, paclitaxel, or 
capecitabine chemotherapy in a tumor-agnostic fashion. 
1.1.6.3 
Arm I:  Trastuzumab Emtansine plus Tucatinib for HER2-
Positive Tumors  
Trastuzumab emtansine (known as ado-trastuzumab emtansine in the United States) is 
a novel ADC, specifically designed for the treatment of HER2-positive cancer.  It is 
composed of the following components:  trastuzumab, a humanized antibody directed 
against the extracellular region of HER2; DM1, an ant-microtubule agent derived from 
maytansine; and SMCC, a thioether linker molecule used to conjugate DM1 to 
trastuzumab.  Trastuzumab emtansine binds to HER2 with an affinity similar to that of 
unconjugated trastuzumab.  It is hypothesized that after binding to HER2, 
trastuzumab- emtansine undergoes receptor-mediated internalization, resulting in 
intracellular release of DM1 and subsequent cell death.  DM1 is an inhibitor of tubulin 
polymerization; it binds to tubulin competitively with vinca alkaloids.  It is thought that 
trastuzumab emtansine provides a dual mechanism of action providing both HER2 
targeted inhibition from the trastuzumab component along with chemotherapy from DM1.  
Tucatinib is a kinase inhibitor approved in the US in combination with trastuzumab and 
capecitabine for treatment of adult patients with advanced unresectable or metastatic 
HER2-positive breast cancer with or without brain metastases who have received one or 
more prior anti-HER2-based regimens in the metastatic setting.  Tucatinib prevents 
phosphorylation of the tyrosine kinase domain of the HER2 receptor, preventing 
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cell proliferation, survival, and metastasis.  In addition to the approved indication in 
breast cancer, preclinical data show activity of tucatinib in a variety of tumor type models 
as a single agent and in combination with other HER2-targeting agents and 
chemotherapy (Peterson et al, 2020).  
The combination of trastuzumab emtansine and tucatinib was examined in a Phase 1b 
study of 57 HER2 positive breast cancer patients (Borges et al, 2018).  The combination 
demonstrated an acceptable safety profile at doses of 3.6mg/kg for trastuzumab 
emtansine every 21 days and 300 mg for tucatinib twice per day.  Additionally, promising 
anti-tumor activity was observed with a response rate of 48%.  
The available clinical and preclinical data support the continued investigation of a dual 
inhibition approach in HER2 positive cancers beyond breast cancer.  The combination of 
trastuzumab emtansine and tucatinib represents a unique opportunity to study the safety 
and efficacy of dual targeting of HER2 with an ADC and kinase inhibitor in a 
tumor-agnostic setting.  
1.1.6.4 
Arm J: Trastuzumab Emtansine plus Atezolizumab for HER2-
Positive and TMB-H/MSI-H/dMMR Tumors 
Trastuzumab emtansine (known as ado-trastuzumab emtansine in the United States) is 
a novel ADC, specifically designed for the treatment of HER2-positive cancer.  It is 
composed of the following components:  trastuzumab, a humanized antibody directed 
against the extracellular region of HER2; DM1, an ant-microtubule agent derived from 
maytansine; and SMCC, a thioether linker molecule used to conjugate DM1 to 
trastuzumab.  Trastuzumab emtansine binds to HER2 with an affinity similar to that of 
unconjugated trastuzumab.  It is hypothesized that after binding to HER2, trastuzumab 
emtansine undergoes receptor-mediated internalization, resulting in intracellular release 
of DM1 and subsequent cell death.  DM1 is an inhibitor of tubulin polymerization; it binds 
to tubulin competitively with vinca-alkaloids.  It is thought that trastuzumab emtansine 
provides a dual mechanism of action providing both HER2 targeted inhibition from the 
trastuzumab component along with chemotherapy from DM1.  Overall response rates in 
patients with NSCLC whose tumors contain HER2 amplification, HER2 mutation, and 
HER2 mutation plus amplification have been reported to be similar (approximately 50%) 
when treated with trastuzumab emtansine (Li et al. 2020). 
Trastuzumab Emtansine (T-DM1) therapeutic activity may be accentuated by enhancing 
anti-tumor immunity.  Recently, it was shown that the precursor of DM1, Ansamitocin P3 
may potentiate antitumor immunity by inducing maturation of dendritic cells, facilitating 
antigen uptake and the migration of tumor-resident dendritic cells to tumor-draining 
lymph nodes (Martin et al. 2014; Müller et al. 2014).  A HER2-positive murine model has 
suggested therapeutic efficacy was dependent on T-DM1 induced infiltration by effector 
T-cells.  After T-DM1 treatment, tumors became more T-cell–inflamed with an increase 
in γδT-cells that may cooperate with cancer immunotherapy, NK-cells, and expansion of 
CD45+ cells.  In addition, paired samples from 28 HER2-positive breast cancer patients 


 
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treated with T-DM1 prior to surgery demonstrated increases in tumor-infiltrating T-cells 
after treatment (Müller et al. 2015). 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells.  
Evidence suggests that treatment with atezolizumab plus an anti-HER2 therapy could 
have greater anti-cancer activity than either agent alone.  Nonclinical studies have 
shown that trastuzumab inhibition of HER2-positive tumors could upregulate PD-L1, 
suggesting that trastuzumab and anti-PD-L1 therapy could be more effective against 
HER2-positive tumors than trastuzumab alone (Chaganty et al. 2018). 
In the KATE2 trial, the addition of atezolizumab to T-DM1 did not demonstrate a 
meaningful PFS benefit in the intent-to-treat (ITT) population; however, an exploratory 
analysis suggested a PFS benefit for the combination in the PD-L1+ (PD-L1 IC 1%) 
subgroup (HR, 0.60 [95% CI: 0.32, 1.11]) [L. Emens et al, SABCS 2018].  Additionally, at 
the second planned interim OS analysis, although the number of OS events were small, 
the results suggested an OS benefit with atezolizumab plus T-DM1 in the PD-L1 immune 
cells positive (IC+) subgroup (1-year survival rate of 94% vs 88%) (Emens et al. 
2019).  While the magnitude of the benefit is uncertain given the limited number of 
patients in this subgroup, and the corresponding wide confidence intervals, these results 
suggest that T-DM1 plus atezolizumab could have greater anti-tumor activity than 
T-DM1 alone in patients with PD-L1+ (PD-L1 IC  1%) metastatic breast cancer.  The 
incidence of Grade 3 to 5 adverse events was generally similar between the 2 arms.  
Overall, the safety profile of the combination was consistent with what is already known 
about the individual drugs, with no new safety signals, suggesting tolerability for the 
combination (see treatment-specific appendix for more on risks and adverse event 
management of the treatment combination). 
The presence of TMB-H and/or MSI-H/dMMR status is known to enhance the activity of 
anti-PD1/PD-L1 targeting agents, but the impact of these biomarkers on the combination 
of T-DM1 plus atezolizumab is not yet well characterized.  The occurrence of dual 
positive biomarkers across tumor types is known to be low (Roche internal analysis) and 
therefore, taking into account the acceptable safety profile demonstrated in the KATE2 
trial, a tumor-agnostic approach to further investigate the combination of these agents is 
warranted in this study.  


 
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1.1.7 
Arms K and L: Ipatasertib Plus Atezolizumab for PI3K 
Activating Mutations or AKT Activating Mutation and/or PTEN 
Loss/Loss of Function 
AKT is the central node of the PI3K-Akt-mTOR signaling axis and represents a major 
downstream effector of receptor tyrosine kinases.  Activation of the PI3K/Akt pathway 
results in essential cellular functions including cell survival, growth, and proliferation, 
which are properties that underlie human cancers.  The PI3K/Akt pathway can be 
activated through loss of the tumor suppressor phosphatase and tensin homolog (PTEN) 
(Li et al. 1997), through activating mutations and/or amplifications in PIK3CA (Bachman 
et al. 2004), or through activating mutations in AKT1 (Carpten et al. 2007). 
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
Blockade of the pathway has shown to be effective in many cancer types.   
Ipatasertib (GDC-0068) is a novel, selective, ATP-competitive small molecule inhibitor of 
all three isoforms of the serine/threonine kinase Akt and the mechanism of action and 
rationale for use as a single agent is described in Section 1.1.4.  Atezolizumab is a 
humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits the interaction 
between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which 
function as inhibitory receptors expressed on T cells.  Therapeutic blockade of PD-L1 
binding by atezolizumab has been shown to enhance the magnitude and quality of 
tumor-specific T-cell responses, resulting in improved anti-tumor activity (Fehrenbacher 
et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding to Fc receptors, 
thus eliminating detectable Fc-effector function and associated antibody-mediated 
clearance of activated effector T cells. 
The combination of ipatasertib and atezolizumab in tumors driven by activation of the 
Akt/PI3K pathway has the potential to provide therapeutic benefit by simultaneously 
addressing multiple nodes in the cancer immunity cycle (Chen and Mellman 2013), 
including release of cancer antigens via cancer cell death and recognition by T-cells. 
Additionally, preliminary evidence suggests that inihibtion of the Akt/PI3K pathway may 
modulate the immune microenvironment, reducing regulatory T-cells and increasing the 
trafficking of CD8 positive effector T-cells into the tumor microenvironment (Lopez et al. 
2020b), potentially further supporting cancer immunity.  
There are several clinical trials investigating combinations of ipatasertib and 
atezolizumab which include an ongoing Phase Ib in metastatic hormone-receptor-
positive, HER-negative breast cancer (CO39611), metastatic TNBC (CO40115) and 
NSCLC (BO39610).  On the basis of these results, combination treatment with these two 
agents can be safely investigated and is expected to have promising therapeutic 
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1.1.8 
Arm M: Ipatasertib Plus Paclitaxel for Co-mutations in the 
PI3K/AKT Pathway 
The PI3K/Akt pathway is more frequently activated by genomic aberrations than any 
other signaling pathway in cancer (LoRusso 2016).  The most common genetic 
alterations in this pathway are activating mutations of phosphatidylinositol-4, 
5bisphosphate 3-kinase, catalytic subunit, alpha (PIK3CA), loss-of-function alterations 
of the tumor suppressor phosphatase and tensin homolog (PTEN), deregulation of 
receptor tyrosine kinase signaling, and amplification and mutations of receptor tyrosine 
kinases (Cancer Genome Atlas Network 2012; Millis et al. 2015).  Alterations in Akt 
itself, including amplification and overexpression of individual Akt isoforms, as well as 
activating mutations in Akt, have been identified in a subset of human cancers 
(Bellacosa et al. 2005; Brugge et al. 2007; Tokunaga et al. 2008).  All of these 
mechanisms of pathway activation ultimately funnel through Akt as the central node that 
drives cell survival, growth, proliferation, angiogenesis, metabolism, and migration 
(Manning and Cantley 2007).  
Genes that encode intracellular signaling proteins of the PI3K/AKT pathway are some of 
the most commonly mutated genes in tumor cells.  Whereas PI3K inhibitors can 
modulate PIK3CA mutation-driven activation of the pathway, mutations in additional 
genes for this pathway (e.g. PTEN or AKT) may lead to worse prognosis and resistance 
to PI3K targeted therapies (Jhaveri et al. 2021).  Pharmacologic modulation of this 
pathway downstream of PI3K may provide a more effective treatment alternative for 
patients whose tumors harbor PIK3CA/PTEN or PIK3CA/AKT co-mutations. 
Upregulation of Akt signaling (whether intrinsic or induced following chemotherapy) 
represents a potentially important survival pathway in response to genotoxic/mitotic 
stress (Xu et al. 2012).  Activation of Akt signaling following chemotherapy (including 
taxanes) may promote cell survival and chemoresistance across several cancer models, 
including breast cancer (Clark et al. 2002).  Conversely, inhibition of the PI3K/Akt 
pathway in diverse cancers leads to radiosensitization and/or chemosensitization 
(Brognard et al. 2001; Solit et al. 2003; Wallin et al. 2010).  
Ipatasertib is a potent, highly selective small-molecule inhibitor of all three isoforms of 
the serine/threonine kinase Akt.  Ipatasertib binds to the activated conformation of Akt 
and is ATP competitive.  Ipatasertib binding inhibits the kinase activity of Akt and 
suppresses the phosphorylation of its direct substrates, including PRAS40, and 
additional downstream targets, such as S6 ribosomal protein (S6RP), resulting in G1 
arrest and/or apoptosis in human cancer cells (Lin et al. 2012).  In clinical tumor 
samples, robust Akt pathway inhibition by ipatasertib can be achieved at clinically 
relevant doses (Yan et al. 2013). 
There are several clinical trials investigating combinations of ipatasertib and paclitaxel 
including a Phase Ib study in HER2-negative breast cancer (STUDY PAM4983g, Arm 
C), a randomized Phase II (GO29227, LOTUS) comparing ipatasertib + paclitaxel versus 


 
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placebo + paclitaxel as first-line treatment for patients with inoperable locally advanced 
or metastatic TNBC and a randomized Phase III (CO40016) comparing ipatasertib + 
paclitaxel versus placebo + paclitaxel in patients with PIK3CA/AKT1/PTEN-altered 
tumors. In GO29227, results from this study showed improvement in PFS in the intent-
to-treat (ITT) population (hazard ratio = 0.60; 6.2 months in the ipatasertib arm 
compared with 4.9 months in the control arm) and more pronounced in the pre-specified 
patient population with PIK3CA/AKT1/PTEN-altered tumors (hazard ratio = 0.44; 
9  months vs 4.9 months).  
On the basis of these results, combination treatment with ipatasertib and paclitaxel in 
tumors with co-mutations of PIK3CA and AKT or PIK3CA and PTEN-alteration status 
can be safely investigated and has the potential to offer therapeutic benefit in solid 
tumors driven by activation of this pathway.  
1.1.9 
Arm N: Tiragolumab Plus Atezolizumab for TMB-
H/MSI-H/dMMR Tumors 
T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel immune inhibitory 
receptor that is a member of the Ig super family (Yu et al. 2009; Manieri et al. 2017).  
TIGIT is expressed on the surface of activated T-cell and natural killer (NK)-cell subsets 
and interacts with high affinity with CD155 (also known as the poliovirus receptor [PVR]) 
(Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice results in exacerbated 
T-cell responses in nonclinical models of autoimmune and viral infections, demonstrating 
the role of TIGIT in inhibiting T-cell responses (Joller et al. 2011; Johnston et al. 2014).   
TIGIT expression is elevated in the tumor microenvironment in many human tumors, is 
coordinately expressed with other checkpoint immune receptors such as programmed 
death1 (PD-1), and is associated with impaired T-cell function and anti-tumor immunity 
(Johnston et al. 2014).  Activation of TIGIT on T cells and NK cells limits cellular 
proliferation, effector cytokine production, and killing of target tumor cells (Stanietsky et 
al. 2009; Yu et al. 2009; Johnston et al. 2014; Wang et al. 2015; Manieri et al. 2017). 
Therefore, in the context of the tumor microenvironment, TIGIT acts to limit anti-tumor 
immune responses.  Interference with TIGITPVR interaction may enhance the 
magnitude and quality of the tumor-specific T-cell responses by means of increased 
expansion of T cells as well as improved T-cell priming and/or effector function.   
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1, described in detail in Section 1.1.5.  Targeting the 
PD-L1 pathway with atezolizumab has demonstrated activity in patients with advanced 
malignancies who have failed standard-of-care therapies.  Objective responses have 
been observed across a broad range of malignancies, including NSCLC, urothelial 
carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head and neck cancer, 
gastric cancer, breast cancer, and sarcoma (see Atezolizumab Investigator's Brochure 
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Because TIGIT and PD-1 are coordinately expressed by infiltrating T cells in several 
human tumors, inhibition of the TIGIT/PVR pathways may complement and potentiate 
the anti-tumor activity of a PD-L1 pathway inhibitor such as atezolizumab.  
In preclinical models, concomitant blockade of TIGIT and PD-L1/PD-1 pathways 
demonstrated superior efficacy over the respective single-agent treatments.  In one such 
preclinical model, tumor-infiltrating T cells demonstrate increased interferon (IFN)- 
expression (a hallmark of activation and anti-tumor activity of T cells) only when both 
TIGIT and PD-1 are blocked concurrently and not when each individual pathway is 
blocked by the respective single-agent treatment.  Notably, co-inhibition of TIGIT and 
PD-L1 in this syngeneic tumor model was not associated with loss of body weight or any 
other observable adverse responses.  On the basis of the results of these studies, it is 
hypothesized that the combination of an anti-TIGIT antibody with antiPD-L1/PD-1 
antibody may result in activation of anti-tumor immune responses leading to enhanced 
killing of T cells and improved clinical responses than with either agent alone.   
Tiragolumab is a fully human IgG1/ monoclonal antibody (MAb) that binds to TIGIT and 
prevents its interaction with PVR.  Refer to the Tiragolumab Investigator's Brochure for 
details on nonclinical and clinical studies.  Atezolizumab is a humanized IgG1 
monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and 
its receptors, PD-1 and B7-1 (also known as CD80), both of which function as inhibitory 
receptors expressed on T cells.  Refer to the Atezolizumab Investigator's Brochure for 
details on nonclinical and clinical studies. 
In the primary analysis of the Phase II study GO40290 (CITYSCAPE) investigating 
atezolizumab in combination with tiragolumab or placebo, 48.7% of patients in the 
tiragolumab plus atezolizumab group versus 27.9% of patients in the placebo plus 
atezolizumab group were still receiving study treatment in the ITT population.  In the 
tumor proportion score (TPS)  50% population, 65.5% of patients in the tiragolumab 
plus atezolizumab group relative to 24.1% of patients in the placebo plus atezolizumab 
group were still receiving study treatment.   
In all randomized patients with TPS 1% (n  135), the confirmed ORR was higher in the 
tiragolumab plus atezolizumab arm (31.3%) than in the placebo plus atezolizumab group 
(16.2%); investigator-assessed PFS was improved in the tiragolumab plus atezolizumab 
group (n  67) relative to placebo plus atezolizumab (n  68) group (stratified HR0.57; 
95% CI: 0.37 to 0.90; median PFS 5.4 vs. 3.6 months, respectively).  Consistent with the 
Phase Ib portion of Study GO30103, the combination of tiragolumab with atezolizumab 
was well tolerated in the Phase II study. 
Taken together with the growing evidence for TMB and MSI-H/dMMR being correlated 
with better clinical outcomes with checkpoint inhibitor therapies in general and the 
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study of the combination is warranted in tumors with these biomarkers in a tumor 
agnostic setting.  
1.1.10 
Arm O: Pralsetinib for RET fusion positive Tumors 
Increasing evidence implicates aberrant activation of the receptor tyrosine kinase RET 
(rearranged during transfection) as a critical driver of tumor growth and proliferation 
across a broad range of solid tumors (Mulligan 2014).  RET, along with glial cell 
line-derived neurotrophic factors (GDNF) and GDNF family receptors- (GFR), 
normally mediates development, maturation, and maintenance of several neural, 
neuroendocrine, and genitourinary tissue types.  Oncogenic RET activation occurs via 
gain-of-function mutations which constitutively activates RET, promoting 
ligand-independent tumor growth.  Oncogenic RET activation was initially described in 
hereditary and sporadic thyroid cancers, and subsequently in NSCLC adenocarcinoma 
(Mulligan 2014).  However, as next-generation DNA sequencing has become more 
prevalent, it has become apparent that oncogenic RET mutations occur in a variety of 
solid tumors.   
1.1.10.1 
RET-altered Thyroid Cancer 
The main histologic types of thyroid cancer are localized differentiated thyroid cancer 
(DTC; ~90% of cases), medullary thyroid cancer (MTC; ~2% of cases) and anaplastic 
thyroid cancer ( 1% of cases).  DTC arises sporadically from thyroid follicular cells and 
consists of papillary thyroid cancer (~90%), follicular thyroid cancer (~5%), and Hürthle 
cell neoplasm (~2%)  (NCCN 2020).  In contrast, MTC arises from parafollicular C cells 
and occurs in both hereditary and sporadic forms.  Oncogenic RET activation has been 
implicated as a driver for both DTC and MTC.  
Gene rearrangements involving RET and a dimerization domain-encoding gene have 
been identified in ~10% of sporadic papillary tumors in adults, and in ~50%80% of 
papillary tumors that occur after radiation exposure or arise in childhood.  RET fusion 
alterations are more prevalent in radiation-exposed populations (Li et al. 2019).  The 
dimerization domain provided by the fusion partner allows for constitutive association of 
RET kinase domains, leading to aberrant kinase activation that promotes tumorigenesis.   
In December 2020, pralsetinib received accelerated approval from the FDA for the 
treatment of adults and pediatric patients  12 years of age with advanced or metastatic 
RET-mutated MTC who require systemic therapy, and adults and pediatric patients 
 12 years of age with advanced or metastatic RET fusion–positive thyroid cancer who 
require systemic therapy and who are radioactive iodine (RAI)-refractory (if RAI is 
appropriate) (GAVRETO [pralsetinib], U.S. Prescribing Information).  
1.1.10.2 
Other RET-driven Cancers  
Emerging genomic and functional data implicate RET as a potential driver in several 
cancers beyond thyroid cancer and NSCLC (Borrello et al. 2013; Mulligan 2014).  
Upregulation of RET, GDNF, and/or GFR has also been detected across solid tumor 


 
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indications, and this may promote RET activation, tumorigenesis, and drug resistance 
(Nakashima et al. 2007; Yang and Horten 2014; Platt et al. 2015).  Thus, it is possible 
that other advanced solid tumors are dependent on RET activity and could respond to 
RET inhibition.   
At present, it is unclear how much of the clinical efficacy associated with multikinase 
inhibitors (MKIs) is caused by RET inhibition, as MKIs do not inhibit RET completely.  
Furthermore, MKIs are associated with significant off-target toxicities.  Thus, there is a 
need for precision therapies that provide durable clinical benefit by selectively targeting 
RET alterations and anticipated resistance mechanisms. 
1.1.10.3 
Pralsetinib Activity 
Pralsetinib (previously known as BLU-667) is a potent and selective oral inhibitor of RET 
fusion proteins and oncogenic RET mutants. Pralsetinib shows potent antitumor activity 
in RET-driven tumor models, and demonstrates tolerability at pharmacologically active 
doses in nonclinical toxicology assays.   
Study BLU-667-1101 (ARROW) is an ongoing Phase I/II study of pralsetinib in patients 
with thyroid cancer, NSCLC, and other advanced solid tumors.  As of 13 February 2020, 
11 of 13 response-evaluable patients with RET fusion-positive thyroid tumors had an 
objective response (ORR: 91% (95% CI: 59% to 100%) (Blueprint Medicines 
Corporation Press Release 2020).  Amongst 48 NSCLC patients, 28 (58%) showed an 
objective response, while 100% experienced disease control.  Of those, patients 
previously treated with platinum agents (n=35) showed a 60% objective response rate, 
while 5 of the 7 patients (71%) without prior treatment achieved confirmed partial 
responses. Pralsetinib once per day (QD) dosing at dose levels  400 mg demonstrated 
acceptable tolerability, as most adverse events were of low grade and reversible. For 
more details about the clinical safety of pralsetinib, please refer to the Pralsetinib 
Investigator’s Brochure.  
Adult patients with RET fusion-positive cancers other than thyroid cancer or NSCLC are 
poorly served by standard of care treatments, which have limited efficacy and/or 
significant off-target toxicity.  Thus, there is a need for personalized therapies that 
selectively target RET alterations to provide lasting clinical benefit.  Given the evidence 
of pralsetinib's clinical efficacy and the unmet medical need, pralsetinib has the potential 
to provide significant benefit to tumor-agnostic, RET positive adults.  As pralsetinib is 
generally well tolerated with an acceptable safety profile, the benefit-risk assessment for 
this cohort is considered to be favorable. 


 
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1.2 
STUDY RATIONALE  
This Phase II, multicenter, non-randomized, open-label, multi-arm study will evaluate the 
efficacy and safety of several agents in patients with advanced unresectable or 
metastatic solid tumors.  Treatment will be based on each patient’s tumor biomarker 
profile, and the trial will aim to include a broad patient population, inclusive of 
demographic populations under-represented in traditional clinical trials and rare tumor 
types.  This will, in turn, broaden patient access to personalized treatments for otherwise 
excluded clinical trial patient populations. 
In order to ensure the study population is diverse in underrepresented groups in clinical 
research, including patients of color, special attention has been paid to the selection of 
eligibility criteria appropriate for consideration of more diverse enrollment while still 
ensuring safety.  An analysis by self-identified race and ethnicity is included to explore 
differences in therapeutic responses and clinical outcomes by ancestral groups.  
The study will focus on the following actionable biomarkers and the corresponding 
targeted agents as shown in Figure 1. 
Table 2 provides estimated pan-tumor prevalence of specific biomarker and overlapping 
biomarker alterations (Foundation Medicine 2020).  
Table 2 
Estimated Pan-tumor Prevalence of Specified Biomarkers 
Target or Immune 
Marker 
Biomarker Classification 
Pan-tumor Prevalence 
ROS1 
Fusion-positive (excluding NSCLC) 
0.11% 
PI3K  
PIK3CA activating mutation(s) 
11.2% 
ALK 
Fusion-positive (excluding NSCLC) 
0.11% 
AKT1/2/3 
AKT-Activating mutation or 
PTEN-Loss (deletion)/LOF 
12.6% 
ERBB2 (HER2) 
Activating mutation or amplification 
(excluding breast cancer) 
4.9% 
PD-L1 
TMB  10 mut/Mb or MSI-H/dMMR 
13.2% 
ERBB2 (HER2) & CD274 
(PD-L1) 
ERBB2 Activating mutation or 
amplification & TMB  10 mut/Mb or 
MSI-H/dMMR  
0.5%  
AKT 
Co-mutations in PIK3CA and PTEN  
Co-mutation in PIK3CA and AKT 
1.4% 
0.09% 
PD-L1 & TIGIT 
TMB  10 mut/Mb or MSI-H/dMMR 
13.2% 
RET 
Fusion-positive (excluding NSCLC, 
thyroid cancer)  
0.48% 


 
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ALK anaplastic lymphoma kinase; dMMR deficient mismatch repair; HER2 human epidermal 
growth factor receptor 2; LOF loss-of-function; MbMegabase; MSI-H microsatellite instability 
high; mutmutations; MTC=medullary thyroid cancer; NSCLCnon-small cell lung cancer; RET 
Rearranged during Transfection; TIGITT-cell immunoreceptor with Ig and ITIM domains; 
TMBtumor mutational burden. 
 
1.3 
RISK/BENEFIT ASSESSMENT 
The conventional tumor histology-specific approach to drug development is not always 
appropriate in the era of precision oncology.  For therapies targeting rare genomic 
alterations that are observed across a variety of tumors, enrolling a large, randomized 
study for each alteration or biomarker in individual tumor types is not feasible because of 
the significant amount of time required to identify a sufficient number of eligible patients.  
New clinical trial designs, including basket and umbrella studies, have been developed 
to overcome these barriers and provide for more efficient development of targeted 
therapies.  Recently, several basket trials have led to health authority approvals of 
pembrolizumab, larotrectinib, and entrectinib in tumor-agnostic indications.  
While these trials and subsequent approvals represent important steps towards 
personalized oncology treatment, many patients still have no targeted therapy options.  
Approximately 75% of oncologists report using next generation sequencing (NGS) 
testing to guide treatment decisions (Barroso-Sousa et al. 2019; Freedman et al. 2018).  
Despite this, only 26.8% of oncologists responded that NGS test results often informed 
treatment recommendations (Freedman et al. 2018), substantiating the need for 
additional drug and diagnostic development for widespread use of precision medicines 
and more personalized healthcare to become a reality.  Of note, in an international 
survey, the barrier most frequently reported by oncologists was the inability to find a 
suitable trial (Barroso-Sousa et al. 2019). 
Patients considered for enrollment in this study will have advanced unresectable or 
metastatic solid tumors and their treating investigator must consider treatment in a 
clinical trial an appropriate option for their care.  This will include patients for whom no 
current available standard therapy exists, or for whom therapies that will convey clinical 
benefit are not available and/or not suitable options per the treating physician’s 
judgment.  
Additionally, the respective safety plan for each arm has been designed to ensure 
patient safety by utilizing inclusion and exclusion criteria that are consistent with the 
known safety profiles of the investigational agents along with treatment-specific toxicity 
management guidelines.  A Steering Committee composed of multidisciplinary members 
of Roche/Genentech and external experts will be set up to review safety data at periodic 
intervals in order to identify the emergence of new or increased safety signals.  


 
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1.3.1 
Risk/Benefit Assessment during COVID-19 
1.3.1.1 
All Treatment Arms 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are a more vulnerable population.  Infection 
with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been 
associated with higher morbidity and mortality in patients with cancer in some 
retrospective analyses.  It is unclear whether or how cancer therapies such as 
chemotherapy, targeted therapy, or immunotherapy impact the incidence or severity of 
COVID-19.  It is not known whether any of the agents being investigated in this study will 
increase the risk of infection with SARS-CoV-2 (see Section 1.3.1.2) for additional 
information regarding atezolizumab).  Patients with a serious infection requiring 
intravenous (IV) antibiotics within 4 weeks prior to initiation of study treatment or any 
active infection that, in the opinion of the investigator, could impact patient safety will be 
excluded from study participation, and patients will be carefully monitored for infections 
during the study. 
1.3.1.2 
Immunotherapy Treatment Arms (Arms containing 
Atezolizumab:  E, F, J, K, L & N) 
In the setting of the COVID-19 pandemic, patients with comorbidities, including those 
with cancer, are considered a more vulnerable population, with the potential for more 
severe clinical outcomes from severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection.  However, it is unclear whether or how systemic cancer 
therapies, such as chemotherapy, targeted therapy, or immunotherapy, impact the 
incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)- (Merad and Martin 2020).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving atezolizumab.  At this time, there 
is insufficient evidence for causal association between atezolizumab and an increased 
risk of severe outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 


 
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features for SARS-CoV-2related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination (SITC 
2020).  
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 vaccination advisory committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors) 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021). Given the lack of clinical data, currently no recommendations can be 
made regarding the optimal sequence of COVID-19 vaccination in patients who are 
receiving cancer immunotherapy (SITC 2020).  For patients enrolling in this study and 
receiving atezolizumab treatment, a decision to administer the vaccine to a patient 
should be made on an individual basis by the investigator in consulation with the patient.  
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.   
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19  vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Concomitant Medications section in 
each atezolizumab-specific appendix).  
Given the mechanism of action for atezolizumab and other combinations within the study 
(Arm E: atezolizumab and chemotherapy [docetaxel, paclitaxel and capecitabine], Arms 
F and J: atezolizumab with trastuzumab emtansine, Arms K and L; atezolizumab plus 
ipatasertib, and Arm N: atezolizumab with tiragolumab), immune mediated adverse 
events are potential overlapping toxicities and should be monitored closely by the 
investigator and site personnel.  
For Arm E (atezolizumab plus chemotherapy), neutropenia and lymphopenia associated 
with chemotherapy may increase the risk for developing an infection in patients receiving 
atezolizumab in combination with chemotherapy. 


 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of multiple therapies that are selected 
based on potential predictive biomarkers identified in patients with solid tumors.  
2.1 
EFFICACY 
2.1.1 
Primary Efficacy Objective  
The primary objective for this study is to evaluate the efficacy of various treatments 
and/or combinations of treatments in eligible patients with advanced unresectable or 
metastatic solid tumors, on the basis of the following endpoint: 
 
The primary endpoint for each arm of this study will be confirmed ORR (cORR) as 
assessed by the investigator and according to response evaluation criteria in solid 
tumors version 1.1 (RECIST v1.1), or Response Assessment in Neuro-Oncology 
[RANO] Criteria for primary CNS tumors [Wen et al. 2017].  The cORR is defined as 
the proportion of patients whose confirmed best response is a complete response 
(CR) or partial response (PR) for those with measurable disease and CR for those 
with non-measurable disease.  
 
2.1.2 
Secondary Efficacy Objective  
The secondary efficacy objectives for this study are to evaluate the efficacy of each 
targeted treatment on the basis of the following endpoints: 
 
PFS, defined as the time from start of treatment to the first occurrence of disease 
progression or death from any cause (whichever occurs first), as determined by the 
investigator according to RECIST v1.1.  
 
DOR, defined as the time from the first occurrence of a documented objective 
response to disease progression or death from any cause (whichever occurs first), 
as determined by the investigator according to RECIST v1.1. 
 
PFS rate at 3 months during treatment and every 3 months thereafter for at least up 
to 1 year, defined as the proportion of patients who have not experienced disease 
progression or death from any cause as determined by the investigator, according to 
RECIST v1.1.   
 
Disease control rate (DCR), defined as the proportion of patients whose best 
response is confirmed CR, confirmed PR, or a response of CR, PR, SD, or non-
CR/non-progressive disease (PD) for a minimum of 98 days for 28-day cycle arms 
or 70 days for 21-day cycle arms after the first treatment date.  DCR will be 
summarized in the same fashion as the primary efficacy endpoint except, for DCR 
we will limit analysis to the subgroup in the efficacy population consisting of those 
with measurable disease.   
 
2.1.3 
Exploratory Efficacy Objectives 
Exploratory efficacy objectives are to evaluate efficacy based following the following: 
 
Analysis of primary and secondary efficacy endpoints when subgrouped by basket, 
tumor site of origin, and/or self-reported race and ethnicity.  
 


 
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2.2 
SAFETY OBJECTIVE  
The safety objective for this study is to evaluate the safety and tolerability of the study 
medications for the tumor types studied based on the following endpoints:  
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0 (NCI CTCAE v5.0) 
 
Change from baseline in targeted clinical laboratory test results 
 
2.3 
BIOMARKERS OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are early surrogates of efficacy or relapse, are associated with a more 
severe disease state (i.e., prognostic biomarkers), are associated with acquired 
resistance to study drug(s), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoint: 
 
The association of baseline and changes in circulating tumor DNA (ctDNA) levels 
with response and progression to therapy. 
 
Determination of baseline and changes in expression or levels of biomarkers in the 
tumor tissue or blood that may be associated with response or resistance to 
therapy. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
MyTACTIC is a Phase II, multicenter, non-randomized, open-label, multi-arm study 
designed to evaluate the safety and efficacy of targeted therapies as single agents or in 
rational, specified combinations in patients with advanced unresectable or metastatic 
solid tumors determined to harbor specific biomarkers.  Patients will be enrolled based 
on local testing performed at a Clinical Laboratory Improvement Amendments 
(CLIA)-certified or equivalently accredited diagnostic laboratory.  For all patients whose 
positive biomarker result is from an assay other than a tissue-based assay conducted by 
Foundation Medicine, Inc. (FMI), central testing of pre-treatment tissue (preferably from 
the most recent block) and blood is required after enrollment.  Pre-treatment tissue will 
be submitted within 21 days after enrollment to a Sponsor-approved laboratory for 
central testing; this testing will not impact the study participation of enrolled patients.   
The multi-arm structure of the MyTACTIC study allows patients with solid tumors to be 
treated with a drug or drug regimen tailored to their biomarker identified at screening.  
Each study treatment arm may have separate endpoints, screening, and treatment 
requirements, defined in the respective appendix.  Futility analyses will be employed on 
all treatment arms to limit enrollment where evidence of very limited or lack of efficacy is 
observed. 


 
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During the study, the following biomarker samples will be collected: 
Tumor tissue  
 
For patients with a positive biomarker result from an assay other than a tissue-
based assay conducted by FMI, pre-treatment tissue samples (archival or recent 
resection or biopsy) must be submitted within 21 days of enrollment at baseline for 
central testing.  If both archival and recent tissue is available, the recent tissue 
should be preferentially submitted.  
 
Blood samples 
 
Mandatory blood samples will be collected at screening, 8 weeks after first 
treatment, and at disease progression (within 7 days after progression) for 
analyses including ctDNA 
 
These samples will be used to evaluate predictive and/or prognostic biomarkers, 
including but not limited to biomarkers related to driver oncogene signaling, response to 
study treatment, tumor pathogenesis, and mechanisms of resistance. 
The requirements for tissue and blood samples for screening and standardized testing 
purposes are described in Section 4.5.7 
Treatment will be assigned by the treating investigator on the basis of relevant specified 
biomarkers, and will continue until radiographic disease progression (per RECIST v1.1 
[Eisenhauer et al. 2009]; RANO Criteria for primary CNS tumors [Wen et al. 2017]), or 
loss of clinical benefit for specific treatment arms with Medical Monitor consultation (see 
Section 3.1.2 for treatment beyond disease progression), unacceptable toxicity, patient 
or physician decision to discontinue, or death, whichever occurs first.  If a patient 
discontinues treatment prior to disease progression (because of adverse event or other 
reason), tumor assessments will continue as specified in the treatment-specific appendix 
until disease progression, death, withdrawal of consent, or arm/study closure by the 
Sponsor, whichever occurs first.   
Patients who do not meet the criteria for participation in this study (screen failure) or the 
timeline for the screening window may qualify for re-screening at the investigator's 
discretion.  Patients must re-sign the consent form prior to rescreening.  The investigator 
will record reasons for screen failure in the screening log.   
Figure 1 presents an overview of the study design. 
 


 
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Figure 1 Study Schema 
  
atezoatezolizumab; chemochemotherapy; dMMRdeficient mismatch repair; Dxdiagnosis; MSImicrosatellite instability; PH FDC SCfixed 
dose combination of trastuzumab and pertuzumab administered subcutaneously; TDM1trastuzumab emtansine; FMIFoundation Medicine, 
Inc.; MSImicrosatelite; Reqrequired; RET= Rearranged during Transfection; TMBtumor mutational burden. 
Note:  If more than one biomarker is identified, the investigator will decide which treatment the patient will receive. 
a For all patients whose positive biomarker result is from an assay other than a tissue-based assay conducted by Foundation Medicine, Inc. 
(FMI), central testing of pre-treatment tissue (preferably from the most recent block) and blood is required after enrollment.  Pre-treatment 
tissue will be submitted within 21 days after enrollment to a Sponsor-approved laboratory for central testing; this testing will not impact the 
study participation of enrolled patients.   
b TMB high is defined as  10 mutations per megabase. 
c Investigator’s choice of docetaxel, paclitaxel, or capecitabine. 


 
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Steering Committee  
A Steering Committee will be formed of multidisciplinary members from 
Roche/Genentech, and external experts to provide clinical and methodological expertise 
to the oversight of the study.  The Steering Committee will review data and provide 
consultation in evaluating efficacy and safety data for each study arm; and, 
subsequently, make recommendations regarding the eligibility of patients, appropriate 
treatment decision, statistical analyses, and clinical trial design.  The committee will 
operate according to a pre-specified charter.  
Safety will be reviewed by the Steering Committee to identify the emergence of new or 
increased safety signals.  The Steering Committee will also review efficacy data and 
advise on an arm’s continued accrual of patients with specific tumor types to targeted 
therapy at interim analyses.  Genentech will consider the Steering Committee’s 
recommendations in any decisions regarding the study conduct.  
3.1.2 
Dosing of Study Treatment beyond Disease Progression 
In the absence of unacceptable toxicity, dosing of study treatment beyond radiographic 
disease progression may be permitted for patients in specific treatment arms upon 
consultation with the Medical Monitor, if evidence of persistent clinical benefit is 
determined by the investigator and documentation is provided to the Sponsor. 
If the above criteria are met, dosing of study treatment will continue until unacceptable 
toxicity, loss of clinical benefit (as determined by the investigator), or withdrawal of 
patient consent.  Loss of clinical benefit is defined as the following: 
 
Appearance of signs and symptoms (including worsening of laboratory values) 
indicating disease progression 
 
Decline in ECOG performance status due to disease progression 
 
Presence of rapid progression of disease or of progressive tumor at critical 
anatomical sites (e.g. cord compression) requiring alternative medical intervention 
 
3.1.3 
Number of Patients 
Approximately 260 patients are anticipated to be enrolled at approximately 60 sites.  
Each arm will be limited to approximately 25 patients or 10 patients, as indicated in the 
Study Schema (Figure 1).   
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV), 
occurs or the date at which the last data point required for statistical analysis or safety 
follow-up is received from the last patient, whichever occurs later.  LPLV is expected to 
occur approximately 1 year after the last patient is enrolled. 


 
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3.3 
RATIONALE FOR STUDY DESIGN 
This modular basket study has been designed to evaluate the safety and efficacy of 
targeted therapies or immunotherapy as single agents or as part of rational combinations 
in patients with advanced unresectable or metastatic solid tumors determined to harbor 
specific biomarkers.  Thus, patients are assigned to treatment arms based on the 
presence of tumor mutations or other biomarkers that are known or expected to be 
predictive of response and/or outcomes.  
The patient population selected for this trial is based on the unmet medical need of 
patients with advanced solid tumors possessing rare oncogenic alterations that may be 
addressed by therapy targeted against these alterations.  Current and potential future 
treatment arms involve biomarkers present across a variety of tumors.   
Targeted or biomarker-driven therapy for patients has proven to be safer and more 
effective compared with conventional chemotherapy (Rosell et al. 2012; Solomon et al. 
2014).  While tissue testing is common for certain markers in some tumor types, a 
multitude of other potential targets have been identified for which testing may not 
routinely be performed.  Further, a significant portion of patients never have their tumor 
tissue molecularly profiled and therefore may receive cytotoxic chemotherapy or 
supportive care only, depending on performance status and other clinical factors.   
Many of the genomic alterations of interest are considered rare, making the ability to 
identify enough patients to conduct an adequate randomized trial very challenging, even 
within a tumor-agnostic umbrella trial design.  Additionally, randomization would be 
challenging not only due to rarity of populations, but in the variability of standards of care 
between tumor types and even between lines of treatment within a tumor type.  A 
single-arm, open-label design is optimal to demonstrate clinically relevant efficacy of a 
personalized biologically directed treatment, as compared with conventional 
chemotherapy or Phase I clinical trials, in the context of biomarker-selected rare-disease 
populations.  
Rationale for the individual treatment arms are contained in the treatment-specific 
appendices.  
3.3.1 
Rationale for Biomarker Assessments  
Cancer is a heterogeneous disease, but selection of patients based on the presence of 
oncodriver alterations allows for more specific targeting of the driver of disease.  Within a 
given treatment arm, the genomic biomarkers under study in this trial may lead to 
variability of clinical responses among the different tumor types enrolled, based on 
relative differences in patient/prognostic factors, oncogenicity of individual alterations 
(e.g., fusion partner), and the presence or absence of intrinsic resistance mechanisms 
(Hartmaier et al. 2017).  Therefore, patients may not benefit equally from study treatment 
in one or more of the study arms.   


 
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The goal is to study treatments based on the biomarkers present in a patient’s 
tumoragnostic to tumor typeand to ultimately determine the population(s) that 
benefit from targeted therapy based on biomarkers previously associated with clinical 
response.  This may be fully tumor/tissue-agnostic or may represent a more limited 
patient population within a biomarker-defined indication.   
A second goal is to better define the reason(s) for observed variations in clinical 
response to alteration-targeted agents among tumor types.  Tissue and blood collected 
prior to dosing will be assessed in an effort to identify those patients with 
biomarker-driven pathogenesis who are most likely to respond to study treatment in the 
assigned study arm, as well as to study potential mechanisms of primary resistance 
where lack of or limited efficacy is observed.  Biomarker samples will be collected at 
disease progression in an effort to monitor recurrence and to identify acquired resistance 
mechanisms to the assigned study treatment arm (blood is mandatory; tissue optional).  
Additionally, the sample(s) may be used for molecular testing.  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study will enroll approximately 260 patients with advanced unresectable or 
metastatic solid tumors with a positive biomarker result (per treatment arm-specific 
definitions) based on local testing results from a CLIA-certified or equivalently accredited 
diagnostic laboratory.  
4.1.1 
Inclusion Criteria 
Patients must meet the following general inclusion criteria to be eligible to enroll in any 
treatment arm:  
 
Signed treatment-specific Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
Positive biomarker results from a CLIA-certified or equivalently accredited diagnostic 
laboratory and availability of a full report of the testing results.  This may be from a 
tissue or blood sample.  
 
For patients with a positive biomarker result from an assay other than a 
tissue-based assay conducted by FMI: Sufficient archival tissue or a recent 
pretreatment tissue sample must be available for central testing (i.e. at least 
11 slides or equivalent block) unless approved by Medical Monitor.  If both archival 
and recent tissues are available, the recent tissue should be preferentially 
submitted.  See Section 4.5.7 for full requirements.   
 
Participation in a clinical trial is an appropriate treatment option, in the opinion of the 
investigator 
 
Ability to comply with the study protocol 


 
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 
Histologically or cytologically confirmed diagnosis of advanced unresectable or 
metastatic solid malignancy 
 
Evaluable or measurable disease (i.e., at least one target or non-target lesion per 
RECIST V1.1 or one measurable or non-measurable lesion per RANO criteria for 
patients with primary CNS tumors)  
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 02 
 
Life expectancy  8 weeks 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
– 
ANC per arm-specific eligibility criteria 
– 
Platelet count  100  109/L (100,000/L) without transfusion  
– 
Hemoglobin  90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
AST, ALT, and alkaline phosphatase (ALP)  3  upper limit of normal (ULN), 
with the following exceptions: 
Patients with documented liver involvement:  AST and ALT  5  ULN 
Patients with documented liver or bone involvement:  ALP  5  ULN 
– 
Total bilirubin  1.5  ULN with the following exception: 
Patients with known Gilbert disease:  total bilirubin  3  ULN 
– 
Serum creatinine  1.5 mg/dL or Glomerular filtration rate  50 mL/min/1.73 m2 
as calculated through use of the Chronic Kidney Disease Epidemiology 
Collaboration equation 
Glomerular filtration rate (GFR) estimation:  GFR141  min(Scr/κ, 1)α  
max(Scr/κ, 1)-1.209  0.993Age  1.018 [if female]  1.159 [if black] where:  
Scr is serum creatinine in mg/dL,  
κ is 0.7 for females and 0.9 for males,  
α is -0.329 for females and -0.411 for males,  
min indicates the minimum of Scr/κ or 1, and  
max indicates the maximum of Scr/κ or 1 
– 
Albumin  25 g/L (2.5 g/dL) 
 
Agrees to take measures to prevent pregnancy in the patient or partner (see 
Appendix 2 for details) 
 
In addition to the general inclusion criteria above, in order to be enrolled in a 
treatment arm of the study, patients must meet all of the treatment-specific inclusion 
criteria for the respective arm as detailed in the treatment-specific appendix (see 
Table 1 for list of treatments and appendices).  
Note:  The requirements for enrollment into a specific arm may be more stringent.   
 


 
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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be ineligible and excluded from study 
entry in any arm: 
 
Current participation or enrollment in another therapeutic clinical trial 
 
Eligible for an approved indication included in the local prescribing information for 
the applicable study treatment   
 
Symptomatic or actively progressing CNS metastases 
Asymptomatic patients with treated or untreated CNS metastases are eligible, 
provided that all of the following criteria are met: 
– 
No ongoing requirement for corticosteroids as therapy for CNS metastases, 
unless noted otherwise in the arm-specific appendix 
– 
No evidence of interim progression between the completion of 
CNS-directed therapy and screening radiographic study 
– 
No history of intracranial hemorrhage or spinal cord hemorrhage 
– 
Evaluable disease must be present outside the CNS 
 
History of leptomeningeal disease, unless noted otherwise in the arm-specific 
appendix  
 
Wide field radiotherapy within 14 days prior to start of study treatment 
 
Stereotactic radiosurgery within 7 days prior to start of study treatment 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infections, or any active infection 
that, in the opinion of the investigator, could impact patient safety 
– 
In the setting of a pandemic or epidemic, screening for active infections should 
be considered according to local or institutional guidelines or those of 
applicable professional societies (e.g., American Society of Clinical Oncology 
[ASCO] or European Society for Medical Oncology [ESMO]). 
 
Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to 
Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to 
Cycle 1, Day 1; recovery of treatment-related toxicity consistent with other eligibility 
criteria 
– 
Androgen blockage may be continued for male patients with prostate cancer 
 
Patients known to be positive for HIV are excluded if they meet any of the following 
criteria: 
– 
CD4+ T-cell count of  350 cells/L 
– 
Detectable HIV viral load 
– 
History of an opportunistic infection within the past 12 months 
– 
On stable antiretroviral therapy for  4 weeks 


 
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 
Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded 
with the following exceptions:  
– 
Patients who are HCV Ab positive but HCV RNA negative due to prior 
treatment or natural resolution are eligible  
– 
Patients with untreated HCV may be enrolled if the HCV is stable, the patient is 
not at risk for hepatic decompensation, and the intended treatment is not 
expected to exacerbate the HCV infection  
– 
Patients on concurrent HCV treatment may be enrolled if they have HCV below 
the limit of quantification  
 
Patients known to have active hepatitis B (chronic or acute; defined as having a 
positive hepatitis B surface antigen [HBsAg] test) 
– 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of 
HBsAg) are eligible only if they are negative for HBV DNA 
 
History of or concurrent serious medical condition or abnormality in clinical 
laboratory tests that, precludes the patient's safe participation in and completion of 
the study or confounds the ability to interpret data from the study (e.g., clinically 
significant cardiovascular, pulmonary or metabolic disease; wound healing 
disorders; ulcers; bone fractures) 
– 
Patients with well-controlled comorbid disease on a stable treatment regimen 
for 4 weeks prior to screening are eligible for the study. 
 
History of malignancy other than disease under study within 3 years prior to 
screening, with the exception of malignancies with a negligible risk of metastasis or 
death (e.g., 5-year OS rate  90%), such as adequately treated carcinoma in situ of 
the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal 
carcinoma in situ, or Stage I uterine cancer 
 
Incomplete recovery from any surgery prior to the start of study treatment that would 
interfere with the determination of safety or efficacy of study treatment 
 
Major surgical procedure, other than for diagnosis, or significant traumatic injury 
within 4 weeks prior to initiation of study treatment, or anticipation of need for a 
major surgical procedure during the study 
 
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or higher), myocardial infarction, or cerebrovascular accident 
within 3 months prior to enrollment, unstable arrhythmias, or unstable angina 
 
Pregnant or breastfeeding, or intending to become pregnant during the study 
 
In addition to the general exclusion criteria above, in order to be enrolled in a 
treatment arm of the study, patients must meet all of the treatment-specific 
exclusion criteria for the respective arm as detailed in the treatment-specific 
appendix (see Table 1 for list of treatments and appendices).   
Note:  The requirements for enrollment into a specific arm may be more stringent 


 
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4.2 
METHOD OF TREATMENT ASSIGNMENT  
4.2.1 
Treatment Assignment 
All patients will be assigned to a specific treatment arm by the treating investigator 
based on the biomarker results of a qualifying assay. 
An interactive voice- or web-based response system (IxRS) will be used to manage 
patient screening, enrollment, and tracking.  Patients who are diagnostic positive for a 
treatment arm, meet the general and applicable treatment-specific eligibility criteria, and 
have provided arm-specific written informed consent will be registered via IxRS. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The study treatment arm designs are provided separately in the appendices.   
Details of each study treatment, recommended concomitant medications, and prohibited 
medications are also contained in the treatment-specific appendices.  
See Table 1 for a full list of treatment arms and the associated appendices. 
4.3.1 
Study Treatment Formulation and Packaging 
Refer to the treatment-specific appendices for details.  
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in the treatment-specific appendices (see 
Table 1). 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of overdose, 
medication error, drug abuse, or drug misuse, along with any associated adverse 
events, should be reported as described in Section 5.3.5.12. 
Patient compliance with self-administration of orally administered study treatment will be 
assessed by medication diary and standard pill counts.  Patients will be required to 
record the time and date they took each dose in a medication diary; missed doses will 
also be recorded.  Patients will be instructed to bring all unused study medication and 
their medication diaries at specified study visits. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in the treatment-specific 
appendices. 
4.3.3 
Investigational Medicinal Product Handling and Accountability 
All investigational medicinal products (IMPs) required for completion of this study will be 
provided by the Sponsor.  The study site (i.e., investigator or other authorized personnel 


 
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or mobile nurse, if applicable]) is responsible for maintaining records of IMP delivery to 
the site, IMP inventory at the site, IMP use by each patient, and disposition or return of 
unused IMP, thus enabling reconciliation of all IMPs received, and for ensuring that 
patients are provided with doses specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the study drug’s Investigator's Brochure or local 
prescribing information for information on IMP handling, including preparation and 
storage, and accountability.  
4.3.4 
Continued Access to Study Treatments 
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMPs as listed in Table 1 or any other study treatments to 
patients who have completed the study.  The Sponsor may evaluate whether to continue 
providing IMPs in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


 
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4.4 
CONCOMITANT THERAPY PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study treatment until 28 days after the last dose of study treatment.  
All such medications should be reported to the Investigator and recorded on the 
Concomitant Medications eCRF. 
Patients who use oral contraceptives or hormone-replacement therapy and do not have 
breast cancer may continue these medications under the supervision of their 
physician.  Androgen blockage may be continued for male patients with prostate 
cancer.  Other medications may be continued unless otherwise indicated in the specific 
study drug appendix.  
Unless noted otherwise in the arm-specific appendix, palliative radiotherapy (e.g., 
treatment of known bony metastases or symptomatic relief of pain), is permitted 
provided it does not interfere with the assessment of tumor lesions (e.g., the lesion being 
irradiated is not a target lesion for response assessments, because that would render 
the patient not evaluable for response by tumor assessments according to RECIST v1.1 
or RANO [for patients with patients with primary CNS tumors]).  
Supportive care, including antiemetic medications, may be administered at the discretion 
of the investigator.  For details on regimen-specific concomitant therapy, prohibited food, 
and additional restrictions; please refer to the appropriate treatment arm-specific 
appendices (see Table 1 for full list of appendices). 
4.5 
STUDY ASSESSMENTS  
The treatment-specific assessments and schedules of activities to be performed during 
the study are provided in the treatment-specific appendices (see Table 1).   
All activities should be performed and documented for each patient.   
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 


 
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Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.  
Screening evaluations are to be performed within 28 days prior to initiation of study 
treatment or as indicated in the schedule of activities.  All screening evaluations must be 
completed and reviewed to confirm that patients meet all eligibility criteria before 
enrollment.  The investigator will maintain a screening log to record details of all patients 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history 
and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to initiation of study treatment will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded.  Demographic data for both enrolled and 
screen-failed patients, as well as reasons for screen failure (if applicable) will be 
captured in the IxRS. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed as clinically 
indicated.  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs should be performed at each visit in accordance with standard clinical 
practice, but the associated data do not need to be recorded on the eCRF (except in the 
case of an adverse event) unless noted in the arm-specific Schedule of Activities. 


 
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4.5.5 
ECOG Performance status 
Performance status will be assessed according to Eastern Cooperative Oncology Group 
(ECOG) definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
4.5.6 
Tumor and Response Evaluations 
All known sites of disease must be assessed and documented at screening and 
reassessed at each subsequent tumor evaluation according to the arm-specific schedule 
of assessments (see arm-specific appendices) until investigator-determined radiographic 
disease progression or loss of clinical benefit (in the case of treatment beyond disease 
progression in applicable arms), withdrawal of consent, termination of an individual study 
arm by the Sponsor, or death, whichever occurs first.  Tumor assessments performed as 
standard of care prior to obtaining informed consent and within 28 days prior to initiation 
of study treatment do not have to be repeated at baseline.  Tumor assessments must be 
performed independently of changes to the study treatment administration schedule (i.e., 
when treatment is withheld).  If a tumor assessment has to be performed early or late, 
subsequent assessments should be conducted according to the original schedule based 
on the date of first study treatment administration on Day 1 of Cycle 1.  At the 
investigator’s discretion, tumor assessments may be repeated at any time if progressive 
disease is suspected.  Objective response (complete response or partial response) must 
be confirmed by repeat assessment at least 4 weeks after initially documented 
response. 
Tumor assessments should be performed using the same modality as baseline 
throughout the course of treatment, unless contraindicated by evolving patient condition.  
Screening assessments must include computed tomography (CT) scans (with oral or IV 
contrast) or magnetic resonance imaging (MRI) scans of the chest, abdomen, pelvis, 
and head.  Bone scan and CT scans of the neck should be performed if clinically 
indicated or if required as specified in the arm-specific appendices.  In the event a 
positron emission tomography (PET)/CT scanner is used for tumor assessments, the CT 
portion of the PET/CT must meet criteria for diagnostic quality.  If a CT scan with 
contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the 
abdomen, pelvis, and head should be performed.  A CT or MRI scan of the head must 
be performed at screening to assess CNS metastasis.  An MRI scan of the brain is 
required to confirm or refute the diagnosis of CNS metastases at baseline in the event of 
an equivocal scan.   
All measurable and evaluable lesions should be re-assessed at each subsequent tumor 
evaluation.  Patients without brain or bone disease at baseline do not need brain or bone 
scans at subsequent tumor assessments unless clinically warranted or if required as 
specified in the arm-specific appendices.  The same radiographic procedure used to 
assess disease sites at screening should be used throughout the study (e.g., the same 


 
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contrast protocol for CT scans).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.  
Response will be assessed by the investigator on the basis of physical examinations, CT 
scans, and MRI scans according to RECIST v1.1 (see Appendix 3) or RANO (see 
Appendix 4), if applicable.  Assessments should be performed by the same evaluator to 
ensure internal consistency across visits.  Results must be reviewed by the investigator 
before dosing at the next cycle.   
Deidentified imaging data may also be used for exploratory research purposes including 
digital image analysis.   
4.5.7 
Laboratory, Biomarker, and Other Biological Samples  
In addition, treatment-specific laboratory assessments will be performed as described in 
the specific appendix for each study drug (See Table 1 for list of appendices). 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology/CBC (WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count) 
 
Chemistry panel (serum or plasma) (glucose, BUN, creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), ALP, AST, ALT, total bilirubin, direct 
bilirubin, total protein, and albumin) 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Pregnancy tests will be performed at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test. 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Blood samples for somatic tumor-specific genetic testing including ctDNA will be 
collected from all patients participating in the trial.  These samples will be used for 
research purposes to identify biomarkers that correlate with treatment response or 
resistance and may be used for diagnostic assay development. 
 
For patients with a positive biomarker result from an assay other than a 
tissue-based assay conducted by FMI:  Archival or recently collected tumor tissue 
sample obtained prior to study treatment must be submitted within 21 days of 
enrollment for central testing, including exploratory research on biomarkers and 
biomarker assay development. In exceptional circumstances, enrollment may be 
allowed without sufficient tissue with Medical Monitor approval.  
– 
A representative formalin-fixed paraffin embedded (FFPE) tumor specimen 
(obtained prior to study treatment) in a paraffin block (preferred) or at least 


 
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11 slides containing unstained, freshly cut, serial sections should be submitted 
within 21 days of Cycle 1, Day 1.  Tumor tissue should be of good quality based 
on total and viable tumor content.  Samples collected via core-needle biopsy (at 
least three cores, embedded into a single paraffin block), or any other 
resection/excisional means are acceptable.  Fine needle aspiration (FNA), 
cytology, or cell pellets from ascites/pleural effusions/lavage samples are 
acceptable with sufficient cellularity to meet tumor content requirements.  
Tumor tissue from bone metastases that are subject to decalcification is not 
acceptable.  
 
Exploratory research on patient tissue or blood samples may involve extraction and/or 
analysis of DNA, cell-free DNA, RNA or proteins for the purposes of addressing 
questions related to biological mechanisms of treatment response and/or resistance, 
oncogenesis and tumor immunity.  Genomic testing may include targeted, whole exome 
and/or whole genome testing methods for assessment of somatic or germline sequence 
variations.  Analysis of gene expression may be tested using RNA and protein 
expression methods such as, but not limited to RNA next generation sequencing and 
immunohistochemistry. 
Screening tumor tissue and blood samples, including those collected from patients who 
do not enroll in the study, may be used for future research and/or development of 
disease-related tests or tools. 
Central NGS analysis may be performed by Foundation Medicine.  If performed by 
Foundation Medicine, the investigator may obtain results through Foundation Medicine's 
web portal.  If allowed by local laws, the investigator may share and discuss the results 
with the patient, unless the patient chooses otherwise.  The NGS report is generated for 
research purposes and is not provided for the purpose of guiding future treatment 
decisions.  Results will not be available for samples that do not meet criteria for testing. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.8.3), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
Blood and tissue samples collected for biomarker research and biomarker assay 
development will be destroyed no later than 5 years after the final Clinical Study 
Report has been completed.   
 
For enrolled patients, remaining tissue blocks will be returned to the site upon 
request or no later than the time of final closure of the study database, whichever 
occurs first.   
 


 
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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
4.5.8 
Optional Samples for Research Biosample Repository  
4.5.8.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.8.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's Institutional Review Board or Ethics Committee (IRB/EC) and, if 
applicable, an appropriate regulatory body.  If a site has not been granted approval for 


 
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RBR sampling, this section of the protocol (Section 4.5.8) will not be applicable at that 
site. 
4.5.8.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to cancer, diseases, or drug 
safety: 
 
Leftover blood, serum, plasma, PBMC, and tumor tissue samples (with the 
exception of remaining archival tissue blocks, which will be returned to sites) and 
any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including leftover 
tissue samples from medically indicated procedures (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) performed at the investigator's 
discretion during the course of the study  
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the IRB/EC 
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.8.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 


 
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Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.8.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Sample Informed 
Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.8.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the Sample Withdrawal of 
Informed Consent eCRF.  If a patient wishes to withdraw consent to the testing of his or 
her RBR samples after closure of the site, the investigator must inform the Sponsor by 
emailing the study number and patient number to the following email address: 
global.rcr-withdrawal@roche.com.  


 
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A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.8.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, ARM AND SITE 
DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients will return to the clinic for an End of Treatment visit at  28 days after last 
treatment.  Patients must permanently discontinue study treatment if they experience 
any of the following: 
 
Disease progression, unless treatment beyond progression is allowed in the 
applicable arm 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 


 
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 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Study Arm Discontinuation 
The Sponsor has the right to close or restrict enrollment to a study arm at any time.  
Reasons for closing or restricting enrollment to a study arm may include, but are not 
limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients or a subset of patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to close any study arm. 
4.6.5 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for dosage modification, if 
applicable, treatment interruption or discontinuation, are provided in the 
treatment-specific arms.  Refer to Table 1 for treatment-specific appendices.  
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for infections prior to and during study participation 
should be performed according to local/institutional guidelines or those of applicable 
professional societies (e.g., ASCO/ESMO).  
A Steering Committee composed of multidisciplinary members of Roche/Genentech and 
external experts will be set up to review safety data at periodic intervals in order to 
identify the emergence of new or increased safety signals. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing protocol-
specified safety laboratory assessments, measuring protocol-specified vital signs, and 
conducting other protocol-specified tests that are deemed critical to the safety evaluation 
of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 and 
Section 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
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 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
(v5.0); see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 


 
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 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected. 
 
Please refer to the following treatment-specific appendices in Table 1 for additional 
adverse events of special interest relevant to the respective study treatment. 
 
5.2.4 
Selected Adverse Events  
Additional data may be required to be collected for selected adverse events.  Please 
refer to the treatment-specific appendices outlined in Table 1 for selected adverse 
events (where applicable) and their management. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1, 
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., 
discontinuation of medications) should be reported (see Section 5.4.2 for instructions for 
reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drugs other than atezolizumab and until 90 days after the final dose of 
atezolizumab. 
Instructions for reporting adverse events that occur after the adverse event reporting 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE (v5.0). 
Table 3 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting selfcare activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE (v5.0)  National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 


 
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accordingly.  The following guidance should be taken into consideration (see also 
Table 4: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon rechallenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions or Injection-Site Reactions (When 
applicable)  
For applicable study treatments, adverse events that occur during or within 24 hours 
after study drug administration and are judged to be related to study drug infusion or 


 
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injection should be captured as a diagnosis (e.g., "infusion-related reaction" or 
"injection-site reaction" "anaphylactic reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction or Injection Reaction 
eCRF.  If a patient experiences both a local and systemic reaction to the same dose of 
study drug, each reaction should be recorded separately on the Adverse Event eCRF, 
with signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction or Injection Reaction eCRF.  For patients receiving atezolizumab, there may be 
significant overlap in signs and symptoms of IRRs and cytokine-release syndrome 
(CRS).  In recognition of the challenges in clinically distinguishing between these two 
events, consolidated guidelines for medical management of IRRs and CRS are provided 
in the atezolizumab treatment-specific appendices. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 


 
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All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 


 
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abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which   35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 
5.3.5.8 
Deaths 
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1) that are attributed by the investigator solely to progression of cancer 


 
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should be recorded on the Death Attributed to Progressive Disease eCRF.  All other 
deaths that occur during the adverse event reporting period, regardless of relationship to 
study drug, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.4.2).  The Steering Committee will monitor the frequency of 
deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v 1.1, RANO (for primary CNS tumors).  In rare 
cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   


 
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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study drug administration)  
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
– 
The patient has not experienced an adverse event 
 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 


 
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event; see Section 5.4.2).  For study treatments adverse events associated with special 
situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with study treatments, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF as 
described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 


 
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 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional significant narrative information on the clinical course of the event 
 


 
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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators. 
Emergency Medical Call Center Help Desk:  
1 (855) 855-9112 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drugs other than 
atezolizumab and until 90 days after the final dose of atezolizumab.  Investigators should 
record all case details that can be gathered immediately (i.e., within 24 hours after 
learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur  28 days after the final dose 
of study treatment (or >90 days after the final dose of atezolizumab) are provided in 
Section 5.6. 


 
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5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study 
and for the timeframe specified in the Table 5 after the final dose of study drug.  A paper 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.   
Table 5 
Pregnancy Reporting Period after the Last Dose of Study Drug 
Study Drug 
Timeframe after the Last Dose of Study Druga 
Females 
Males 
Alectinib 
90 days 
90 days 
Atezolizumab 
5 months 
Not applicable 
Capecitabine 
6 months 
3 months 
Docetaxel 
6 months 
3 months 
Entrectinib 
5 weeks 
90 days 
Inavolisib (GDC-0077) 
60 days 
98 days 
Ipatasertib 
28 days 
28 days 
Paclitaxel 
6 months 
3 months 
PH FDC SC 
7 months 
7 months 
Pralsetinib 
2 weeks 
1 week 
Tiragolumab 
90 days 
90 days 
Trastuzumab emtansine 
7 months 
7 months 
Tucatinib 
1 week 
1 week 
a If patient is receiving a combination of study drugs, the reporting period should be whichever is 
longer. 
Instructions regarding pregnancy and contraception are provided in Appendix 2. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within the 
timeframe specified in Table 5 after the final dose of study drug.  The investigator should 


 
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report the pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit 
the form to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Attempts should be made to 
collect and report details of the course and outcome of any pregnancy in the partner of a 
male patient exposed to study drug.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available.  An investigator who is contacted by the male patient 
or his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
Instructions regarding pregnancy and contraception are provided in Appendix 2. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).  
The female partner of a male patient exposed to study drug should be classified as a 
serious adverse event and recorded as described in paragraph above. 


 
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5.4.4 
Reporting Requirements for Special Situations and 
Non-Serious Adverse Events Associated with a Special 
Situation 
After initiation of study drug, special situations and adverse events associated with 
special situations will be reported until 28 days after the final dose of study drugs other 
than atezolizumab and until 90 days after the final dose of atezolizumab.  Investigators 
should record all case details that can be gathered on the Adverse Event eCRF and 
submit the report via the electronic data capture (EDC) system within 30 calendar days 
of awareness.  A report will be generated and sent to Roche Safety Risk Management 
by the EDC system. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drugs other than atezolizumab and 90 days after the 
final dose of atezolizumab), if the event is believed to be related to prior study drug 
treatment.  These events should be reported through use of the Adverse Event eCRF.  
However, if the EDC system is not available, the investigator should report these events 
directly to the Sponsor or its designee, either by faxing or by scanning and emailing the 
paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form using the fax number or email address provided to investigators. 


 
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRbs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Arm A:  Entrectinib  
Entrectinib Investigator’s Brochure 
Arm B:  Inavolisib 
Inavolisib (GDC-0077) Investigator’s Brochure  
Arm C:  Alectinib  
Alectinib Investigator’s Brochure 
Arm D:  Ipatasertib  
Ipatasertib Investigator’s Brochure 
Arm E:  Atezolizumab plus 
chemotherapy  
Atezolizumab Investigator’s Brochure 
Docetaxel USPI  
Paclitaxel USPI  
Capecitabine USPI  
Arm F: Trastuzumab 
emtansine plus 
atezolizumab 
Trastuzumab emtansine Investigator’s Brochure 
Atezolizumab Investigator’s Brochure 
Arm G: PH FDC SC 
PH FDC SC Investigator’s Brochure 
Arm H: PH FDC SC plus 
chemotherapy 
PH FDC SC Investigator’s Brochure 
Docetaxel USPI  
Paclitaxel USPI  
Capecitabine USPI  
 Arm I: Trastuzumab 
emtansine plus 
tucatinib 
Trastuzumab emtansine Investigator’s Brochure 
Tucatinib USPI  
Arm J: Trastuzumab 
emtansine plus 
atezolizumab 
Trastuzumab emtansine Investigator’s Brochure 
Atezolizumab Investigator’s Brochure 
Arm K: Ipatasertib plus 
atezolizumab 
Ipatasertib Investigator’s Brochure 
Atezolizumab Investigator’s Brochure 
Arm L: Ipatasertib plus 
atezolizumab 
Ipatasertib Investigator’s Brochure 
Atezolizumab Investigator’s Brochure 
Arm M: Ipatasertib plus 
paclitaxel 
Ipatasertib Investigator’s Brochure 
Paclitaxel USPI  


 
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Drug 
Document 
Arm N: Atezolizumab plus 
tiragolumab 
Atezolizumab Investigator’s Brochure 
Tiragolumab Investigator’s Brochure 
Arm O: Pralsetinib 
Pralsetinib’s Investigator Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Details of criteria and statistical analyses will be provided in the Statistical Analysis Plan.  
The efficacy and safety analyses will be performed on the treated study population, 
which includes all enrolled patients who receive at least one dose of study medication.   
Given this study consists of many single arms according to molecular alterations we will 
be estimating (providing confidence intervals and summary statistics) as opposed to 
formal statistical hypothesis testing.   
6.1 
DETERMINATION OF SAMPLE SIZE 
The focus for this study will be estimation since the study is composed of many single 
arms specific to a targeted therapy.  Estimation of the primary endpoint will be 95% 
confidence intervals using the Clopper-Pearson method.  As such, the maximum margin 
of error for sample sizes 25, 50, and 75 are 20.7%, 14.5%, and 11.8%, respectively.  On 
a per arm basis, if the lower bound of the confidence interval is larger than a benchmark 
specific to that arm, then we will consider the given treatment as a significant 
improvement over the benchmark.   
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by arm and, if applicable, by biomarker.  The incidence of study treatment 
discontinuation for reasons other than disease progression will be tabulated similarly.  
Protocol deviations, including major deviations of inclusion/exclusion criteria, will be 
summarized in a similar manner by arm and, if applicable, biomarker. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity, baseline 
disease characteristics, and medical history, including number of previous regimens) will 
be summarized using means, standard deviations, medians, and ranges for continuous 


 
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variables and proportions for categorical variables, as appropriate.  Summaries will be 
presented overall and by treatment arm in the efficacy population (same as safety 
population), which includes all patients with at least one dose of study treatment.  
6.4 
EFFICACY ANALYSES 
The efficacy-evaluable population is defined as all enrolled patients who meet arm 
specific inclusion/exclusion criteria and have received at least one dose of study 
treatment. 
6.4.1 
Primary Efficacy Endpoint 
The primary endpoint for this study will be cORR as assessed by the investigator and 
according to the corresponding assessment criteria (RECIST v1.1 or RANO).  The 
cORR is defined as the proportion of patients whose confirmed best response is a CR or 
PR for those with measurable disease and CR for those with non-measurable disease.  
Confidence intervals at both 70% and 95% nominal levels will be reported using the 
Clopper-Pearson method.  The primary efficacy endpoint will be computed for all 
treatment arms.  If a patient receives at least one dose of study treatment and 
discontinues the study for any reason before confirmed response can be assessed, the 
patient will be considered a non-responder (not PR and not CR) and will be added to the 
denominator of the computation of cORR.   
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for each treatment arm will consist of DCR, PFS, and 
DOR, which are listed and defined below.  All secondary endpoints will be computed for 
all treatment arms and will be computed on the efficacy evaluable population 
 
PFS, defined as the time from start of treatment to the first occurrence of disease 
progression or death from any cause (whichever occurs first), as determined by the 
investigator according to the corresponding assessment criteria (RECIST v1.1 or 
RANO).  The PFS will be estimated using the Kaplan-Meier method.  Median PFS 
and 95% confidence interval will be computed using the Brookmeyer-Crowley 
method.   
 
DOR, defined as the time from the first occurrence of a documented objective 
response to disease progression or death from any cause (whichever occurs first), 
as determined by the investigator according to the corresponding assessment 
criteria (RECIST v1.1 or RANO).  The DOR will be estimated using the 
Kaplan-Meier method.  Median DOR and 95% confidence interval will be computed 
using the Brookmeyer-Crowley method.   
 
PFS rate at 3 months and every 3 months thereafter for at least up to 1 year, 
defined as the proportion of patients who have not experienced disease progression 
or death from any cause as determined by the investigator, according to RECIST 
v1.1.  PFS rates will be computed using the Kaplan-Meier method with 95% 
confidence intervals for each rate given by Greenwood’s formula. 


 
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 
DCR is defined as the proportion of patients whose best response is confirmed CR, 
confirmed PR, or a response of CR, PR, SD, or non-CR/non-PD for a minimum of 
98 days for 28-day cycle arms or 70 days for 21-day cycle arms after the first 
treatment date.  DCR will be summarized in the same fashion as the primary 
efficacy endpoint except, for DCR we will limit analysis to the subgroup in the 
efficacy population consisting of those with measurable disease.   
 
6.5 
EXPLORATORY EFFICACY  
6.5.1 
Exploratory Efficacy Objectives 
Exploratory efficacy objectives are to evaluate efficacy when subgrouped by tumor site 
of origin, and/or self-reported race and ethnicity.   
6.6 
SAFETY ANALYSES 
The safety analysis population will include all patients who received at least one dose of 
study drug.  Safety will be assessed through summaries of exposure to study treatment, 
adverse events, and changes in laboratory test results.  Study treatment exposure (such 
as treatment duration, total dose received, and number of cycles and dose 
modifications) will be summarized with descriptive statistics.  All verbatim adverse event 
terms will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) 
thesaurus terms, and adverse event severity will be graded according to the NCI CTCAE 
(v5.0).  All adverse events, serious adverse events, adverse events leading to death, 
adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur on or after the first dose of study treatment (i.e., treatment-
emergent adverse events) will be summarized by mapped term, appropriate thesaurus 
level, and severity grade.  For events of varying severity, the highest grade will be used 
in the summaries.  Deaths and cause of death will be summarized.  A shift table of 
selected laboratory tests will be used to summarize the baseline and maximum post 
baseline severity grade.  
6.7 
BIOMARKER ANALYSES  
 
For all treatment arms, descriptive statistics of biomarker data will include means 
medians, ranges, and standard deviations, as appropriate.  For categorical 
analyses, frequency distributions will be tabulated as appropriate.  
 
Biomarker data in blood and tumor tissue and biomarker data collected over time (if 
available) will be used for additional subgroup analyses where primary and 
secondary efficacy endpoints and safety will be evaluated.   
 
Although no formal statistical analysis of exploratory biomarkers will be performed, in an 
effort to understand the association of these markers with study treatment response, 
data may be analyzed in the context of this study and in aggregate with data from other 
studies.  Results will be presented in a separate report.  


 
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6.8 
NON-BINDING FUTILITY ANALYSES 
For some arms, limited data are available regarding the efficacy and safety of the 
treatment across the eligible tumor population(s).  Therefore, data from the first 
12 efficacy-evaluable patients in a given arm will be used to conduct non-binding interim 
tumor agnostic futility analyses.  Futility analyses for some arms may be conducted with 
the integration of data from other ongoing studies (see the Statistical Analysis Plan 
[SAP] for details).  These analyses will be used to identify whether a treatment may be 
ineffective in a tumor agnostic population due to limited or lack of efficacy, and further 
accrual into such an arm may be stopped.  Enrollment will not be stopped while awaiting 
results of the tumor agnostic futility analysis.  To perform the analysis we will use 
Bayesian gating with arm-specific gating criteria and non-informative prior where futility 
will be declared if there is a posterior probability of greater than 60% that the true cORR 
is less than an arm-specific unacceptable level. 
6.9 
OPTIONAL INTERIM ANALYSES 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses.  The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor's trial master 
file prior to the conduct of the interim analysis.  The interim analysis will be performed 
and interpreted by Sponsor study team personnel. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization/Functional Service Provider (CRO/FSP) will be 
responsible for the data management of this study, including quality checking of the 
data.  Data entered manually will be collected via EDC through use of eCRFs.  Sites will 
be responsible for data entry into the EDC system.  In the event of discrepant data, the 
CRO will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will perform oversight of the data management of this study.  The Sponsor 
will produce an EDC Study Specification document that describes the quality checking to 
be performed on the data.  Central laboratory data and other non-CRF data will be sent 
directly to the Sponsor and or the CRO, using the Sponsor's standard procedures to 
handle and process the electronic transfer of these data. 
eCRFs and correction will be maintained in the EDC system's audit trail.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor's standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  


 
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eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a clinical 
trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial 
related monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
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of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, images, and medication inventory records, must be 
retained by the Principal Investigator for 15 years after completion or discontinuation of 
the study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 


 
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If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  


 
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The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication (see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 


 
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Study data, which may include imaging data and data on genomic variants, may be 
submitted to government or other health research databases or shared with researchers, 
government agencies, companies, or other groups that are not participating in this study.  
These data may be combined with or linked to other data and used for research 
purposes, to advance science and public health, or for analysis, development, and 
commercialization of products to treat and diagnose disease.  In addition, redacted 
Clinical Study Reports and other summary reports will be provided upon request (see 
Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  
Prior to study treatment initiation, the Sponsor will identify potential risks associated 
with critical trial processes and data and will implement plans for evaluating and 


 
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controlling these risks.  Risk evaluation and control will include the selection of risk-
based parameters (e.g., adverse event rate, protocol deviation rate) and the 
establishment of quality tolerance limits for these parameters prior to study treatment 
initiation.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and 
monitoring of quality tolerance limits will be provided in a Quality Tolerance Limit 
Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IrBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will provide 
clinical operations management, data management, and medical monitoring. 
Approximately 60 sites will participate to enroll approximately 200 patients.  Enrollment 
will occur through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., biomarker analyses), as specified in Section 4.5.  Accredited local laboratories will 
be used for routine monitoring; local laboratory ranges will be collected.  
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 


 
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country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


 
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Appendix 2  
Contraception and Pregnancy Requirements 
CONTRACEPTION REQUIREMENTS DURING THE TREATMENT PERIOD 
FOR WOMEN OF CHILDBEARING POTENTIAL 
Female patients of childbearing potential must agree to remain abstinent (refrain from 
heterosexual intercourse) or use effective contraceptive methods with a failure rate of 
 1% per year during the treatment period and until the study drug-specific time period 
listed in Table 1.  Women must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations. 
CONTRACEPTION REQUIREMENTS DURING THE TREATMENT PERIOD 
FOR MEN  
Male patients must agree to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as defined 
below: 
 
With a female partner of childbearing potential who is not pregnant, men who are 
not surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of < 1% per year during 
the treatment period and until the study drug-specific time period listed in Table 1. 
 
With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period until the study drug-specific time period listed in Table 1. 
 
CONTRACEPTIVE METHODS 
Abstinence is defined as true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.   
Examples of contraceptive methods with a failure rate of  1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-
releasing- intrauterine devices, and copper intrauterine devices.  Note that female 
patients taking pralsetinib must use effective non-hormonal contraceptive methods; 
hormonal contraceptive methods must be supplemented by a barrier method. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 


Appendix 2:  Contraception and Pregnancy Requirements (cont.) 
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not acceptable methods of contraception.  If required per local guidelines or regulations, 
locally recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
Table 1 
Contraception Requirements after the Last Dose of Study Drug 
Study Drug 
Timeframe after the Last Dose of Study Druga 
Females 
Males 
Alectinib 
90 days 
90 days 
Atezolizumab 
5 months 
Not applicable 
Capecitabine 
6 months 
3 months 
Docetaxel 
6 months  
3 months 
Entrectinib 
5 weeks 
90 days 
Inavolisib (GDC-0077) 
60 days 
120 days 
Ipatasertib 
28 days 
28 days 
Paclitaxel 
6 months 
3 months 
PH FDC SC 
7 months 
7 months 
Pralsetinib 
2 weeks 
1 week 
Tiragolumab 
90 days 
90 days 
Trastuzumab 
emtansine 
7 months 
7 months 
Tucatinib 
1 week 
1 week 
a If patient is receiving a combination of study drugs, the requirement will last for the time 
period that is longer. 
 


 
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Appendix 3  
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
nonmeasurable as described below.  All measurable and non-measurable lesions should 
be assessed at screening and at subsequent protocol-specified tumor assessment 
timepoints.  Additional assessments may be performed as clinically indicated for 
suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
nonmeasurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
                                            
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 


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mass/abdominal organomegaly- identified by physical examination that is not 
measurable by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.   
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 


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CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
nontarget disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 


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ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis  10 mm 
but  15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
nonmeasurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple nontarget lesions involving the same organ as a single item 


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on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual 
measurement, that should be recorded, even if it is  5 mm, and in that case 
"too small to measure" should not be ticked. 


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Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities. 


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 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.  


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Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease. 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1.  


Appendix 3:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
 
MyTACTIC Study—Genentech, Inc. 
165/Protocol ML42439, Version 6 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.   
 


 
MyTACTIC Study—Genentech, Inc. 
166/Protocol ML42439, Version 6 
Appendix 4  
Response Assessment in Neuro-Oncology (RANO) Criteria 
RANO CRITERIA FOR HIGH-GRADE GLIOMA 
Response  
Criteria for High-Grade Glioma 
Complete 
response 
Requires all of the following: 
 
Complete disappearance of all enhancing measurable and nonmeasurable 
disease sustained for at least 4 weeks 
 
No new lesions  
 
Stable or improved non-enhancing (T2/FLAIR) lesions 
 
Patients must be off corticosteroids (or on physiological replacement doses 
only) 
 
Clinical status is stable or improved 
Partial 
response 
Requires all of the following: 
 
 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks 
 
No progression of nonmeasurable T1 enhancing disease 
 
No new lesions 
 
Stable or improved non-enhancing (T2/FLAIR) lesions on the same or lower 
dose of corticosteroids compared to baseline 
 
Clinical status is stable or improved 
Note:  Patients with nonmeasurable disease only cannot have a partial 
response; the best response possible is stable disease 
Stable 
disease 
Requires all of the following: 
 
Patient does not qualify for complete response, partial response, or 
progression 
 
Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline  
 
Clinical status is stable or improved 
Note:  In the event that the corticosteroid dose was increased for new 
symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan 
considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. 
 
Response  
Criteria for High-Grade Glioma (cont.) 
Progression 
Defined by any of the following: 
 
 25% increase in sum of the products of perpendicular diameters 
of enhancing lesions compared with the smallest tumor 
measurement obtained either at baseline (of no decrease) or best 
response, on a stable or increasing dose of corticosteroids 


Appendix 4:  Response Assessment in Neuro-Oncology (RANO) Criteria 
 
MyTACTIC Study—Genentech, Inc. 
167/Protocol ML42439, Version 6 
Response  
Criteria for High-Grade Glioma (cont.) 
 
Significant increase in T2/FLAIR non-enhancing lesions on stable 
or increasing doses of steroids compared with baseline scan or 
best response after initiation of therapy, not caused by comorbid 
events (e.g., radiation therapy, demyelination, ischemic injury, 
seizures, postoperative changes, or other treatment effects) 
 
Presence of any new lesions 
 
Clear clinical deterioration not attributable to other causes apart 
from the tumor (e.g., seizures, medication adverse effects, 
complications of therapy, cerebrovascular events, infection, and 
so on) or decreases in corticosteroid dose 
 
Failure to return for evaluation due to death or deteriorating 
condition 
 
Clear progression of nonmeasurable disease 
FLAIRfluid-attenuated inversion recovery; RANOResponse Assessment in Neuro-
Oncology. 
Note:  Adapted from Wen PY, Macdonald DR, Reardon DA, et al. Updated response 
assessment criteria for high-grade gliomas: Response assessment in neuro-oncology 
working group. J Clin Oncol 2012;28:196372. 
 
RANO CRITERIA FOR LOW-GRADE GLIOMA 
Response  
Criteria for Low-Grade Glioma 
Complete 
response 
Requires all of the following criteria compared with the baseline scan: 
 
Complete disappearance of the lesion on T2 or FLAIR imaging (if 
enhancement had been present, it must have resolved completely) 
 
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effects, and no new or increased 
enhancement 
 
Patients must be off corticosteroids or only on physiological 
replacement doses 
 
Patients should be stable or improved clinically 
Partial 
response 
Requires all of the following criteria compared with the baseline scan: 
 
 50% decrease in the product of perpendicular diameters of the 
lesion on T2 or FLAIR imaging sustained for at least 4 weeks 
compared with baseline 
 
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effects, and no new or increased 
enhancement 
 
Patients should be on a corticosteroid dose that should not be 
greater than the dose at time of baseline scan and should be stable 
or improved clinically 
Minor 
response 
Requires the following criteria compared with baseline: 
 
A decrease of the area of non-enhancing lesion on T2 or FLAIR 
magnetic resonance imaging between 25% and 50% compared with 
baseline 


Appendix 4:  Response Assessment in Neuro-Oncology (RANO) Criteria 
 
MyTACTIC Study—Genentech, Inc. 
168/Protocol ML42439, Version 6 
Response  
Criteria for Low-Grade Glioma 
 
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effect, and no new or increased 
enhancement  
 
Patients should be on a corticosteroid dose that should not be 
greater than the dose at time of baseline scan and should be stable 
or improved clinically 
Stable 
disease 
Is present if the changes do not qualify for complete, partial, or minor 
response, or progression and requires: 
 
Stable area of non-enhancing abnormalities on T2 or FLAIR imaging 
 
No new lesions, no new T2 or FLAIR abnormalities apart from those 
consistent with radiation effect, and no new or increased 
enhancement 
 
Patients should be on a corticosteroid dose that should not be 
greater than the dose at time of baseline scan and should be stable 
or improved clinically 
 
Response  
Criteria for Low-Grade Glioma (cont.) 
Progression 
Defined by any of the following: 
 
Development of new lesions or increase of enhancement 
(radiological evidence of malignant transformation) 
 
A 25% increase of the T2 or FLAIR non-enhancing lesion on 
stable or increasing doses of corticosteroids compared with 
baseline scan or best response after initiation of therapy, not 
attributable to radiation effect or to comorbid events 
 
Definite clinical deterioration not attributable to other causes apart 
from the tumor or decrease in corticosteroid dose 
 
Failure to return for evaluation because of death or deteriorating 
condition, unless caused by documented non-related disorders 
FLAIRfluid-attenuated inversion recovery; RANOResponse Assessment in 
Neuro-Oncology. 
Note:  Adapted from Wen PY, Macdonald DR, Reardon DA, et al. Updated response 
assessment criteria for high-grade gliomas: Response assessment in neuro-oncology 
working group. J Clin Oncol 2012;28:196372. 


 
MyTACTIC Study—Genentech, Inc. 
169/Protocol ML42439, Version 6 
Appendix 5  
Performance Status Scales 
ECOG PERFORMANCE STATUS SCALE  
Grade 
Description 
0 
Fully active; able to carry on all predisease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework or office 
work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about  50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair  50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to 
bed or chair. 
5 
Dead. 
ECOGEastern Cooperative Oncology Group. 
 


 
MyTACTIC Study—Genentech, Inc. 
170/Protocol ML42439, Version 6 
Appendix 6  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 


 
MyTACTIC Study—Genentech, Inc. 
171/Protocol ML42439, Version 6 
Appendix 7  
Moderate and Strong CYP450 Inhibitors, Inducers and 
Enzyme- and Transporter-Specific Substrates 
Examples of strong and moderate CYP3A inhibitors and inducers and combined P-gp 
and strong CYP3A4 inhibitors are outlined in Table 1. 
Examples of cytochrome enzyme-specific substrates are outlined in Table 2 
Please note that this is not a comprehensive list of all CYP450 inhibitors, inducers, 
combined P-gp and strong CYP3A4 inhibitors, and enzyme-/transporter- specific 
substrates. CYP2C8 inhibitors and inducers include but are not limited to those listed in 
Table 3.  There could also be additional new drugs and marketed drugs that could be 
identified as inhibitors/inducers with continued research. 
Table 1 
Examples of CYP3A Inhibitors, Inducers, and Combined P-gp and 
Strong CYP3A4 Inhibitors 
CYP3A Inhibitors or Inducers 
Strong Inhibitors 
Strong Inducers 
Atazanavir, boceprevir, danoprevir and 
ritonavir, elvitegravir and ritonavir, grapefruit, 
grapefruit juice, idelalisib, indinavir and 
ritonavir, ketoconazole, nefazodone, 
ombitasvir and/or dasabuvir, paritaprevir and 
ritonavir, posaconazole, ribociclib, Seville 
oranges, starfruit, telithromycin, 
troleandomycin, voriconazole 
Apalutamide, carbamazepine, enzalutamide, 
mitotane, primidone, phenobarbital, phenytoin, 
rifampin, St. John’s wort 
 
Moderate Inhibitors 
Moderate Inducers 
Aprepitant, cimetidine, ciprofloxacin, 
conivaptan, crizotinib, cyclosporine, 
diltiazem, dronedarone, erythromycin, 
fluconazole, fluvoxamine, imatinib, tofisopam, 
verapamil 
Bosentan, efavirenz, etravirine, modafinil 
Combined P-gp and Strong CYP3A4 Inhibitors 
Clarithromycin, cobicistat, itraconazole, lopinavir and ritonavir, mifebradil, nelfinavir, ritonavir, 
saquinavir and ritonavir, telaprevir, tipranavir, ritonavir  
Note:  This is not a comprehensive list of all CYP3A inhibitors, inducers, and combined P-gp and 
strong CYP3A4 inhibitors. 


Appendix 7:  Moderate and Strong CYP450 Inhibitors, Inducers and Enzyme-Specific 
Substrates 
MyTACTIC Study—Genentech, Inc. 
172/Protocol ML42439, Version 6 
 
Table 2   Examples of Enzyme-/Transporter-Specific Substrates 
Enzyme/Transporter 
Sensitive Substrates 
Substrates with  
Narrow Therapeutic 
Range 
CYP2C8 
Repaglinide  
 
CYP2C9 
Celecoxib 
Warfarin, phenytoin, 
tolbutamide  
CYP2C19 
Omeprazole  
 
CYP2D6 
Atomoxetine, desipramine, 
dextromethorphan, metoprolol, nebivolol, 
perphenazine, tolterodine, venlafaxine 
Thioridazine, pimozide 
CYP3A4 
Alfentanil, aprepitant, budesonide, 
buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, 
eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, 
maraviroc, midazolam, nisoldipine, 
quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, 
tipranavir, triazolam, ticagrelor, vardenafil 
Alfentanil, cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus  
P-gp 
Digoxin, dabigatran etexilate, 
fexofenadine 
 
BCRP 
Rosuvastatin, sulfasalazine, 
methotrexate, mitoxantrone, topotecan, 
lapatinib  
 
OATP1B1/OATP1B3 
Asunaprevir, atorvastatin, bosentan, 
danoprevir, docetaxel, fexofenadine 
glyburide, nateglinide, paclitaxel, 
pitavastatin, pravastatin, repaglinide, 
rosuvastatin, simvastatin acid 
 
OAT1 
Adefovir, cefaclor, ceftizoxime, 
famotidine, furosemide, ganciclovir 
methotrexate, oseltamivir, carboxylate 
penicillin G 
 
MATE1/MATE2-K 
Metformin  
 
Note:  This is not a comprehensive list of all enzyme- or transport-specific substrates. 
 


Appendix 7:  Moderate and Strong CYP450 Inhibitors, Inducers and Enzyme-Specific 
Substrates 
MyTACTIC Study—Genentech, Inc. 
173/Protocol ML42439, Version 6 
 
Table 3   CYP2C8 inhibitors/inducers and Their Elimination Half-Lives 
Druga,b 
Elimination Half-lifec 
Strong Inhibitors 
 
Gemfibrozil 
1–2 hours 
Moderate Inhibitors 
 
 
Clopidogrel 
6 hours 
 
Deferasirox 
8-16 hours 
 
Teriflunomide 
18-19 days 
Moderate Inducer 
 
Rifampin 
3–5 hours 
Note: Any additional CYP2C8 inhibitors/inducers that are identified or become commercially available while 
the clinical trial is ongoing are also prohibited. 
a 
FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/u
cm093664.htm#potency) 
b 
EMA. “Guideline on the investigation of drug interactions” 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf)  
c 
Drug package insert 
 


 
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174/Protocol ML42439, Version 6 
Appendix 8  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or lifethreatening 
skin adverse reaction or pericardial disorder while receiving another immunostimulatory 
anti-cancer agent.  Contact the Medical Monitor regarding any uncertainty over 
autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Antiphospholipid antibody 
syndrome 
 Aplastic anemia 
 Autoimmune hemolytic 
anemia 
 Autoimmune hepatitis 
 Autoimmune 
hypoparathyroidism 
 Autoimmune hypophysitis 
 Autoimmune myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease  
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel 
disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anemia 
 Polyarteritis nodosa 
 Polyarthritis 
 Polyglandular autoimmune 
syndrome 
 Primary biliary cholangitis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 
 Wegener granulomatosis 
 


 
MyTACTIC Study—Genentech, Inc. 
175/Protocol ML42439, Version 6 
Appendix 9  
NYHA Functional Classification System for Heart Failure and 
LVSD NCI CTCAE V5.0 Grading 
NYHA Functional Classification System for Heart Failure 
Class 
Description 
I 
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea. 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
III 
Marked limitation of physical activity.  Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
IV 
Inability to carry on any physical activity without discomfort.  
Symptoms of cardiac insufficiency at rest.  If any physical activity is 
undertaken, discomfort is increased. 
NYHANew York Heart Association. 
LVSD NCI CTCAE V5 Grading 
Investigations 
 
Grade 
1 
2 
3 
4 
5 
EF decreased 
[a] 
— 
Resting 
EF 
50%40%; 
10%19% 
drop from 
baseline 
Resting EF 
39%20%; 
 20% drop 
from baseline 
Resting EF  
 20% 
— 
Cardiac Disorders 
 
Grade 
1 
2 
3 
4 
5 
Heart failure 
[b]  
Asymptomatic 
with laboratory 
(e.g., BNP) or 
cardiac 
imaging 
abnormalities 
Symptoms 
with 
moderate 
exertion 
Symptoms at 
rest or with 
minimal activity 
or exertion; 
hospitalization; 
new onset of 
symptoms 
Life-threatening 
consequences; 
urgent intervention 
indicated 
(e.g., continuous IV 
therapy or 
mechanical 
hemodynamic 
support) 
Death 
BNPB-natriuretic peptide; EFejection fraction; IVintravenous; LVSDleft ventricular systolic 
dysfunction. 
a The percentage computed when the amount of blood ejected during a ventricular contraction 
of the heart is compared to the amount that was present prior to the contraction. 
b A disorder characterized by the inability of the heart to pump blood at an adequate volume to 
meet tissue metabolic requirements, or, the ability to do so only at an elevation in the filling 
pressure. 
https://www.eortc.be/services/doc/ctc/CTCAE_v5_Quick_Reference_5x7.pdf 


 
MyTACTIC Study—Genentech, Inc. 
176/Protocol ML42439, Version 6 
Appendix 10  
Arm A: Entrectinib in Patients with ROS1 Fusion-Positive Tumors 
11. 
ARM A:  ENTRECTINIB IN PATIENTS WITH ROS1 FUSION-POSITIVE 
TUMORS 
TABLE OF CONTENTS 
A.4 
MATERIALS AND METHODS ............................................... 177 
A.4.1 
Patients .................................................................................. 177 
A.4.1.1 
Additional Inclusion Criteria .................................................... 177 
A.4.1.2 
Additional Exclusion Criteria ................................................... 177 
A.4.2 
Study Treatment ..................................................................... 178 
A.4.2.1 
Formulation and Packaging .................................................... 178 
A.4.2.2 
Dosage, Administration, and Compliance .............................. 178 
A.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 179 
A.4.3.1 
Permitted Therapy .................................................................. 179 
A.4.3.2 
Prohibited Therapy ................................................................. 181 
A.4.3.3 
Prohibited Food ...................................................................... 182 
A.4.4 
Entrectinib-Specific Assessments .......................................... 182 
A.5 
Safety Plan ............................................................................. 182 
A.5.1 
Risks Associated with Entrectinib ........................................... 182 
A.5.2 
Management of Patients Who Experience Adverse Events with 
Entrectinib .............................................................................. 183 
A.5.2.1 
Dose Modifications and Interruptions ..................................... 183 
A.5.2.2 
Guidelines for Management of Specific Adverse Events ........ 186 
A.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) ........................................................................... 187 
A.6 
Schedule of Activities ............................................................. 188 
 


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
177/Protocol ML42439, Version 6 
A.4 
MATERIALS AND METHODS 
A.4.1 
Patients 
To be enrolled in Arm A:  entrectinib treatment, patients must have met and continue to meet all 
general eligibility criteria (see Section 4.1), in addition to the arm-specific criteria below.   
A.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm A: entrectinib 
treatment: 
 
ROS1 gene fusion positivity, except patients with non-small cell lung cancer (NSCLC), as 
determined by a Clinical Laboratory Improvement Amendments (CLIA) or equivalently 
certified next-generation sequencing (NGS) assay (tissue or blood) 
Gene fusion positivity is defined as a 3’ ROS1 fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain.  
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Ability to swallow entrectinib intact, without chewing, crushing, or opening the 
capsules/tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
 1% per year during the treatment period and for at least 5 weeks after the last dose of 
entrectinib; and agreement to refrain from donating eggs during this same period.  See 
Appendix 2 for details on contraception requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
 1% per year during the treatment period and for at least 3 months after the last dose of 
entrectinib, and agreement to refrain from donating sperm during this same period.  See 
Appendix 2 for details on contraception requirements. 
 
A.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into Arm A: 
entrectinib treatment: 
 
ROS1 fusion-positive NSCLC 
 
Prior treatment with crizotinib 
 
Whole-brain radiotherapy and/or stereotactic radiosurgery for CNS disease within 14 days 
prior to the start of entrectinib treatment. 
 
Symptomatic or uncontrolled CNS involvement 
– 
Patients with CNS involvement, including leptomeningeal carcinomatosis or prior brain 
metastases, which are either asymptomatic or previously treated and controlled, are 
allowed.   


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
178/Protocol ML42439, Version 6 
– 
Patients requiring corticosteroids must be at stable or decreasing doses for at least 
2 weeks prior to the start of entrectinib treatment. 
 
Requirement for enzyme inducing anti-epileptic drugs (EIAEDs) or use within 14 days or 5 
half lives (whichever is longer) prior to the start of entrectinib treatment 
– 
Use of seizure prophylaxis is allowed as long as patients are taking non-enzyme 
inducing anti-epileptic drugs (non-EIAEDs).  
– 
If patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used 
such as levetiracetam, valproic acid, gabapentin, topiramate, or lacosamide.  
Moderate inducers of CYP450, such as dexamethasone or other glucocorticoids, may 
be used at the discretion of the investigator.   
 
History of non-pharmacologically induced prolonged corrected QT (QTc) interval 
(e.g., repeated demonstration of a QTc interval  450 ms from ECGs performed at least 
24 hours apart) 
 
History of recent (within the past 3 months) symptomatic congestive heart failure or 
ejection fraction  50% observed during screening for the study 
 
History of additional risk factors for torsade de pointes (e.g., family history of long QT 
syndrome) 
 
Grade  2 peripheral neuropathy  
 
Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut 
syndrome) or other malabsorption syndromes that would reasonably affect drug absorption 
 
Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase 
inhibitorinduced pneumonitis  
Note:  Radiation-induced lung disorders are not included in this exclusion criterion. 
A.4.2 
Study Treatment 
Study treatment in this arm will consist of entrectinib. 
A.4.2.1 
Formulation and Packaging 
Entrectinib will be supplied by the Sponsor as 100-mg and 200-mg capsules.   
The study drug will be periodically tested and monitored for its acceptable shelf life.  Any study 
drug that fails to comply with the manufactured specifications will be promptly removed from the 
clinical trial site and replaced with new supplies by the Sponsor (or designee). 
Each bottle will be labeled with the required regulatory agency warning statement, the protocol 
number, the Sponsor’s name, and directions for patient use and storage.  The investigator 
should ensure that the study drug is stored in appropriate conditions in a secure location with 
controlled access. For information on the packaging, handling, and storage, see the Pharmacy 
Manual and Entrectinib Investigator's Brochure. 
A.4.2.2 
Dosage, Administration, and Compliance 
Study treatment will be administered in 28 day cycles. 


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
179/Protocol ML42439, Version 6 
Entrectinib will be self-administered by patients orally at home (except on clinic days
Section A.6), at the same time each day, on a starting dose of 600 mg/day (three 200-mg 
capsules per day) once a day (QD) until disease progression, intolerable toxicity, or consent 
withdrawal.  Modification may be needed in cases of coadministration with moderate or strong 
CYP3A4 inducers (See Section A.4.3.2).  For more specific dosing instructions, refer to the 
pharmacy manual.
The capsules should not be opened and the contents of the capsules should not be dissolved. 
Entrectinib can be taken with or without food.  For patients experiencing fatigue, nausea, or 
other mild tolerability issues, an evening time administration is recommended.
For entrectinib doses to be administered at home, a sufficient number of tablets should be 
dispensed to the patient to last until the next visit, or at the investigator’s discretion, through
one cycle.  Patients will be asked to record in a medication diary the time and date for each 
dose taken.  On Day 1 and on clinic visit days, entrectinib should be taken at the clinic after all 
the predose assessments have been conducted, at the direction of the study research nurse or 
treating physician.
A missed dose can be taken within 12 hours of the scheduled time. After that, patients should 
take the next dose the following day, without compensating for the missed dose (including 
vomited doses)
Guidelines for entrectinib dosage modification and treatment interruption or discontinuation are 
provided in Section A.5.2.1.
See Section 4.3.2 for details on assessment of compliance for self-administered oral study 
drugs.
Accidental overdose or medication errors should be noted on the Study Drug Administration 
electronic Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should also be reported as described in Section 5.3.5.12.
At the end of the study, the Sponsor will provide instructions as to the disposition of any unused 
study drug.
A.4.3 
Concomitant Therapy, Prohibited Food, and Additional Restrictions 
A.4.3.1 
Permitted Therapy
Seizure prophylaxis with any of the following non-EIAEDs is allowed during the study for pa-
tients with controlled asymptomatic CNS involvement:  levetiracetam, valproic acid, lacosamide, 
gabapentin, topiramate, lamotrigine, tiagabine, zonisamide, clonazepam, clobazam, or 
pregabalin.  Note:  EIAEDs are not allowed (see Section A.4.3.2).
Moderate inducers of CYP3A, CYP3A4, or CYP3A4/5, such as dexamethasone or other 
glucocorticoids, may be used at the discretion of the investigator for CNS metastasis.  See 
Appendix 7 for examples of CYP450 inducers, inhibitors, and enzyme-specific substrates.


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
180/Protocol ML42439, Version 6 
In certain instances, palliative radiotherapy to specific sites is permitted if considered medically 
necessary by the investigator.  The Sponsor must be notified if palliative radiotherapy is started; 
however, the need for radiotherapy will generally be considered indicative of progressive 
disease. 
It is recommended to avoid radiotherapy for at least 5 days after the last dose of entrectinib.  
The irradiated area should be as small as possible and  25% of the bone marrow reserve.  
Entrectinib administration should be withheld during the period of irradiation and for 2 weeks 
thereafter.  If radiation-related toxicities (other than xerostomia) have not normalized to 
preirradiation levels after 2 weeks of rest, the patient should be discontinued from the study. 
Entrectinib treatment has not been specifically observed to interfere with wound healing; 
therefore, caution is advised on theoretical grounds.  Based upon pharmacokinetic 
considerations, stopping entrectinib treatment is recommended at least 57 days prior to major 
elective surgery and 23 days prior to minor surgical procedures.  Postoperatively, the decision 
to reinitiate treatment with entrectinib should be based upon clinical assessment of satisfactory 
wound healing and recovery from surgery. 
No other approved or investigational anti-cancer therapy is permitted during study participation, 
including chemotherapy, immunotherapy, biological response modifiers, and/or hormonal 
therapy. 
Bone-sparing agents (e.g., bisphosphonates, denosumab) for palliation of bone metastases or 
for the treatment of osteoporosis or osteopenia are allowed, but initiation of such agents or 
modification of the pre-study bisphosphonate or denosumab treatment regimen should be done 
in consultation with the Medical Monitor. 
Therapies considered necessary for the patient’s well-being (e.g., therapies to manage 
concomitant chronic pathologies or therapies required for life-threatening medical conditions) 
may be administered as per the investigator’s discretion.  For seasonal flu shots, inactivated 
vaccines are allowed. 
Use of concomitant medications that increase or possibly increase the risk of QTc prolongation 
and/or induce torsades de pointes ventricular arrhythmia must be done with caution or avoided 
if possible during study participation (see Table 1). 


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
181/Protocol ML42439, Version 6 
Table 1 
Concomitant Medications to Be Used with Caution 
Antiarrhythmics 
Amiodarone 
Procainamide  
Disopyramide 
Quinidine  
Dofetilide 
Sotalol  
Ibutilide  
Antipsychotics 
Chlorpromazine Quetiapine  
Clozapine 
Risperidone 
Haloperidol 
Thioridazine 
Antibiotics 
Azithromycin 
Ketoconazole  
Ciprofloxacin 
Levofloxacin  
Clarithromycin 
Moxifloxacin  
Erythromycin 
Ofloxacin  
Fluconazole 
Sparfloxacin  
Gatifloxacin 
Telithromycin  
Itraconazole 
Trimethoprim-sulfa  
Antidepressants 
Amitriptyline 
Imipramine  
Citalopram 
Nortriptyline  
Desipramine 
Paroxetine  
Doxepin 
Sertraline  
Fluoxetine 
Venlaxafine  
Antiemetics 
Ondansetron 
Prochlorperazine  
 
A.4.3.2 
Prohibited Therapy 
The following EIAEDs are prohibited during the study and for at least 14 days or 5 halflives 
(whichever is longer) prior to initiation of entrectinib:  carbamazepine, oxcarbazepine, 
phenytoin, fosphenytoin-, phenobarbital, and primidone.  See Section A.4.3.1 above for 
alternative anti-epileptic treatment options. 
Use of herbal medications (e.g., St. John’s Wort) should be avoided when possible. 
Entrectinib is mainly eliminated through hepatic clearance and CYP3A4 plays a significant role 
in the biotransformation of entrectinib.  Co-administration of strong or moderate CYP3A4 
inhibitors and inducers should be avoided.  However, moderate inducers of CYP3A, CYP3A4, 
or CYP3A4/5, such as dexamethasone or other glucocorticoids, may be used at the discretion 
of the investigator as clinically indicated per local institutional guidelines.  See Appendix 7 or 
examples of CYP450 inducers, inhibitors, and enzyme-specific substrates. 
In vitro, entrectinib exhibited potential to inhibit and induce the activities of CYP3A, and 
potential for inhibition of CYP2C9 and CYP2D6, which suggests a potential for interaction with 
other drugs metabolized by these isoforms.  


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
182/Protocol ML42439, Version 6 
Because of this potential, entrectinib should be avoided or, if necessary, administered with 
caution with strong CYP3A inhibitors or inducers.  Examples of strong and moderate CYP3A 
inhibitors and inducers are listed in Appendix 7.  If coadministration of strong or moderate 
CYP3A inhibitors with entrectinib is unavoidable, reduce the dose of entrectinib as follows: 
 
Moderate CYP3A Inhibitors:  200 mg orally once daily 
 
Strong CYP3A inhibitors:  100 mg orally once daily 
 
A.4.3.3 
Prohibited Food 
Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or star fruit should be avoided during the treatment period. 
A.4.4 
Entrectinib-Specific Assessments 
In addition to the study assessments described in Section 4.5, the following assessments are 
required for patients in the entrectinib treatment arm.  Refer to the schedule of activities 
(Section A.6) for arm-specific assessment timepoints. 
Local Laboratory Assessments  
Samples for the following laboratory tests will be sent to the study site's local laboratory for 
analysis: 
 
Coagulation:  INR and aPTT 
 
Lipids:  total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides 
 
Functional Assessments 
 
Left-ventricular ejection fraction (LVEF) assessment:  echocardiogram (ECHO) or multiple-
gated acquisition (MUGA) 
 
Ophthalmological examinations:  visual acuity and slit-lamp test 
 
Single ECG 
 
Fall risk factor evaluation and monitoring  
 
A.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety in this 
study.  Following are further instructions specific to Arm A:  entrectinib treatment. 
A.5.1 
Risks Associated with Entrectinib 
Entrectinib has been associated with risks such as the following:  cognitive disorders (including 
confusion, mental status changes, memory impairment, and hallucinations), congestive heart 
failure (CHF), bone fractures, and QT prolongation.  Refer to the Entrectinib Investigator’s 
Brochure for a detailed description of anticipated safety risks for entrectinib. 


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
183/Protocol ML42439, Version 6 
A.5.2 
Management of Patients Who Experience Adverse Events with 
Entrectinib 
Guidelines for management of specific adverse events and dose modification or interruption are 
outlined below.  These guidelines are intended to inform rather than supersede clinical 
judgment and the benefit-risk balance as assessed by the investigator in managing individual 
cases.   
A.5.2.1 
Dose Modifications and Interruptions 
Adverse events associated with entrectinib can often be managed with concomitant 
medications, supportive care (see Section A.4.3.1 and  Section A.5.2.2), and/or dose 
modifications as per Table 3. 
If an adverse event is considered unrelated to study treatment and results in dose interruption, 
treatment may resume at the initial dose after the adverse event stabilizes or resolves to Grade 
1 or better, as per the investigator’s discretion. 
If toxicities that are possibly related to entrectinib are not easily managed or corrected, and are 
not tolerable to the patient, or if there are adverse events that are not acceptable in the 
investigator’s judgment, the patient should have study treatment interrupted until the adverse 
event resolves to Grade 1 or better.  If study treatment is interrupted, dose reduction (if 
mandated) should occur when study treatment is resumed.  All dose reductions should be 
based on the most severe toxicity observed that is attributable to entrectinib. 
If needed, dose reductions may occur in decrements of 200 mg and no more than two dose 
reductions will be allowed.  Accordingly, the possible daily doses of entrectinib are shown in 
Table 2.  For patients on an already reduced dose due concomitant CYP3A4 inducer use, 
additional dose modification should be done in consultation with Medical Monitor.  Dose re-
escalation is not permitted for entrectinib.  
Table 2 
Entrectinib Dose Reductions 
Dose Level 
Dose (mg QD) 
Starting Dose 
600 
First reduction 
400 
Second reduction 
200 
QD  once a day. 
Entrectinib treatment may be interrupted for a maximum of 28 days to allow sufficient recovery 
from any toxicity if a patient is still deriving clinical benefit in the judgment of the investigator. 


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
184/Protocol ML42439, Version 6 
Table 3 
Dose Modifications and Interruptions for Entrectinib-Related Adverse 
Events 
Adverse Drug 
Reaction 
Severity a 
Dose Modification 
Anemia or 
Neutropenia  
Grade 3 or Grade 4 
 
Withhold entrectinib until recovery to Grade ≤ 2 
or to baseline, then resume treatment at same 
dose level or reduced dose, as clinically 
needed. 
Cognitive 
Disorders 
Grade ≥ 2  
 
Withhold entrectinib until recovery to Grade ≤ 1 
or to baseline, then resume treatment at 
reduced dose.  
 
If event recurs, further reduce dose. 
 
For prolonged, severe, or intolerable events, 
discontinue as clinically appropriate. 
Transaminase 
Elevations  
Grade 3  
 
Withhold entrectinib until recovery to less than 
or equal to Grade 1 or to baseline.  
 
Resume at same dose if resolution occurs 
within 4 weeks.  
 
Permanently discontinue if adverse reaction 
does not resolve within 4 weeks.  
 
Resume at a reduced dose for recurrent 
Grade 3 events that resolve within 4 weeks.  
Grade 4 
 
Withhold entrectinib until recovery to less than 
or equal to Grade 1 or to baseline.  
 
Resume at reduced dose if resolution occurs 
within 4 weeks.  
 
Permanently discontinue if adverse reaction 
does not resolve within 4 weeks.  
 
Permanently discontinue for recurrent Grade 4 
events.  
ALT or AST elevation 
greater than 3 times ULN 
with total bilirubin elevation 
greater than 2 times ULN 
in the absence of 
cholestasis or hemolysis 
 
Permanently discontinue entrectinib.  
 
 
 
 
 
 


Arm A:  Entrectinib in Patients With ROS1 Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
185/Protocol ML42439, Version 6 
Table 3 
Dose Modifications and Interruptions for Entrectinib-Related Adverse 
Events (cont) 
Adverse Drug 
Reaction 
Severity a 
Dose Modification 
Hyperuricemia   
Symptomatic or Grade 4  
 
Initiate urate-lowering medication 
 
Withhold entrectinib until improvement of signs 
or symptoms 
 
Resume entrectinib at same or reduced dose  
Congestive Heart 
Failure 
 
Grade 2 or 3 
 
Withhold entrectinib until recovered to less 
than or equal to Grade 1 
 
Resume at reduced dose 
Grade 4 
 
Withhold entrectinib until recovered to less 
than or equal to Grade 1 
 
Resume at reduced dose or discontinue as 
clinically appropriate  
QT Interval 
Prolongation 
QTc 481 to 500 ms 
 
Withhold entrectinib until recovered to baseline  
 
Resume treatment at same dose 
QTc greater than 
500 ms 
 
Withhold entrectinib until QTc interval recovers 
to baseline 
 
Resume at same dose if factors that cause QT 
prolongation are identified and corrected 
 
Resume at reduced dose if other factors that 
cause QT prolongation are not identified 
Torsade de pointes; 
polymorphic ventricular 
tachycardia; 
signs/symptoms of serious 
arrhythmia  
 
Permanently discontinue entrectinib 
Other clinically 
relevant adverse 
reactions  
Grade 3 or 4  
 
Withhold entrectinib until adverse reaction 
resolves or improvement to Grade 1 or 
baseline   
 
Resume at the same or reduced dose, if 
resolution occurs within 4 weeks 
 
Consider permanent discontinuation if adverse 
reaction does not resolve within 4  weeks 
 
Permanently discontinue for recurrent Grade 4 
events  
a Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) 


Arm A:  Entrectinib In Patients with ROS1 Fusion-Positive Tumors 
MyTACTIC Study—Genentech, Inc. 
186/Protocol ML42439, Version 6 
A.5.2.2 
Guidelines for Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in the subsections below. 
A.5.2.2.1 
Nausea and Emesis 
For nausea and emesis, treat with standard antiemetics; prophylactic antiemetics are permitted 
as necessary using institutional guidelines for treatment and/or published guidelines.  Refer to 
Table 1 for concomitant medications that should be administered with caution. 
A.5.2.2.2 
Diarrhea 
Treatment with antidiarrheal drugs may be warranted and should follow institutional and/or 
published guidelines.  If no guidelines exist, then the following recommendations may be 
instituted: 
 
For Grade 1 diarrhea, treat with loperamide if needed; no dose modification is necessary. 
 
For Grade 2 diarrhea, treat with loperamide (4 mg at first onset, then 2 mg every 24 hours 
or after each loose stool, until symptom free for 12 hours).  No dose modification is 
necessary unless the patient is intolerant or symptom is recurrent. 
 
For Grade  3 diarrhea (despite use of loperamide), treatment should be withheld until 
recovery to Grade 1 or better. 
 
A.5.2.2.3 
Severe Neutropenia or Anemia 
Prophylactic use of granulocyte colony-stimulating factor (G-CSF) or initiation of erythropoietin 
may be instituted according to the American Society of Clinical Oncology guidelines in patients 
who are having difficulty with severe neutropenia or anemia.  Patients who have been treated 
for  4 weeks with erythropoietin prior to enrolling in the study may continue on the existing 
treatment. 
Patients with neutropenic fever or infection should be hospitalized promptly for intravenous (IV) 
antibiotic therapy and may receive therapeutic colony stimulating factors as appropriate. 
Red blood cell and platelet transfusions should be administered as warranted. 
A.5.2.2.4 
Pneumonitis or Pneumonia 
Investigators must thoroughly evaluate patients who demonstrate potential signs and symptoms 
of pneumonitis or pneumonia.  If a patient has a potential diagnosis of pneumonitis or study 
drugrelated lung injury, the following evaluations and procedures should be considered to 
assist or exclude the diagnosis of pneumonitis during this period: 
 
A sputum gram stain and culture (induced sputum if needed) for bacteria, viruses, fungi, 
protozoa, and mycobacteria 
 
Blood culture for febrile patients 
 
Thoracentesis if pleural fluid is present (examined for same pathogens as sputum) 


Arm A:  Entrectinib In Patients with ROS1 Fusion-Positive Tumors 
MyTACTIC Study—Genentech, Inc. 
187/Protocol ML42439, Version 6 
 
Bronchoscopy with bronchoalveolar lavage (BAL), if appropriate.  BAL fluid should be sent 
for culture and cytology (examined for same pathogens as sputum) 
 
Lung biopsy (e.g., open or thorascopic preferable; bronchoscopy with transbronchial 
biopsy), if appropriate 
 
A plasma sample for B-type natriuretic peptide to evaluate for evidence of congestive heart 
failure 
 
For Asian patients, a blood sample for -D-glucan to evaluate for the presence of protozoal 
pneumonia (e.g., Pneumocystis jiroveci) 
 
If clinically appropriate, high-dose corticosteroid treatment should be initiated.  Should the event 
be fatal, an autopsy is highly recommended to confirm or to exclude the diagnosis.  For any 
case of suspected pneumonitis, please contact the Sponsor.  See Table 3 for appropriate dose 
modifications. 
A.5.2.2.5 
QT Interval Prolongation 
In cases of Grade 2 or 3 QT interval prolongation, assess and correct electrolytes and 
concomitant medications and follow dose modification guidelines in Table 3.  In cases of Grade 
4 QT interval prolongation, entrectinib should be permanently discontinued.   
A.5.3 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be reported by 
the investigator to the Sponsor immediately for all study treatments, and Section 5.4.2 provides 
reporting instructions.  In addition to the adverse events of special interest specified in 
Section 5.2.3, the following adverse events are required to be reported by the investigator 
immediately for patients in the Entrectinib treatment arm: 
 
Bone fractures:  All grades 
 
Cognitive disturbances:  Grade  2 
 
Congestive cardiac failure:  Grade  2 
 
QT prolongation:  Grade  2 
 
Syncope:  All grades 
 


Arm A:  Entrectinib In Patients with ROS1 Fusion-Positive Tumors 
MyTACTIC Study—Genentech, Inc. 
188/Protocol ML42439, Version 6 
A.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit b Follow-Up c 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified
 
 
Every 3 
M onths 
After Last 
Dose 
(Window) 28 TO 1 A 
(3) 
(3) 
≤ 28 days from 
last study dose 
(14) 
Informed consent d 
x 
 
 
 
 
Documentation of positive ROS1 
gene fusion status by local test e 
x 
 
 
 
 
Medical history and baseline 
conditions f  
x 
 
 
 
 
Physical Examination g 
x 
As clinically indicated 
 
ECOG Performance Status h 
x 
x 
 
x 
 
Pregnancy test i 
x 
x 
 
x 
 
Chemistry j  
x 
x 
 
x 
  
Hematology/CBC with differential k 
x 
x 
 
x 
  
Coagulation panel l 
x 
 
 
 
 
Lipid panel m 
x 
 
 
 
 
ECHO/MUGA n 
x 
C3, D1 and as clinically indicated 
x n 
 
Single ECG o 
x 
D1 of C1C3 and every 2 cycles thereafter, and as clinically indicated 
 
Opthamalogical examinations p 
x 
C2, D1 and as clinically indicated 
x 
 
Fall risk factor evaluation and 
monitoring q 
x 
x 
 
x 
 
Response assessment r, s 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) 
weeks 
 
 


Arm A:  Entrectinib In Patients with ROS1 Fusion-Positive Tumors 
MyTACTIC Study—Genentech, Inc. 
189/Protocol ML42439, Version 6 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit b Follow-Up c 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
Every 3 
M onths 
After Last 
Dose 
(Window) 28 TO 1 A 
(3) 
(3) 
≤ 28 days from 
last study dose 
(14) 
Pre-treatment tumor tissue sample 
for central testing (if applicable) t 
 
Submit within 21 days of Cycle 1 Day 1 
 
 
 
Whole blood samples u  
x 
 
see footnote u  
 
 
Study drug compliance assessment v 
 
x 
 
x 
 
Study drug dispensing 
 
x 
 
 
 
Adverse events w  
 
Collected on an ongoing basis 
 
Concomitant medications x 
 
Collected on an ongoing basis 
 
Survival follow-up and anticancer 
therapy y 
 
 
 
 
x 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; ECGelectrocardiogram; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; 
eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular 
ejection fraction; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; RANOResponse Assessment 
in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious adverse event. 
Note: Cycle28 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if 
the hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1.  Scans to 
document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may 
take place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to collect AE data and 
any standard of care laboratory and CT data, if performed 


Arm A:  Entrectinib In Patients with ROS1 Fusion-Positive Tumors 
MyTACTIC Study—Genentech, Inc. 
190/Protocol ML42439, Version 6 
c Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months for up to at least 1 year, until death, loss 
to follow-up, or study termination by the Sponsor, whichever occurs first. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive ROS1 gene fusion status should occur prior to performing other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) 
used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.   
j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent 
chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
k Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.   
l Coagulation includes aPTT and INR. 
m Lipids include total cholesterol, triglycerides, LDL, and HDL. 
n LVEF assessment by ECHO or MUGA to be performed at screening, Cycle 3 Day 1 (7 days), as clinically indicated, and at the end of 
treatment (if patient experienced Grade 2 or higher ejection fraction decrease at Cycle 3 or at any time during treatment, or if clinically 
indicated).  The end-of-treatment LVEF is not necessary if the last LVEF assessment was performed within 1 week prior to the end of treatment 
visit and if the investigator deems it is not clinically indicated.  Evaluation of LVEF must be performed by the same method (ECHO or MUGA) 
for each patient.  It is strongly recommended that the same laboratory and operator perform ECHO/MUGA scan for each individual patient. 
o At study treatment visits (Day 1 of a given cycle), perform pre-dose and 4 hours [ 15 min] post-dose for Cycles 13, and pre-dose every 2 
cycles thereafter.  Patients should be resting in a supine position for at least 10 minutes prior to ECG recording. 


Arm A:  Entrectinib In Patients with ROS1 Fusion-Positive Tumors 
MyTACTIC Study—Genentech, Inc. 
191/Protocol ML42439, Version 6 
p Ophthalmologic examinations including at least visual acuity and slit-lamp tests (which may be performed by an optometrist) will be required at 
Screening, Cycle 2 Day 1, at the end of treatment, and as clinically indicated.  Note: The time window for ophthalmologic examinations is 1 
week. 
q Fall risk evaluation and monitoring: at every visit, patients will be asked about risk factors of fall, weight, nutritional intake, nutritional 
deficiencies, impaired cognition and health deterioration. Relevant findings will be recorded as adverse events.  Additional assessments may be 
performed at the discretion of the treating physician. 
r All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
s At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
t For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
u Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression for analyses including ctDNA.   
v Study drug compliance will be reviewed with the patient. 
w After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all 
deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
x Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study drug. 
y After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy) will be collected via 
telephone calls, patient medical records, and/or clinic visits approximately every 3 months for at least up to 1 year or until death (unless the 
patient withdraws consent, is lost to follow up or the Sponsor terminates the study), whichever comes first.  If a patient requests to be withdrawn 
from follow-up, this request must be documented in the source documents and signed by the investigator.  If the patient withdraws from the 
study, the study staff may use a public information source (e.g., county records) to obtain information about survival status only.     


 
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Appendix 11  
Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) 
Activating MutationPositive Tumors 
12. 
ARM B:  INAVOLISIB (GDC-0077) IN PATIENTS WITH PI3K 
(PIK3CA) ACTIVATING MUTATIONPOSITIVE TUMORS 
TABLE OF CONTENTS 
 
B.4 
Material and Methods .................................................... 193 
B.4.1 
Patients ......................................................................... 193 
B.4.1.1 
Additional Inclusion Criteria ........................................... 193 
B.4.1.2 
Additional Exclusion Criteria .......................................... 194 
B.4.2 
Study Treatment ............................................................ 195 
B.4.2.1 
Formulation and Packaging........................................... 195 
B.4.2.2 
Dosage, Administration, and Compliance ..................... 195 
B.4.3 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ................................................... 196 
B.4.3.1 
Permitted Therapy ......................................................... 196 
B.4.3.2 
Prohibited Foods and Therapies ................................... 196 
B.4.4 
Arm-Specific Assessments ............................................ 197 
B.5 
Safety Plan .................................................................... 198 
B.5.1 
Risks Associated with Invasolibi (GDC-0077) ............... 198 
B.5.2 
Management of Patients Who Experience Adverse 
Events with Inavolisib (GDC-0077) ............................... 198 
B.5.2.1 
Dose Modifications and Interruptions ............................ 198 
B.5.2.2 
Guidelines for Management of Specific Adverse 
Events ........................................................................... 199 
B.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ........................................... 207 
B.6 
Schedule of Activities .................................................... 208 
B.7 
References .................................................................... 213 
 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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B.4 
MATERIAL AND METHODS 
B.4.1 
Patients 
To be enrolled in Arm B: Inavolisib (GDC-0077) treatment, patients must have met and 
continue to meet all general eligibility criteria (see Section 4.1), in addition to arm-
specific criteria below.  
B.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm B: 
Inavolisib (GDC-0077) treatment: 
 
PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
PIK3CA mutation positivity is defined by the presence of at least one nucleotide 
variant listed below: 
– 
H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V 
– 
Other activating mutations with Medical Monitor approval 
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Fasting glucose  126 mg/dL and glycosylated hemoglobin (HbA1c)  5.7%  
 
Willingness and ability to swallow inavolisib (GDC-0077) intact, without chewing, or 
crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
60 days after the last dose of inavolisib (GDC-0077); and agreement to refrain from 
donating eggs during this same period.  For all other women, documentation must 
be present in medical history confirming that patient is not of childbearing potential.  
See Appendix 2 for details regarding contraception requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of  1% per year during the treatment period and for at least 120 days 
after the last dose of inavolisib (GDC-0077), and agreement to refrain from donating 
sperm during this same period.  See Appendix 2 for details regarding contraception 
requirements. 
 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
Tumors 
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194/Protocol ML42439, Version 5 
B.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm B:  inavolisib (GDC-0077) treatment: 
 
Primary CNS tumors 
 
Type 2 diabetes requiring antihyperglycemic medication or any history of type 1 
diabetes 
 
Patients with elevated fasting glucose at baseline (fasting glucose  126 mg/dL 
[ 7.0 mmol/L]) or HbA1c  5.7% will be excluded from the study 
 
Malabsorption syndrome or other condition that would interfere with 
enteral absorption 
 
Uncontrolled pleural effusion or ascites requiring recurrent drainage procedures 
twice monthly or more frequently  
Indwelling pleural or abdominal catheters are allowed provided the patient has 
adequately recovered from the procedure, is hemodynamically stable and 
symptomatically improved  
 
Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) 
that, in the opinion of the investigator and/or study ophthalmologist, would require 
medical or surgical intervention during the study period to prevent or treat vision loss 
that might result from that condition 
 
Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, 
scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or 
autoimmune-associated uveitis in either eye 
 
Patients requiring any daily supplemental oxygen 
 
History of or active inflammatory disease (e.g., Crohn’s disease or ulcerative colitis) 
or any active bowel inflammation (including diverticulitis)  
Patients currently receiving immunosuppressants (e.g., sulfasalazines) are 
considered to have active disease and are, therefore, ineligible. 
 
Symptomatic hypercalcemia requiring continued use of bisphosphonate or 
denosumab therapy 
Bisphosphonate and denosumab therapy for bone metastases or 
osteopenia/osteoporosis is allowed. 
 
Clinically significant and active history of liver disease, including severe liver 
impairment (ChildPugh score B/C), current alcohol abuse, or cirrhosis  
 
Congenital long QT syndrome or QT interval corrected using Fridericia’s formula 
(QTcF)   470 ms demonstrated by at least two ECGs  30 minutes apart, or family 
history of sudden unexplained death or long QT syndrome 
 
Current treatment with medications that are well known to prolong the QT interval  
 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
Tumors 
MyTACTIC Study—Genentech, Inc. 
195/Protocol ML42439, Version 5 
 
Allergy or hypersensitivity to components of the GDC-0077 formulation 
 
Any symptomatic active lung disease, including pneumonitis 
 
B.4.2 
Study Treatment 
Study treatment in this arm will consist of inavolisib (GDC-0077). 
B.4.2.1 
Formulation and Packaging 
Inavolisib (GDC-0077) will be supplied by the Sponsor as an immediate-release tablet 
formulation (3-mg and 9-mg).  
The 3-mg and 9-mg tablets should be stored at or below 86°F (30°C) and protected from 
light.  Patients should be cautioned to keep the tablets in the foil-protected cards 
supplied, and to NOT remove them except immediately prior to consumption. 
For information on the packaging, handling and storage, see the Pharmacy Manual and 
Inavolisib (GDC-0077) Investigator's Brochure. 
B.4.2.2 
Dosage, Administration, and Compliance 
Study treatment will be administered in 28-day cycles. 
Inavolisib (GDC-0077) will be self-administered by patients orally at home (except on 
clinic days) at the same time each day, on a starting dose of 9 mg/day (one 9-mg tablet 
per day) once a day (QD) until disease progression, intolerable toxicity, or consent 
withdrawal.  For more specific dosing instructions, refer to the pharmacy manual. 
The tablets will be swallowed whole (not chewed) with 8 ounces (240 mL) of fluid, 
preferably water. 
For inavolisib (GDC-0077) doses to be administered at home, a sufficient number of 
tablets should be dispensed to the patient to last until the next visit, or at the 
investigator’s discretion, through one cycle.  Patients will be asked to record in a 
medication diary the time and date for each dose taken. 
A missed dose can be taken within 9 hours of the scheduled time.  After that, patients 
should take the next dose the following day, without compensating for the missed dose 
(including vomited doses). 
Guidelines for inavolisib (GDC-0077) dosage modification and treatment interruption or 
discontinuation are provided in Section B.5.2.1.  
See Section 4.3.2 for details on assessment of compliance for self-administered oral 
study drugs. 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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MyTACTIC Study—Genentech, Inc. 
196/Protocol ML42439, Version 5 
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug. 
B.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
B.4.3.1 
Permitted Therapy  
Patients who experience toxicities should be treated symptomatically as clinically 
indicated.   
Patients treated with antiseizure medications or warfarin should have levels monitored 
regularly. 
Patients who use oral contraceptives or other allowed maintenance therapy as specified 
in the eligibility criteria (see Section B.4.1.1 and Appendix 2) should continue their use.  
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drug.  At the discretion of the investigator, prophylactic 
anti-emetic and anti-diarrheal medication(s) may be used as per standard clinical 
practice before subsequent doses of study drug. 
Pain medications administered per standard clinical practice are acceptable while the 
patient is enrolled in the study. 
Bisphosphonate and denosumab therapy for bone metastases or 
osteopenia/osteoporosis is allowed. 
Multivitamins, calcium, and vitamins C, D, and E supplements are allowed.  However, 
due to the potential for drug-supplement interactions, and variability among suppliers 
and batches, the use of other dietary supplements is cautioned.  
B.4.3.2 
Prohibited Foods and Therapies 
Use of the following foods and therapies is prohibited during the study and for at least 
7 days prior to initiation of study treatment, unless otherwise specified below: 
 
Any concomitant therapy intended for the treatment of cancer, whether approved by 
the U.S. Food and Drug Administration (FDA) or experimental, including 
chemotherapy, radiotherapy, immunotherapy, biologic therapy, herbal therapy, or 
hormonal therapy, except for those administered as study treatment.  


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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MyTACTIC Study—Genentech, Inc. 
197/Protocol ML42439, Version 5 
 
Primary prophylactic use of hematopoietic growth factors (e.g., erythropoietins, 
granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage 
colony-stimulating factor [GM-CSF]) is not permitted, however, they may be used to 
treat treatment-emergent neutropenia or anemia as indicated by the current 
American Society of Clinical Oncology (ASCO) guidelines or as secondary 
prophylaxis if dose reduction or delay is not considered a reasonable alternative 
after discussion with the Sponsor.  
 
Patients who require the use of any prohibited therapies will be discontinued from study 
treatment and followed for safety outcomes for 28 days after their last dose of inavolisib 
(GDC-0077), or until they receive another anticancer therapy, whichever occurs first. 
In vitro data suggest that inavolisib (GDC-0077) is metabolized by cytochrome P450 3A4 
(CYP3A4) and that there is a low to moderate potential for a drug-drug interation (DDI) 
with any medication that strongly inhibits or induces this enzyme.  Therefore, 
strong/moderate CYP3A4 inhibitors and inducers should be avoided (see Appendix 7).  
If use of one of these medications is necessary, the risks and benefits should be 
discussed with the Medical Monitor prior to its concomitant administration with inavolisib 
(GDC-0077). 
In vitro data also suggest that inavolisib (GDC-0077) is a substrate of the efflux 
transporter P-glycoprotein (P-gp) and concomitant use of inhibitors of P-gp is not 
recommended in this study. 
 
Inhibitors of P-gp include, but not limited to:  ritonavir, cyclosporine, verapamil, 
erythromycin, ketoconazole, itraconazole, quinidine, elacridar, valspodar, grapefruit 
juice, grapefruit supplements, and Seville oranges  
 
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication strongly inhibits or induces CYP3A4, or inhibits P-gp.  In addition, the 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above. 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers 
 
B.4.4 
Arm-Specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in the inavolisib (GDC-0077) treatment arm.  
Refer to the schedule of activities (Section B.6) for arm-specific assessment timepoints. 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
Tumors 
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198/Protocol ML42439, Version 5 
Local Laboratory Assessments 
 
Coagulation panel:  INR and aPTT 
 
Fasting blood glucose, HbA1c 
 
Amylase, lipase 
 
Fasting lipid panel:  total cholesterol, triglycerides, LDL, and HDL 
 
Functional Assessments 
 
Ophthalmologic examination (slit-lamp tests and visual acuity) 
 
12 lead electrocardiogram (ECG) 
 
B.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm B:  inavolisib (GDC-007) 
treatment. 
B.5.1 
Risks Associated with Inavolisib (GDC-0077) 
Inavolisib (GDC-0077) has been associated with risks such as the following:  
hyperglycemia, stomatitis/mucositis, gastrointestinal inflammation, rash, lung 
inflammation/pneumonitis, immunosuppression with increased risk of infection, potential 
permanent reproductive sterility, ocular toxicity, and potential drug-drug interaction with 
CYP3A4, as their concentration may be decreased with concomitant administration.  
Refer to the Inavolisib (GDC-0077) Investigator's Brochure for a detailed description of 
anticipated safety risks for inavolisib (GDC-0077). 
B.5.2 
Management of Patients Who Experience Adverse Events with 
Inavolisib (GDC-0077) 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.  In general, for the management of specific adverse 
events of Grade  3 outlined below, inavolisib (GDC-0077) administration should be 
interrupted. 
B.5.2.1 
Dose Modifications and Interruptions 
Any dose modification should be noted on the corresponding Study Drug Administration 
eCRF.  Cases of accidental overdose or medication error, along with any associated 
adverse events, should be reported as described in Section 5.3.5.12. 
Patients may hold the inavolisib (GDC-0077) for up to 28 consecutive days in order to 
recover from toxicity or an adverse event related to the study drug. 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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199/Protocol ML42439, Version 5 
If needed, dose reductions may occur in decrements of 3 mg and no more than two dose 
reductions will be allowed.  Accordingly, the possible daily doses of inavolisib 
(GDC-0077) are shown in Table 1. 
If the patient continues to experience specified drug-related adverse events after the 
second reduction, the treatment should be discontinued.  Dose re-escalation is not 
permitted for inavolisib (GDC-0077). 
Table 1 
Inavolisib (GDC-0077) Dose Reductions 
Dose Level  
Inavolisib (GDC-0077) 
Starting dose 
9 mg QD 
First dose reduction 
6 mg QD 
Second dose reduction 
3 mg QD 
Third dose reduction 
Not permitted 
QD  once a day. 
Inavolisib (GDC-0077) treatment may be temporarily interrupted in patients who 
experience toxicity considered to be related to study drug.  If inavolisib (GDC-0077) has 
been withheld for > 28 consecutive days because of treatment-related toxicity, the 
patient should be discontinued from inavolisib (GDC-0077).  Inavolisib (GDC-0077) may 
be suspended for reasons other than toxicity (eg, surgical procedures), however 
inavolisib (GDC-0077) should be interrupted at least 48 hours in advance of surgery and 
resumed only upon resolution to baseline of any sequelae of the procedure, including 
adequate wound healing.  If, in the judgment of the investigator, the patient is likely to 
derive clinical benefit from resuming study treatment after a hold of  28 consecutive 
days, study drug may be restarted upon consultation with the Medical Monitor. 
B.5.2.2 
Guidelines for Management of Specific Adverse Events 
Guidelines for management of specific adverse events are provided in the subsections 
below. 
B.5.2.2.1 
Hyperglycemia 
Guidelines for management of hyperglycemia are summarized in Table 2. 
 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive Tumors 
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Table 2 
Management of Hyperglycemia 
Fasting Glucose 
Value 
Action to be Taken 
 ULN to 160 mg/dL 
(8.9 mmol/L) 
 
Encourage patients to adopt a diabetic diet 
 
Consider consultation with endocrinologist or diabetologist 
 
Provide home glucose monitoring to high risk patients and educate to check 
fasting glucose at home a 
 
Consider oral anti-diabetic medications (e.g., metformin) for high risk patients a 
 
Recheck in 3 days and adjust medications as needed b 
 
Continue current dose level of inavolisib (GDC-0077) 
 160 to 250 mg/dL 
( 8.913.9 mmol/L)  
 
Interrupt inavolisib (GDC-0077) dose until hyperglycemia resolves to 
 160 mg/dL or 8.9 mmol/L f 
 
Start or increase dose for an oral anti-diabetic medication (e.g., metformin, 
SGLT2 inhibitor) c 
 
Recheck in 3 days and adjust or add anti-diabetic medications as needed b 
 
Encourage patients to adopt a diabetic diet 
 
Consider consultation with endocrinologist or diabetologist 
 
Initiate fasting home glucose monitoring 
 
Resume current dose level of inavolisib (GDC-0077) when hyperglycemia 
resolves to  160 mg/dL or 8.9 mmol/L  
 
If fasting blood glucose persists  200250 mg/dL or  13.927.8 mmol/L for 
7 days despite above interventions, discuss with Medical Monitor f 
 250 to 500 mg/dL 
( 13.927.8 
mmol/L) 
 
Interrupt inavolisib (GDC-0077)  
 
Manage hyperglycemia as per standard of care c,d 
 
Start or increase dose for an oral anti-diabetic medication (e.g., metformin, 
SGLT2 inhibitor) c 
 
Recheck in 3 days and adjust or add anti-diabetic medications as needed b 
 
Encourage patients to adopt a diabetic diet 
 
Consider consultation with endocrinologist or diabetologist 
 
Initiate fasting home glucose monitoring 
 
If hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L within 7 days, may 
resume at current dose level of inavolisib (GDC-0077) 
 
If hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L in  8 days, reduce 
inavolisib (GDC-0077) dose by one dose level when treatment resumes e 
 
If hyperglycemia  250500 mg/dL or  13.927.8 mmol/L recurs within 30 
days, reduce inavolisib (GDC-0077) dose by one dose level e 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive Tumors 
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Table 2 
Management of Hyperglycemia (cont.)  
Fasting 
Glucose 
Values 
Action to be Taken 
 500 mg/dL  
( 27.8 
mmol/L) 
 
Interrupt inavolisib (GDC-0077)  
 
Manage hyperglycemia as per standard of care c,d 
 
Assess for volume depletion and ketosis and administer appropriate intravenous or 
oral hydration 
 
Start or increase the dose for an oral anti-diabetic medication (e.g., metformin, 
SGLT2 inhibitor) c 
 
Recheck in 3 days and adjust or add anti-diabetic medications as needed b 
 
Encourage patients to adopt a diabetic diet 
 
Consider consultation with endocrinologist or diabetologist 
 
Initiate fasting home glucose monitoring  
 
When hyperglycemia resolves to  160 mg/dL or 8.9 mmol/L, reduce inavolisib (GDC-
0077) dose by one dose level when treatment resumes e 
 
If hyperglycemia  500 mg/dL or  27.8 mmol/L recurs within 30 days, permanently 
discontinue inavolisib (GDC-0077) 
BMI  body mass index; SGLT2  sodium-glucose transport protein 2; ULN  upper limit of normal. 
a High-risk factors for diabetes include pre-diabetes, overweight, obese, BMI  30 kg/m2, hemoglobin A1C 
 5.7%, over 45 years of age, family history of diabetes, certain ethnicities, inactive lifestyle, and history 
of gestational diabetes 
b Fasting glucose should be checked by finger stick or lab value (if patient has scheduled appointment) 
PRIOR to dosing.  Oral anti-diabetic medications should be titrated to the maximum allowed dosages 
to achieve control of blood glucose to  160 mg/dL or 8.9 mmol/L.  For example, metformin may be 
administered to a maximum dose allowed as per local prescribing information, given in divided doses, 
as tolerated.  Please see local prescribing information of individual oral anti-diabetic agent for dosing 
guidelines 
c There is a risk of hypoglycemia if insulin or sulfonylureas are used, particularly if these agents are 
started during periods of inavolisib (GDC-0077) exposure and doses are not adjusted appropriately 
during periods of treatment interruption, during which patients’ insulin sensitivity may increase rapidly.  
Short term insulin is allowed to control blood glucose levels, but goal should be to maintain on oral 
agents once acute episode resolves. 
d It is recommended that the patient is re-assessed within 24 hours and preferably the same day for 
assessments of hydration status and renal function. 
e A maximum of two dose reductions will be allowed.  
f If, in the investigator’s opinion, the benefit-risk assessment favors continued inavolisib (GDC-0077) 
dosing without interruption, inavolisib (GDC-0077) may be continued without interruption upon 
discussion with Medical Monitor once patients are managed on anti-diabetic agent(s) and fasting 
glucose  200 mg/dL or  11.1 mmol/L.  It is recommended that patients be instructed to utilize a 
glucometer to monitor fasting glucose and to call the clinic if fasting glucose  200 mg/dL or  11.1 
mmol/L prior to inavolisib (GDC-0077) dosing at home 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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MyTACTIC Study—Genentech, Inc. 
202/Protocol ML42439, Version 5 
The anti-hyperglycemic agent metformin should be used first-line for the management of 
sustained Grade 2 and Grade 3 hyperglycemia.  Investigators should exercise caution in 
the dosing and management of patients receiving metformin in combination with 
inavolisib (GDC-0077) and must be vigilant for signs of renal impairment and metformin 
toxicity.  In the event metformin is not tolerated or not sufficient, another 
anti-hyperglycemic medication(s) may be added to or used in place of metformin.  
Preferred agents include sodium-glucose transport protein 2 (SGLT2) inhibitors, 
pioglitazone, and dipeptidyl peptidase 4 (DPP4) inhibitors, where available and 
considered appropriate by investigators.  
Patients at risk for developing hyperglycemia, such as obese and pre-diabetic patients, 
may initiate treatment with metformin on Day 1 of the study at the treating investigator’s 
discretion. 
B.5.2.2.2 
Diarrhea 
Guidelines for management of diarrhea are summarized in Table 3. 
Table 3 
Management of Diarrhea 
Diarrhea 
Action to Be Taken 
Grade 1 
 
Adequate treatment with anti-diarrheals a and maximum supportive care b  
Grade 2 
 
Adequate treatment with anti-diarrheals and maximum supportive care  
 
Close monitoring 
 
Interrupt inavolisib (GDC-0077) until recovery to Grade  1, then may resume 
at the same dose 
 
If recurs within 30 days, reduce inavolisib (GDC-0077) by one dose level 
Grade 3  
 
Interrupt inavolisib (GDC-0077) until recovery to Grade  1, then reduce by 
one dose level.  Manage as per Grade 2 diarrhea guidelines. 
 
If recurs within 30 days after initiation of the first dose reduction, reduce 
inavolisib (GDC-0077) by one dose level.  If recurs within 30 days from the 
second dose reduction, permanently discontinue inavolisib (GDC-0077).  
Grade 4 
 
Permanently discontinue inavolisib (GDC-0077) 
a Initiate loperamide (Imodium®) dose with 4 mg, then 2 mg every loose stool up to 16 mg/day.  
May consider using combination of loperamide and Lomotil® (diphenoxylate and atropine).  
May initiate second-line therapy (e.g., octreotide) if Grade  2 diarrhea persists after 48 hours 
of treatment with loperamide and/or Lomotil®. 
b Supportive care:  initiate appropriate dietary modification, hydration therapy and electrolyte 
supplements when clinically indicated.  Dietary modification:  stop all lactose-containing 
products and eat small meals; encourage adequate hydration with salt-containing liquids such 
as broth or Gatorade®. 
 
 


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B.5.2.2.3 
Inflammatory Colitis 
Guidelines for management of diarrhea are summarized in Table 4. 
Table 4 
Management of Inflammatory Colitis 
Colitis 
Action to Be Taken 
Grade 1 
 
Close monitoring and treat as appropriate 
Grade 2 
 
If colitis-related symptoms do not improve to Grade  1 after 48 hours of 
anti-diarrheals, start treatment with oral corticosteroid a 
 
Interrupt inavolisib (GDC-0077) until recovery to Grade  1, then may 
resume at the same dose or one dose level lower per investigator evaluation 
 
If recurs within 30 days, reduce inavolisib (GDC-0077) by one dose level  
Grade  3  
 
Treat with high dose corticosteroids (IV solumedrol or PO prednisone) b 
 
Consider colonoscopy 
 
Interrupt inavolisib (GDC-0077) until recovery to Grade  1, then reduce by 
one dose level  
 
If Grade 3 recurs, permanently discontin inavolisib (GDC-0077)  
 
If Grade 4, permanently discontinue inavolisib (GDC-0077) 
IV  intravenous; PO  by mouth; QD  once daily. 
a 2040 mg prednisone PO QD (starting dose).   
b For severe grades, may also consider IV solumedrol 16  20 mg every 8 hours, or prednisone 
60  80 mg PO QD equivalent to start. 
 
B.5.2.2.4 
Stomatitis/Oral Mucositis 
Guidelines for management of stomatitis/oral mucositis are summarized in Table 5. 
For any grade stomatitis/mucosal inflammation, aggressive mouth care that includes 
mouthwash formulations (e.g., combinations of corticosteroid, local anesthetic, 
antihistamine, antacid, antifungal and/or antibiotics) may be implemented to help 
manage symptoms.  Diet should be modified (e.g., avoidance of spicy foods) and harsh 
mouth washes (e.g., Listerine) should be avoided. 
A compounded alcohol-free mouthwash of dexamethasone (0.5 mg in 5 mL) is 
recommended for prophylaxis or treatment of stomatitis/mucositis.  As per the SWISH 
study (Rugo et al. 2017), patients may use 4 times daily for 8 weeks (10 mL swished for 
2 minutes and spat) started concurrently with study treatment, and/or used reactively 
with the first appearance of symptoms.  No food or drink should be consumed for at least 
1 hour after swishing and spitting the dexamethasone mouthwash.  Additional 
mouthwash formulations (e.g., combinations of local anesthetic, antihistamine, 
corticosteroid, antacid, antifungal and/or antibiotics) or topical corticosteroids 
(e.g., triamcinolone acetonide 0.050.5%, fluocinolone acetonide 0.0250.05%, 
clobetasol propionate 0.025%) may be implemented.  Patients should avoid alcohol-, 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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hydrogen peroxide-, iodine-, or thyme-containing products as they may exacerbate the 
condition.  Died should be modified (e.g., avoidance of spicy foods), and harsh mouth 
washes (e.g., Listerine®) should be avoided. 
Table 5 
Management of Stomatitis/Oral Mucositis 
Stomatitis/ 
Mucosal Inflammation 
Action to Be Taken 
Grade 1 
 
Monitor symptoms and initiate management (see above).  
Re-evaluate within 48  72 hours 
Grade 2 
 
Interrupt inavolisib (GDC-0077) and manage until Grade  1 
 
When stomatitis/oral mucositis improves to Grade  1, resume 
dosing at the same dose  
 
For recurrent Grade 2 stomatitis or oral mucositis within 30 days, 
resume dosing at one dose level lower  
Grade   3  
 
Interrupt inavolisib (GDC-0077) and manage until Grade  1 
 
When stomatitis/oral mucositis improves to Grade  1, resume 
dosing at one dose level lower  
 
If Grade 4, permanently discontinue inavolisib (GDC-0077) 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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205/Protocol ML42439, Version 5 
B.5.2.2.5 
Rash 
Guidelines for management of rash are summarized in Table 6. 
Table 6 
Management of Rash 
Rash 
Action to Be Taken 
Grade 1 
 
Continue inavolisib (GDC-0077) dosing and monitor for changes in severity 
 
Consider prescribing topical corticosteroids a and/or antihistamines 
Grade 2 
 
Interrupt inavolisib (GDC-0077) treatment  
 
Treat rash per standard of care, including topical and/or oral corticosteroids, b 
and/or antihistamines 
 
When rash resolves to Grade  1, resume inavolisib (GDC-0077) at the same 
dose or one dose level lower per investigator evaluation  
 
If Grade 2 rash recurs within 30 days, reduce inavolisib (GDC-0077) by one 
dose level when treatment resumes  
Grade  3  
 
Interrupt inavolisib (GDC-0077) treatment   
 
Treat rash with topical and/or systemic corticosteroids (oral or IV) and 
antihistamines 
 
If rash resolves to Grade  1  within 28 days of interruption, reduce inavolisib 
(GDC-0077) by one dose level when treatment resumes  
 
If rash does not resolve to Grade  1 within 28 days or interruption, 
discontinue inavolisib (GDC-0077) 
 
Consider dermatologist consultation and skin biopsy  
IV  intravenous. 
a Suggested topical steroids include hydrocortisone 2.5% to face 2   daily, triamcinolone 0.1% or 
fluocinonide 0.1% cream to body 2   daily. 
b Suggested oral steroids include methylprednisolone dose pack or prednisone 60 mg daily 
followed by taper (e.g., 60 mg  2 days, 40 mg  2 days, 20 mg  2 days, etc.).   
 
Patients with severe rash should also be monitored for associated signs and symptoms 
such as fever and hypotension that may be suggestive of a systemic hypersensitivity 
reaction.  Permanently discontinue patients for any rash with concurrent signs/symptoms 
strongly suggestive of a severe Type I hypersensitivity or anaphylactic/anaphylactoid 
reaction or with painful desquamation or mucosal involvement suggestive of 
Stevens-Johnson syndrome/toxic epidermal necrolysis or with other life-threatening 
complications.  Dermatological consultation is recommended. 
B.5.2.2.6 
Pneumonitis 
Guidelines for management of pneumonitis are summarized in Table 7. 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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Table 7 
Management of Pneumonitis 
Grade 
Intervention 
Investigation 
Inavolisib (GDC-0077)  
Dose Modification and 
Management 
Grade 1  
No specific therapy 
required  
Chest CT scan.  
Repeat CT at least every 
8 weeks until return to 
baseline.  
Consider pulmonologist/ 
respirologist consult.  
Advise patient to promptly 
report new or worsening 
respiratory symptoms.  
No action  
Grade 2  
Prescribe 
corticosteroids if 
cough is 
troublesome and 
infectious etiology is 
ruled out.  
Taper as clinically 
indicated 
Chest CT scan.  
Repeat CT at least every 
8 weeks until return to 
baseline.   
Consider PFTs.  
Obtain pulmonologist/ 
respirologist consult.  
Hold inavolisib (GDC-0077) as 
long as corticosteroids are being 
given.  When pneumonitis 
improves to Grade  1 and upon 
completion of any corticosteroid 
treatment, resume inavolisib 
(GDC-0077) dosing at the same 
inavolisib (GDC-0077) dose or 
one dose level lower per 
investigator evaluation.  For 
recurrent Grade 2 event, resume 
inavolisib (GDC-0077) dosing at 
one dose level lower. 
Grade 3  
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out.  
Taper as clinically 
indicated 
Chest CT scan.   
Repeat CT at least every 
8 weeks until return to 
baseline.   
Consider PFTs and 
bronchoscopy.  
Obtain pulmonologist/ 
respirologist consult.  
Hold inavolisib (GDC-0077) as 
long as corticosteroids are being 
given.  When pneumonitis 
improves to Grade  1 and upon 
completion of any corticosteroids, 
resume inavolisib (GDC-0077) 
dosing at one dose level lower.   
Grade 4  
Prescribe 
corticosteroids if 
infectious etiology is 
ruled out. 
Taper as clinically 
indicated 
Chest CT scan.   
Repeat CT at least every 
8 weeks until return to 
baseline.   
Consider PFTs. 
Obtain pulmonologist/ 
respirologist consult.  
Bronchoscopy is 
recommended. 
Permanently discontinue 
inavolisib (GDC-0077).   
CT  computed tomography (scan); PFT  pulmonary function tests. 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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B.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients receiving inavolisib (GDC-0077): 
 
Grade  3 hyperglycemia  
 
Grade  3 stomatitis or mucosal inflammation 
 
Grade  3 rash  
 
Grade  3 diarrhea 
 
Grade  2 pneumonitis 
 
Grade  2 colitis or enterocolitis  
 
Grade  3 ALT or AST elevation   
 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive Tumors 
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B.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 28 to 1 a 
(3) 
 (3) 
≤ 28 days after 
last study dose 
Informed consent d 
x 
 
 
 
Documentation of positive PIK3CA 
activating mutation status by local test e 
x 
 
 
 
Medical history and baseline conditions 
f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
ECOG Performance Status h 
x 
x 
 
x 
Pregnancy test i 
x 
x 
 
x 
Chemistry j  
x 
x 
 
x c 
Hematology/CBC with differential k 
x 
x 
 
x c 
Coagulation panel l 
x 
x 
 
x 
Fasting lipid panel, amylase, lipase m 
x 
x 
 
x 
Fasting HbA1C n 
x 
 
 
 
Fasting blood glucose o 
x 
x 
see footnote o 
 
Ophthalmologic examination p 
x 
C6, D1 and as clinically indicated 
x 
12-lead ECG y 
x 
As clinically indicated 
 
Response assessment q, r 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) s 
 
Submit within 21 days of C1, D1 
 
 
Whole blood samples t 
x 
 
see footnote t 
 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive Tumors 
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Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 28 to 1 a 
(3) 
 (3) 
≤ 28 days after 
last study dose 
Study drug compliance assessment u  
 
x 
 
x 
Study drug dispensing 
 
x 
 
 
Post-treatment hyperglycemia follow-up 
v 
 
As clinically indicated 
Adverse events w 
x q 
Collected on an ongoing basis 
x w 
Concomitant medications x 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic Case Report Form; 
FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; MRImagnetic resonance imaging; PDprogressive disease; 
RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious adverse 
event. 
Note: Cycle28 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if 
the hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1, with the 
exception of glucose.  Scans to document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to 
initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may 
take place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to collect AE data and 
any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive Tumors 
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e Confirmation of positive PIK3CA activating mutation status should occur prior to performing other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) 
used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any 
abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-
directed physical examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient 
notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients 
who have a positive pregnancy test must not receive study drug.     
j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  With the exception of fasting blood glucose, results that are obtained within 7 days of Cycle 1, Day 1 do not have to 
be repeated on Cycle 1 Day 1; fasting blood glucose must be assessed within 24 hours of Cycle 1, Day 1.  Subsequent chemistry evaluations 
should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
k Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.   
l Coagulation includes aPTT and INR. 
m Fasting lipid panel (total cholesterol, triglycerides, LDL, HDL) and amylase and lipase.  Patients must have been fasting 8 hours prior to blood 
draw.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  
n Repeat HbA1c should be performed after 3 months if the last value was more than 7.5% or as clinically indicated. 


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o Fasting ( 8-hour fast) glucose sample.  For the first cycle, glucose should be measured in-clinic on C1D1 and daily by home glucometer after 
overnight fasting, with weekly phone visits with site staff to review results and assess any potential signs or symptoms of hyperglycemia.  For 
Cycle 2, fasting glucose should be measured twice weekly at home.  Patients should notify their physician if any abnormal values are 
measured.  Additionally, fasting plasma glucose should be checked in-clinic (or at an offsite lab if in-clinic is not feasible) for Day 1 of each 
subsequent cycle, as well as Day 15 of cycles 1 and 2 and recorded in the CRF.  If an offsite lab is used to assess glucose, a phone visit 
should be conducted to review results and assess any potential signs or symptoms of hyperglycemia.  For Cycle 1 and Cycle 2, samples should 
be drawn within 24 hours; for all other subsequent cycles, samples should be drawn within 48 hours prior to study drug administration at the 
clinic; glucose results must be available and reviewed prior to dosing.  In addition, patients may be instructed to monitor fasting glucose more 
frequently via use of home glucometer. 
p Ophthalmologic examinations including at least visual acuity and slit-lamp tests (which may be performed by an optometrist) will be required at 
screening, at Cycle 6, at the end of treatment, and as clinically indicated.  Note: The time window for ophthalmologic examinations is 1 week. 
q All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
r At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
s For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing. If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
t Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.  
u Study drug compliance will be reviewed with the patient.  
v Patients on anti-hyperglycemic agents for the treatment of hyperglycemia during the study treatment and those patients with events of 
hyperglycemia ongoing at the end of the 28-day safety follow-up, will undergo additional safety follow-up assessments monthly until resolution 
of their fasting glucose to baseline levels, complete down-titration of their anti-hyperglycemic medications, or up to approximately 3 months 
after the final dose of study treatment, even if the patient initiates another anti-cancer therapy. 


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w After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all 
deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
x Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study drug. 
y A single 12-lead ECG should be performed as specified, and additionally if clinically indicated during the study treatment period.  Patients 
should be resting in a supine position for at least 10 minutes prior to ECG recording. 
 
 


Arm B:  Inavolisib (GDC-0077) in Patients with PI3K (PIK3CA) Activating MutationPositive 
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B.7 
REFERENCES 
Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in 
women with hormone receptor-positive, HER2-negative metastatic breast cancer 
using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol 
2017;18:65462 


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Appendix 12  
Arm C:  Alectinib in Patients with ALK Gene Fusion-Positive 
Tumors 
13.
ARM C:  ALECTINIB IN PATIENTS WITH ALK GENE FUSION-
POSITIVE TUMORS
TABLE OF CONTENTS 
C.4
Materials and Methods ................................................... 215 
C.4.1
Patients .......................................................................... 215 
C.4.1.1
Additional Inclusion Criteria ........................................... 215 
C.4.1.2
Additional Exclusion Criteria .......................................... 215 
C.4.2
Study Treatment ............................................................ 216 
C.4.2.1
Formulation and Packaging ........................................... 216 
C.4.2.2
Dosage, Administration, and Compliance ...................... 216 
C.4.3
Concomitant Therapy ..................................................... 217 
C.4.3.1
Permitted Therapy ......................................................... 217 
C.4.3.2
Prohibited Therapy......................................................... 218 
C.4.4
Arm-specific Assessments ............................................. 218 
C.5
Safety Plan .................................................................... 220 
C.5.1
Risks Associated with Alectinib ...................................... 220 
C.5.2
Management of Patients Who Experience Adverse 
Events with Alectinib ...................................................... 220 
C.5.2.1
Dose Modifications and Interruptions ............................. 220 
C.5.2.2
Guidelines for Management of Specific Adverse Events221 
C.5.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ............................................ 226 
C.6
Schedule of Activities ..................................................... 227 


Arm C:  Alectinib in Patients with ALK Gene Fusion-Positive Tumors 
 
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215/Protocol ML42439, Version 5 
 
C.4 
MATERIALS AND METHODS 
C.4.1 
Patients 
To be enrolled in Arm C: alectinib treatment, patients must have met and continue to meet 
all general eligibility criteria (see Section 4.1), in addition to the arm-specific criteria below. 
C.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm C: alectinib 
treatment: 
 
ALK gene fusion positivity, in indications other than NSCLC, as determined by a 
Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified 
next generation sequencing (NGS) assay (tissue or blood) 
Gene fusion positivity is defined as a 3’ ALK fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain.  
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure 
rate of  1% per year during the treatment period and for at least 90 days after the last 
dose of alectinib; and agreement to refrain from donating eggs during this same 
period.  See Appendix 2 for detailed contraception requirements. 
 
For males with female partners of childbearing potential:  Agreement to remain 
abstinent (refrain from heterosexual intercourse) or use a condom plus an additional 
contraception method that together result in a failure rate of  1% per year during the 
treatment period and for at least 90 days after the last dose of alectinib, and 
agreement to refrain from donating sperm during this same period.  See Appendix 2 
for detailed contraception requirements. 
 
C.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm C: alectinib treatment: 
 
ALK-positive non-small cell lung cancer (NSCLC) 
 
Inability to swallow pills 
 
Any gastrointestinal disorder that may affect absorption of oral medications, such as 
refractory vomiting, malabsorption syndrome, external biliary shunt, or significant 
bowel resection that would preclude absorption of alectinib 
 
Detection of the following ALK point mutations:  I1171N/S, G1202R 
 
Symptomatic or uncontrolled CNS involvement 


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– 
Patients with CNS involvement, including leptomeningeal carcinomatosis or prior 
brain metastases, which are either asymptomatic or previously treated and 
controlled, are allowed.   
– 
Patients requiring corticosteroids must be at stable or decreasing doses for at 
least 2 weeks prior to the start of alectinib treatment. 
 
Liver disease, characterized by any of the following: 
– 
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal 
varices 
– 
Active autoimmune, alcoholic, or other types of acute hepatitis 
 
History of organ transplant 
 
Symptomatic bradycardia 
 
History of hypersensitivity to any of the additives in the alectinib drug formulation 
This includes, but is not limited to, patients with galactose intolerance, a 
congenital lactase deficiency, or glucose-galactose malabsorption. 
 
C.4.2 
Study Treatment 
Study treatment in this arm will consist of alectinib. 
C.4.2.1 
Formulation and Packaging 
Alectinib will be supplied by the Sponsor as 150-mg capsule.  Each capsule contains 
150 mg of alectinib hydrochloride (as free base), lactose monohydrate, 
hydroxypropylcellulose, sodium lauryl sulfate (SLS), magnesium stearate and 
carboxymethylcellulose calcium, encapsulated in a capsule shell consisting of 
hypromellose, carrageenan, potassium chloride, titanium dioxide, and carnauba wax.  
The formulation contains SLS as a surfactant excipient.  This excipient is known to be 
associated potentially with gastrointestinal (GI) adverse events such as nausea, vomiting, 
diarrhea, and abdominal pain. 
For information on the packaging, handling and storage, see the Pharmacy Manual and 
Alectinib Investigator's Brochure. 
C.4.2.2 
Dosage, Administration, and Compliance 
Study treatment will be administered in 28 day cycles. 
Alectinib will be self-administered by patients orally at home (except on clinic days), at the 
same times each day, on a starting dose of 600 mg (four 150-mg capsules) twice a day 
(BID) until disease progression, intolerable toxicity, or consent withdrawal.  For more 
specific dosing instructions, refer to the pharmacy manual. 


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The capsules should not be opened and the contents of the capsules should not be 
dissolved.  Alectinib should be taken with food.  
For alectinib doses to be administered at home, a sufficient number of capsules should be 
dispensed to the patient to last until the next visit, or at the investigator’s discretion, 
through one cycle.  Patients will be asked to record in a medication diary the time and date 
for each dose taken. 
A missed dose can be taken within 6 hours of the scheduled time.  If the missed dose time 
is greater than 6 hours, or if the patient vomits the dose, the patient should wait until the 
next scheduled time and take the next scheduled dose.  Patients should not take two 
doses at the same time to make up for a missed dose.  
Guidelines for alectinib dosage modification and treatment interruption or discontinuation 
are provided in Section C.5.2.1.  
See Section 4.3.2 for details on assessment of compliance for self-administered oral study 
drugs. 
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug. 
C.4.3 
Concomitant Therapy 
C.4.3.1 
Permitted Therapy 
The medications and/or treatments below are permitted: 
 
Local therapy (e.g., stereotactic radiotherapy or surgery) may be given in patients with 
isolated asymptomatic CNS progression (e.g., new CNS oligometastases) after 
discussion with the Sponsor.  
 
Caution should be exercised when the following medications are co-administered with 
alectinib: 
 
For medications that are substrates of P-gp transporter or breast cancer resistance 
protein transporter, the investigator should carefully assess the risks against the 
benefits when considering concomitant use of alectinib.  Alectinib has been shown to 
have potential for inhibition of these transporters.  Substrates with a narrow 
therapeutic index (e.g., methotrexate, digoxin) should be avoided.  If co-administration 


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cannot be avoided, it is recommended that drug levels and/or signs for toxicity are 
carefully monitored.  
 
C.4.3.2 
Prohibited Therapy 
Use of the following therapies (e.g. prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of alectinib treatment, unless otherwise specified below.  
Exceptions to restrictions of the concomitant therapies listed below may be made if the 
rationale is discussed and documented between the investigator and the Sponsor’s 
Clinical Pharmacologist. 
 
Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents (other 
than study drug treatment), ergot derivatives, probenecid, and bile acid-binding resins 
while on study treatment  
Note: The use of systemic corticosteroids for the management of CNS 
metastases may be permitted upon discussion with the Sponsor.  
 
Systemic chemotherapy 
 
Radiotherapy/radionuclide therapy except for palliative radiotherapy to bone lesions or 
for pain control  
If palliative radiation is indicated, palliative radiation may start within 24 hours of 
the last dose of alectinib, unless, in the judgment of the investigator, patient 
safety will require a longer washout period prior to palliative therapy.  Dosing of 
alectinib may resume with the resolution of any radiation toxicity to Grade 1 or 
better.  
 
Additional investigational drug (except during the follow-up period) 
The list of medications provided above is not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication as 
well as the Internet reference provided below when determining whether a certain 
medication may interact with alectinib.  In addition, the investigator should contact the 
Sponsor if questions arise regarding medications not listed above.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/UCM292362.pdf 
C.4.4 
Arm-specific Assessments 
Arm-specific assessments for patients receiving alectinib are displayed in the Schedule of 
Activities (see Section C.6). 
Local Laboratory Assessments 
 
Chemistry: blood creatine phosphokinase (CPK)  
 
Liver Function: ALT, AST, total bilirubin, direct bilirubin 


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Vital Signs 
Vital signs will include measurements of pulse rate, systolic and diastolic blood pressure 
while the patient is in a seated position, and temperature.  
Electrocardiograms (ECGs) 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedules of activities (see Section C.6), and may be obtained at unscheduled timepoints 
as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  Lead 
placement should be as consistent as possible.  ECG recordings must be performed after 
the patient has been resting in a supine or semi-supine position for at least 5 minutes.  
The same recording position (supine or semi-supine) should be used for each patient 
throughout the study.  All ECGs are to be obtained prior to other procedures scheduled at 
that same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at the site.  In the event that the ECG 
machine does not directly provide results for RR and/or QTcF, these parameters can be 
derived using the following formulae: 
 
QTcFFridericia’s correction for QTc measurement (if not provided directly by the ECG 
machine): 
𝑄𝑇𝑐𝐹 (𝑚𝑠) = 
𝑄𝑇 (𝑚𝑠)
√𝑅𝑅 (𝑚𝑠)/1000
3
 
 
RR Interval Formula (if not provided directly by the ECG machine): 
 
RR (ms) = 60000/heart rate (bpm) 
Any morphologic waveform changes or other ECG abnormalities must be documented on 
the eCRF.  If considered appropriate by the Sponsor, ECGs may be analyzed 
retrospectively at a central laboratory. 
If at a particular postdose timepoint the mean QTcF is  500 ms and/or  60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 5 minutes, 
and ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  
Standard-of-care treatment may be instituted per the discretion of the investigator.  The 


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investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia). 
C.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety in 
this study.  Following are further instructions specific to Arm C: alectinib treatment. 
C.5.1 
Risks Associated with Alectinib 
Alectinib has been associated with risks such as the following:  interstitial lung disease 
including pneumonitis, hepatotoxicity, anemia including hemolytic anemia, gastrointestinal 
disorders (nausea, vomiting, constipation, diarrhea, stomatitis), photosensitivity, skin rash, 
vision disorders (including blurred vision, visual impairment, vitreous floaters, reduced 
visual acuity, asthenopia and diplopia), edema, bradycardia, abnormal renal function 
(elevated serum creatinine, acute kidney injury), severe myalgia and blood CPK increase, 
dysgeusia, increased alkaline phosphatase, and weight increase.  Refer to the Alectinib 
Investigator's Brochure for a detailed description of anticipated safety risks for alectinib. 
C.5.2 
Management of Patients Who Experience Adverse Events with 
Alectinib 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
C.5.2.1 
Dose Modifications and Interruptions 
The dose of alectinib can be reduced in steps of 150 mg up to 2 times for management of 
drug-related toxicities (i.e., from 600 mg BID to 450 mg BID and then from 450 mg BID to 
300 mg BID) (see Table 1). Dose re-escalation is not permitted for alectinib. 
Table 1 
Alectinib Dose Reductions 
Dose Reduction Schedule 
Dose Level 
Starting dose 
600 mg twice daily 
First dose reduction 
450 mg twice daily 
Second dose reduction 
300 mg twice daily 
 
If further dose reduction is indicated after two dose-reductions, the patient must 
discontinue alectinib.  Administration of a dose below 300 mg BID is not allowed.   


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If alectinib has been withheld for  21 days because of toxicity, the patient should be 
discontinued from alectinib.  Alectinib treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) in consultation with the Medical Monitor.  The 
investigator and the Sponsor will determine the acceptable length of treatment interruption. 
C.5.2.2 
Guidelines for Management of Specific Adverse Events 
Guidelines for management of specific adverse events are provided in the subsections 
below (Table 2). 


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Table 2 
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities Associated with Alectinib 
Event 
Action to Be Taken 
All AEs related a to 
alectinib (unless 
otherwise specified 
in this table) 
 
Hepatotoxicity AEs 
(irrespective of 
relatedness) 
 
Grade 4: 
Temporarily interrupt alectinib for a maximum of 21 days after which the 
drug must be permanently withdrawn.  If improvement to Grade  1 or 
baseline does not occur within 3 weeks, permanently discontinue 
alectinib. 
First episode:  If improvement to Grade  1 or baseline within 21 days, 
decrease the current dose of alectinib by 150 mg (1 capsule) BID. 
Second episode:  If improvement to Grade  1 or baseline within 21 days, 
decrease the current dose of alectinib by another 150 mg (1 capsule) BID. 
Third episode:  Permanently discontinue alectinib. 
Please note that dose should not be reduced below 300 mg BID. 
 
Grade 3: 
Temporarily interrupt alectinib for a maximum of 21 days after which drug 
must be permanently withdrawn. 
First episode:  If improvement to Grade  1 or baseline occurs within 
10 days, alectinib may be restarted at the original dose or dose reduced 
by 150 mg (1 capsule) as per investigator discretion.  If improvement to 
Grade  1 or baseline occurs after 10 days but within 21 days, then 
alectinib dose must be decreased by 150 mg (1 capsule BID). 
Second episode:  If improvement to Grade  1 or baseline occurs within 
21 days, decrease the current dose of alectinib by 150 mg (1 capsule) 
BID. 
Third episode: Permanently discontinue alectinib. 
 
Grade 2: 
To be managed at the investigator’s discretion.  Please note that alectinib 
cannot be interrupted for more than 21 days and cannot be dose reduced 
below 300 mg BID. 
 
Grade 1:  No action required 
Interstitial lung 
disease/pneumonitis 
 
Patients should be monitored for pulmonary symptoms indicative of 
interstitial lung disease/pneumonitis. 
Regardless of relatedness to alectinib, study drug should be 
permanently discontinued in patients diagnosed with interstitial lung 
disease/pneumonitis of any grade. 
Hepatotoxicity 
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.5 and Section 5.3.5.7  
At any time during the study treatment, if symptoms compatible with liver 
injury are observed, liver enzymes should be measured as soon as 
possible. 


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Table 2 
Guidelines for Management of Risks, Adverse Events, and Selected 
Laboratory Abnormalities Associated with Alectinib (cont.) 
 
Event 
Action to Be Taken 
Hepatotoxicity (cont.) Regardless of relatedness to alectinib, the grade-dependent rules for dose 
interruptions and dose modification outlined in the first section of this table 
must be followed. 
In addition, study drug treatment has to be permanently discontinued if 
any of the following occurs: 
 
First observation of ALT or AST  8  ULN 
 
ALT or AST  5  ULN for more than 2 weeks 
 
First observation of ALT or AST  3  ULN and total bilirubin  2  ULN 
 
First observation of ALT or AST  3  ULN and the appearance of 
jaundice or signs of hepatic dysfunction or other symptoms (such as 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, or eosinophilia [ 5%]). 
 
Following study drug discontinuation, weekly monitoring of laboratory 
values should continue until the abnormal values have normalized to 
pretreatment levels and/or an adequate explanation of the abnormal 
value is found. 
 
Resumption of study drug is not allowed in patients discontinuing 
because of any of the above criteria. 
Gastrointestinal tract 
AEs (e.g., nausea, 
vomiting, diarrhea, 
stomatitis)  
The events are expected to be minimized by taking the study drug with a 
meal.  If GI events occur, appropriate measures should be taken in 
accordance with local clinical practice guidelines.  
In case of AEs related to alectinib, follow the grade-dependent rules for 
dose interruption and modification outlined in the first section of this table. 
Skin disorder AEs 
(e.g., phototoxicity, 
rash) 
Patients should be advised to avoid prolonged sun exposure while taking 
alectinib and for at least 7 days after study drug discontinuation.  Patients 
should also be advised to use a broad-spectrum sunscreen and lip balm 
of at least SPF 50 to help protect against potential sunburn during this 
period.  
In case of AEs related to alectinib, follow the grade-dependent rules for 
dose interruption and modification outlined in the first section of this table. 
Vision disorders 
Investigators should consider referring the patients for an ophthalmologic 
evaluation according to local clinical practice guidelines if vision disorders 
persist or worsen in severity and to advise patients to exercise caution 
when driving or operating machinery due to the risk of developing a vision 
disorder.  
In case of AEs related to alectinib, follow the grade-dependent rules for 
dose interruption and modification outlined in the first section of this table. 


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Table 2 
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities Associated with Alectinib 
(cont.) 
 
Event 
Action to Be Taken 
Edema 
Physical examinations will be performed routinely in clinical trials.  In case 
edema events occur, appropriate measures should be taken in 
accordance with local clinical practice guidelines.  
In case of AEs related to alectinib, follow the grade-dependent rules for 
dose interruption and modification outlined in the first section of this table. 
Abnormal renal 
function AEs 
Kidney function laboratory abnormalities are to be reported as AEs if they 
fulfil the criteria listed in Section 5.3.5.5. 
If at any time during the study treatment serum creatinine increases by 
 2 over the baseline visit value, the patient has to be carefully 
monitored.  All underlying factors that may have acutely impacted serum 
creatinine levels need to be evaluated and corrected (e.g., dehydration, 
recent exposure to contrast media, increased amount of cooked meat in 
diet, concomitant medications affecting renal function as appropriate, 
etc.). 
Any serum creatinine value that is increased by  2 over the baseline-
visit value requires repeat testing. 
 
For Grade 1 and Grade 2 AEs related to alectinib, follow the grade-
dependent rules for dose interruption and modification outlines in the 
first section of this table. 
 
For Grade 3 AEs related to alectinib, temporarily interrupt alectinib 
until serum creatinine recovers to Grade 1 or baseline, then resume at 
reduced dose. 
 
For Grade 4 AEs related to alectinib, permanently discontinue study 
drug.  
Severe myalgia and 
CPK elevations  
CPK laboratory abnormalities are to be reported as AEs if they fulfil the 
criteria listed in Section 5.3.5.5. 
Myopathy should be considered in any patient with diffuse myalgia, 
muscle tenderness or weakness, and/or marked elevations of CPK levels.  
Patients should promptly report unexplained muscle pain, tenderness, or 
weakness, particularly if accompanied by malaise or fever.  CPK levels 
should be monitored in patients reporting these symptoms.  
In case of AEs related to alectinib, follow the grade-dependent rules for 
dose interruption and modification outlined in the first section of this table. 
 
 


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Table 2 
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)  
Bradycardia b  
Grade 2 or Grade 3 (symptomatic; may be severe and medically 
significant, medical intervention indicated) 
 
Temporarily withhold for a maximum of 21 days (after which the drug 
must be permanently withdrawn) until recovery to  Grade 1 
(asymptomatic) bradycardia or to a heart rate of  60 bpm.  Evaluate 
concomitant medicinal products known to cause bradycardia, as well 
as anti-hypertensive medicinal products. 
 
If a contributing concomitant medicinal product is identified and 
discontinued, or its dose is adjusted, resume at previous dose upon 
recovery to  Grade 1 (asymptomatic) bradycardia, or to a heart rate of 
 60 bpm. 
 
If no contributing concomitant medicinal product is identified, or if 
contributing concomitant medicinal products are not discontinued or 
dose modified, resume at reduced dose (refer to Section C.5.2.1) upon 
recovery to  Grade 1 (asymptomatic) bradycardia or to a heart rate of 
 60 bpm. 
Grade 4 (life-threatening consequences; urgent intervention indicated) 
 
Permanently discontinue if no contributing concomitant medicinal 
product is identified. 
 
If a contributing concomitant medicinal product is identified and 
discontinued, or its dose is adjusted, resume at reduced dose (refer to 
Section C.5.2.1) upon recovery to  Grade 1 (asymptomatic) 
bradycardia or to a heart rate of  60 bpm within 21 days, with frequent 
monitoring as clinically indicated. 
 
Permanently discontinue in case of recurrence. 
Hemolytic anemia 
 
If hemoglobin concentration is <10 g/dl (Grade ≥2) and hemolytic 
anemia is suspected, withhold alectinib and initiate appropriate 
laboratory testing, in accordance with local clinical practice guidelines. 
If hemolytic anemia is confirmed, resume alectinib at a reduced dose 
(refer to Section  C.5.2.1 upon resolution, with improvement of 
hemoglobin to Grade ≤ 1 or baseline, or permanently discontinue 
alectinib. 
 
In case of anemia of non-hemolytic mechanism assessed as related to 
alectinib, follow the grade-dependent rules for dose interruption and 
modification outlined in the first section of this table. 
AE  adverse event; BID  twice a day; CPK   creatine phosphokinase; GI  gastrointestinal; 
ULN  upper limit of normal. 
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Preexisting pleural effusion will not be considered as an adverse 
event. 
a Please refer to Section 5.3.4 to determine whether event should be assessed as related or 
unrelated. 
b Heart rate less than 60 bpm. 
 


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C.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
There are no additional adverse events of special interest for Arm C other than those 
specified in Section 5.2.3. 


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C.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
Day (Window) 28 to 1 a 
(3) 
(3) 
≤ 28 days 
after last 
study dose 
Informed consent c 
x 
 
 
 
Documentation of positive ALK gene fusion 
status by local test d 
x 
 
 
 
Medical history and baseline conditions e 
x 
 
 
 
Physical Examination f 
x 
As clinically indicated 
Vital Signs g 
x 
x 
 
 
ECOG Performance Statush 
x 
x 
 
x 
Pregnancy test i 
x 
x 
 
x 
Chemistry j 
x 
x 
D15 of first 3 cycles k 
x  
Hematology/CBC with differential l 
x 
x 
 
x  
CPK 
x 
C1, D1 and as clinically indicated 
C1, D15 
 
12-lead ECG m 
x 
As clinically indicated 
Response assessments o, p 
x 
Every 8 ( 1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for central 
testing (if applicable) q 
 
Submit within 21 days of C1, D1 
 
 
Whole blood samples r 
x 
 
See footnote s 
 
Study drug compliance assessment n 
 
x 
 
x 
Study drug dispensing 
 
x 
 
 
Adverse events s 
x  
Collected on an ongoing basis 
x s 
Concomitant Medications t 
x 
Collected on an ongoing basis 


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AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CPK=creatine phosphokinase; CTcomputerized 
tomography; ctDNAcirculating tumor DNA; Dday; ECGelectrocardiogram; ECOG PSEastern Cooperative Oncology Group Performance 
Status; eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; MRImagnetic 
resonance imaging; PDprogressive disease; RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in 
Solid Tumors, Version 1.1; SAEserious adverse event. 
Note: Cycle28 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if 
the hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1.  Scans to 
document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may take 
place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to collect AE data and any 
standard of care laboratory and CT data, if performed.   
c Informed consent must be documented before any study-specific screening procedure is performed. 
d Confirmation positive ALK gene fusion status should occur prior to performing other trial-related eligibility assessments. 
e Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
f A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
g Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who 
have a positive pregnancy test must not receive study drug.  


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j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent 
chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
k On Day 15 of the first 3 cycles, only ALT, AST, total bilirubin, direct bilirubin need to be assessed. 
l  Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.   
m A single 12-lead ECG should be performed as specified, and additionally if clinically indicated during the study treatment period.  Patients 
should be resting in a supine position for at least 10 minutes prior to ECG recording. 
n Study drug compliance will be reviewed with the patient. 
o All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
p At each subsequent tumor assessment, all measurable, and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
q For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing. If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
r Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   
s After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug. 
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all 
deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
t Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study drug. 




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D.4 
MATERIALS AND METHODS 
D.4.1 
Patients 
To be enrolled in Arm D: ipatisertib treatment, patients must have met and continue to 
meet all general eligibility criteria (see Section 4.1), in addition to the arm-specific criteria 
below. 
D.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm D: 
ipatisertib treatment: 
 
AKT1/2/3 mutant positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as 
listed below: 
– 
AKT1:  E17K; L52R; Q79K 
– 
AKT2:  E17K 
– 
AKT3:  E17K; L51R; Q78K 
 
or PTEN protein loss of function or protein loss as determined by a CLIA or 
equivalently certified tissue-based NGS, in situ hybridization (ISH), or 
immunohistochemistry (IHC) assay (See Appendix 1 for details) 
 
ANC  1000/l within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c)  7.5% 
 
Ability to swallow ipatasertib intact, without chewing or crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
28 days after the last dose of ipatasertib; and agreement to refrain from donating 
eggs during this same period.  See detailed contraception requirements in 
Appendix 2. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of  1% per year during the treatment period and for at least 28 days 
after the last dose of ipatasertib, and agreement to refrain from donating sperm 
during this same period.  See detailed contraception requirements in Appendix 2. 
 
D.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm D: ipatasertib treatment: 


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 
Triple negative adenocarcinoma of the breast (TNBC) 
TNBC tumors are defined as HER2 negative, estrogen receptor (ER) negative, and 
progesterone receptor (PgR) negative 
– 
ER or PgR negativity is defined as  1% of tumor cell nuclei immunoreactive to 
the respective hormonal receptor 
– 
HER2 negativity is assessed by IHC and/or in situ hybridization according to 
2018 American Society of Clinical Oncology/College of American Pathologists 
(ASCO/CAP) guidelines (https://www.cap.org/protocols-and-guidelines/cap-
guidelines/current-cap-guidelines/recommendations-for-human-epidermal-
growth-factor-2-testing-in-breast-cancer) 
 
History of malabsorption syndrome or other condition that would interfere with 
enteral absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class 
B or C, current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection 
fraction (LVEF)  50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia's 
formula (QTcF)  480 milliseconds  
 
History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion (including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of  10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants 
for a chronic disease.  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to 
initiation of study treatment are eligible for enrollment.  
 
Grade  2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia  
 
History of or active inflammatory bowel disease (e.g., Crohn's disease and 
ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)  
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, 
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A 
inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to 
initiation of study treatment (see Appendix 7) 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites 


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D.4.2 
Study Treatment 
Study treatment in this arm will consist of ipatasertib. 
D.4.2.1 
Formulation and Packaging 
Ipatasertib will be supplied by the Sponsor as 100-mg and 200-mg tablets.   
The study drug will be periodically tested and monitored for its acceptable shelf life.  Any 
study drug that fails to comply with the manufactured specifications will be promptly 
removed from the clinical trial site and replaced with new supplies by the Sponsor (or 
designee). 
Each bottle will be labeled with the required regulatory agency warning statement, the 
protocol number, the Sponsor’s name, and directions for patient use and storage.  The 
investigator should ensure that the study drug is stored in appropriate conditions in a 
secure location with controlled access. 
For information on the packaging, handling and storage, see the Pharmacy Manual and 
Ipatasertib Investigator's Brochure. 
D.4.2.2 
Dosage, Administration, and Compliance 
Study treatment will be administered in 28 day cycles. 
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at 
the same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) 
once a day (QD) until disease progression, intolerable toxicity or consent withdrawal.  
For more specific dosing instructions, refer to the pharmacy manual. 
The tablets will be swallowed whole (not chewed) with 3 ounces (90 mL) of fluid.  
Ipatasertib is recommended to be taken at least 2 hours after the last meal of the day, 
and patients should refrain from eating overnight.  Patients are required to receive 
prophylaxis (see Section D.5.2.2.1) with loperamide throughout the first cycle and at 
subsequent cycles as clinically indicated.  
For ipatasertib doses to be administered at home, a sufficient number of tablets should 
be dispensed to the patient to last until the next visit, or at the investigator’s discretion, 
through one cycle.  Patients will be asked to record in a medication diary the time and 
date for each dose taken. 
A missed dose can be taken within 8 hours of the scheduled time.  After that, patients 
should take the next dose the following day, without compensating for the missed dose 
(including vomited doses).  


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Guidelines for ipatasertib dosage modification and treatment interruption or 
discontinuation are provided in Section D.5.2.1. 
See Section 4.3.2 for details on assessment of compliance for self-administered oral 
study drugs. 
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug. 
D.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug until 28 days after the last dose of study drug.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
D.4.3.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study:  
 
Oral contraceptives, as allowed per local guidelines 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:  
Palliative radiotherapy is permitted for a preexisting lesion, provided it does not 
interfere with the assessment of tumor target lesions (e.g., the lesion to be 
irradiated must not be a site of measurable disease).  Study treatment should 
be suspended during palliative radiotherapy (see Section D.4.3.3).  Treatment 
with ipatasertib should be temporarily held for at least 7 days before and after 
the procedure (at least 14 days after radiation is recommended).  For a single 
fraction of radiotherapy, this hold may be shorter, if discussed by the 
investigator with the Medical Monitor.  The patient may continue ipatasertib 
treatment after treatment holding has been completed and the patient has 
sufficiently recovered.  
 
Prophylaxis use of loperamide is mandated in the first cycle and as clinically 
indicated in subsequent cycles to prevent diarrhea.  Patients who experience 
diarrhea should be on treatment doses of loperamide per the management 
guidelines provided in Section D.5.2.1; please refer to that section for additional 


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details.  Patients should be educated/reminded to be cognizant of the onset, 
duration, severity, and frequency of symptoms and the medications administered.  
 
Granulocyte colony-stimulating factor treatment is permitted.  The primary 
prophylaxis should be administered per the American Society of Clinical Oncology 
(ASCO), European Organization for Research and Treatment of Cancer (EORTC), 
and European Society for Medical Oncology (ESMO) guidelines; namely, in patients 
who are  60 years of age and/or with comorbidities (Smith et al. 2006; Aapro et al. 
2011) 
 
Bisphosphonate therapy or RANKL inhibitor therapy (e.g., zolendronic acid and 
denosumab) used specifically to prevent skeletal events (e.g., bone metastasis, 
osteoporosis) is allowed.  Both types of agents have potential immunomodulatory 
properties, but may be used as clinically indicated.  
 
Luteinizing hormone-releasing hormone or gonadotropin-releasing hormone 
agonists for ovarian function preservation are allowed.  
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)  
 
Inactivated influenza vaccinations  
 
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and per institutional practice.  For example, patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per institutional practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists; see Appendix 6). 
D.4.3.2 
Cautionary Therapy  
Patients who require radiation or surgery as part of medical treatment in the absence of 
radiographic disease progression must exercise caution, and all study treatment should 
be temporarily held for at least 7 days before and after the procedure (at least 14 days 
after radiation is recommended).  For minor surgeries or single-day radiotherapy, this 


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hold may be shorter, if discussed by the investigator with the Medical Monitor.  After the 
temporary treatment hold is complete, study treatment may be re-initiated when the 
patient has sufficiently recovered.  Systemic corticosteroids are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events (refer to 
Section D.5.2.2.6 and Section D.5.2.2.7 for details).  All study treatment should be 
temporarily held during systemic corticosteroids treatment  
D.4.3.2.1 
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
In vitro data suggest that ipatasertib is metabolized by CYP3A and may be a time-
dependent inhibitor of CYP3A4.  A clinical drug−drug interaction (DDI) study with 
midazolam (a sensitive CYP3A substrate) showed a 2.2-fold increase in midazolam 
exposures in presence of steady-state ipatasertib dosed at 600 mg QD.  Therefore, 
sensitive CYP3A substrates with narrow therapeutic window should be avoided.  Given 
that ipatasertib is primarily metabolized by CYP3A, there is a high potential for 
drug−drug interactions of ipatasertib with any medication that strongly inhibits or induces 
CYP3A.  Data from a clinical study showed that ipatasertib exposures were reduced by 
~50% when co-administered with enzalutamide, a strong CYP3A inducer.  Strong 
CYP3A inhibitors are expected to increase ipatasertib exposures significantly.  
Therefore, strong CYP3A4/5 inhibitors or inducers or CYP3A4/5 substrates with a 
narrow therapeutic index should be avoided or used with caution (see Appendix 7).  
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment 
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients are permitted to take moderate inhibitors of CYP3A4 with caution.  
Patients should be closely monitored.  Refer to the following information for further 
guidance on CYP450−drug interactions and a list of common substrates, inhibitors, and 
inducers:  
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors 
and Inducers (U.S. Food and Drug Administration [FDA]): 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentReso
urces/ DrugInteractionsLabeling/ucm093664.htm  
The above lists of medications are not comprehensive.  The investigator should consult 
the prescribing information when determining whether a concomitant medication can be 
safely administered with study treatment.  In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications not listed above. 


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D.4.3.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug−drug interactions (DDIs) are 
generally unknown.  However, herbal therapies not intended for the treatment of cancer 
may be used during the study at the discretion of the investigator. 
D.4.3.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 21 days prior to initiation of study treatment and during study treatment.  
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy) is prohibited  
 
Chronic use of a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A 
substrates with a narrow therapeutic window that are deemed not permissible by the 
Medical Monitor after enrollment (refer to the guidance in Section D.4.3.2.1) 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, 
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment 
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients should be closely monitored.  Patients who require short-term use of 
moderate CYP3A4 inhibitors may continue study treatment with caution.  
Refer to the following information for further guidance on CYP450drug interactions and 
a list of common substrates, inhibitors, and inducers:  
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers (U.S. Food and Drug Administration [FDA]): 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ 
DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 
 
D.4.3.4 
Prohibited Food 
Use of the following foods is prohibited as described below:  
 
Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit, potent CYP3A4 enzyme 
inhibitors, is prohibited during the study treatment period and for 10 days after the 
last dose of study treatment. 
 
Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, is prohibited for 
up to 14 days prior to and during the study treatment period, and for 10 days after 
the last dose of study treatment. 


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D.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in the Arm D: Ipatasertib treatment.  Refer to the 
schedule of activities (Section D.7) for arm-specific assessment timepoints. 
Local Laboratory Assessments 
 
Coagulation panel:  INR and aPTT 
 
HbA1c, blood glucose (fasting) 
 
Amylase, lipase (fasting) 
 
Lipid panel (fasting):  total cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides 
 
Functional Assessments 
 
LVEF assessment:  echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
 
D.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm D: ipatisertib treatment. 
D.5.1 
Risks Associated with Ipatasertib 
Ipatasertib has been associated with risks such as the following: nausea, vomiting, 
diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, erythema 
multiforme, and rash.  Ipatasertib’s potential risks include hematologic or 
immunosuppressant effects, hyperlipidemia, hepatotoxicity, pneumonitis, colitis, and 
developmental toxicity.  Refer to the Ipatasertib Investigator’s Brochure for a detailed 
description of anticipated safety risks for ipatasertib. 
D.5.2 
Management of Patients Who Experience Adverse Events with 
Ipatasertib 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
D.5.2.1 
Dose Modifications and Interruptions 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided below. 
Dose modifications will be performed as clinically appropriate based on the investigator’s 
medical judgment.  Details in this section can be used as guidance; however, only the 
specific dose levels shown should be used (Table 1).   


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Any dose modification should be noted on the corresponding Study Drug Administration 
eCRF.  Cases of accidental overdose or medication error, along with any associated 
adverse events, should be reported as described in Section 5.3.5.12. 
Patients may hold the ipatasertib for up to 28 consecutive days in order to recover from 
toxicity or an adverse event related to the study drug. 
If the patient does not tolerate the QD dosing of ipatasertib, dosing with food may be 
used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or diarrhea.  
No more than two dose reductions of ipatasertib per patient (i.e., doses below 
200 mg/day of ipatasertib) will be allowed (see Table 1).  Dose re-escalation is not 
permitted for ipatasertib. 
If needed, dose reductions may occur in decrements of 100 mg and no more than two 
dose reductions will be allowed.  Accordingly, the possible daily doses of ipatasertib are 
shown in Table 1. 
If the patient continues to experience specified drug-related adverse events after the 
second reduction, the treatment should be discontinued. 
Table 1 
Ipatasertib Dose Reductions 
Dose Level a 
Ipatasertib Dose 
Starting dose 
400 mg 
First dose reduction 
300 mg 
Second dose reduction 
200 mg 
Third dose reduction 
Not permitted 
 
Ipatasertib treatment may be temporarily interrupted in patients who experience toxicity 
considered to be related to study drug.  If ipatasertib has been withheld for 
28 consecutive days because of treatment-related toxicity, the patient should be 
discontinued from ipatasertib.  Ipatasertib may be suspended for reasons other than 
toxicity (e.g., surgical procedures) in consultation with the Medical Monitor.  If, in the 
judgment of the investigator, the patient is likely to derive clinical benefit from resuming 
study treatment after a hold of  28 consecutive days, study drug may be restarted in 
consultation with the Medical Monitor. 
D.5.2.2 
Guidelines for Management of Specific Adverse Events 
Associated with Ipatasertib 
Guidelines for management of specific adverse events are provided in the subsections 
below. 


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D.5.2.2.1 
Diarrhea 
Specific guidelines for managing diarrhea to improve safety and tolerability are provided 
in Table 2.  In this study, all patients should receive loperamide (2 mg oral twice a day or 
4 mg once a day) as prophylaxis for diarrhea in the first cycle if allowed by local 
guidance.  Investigators are encouraged to continue this dosing for the remainder of the 
study, and the prophylaxis dose may be adjusted as necessary, using their discretion 
based on clinical judgment and per local guidance.  
Treatment modifications for diarrhea (any grade), when it occurs, should be instituted as 
early as possible.  Guidelines for treatment of diarrhea following the prophylactic dose of 
loperamide (where allowed) includes use of loperamide 2 mg every 4 hours or after each 
loose, watery stool, up to the maximum total dose of 16 mg/day or per institutional 
guidelines and standard of care, including, but not limited to, additional therapy with 
Lomotil (diphenoxylate and atropine), codeine, or octreotide.  Duration of diarrhea may 
be minimized by taking ipatasertib with food, avoiding lactose-containing foods, and 
hydrating with 810 glasses per day (~12 oz/glass) of electrolyte-containing clear liquid, 
such as broth or low-calorie drinks.   
For diarrhea that persists for more than 5 days, despite treatment with anti-diarrheal 
agent(s) and/or withholding dosing of ipatasertib, gastroenterologists should be 
consulted to rule out the risk of colitis and infection (e.g., obtaining computed 
tomography (CT) images or a stool culture for infectious workup [Clostridium difficile, 
enteric bacteria, cytomegalovirus]).  Patients should be educated on the symptoms and 
importance of early reporting of diarrhea to receive instructions of treatment and 
prevention of dehydration so that patients can be promptly and appropriately managed.  
Educational materials will be provided to investigators and patients outlining these 
guidelines.  
Dose reductions of ipatasertib will be by one level at a time (e.g., 400 to 300 mg; 300 to 
200 mg) as outlined in Section D.5.2.1 and Table 1.  If Grade  2 diarrhea persists 
following dose reductions of ipatasertib to 200 mg daily and with maximum treatment for 
diarrhea, ipatasertib should be discontinued.   


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Table 2 
Diarrhea Management Guidelines 
Severity of Diarrhea a 
Management Guideline 
Prevention 
 
All patients are mandated to receive loperamide (2 mg BID 
or 4 mg QD) as prophylaxis for diarrhea in the first cycle, if 
allowed by local guidance.  If there are clinical concerns 
that preclude the use of loperamide prophylaxis in Cycle 1, 
discussion with the Medical Monitor is required.  
Loperamide dose adjustment may be made per 
investigator discretion after discussion with the Medical 
Monitor. 
 
After the first cycle, investigators are encouraged to 
continue this dosing for the remainder of the study using 
their discretion as clinically indicated. 
Grade 1 
Increase of  4 stools per day 
over baseline; mild increase 
in ostomy output compared 
with baseline 
 
Continue study drugs at the current dose level. 
 
Manage with loperamide 4 mg initially and then 2 mg every 
4 hours or after every unformed stool until after 12hour 
diarrhea free interval.  
 
Dietary modifications, such as avoiding any 
lactosecontaining foods and eating small meals. 
 
Hydration with 810 glasses per day (~12 oz/glass) of 
clear liquid, such as broth or lowcalorie- drinks with 
electrolytes. 
 
Upon resolution, loperamide prophylaxis can be 
considered and continues as clinically indicated, if allowed 
by local guidance. 
Grade 2 
Increase of 46 stools per 
day over baseline; moderate 
increase in ostomy output 
compared with baseline 
 
Rule out infectious etiology. 
 
Manage with loperamide as early as possible 4 mg initially 
and then 2 mg every 4 hours or after every unformed stool 
until after 12-hour diarrhea free interval.  
 
Dietary modifications, such as avoiding any 
lactosecontaining foods and eating small meals.  
 
Hydration with 810 glasses per day (~12 oz/glass) of 
clear liquid, such as broth or lowcalorie- drinks with 
electrolytes. 
 
For non-infectious diarrhea lasting more than 48 hours 
despite optimal loperamide treatment, manage with 
second-line anti-diarrheal agents, including, but not limited 
to Lomotil, codeine, or octreotide, or as per institutional 
guidelines. 
 
Interrupt ipatasertib until diarrhea improves to Grade 1 or 
better.  Ipatasertib can be resumed at the same dose or 
one dose lower per investigator's evaluation upon 
improvement to Grade 1 or better. 
 
Reduce ipatasertib by one (or one additional) dose level 
(see Table 1) for recurrent Grade 2 diarrhea. 
 
When study treatment is resumed, loperamide 
prophylaxis should also be resumed and continues as 
clinically indicated, if allowed by local guidance. 


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Table 2 
Diarrhea Management Guidelines (cont.) 
 
Severity of 
Diarrhea a 
Management Guideline 
Grade 3 
Increase of  7 stools per 
day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in 
ostomy output compared 
to baseline; limiting self-
care ADL 
 
Rule out infectious etiology. 
 
Treat per Grade 2 management guidelines and supportive 
care. 
 
Interrupt ipatasertib until diarrhea improves to Grade 1 or 
better.  Ipatasertib should be reduced by one dose level (see 
Table 1) when treatment is restarted.   
 
For recurrent Grade 3 diarrhea, reduce ipatasertib dose by 
one additional dose level (see Section D.5.2).  
 
When study treatment is resumed, loperamide prophylaxis 
should also be resumed and continues as clinically indicated, if 
allowed by local guidance. 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
 
Rule out infectious etiology. 
 
Treat per Grade 2 management guidelines and supportive 
care. 
 
Permanently discontinue ipatasertib. 
ADL  activities of daily living; BID  twice a day; NCI CTCAE v5.0  National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0; QD  once a day. 
a  Diarrhea, as defined by NCI CTCAE v5.0, a disorder characterized by frequent and watery 
bowel movements. 
 
D.5.2.2.2 
Fasting Hyperglycemia 
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours. 
Dose modification guidelines for fasting hyperglycemia attributable to study treatment 
are outlined Table 3 and are intended to provide guidance for fasting glucose 
measurements assessed in the clinic.  Decisions regarding study treatment should be 
made on fasting levels drawn in the clinic whenever possible. 
Home glucose measurements may be used to trigger contact between patient and the 
investigative site team and may lead to an unscheduled clinic visit to assess fasting 
glucose.  Guidance for when to call the investigator/site staff (or designated 
endocrinologist, if applicable) should be provided to patients for hypoglycemia 
(e.g., glucose value under 70 mg/dL) and hyperglycemia (e.g., glucose value over 
300 mg/dL).  For any patients performing home glucose monitoring, the blood glucose 
log should be reviewed at each clinic visit.   
In the event of ipatasertib interruption, anti-diabetic medications may need to be held or 
reduced (per investigator judgement) and glucose should be monitored closely to 
minimize the risk of hypoglycemia. 


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Table 3 
Fasting Hyperglycemia Management Guidelines 
Severity of Fasting 
Hyperglycemia 
Management Guideline 
Fasting glucose 
value  ULN to 
160 mg/dL (8.9 mmol/L) a 
 Monitor fasting glucose per protocol  
 Consider initiating home glucose monitoring  
Fasting glucose value 
 160 to 250 mg/dL 
( 8.913.9 mmol/L) a 
 Interruption of ipatasertib until fasting hyperglycemia resolves to 
 160 mg/dL. 
 Initiate home glucose monitoring 
 Start oral anti-diabetic medications (e.g., metformin).  
 If patient is already on an oral anti-diabetic medication, the dose of 
ipatasertib should be reduced by one dose level (refer to Table 1). 
 If the patient previously has not been receiving any oral antidiabetic 
medication, ipatasertib may be resumed at the previous dose level 
with initiation of oral anti-diabetic medication. 
Glucose value 250 to 
500 mg/dL ( 13.927.8 
mmol/L) a 
 Interrupt ipatasertib dosing until fasting hyperglycemia resolves to 
 160 mg/dL.  
 Initiate home glucose monitoring 
 Treat hyperglycemia as medically appropriate.  Start (or increase 
dose of) oral antidiabetic medications (e.g., metformin). 
 If the patient is already on an oral anti-diabetic medication, ipatasertib 
should be reduced by one dose level when treatment is restarted. 
 If previously, the patient has not been receiving any oral anti-diabetic 
medication, ipatasertib may be resumed at the previous dose level 
with initiation of oral anti-diabetic medication. 
 If fasting hyperglycemia  250 mg/dL recurs, the dose of ipatasertib 
should be reduced by one dose level when treatment is restarted.   
Glucose 
value  500 mg/dL 
( 27.8 mmol/L); 
life-threatening 
consequences a 
 Interrupt ipatasertib dosing until resolution to  160 mg/dL. 
 Treat hyperglycemia as medically appropriate.   
 Initiate home glucose monitoring 
 Start (or increase dose of) oral anti-diabetic medications (e.g., 
metformin). 
 Assess for volume depletion and appropriate intravenous or oral 
hydration. 
 Reduce ipatasertib by one dose level if and when treatment is 
restarted. 
 If hyperglycemia  500 mg/dL recurs, permanently discontinue 
ipatasertib. 
ULN  upper limit of normal. 
a For all grades, the patient should receive education on a diabetic diet. 
 
D.5.2.2.3 
Neutropenia and/or Thrombocytopenia 
Addition of hematopoietic growth factors is allowed.  If a dose delay is required as a 
result of neutropenia at any grade, patients should receive prophylactic granulocyte 
colony-stimulating factor or granulocyte-macrophage colony-stimulating factor per 
institutional standards.  Patients should be counseled as to the risk of fever and infection 


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and to the importance of contacting their treating physician immediately if these 
conditions occur so that they can be promptly and appropriately managed.  Dosage 
modification guidelines for neutropenia and/or thrombocytopenia attributable to 
ipatasertib Table 4. 
Table 4 
Neutropenia and Thrombocytopenia Management Guidelines 
Severity of Neutropenia 
and/or Thrombocytopenia 
Management Guideline 
Grade 2 
 
Ipatasertib may be continued at the original dose 
Grade 3 
 
Ipatasertib should be held until recovery to Grade 1 and if 
clinically appropriate based on the investigator’s medical 
judgment to Grade 2 as long as G-CSF is used to manage the 
neutropenia.  Please see guidelines in this table regarding 
treatment for ongoing Grade 2 hematological toxicities.   
– 
First episode:  If recovery is to Grade 1, resume the original 
dose.  If recovery to Grade 1 is achieved with the use of G-
CSF, then continued use of G-CSF is recommended once 
dosing of the study drug is resumed.  If recovery is to 
Grade 2, follow the guidance above.  
– 
Recurrent episode: Ipatasertib should be reduced by one 
dose level when treatment is restarted.  If patient has had 
more than three Grade 3 neutropenia episodes on study, 
the patient may continue to receive ipatasertib following 
discussion with the Medical Monitor.  
 
Following a treatment hold of up to 4 weeks, if recovery to 
Grade 2 or better neutropenia does not occur, the patient may 
continue ipatasertib following discussion with the Medical 
Monitor. 
Febrile neutropenia and 
Grade 4 neutropenia 
 
Ipatasertib should be held until recovery to Grade 1, and if 
clinically appropriate based on the investigator’s medical 
judgment to Grade 2, as long as G-CSF is used to manage the 
neutropenia.  Please see guidelines in this table regarding 
treatment for ongoing Grade 2 hematological toxicities.  
First episode:  Ipatasertib should be reduced by one dose level 
when treatment is restarted.   
Recurrent episode:  Ipatasertib should be discontinued.  
 
Following a treatment hold of up to 4 weeks, if recovery to 
Grade 2 or better neutropenia does not occur, the patient will 
permanently discontinue ipatasertib treatment. 
G-CSF granulocyte colony-stimulating factor. 
 
D.5.2.2.4 
Nausea and/or Vomiting 
Dose reductions for nausea and/or vomiting should occur only if the symptoms persist 
despite a minimum of two treatments with adequate (combination) anti-emetic 
treatment(s), including ondansetron and other anti-emetics (i.e., prochlorperazine or 


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metoclopramide per institutional guidelines; see Table 5).  For persistent nausea and/or 
vomiting attributable to ipatasertib, dosage modification guidelines are outlined in 
Section D.5.2, Table 1, and Table 5.  
Table 5 
Nausea and Vomiting Management Guidelines 
Severity of Nausea 
and /or Vomiting 
Management Guideline 
Grade 1 
 
Provide supportive care as needed. 
Grade 2 
 
Provide maximum supportive care as needed per local guidelines, 
with a minimum of two anti-emetics, including ondansetron. 
Grade  3 
 
Interrupt ipatasertib until nausea or vomiting resolves to Grade 2 
or better. 
 
Provide maximum supportive care per local guidelines, with a 
minimum of two anti-emetics, including ondansetron. 
 
If Grade  3 nausea or vomiting recurs, ipatasertib should be 
reduced by one dose level (see Table 1) when treatment is 
restarted.   
 
D.5.2.2.5 
Hepatotoxicity 
Permanently discontinue ipatasertib for any patients who develop a concurrent elevation 
of ALT and/or AST greater than 3  ULN (or baseline, if baseline was abnormal) and total 
bilirubin greater than 2  ULN and/or clinical jaundice in the absence of biliary obstruction 
or other causes responsible for the concurrent elevation, including patients having 
abnormal liver function tests that meet Hy’s law criteria.  Dosage modification and 
symptom management guidelines for hepatotoxicity, attributable to study treatment are 
shown below (see Table 6) 


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Table 6 
Hepatotoxicity Management Guidelines 
Severity of LFT Elevation 
Management Guideline 
Grade 1  
AST or ALT  baseline  
3.0  ULN if baseline was 
normal; 1.53.0  baseline if 
baseline was abnormal  
or  
T bilirubin  baseline 
1.5  ULN if baseline was 
normal;  1.01.5  baseline if 
baseline was abnormal 
 
Continue study drugs. 
Grade 2  
AST or ALT  3.0–5.0  ULN if 
baseline was normal; 3.0–
5.0  baseline if baseline was 
abnormal  
or 
T bilirubin  1.5–3.0  ULN if 
baseline was normal; 
 1.53.0  baseline if baseline 
was abnormal 
 
Continue study drugs.  
 
The frequency of liver function test monitoring should be 
increased as clinically indicated if the investigator judges 
that the laboratory abnormalities are potentially related to 
study medication. 
Grade 3  
AST or ALT   5.0–20.0  ULN 
if baseline was normal; 5.0–
20.0  baseline if baseline was 
abnormal  
or 
T bilirubin  3.0–10.0  ULN if 
baseline was normal;  3.0–
10.0  baseline if baseline was 
abnormal 
 
Immediately interrupt ipatasertib. 
 
On return of LFTs to baseline or to AST and ALT 
 2.5  ULN and total bilirubin  1.5  ULN levels, restart 
ipatasertib/ at previous dose level (refer to Table 1)  
 
Following treatment resumption, monitor serum 
transaminases and bilirubin at a minimum every 2 weeks 
for 3 months and monthly thereafter. 
 
If another Grade 3 event occurs, interrupt ipatasertib/.  
On return of LFTs to baseline or AST and ALT  2.5 x 
ULN and total bilirubin  1.5 x ULN levels, restart 
ipatasertib/, reducing the dose by one level  
 
Further Grade 3 occurrences must result in permanent 
discontinuation of ipatasertib. 
Grade 4 
AST or ALT  20.0  ULN if 
baseline was normal; 
 20.0  baseline if baseline 
was abnormal  
or 
T bilirubin  10.0  ULN if 
baseline was normal; 
 10.0  baseline if baseline 
was abnormal 
 
Permanently discontinue ipatasertib. 
LFT  liver function test; QD  once daily; ULN  upper limit of normal. 
 


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D.5.2.2.6 
Rash 
Ipatasertib should be permanently discontinued for rash associated with 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, or other 
suspected severe hypersensitivity or allergic reaction.  Dosage modification and 
symptom management guidelines for skin toxicity attributable to study treatment are 
shown in Table 7 (see Section D.5.2 and Table 1 for dose modifications). 
Table 7 
Rash Management Guidelines 
Severity of 
Rash 
Management Guideline 
Grade 1 
 
Continue study drugs.  
 
Consider topical corticosteroids. 
Grade 2 
 
Interrupt ipatasertib treatment until resolution to Grade 1 or better or the 
toxicity is no longer clinically significant.  
 
Treat rash with topical corticosteroids. 
 
Consider treatment of rash with oral corticosteroids. 
Grade 3 
 
Interrupt ipatasertib treatment until resolution to Grade 1 or better or the 
toxicity is no longer clinically significant.  
 
Treat rash with topical and systemic corticosteroids. 
 
Consider dermatological consultation. 
 
If the skin toxicity resolves to Grade 1 or better or is no longer clinically 
significant within 28 days, following completion of the steroid taper, 
ipatasertib may be resumed at one dose level below the previous dose 
(see Table 1). 
 
If recovery of the skin toxicity to Grade 1 or better does not occur or skin 
toxicity remains clinically significant continuously for 4 weeks, or Grade 
3 rash recurs, permanently discontinue ipatasertib. 
Grade 4 
 
Administration of systemic steroids (oral or intravenous) is 
recommended.  Consider dermatological consultation and skin biopsy.  
Ipatasertib should be permanently discontinued. 
 
D.5.2.2.7 
Pneumonitis 
Pneumonitis is not known to be causally related to any of the study drugs; however, it 
has been observed with other drugs treating pathways similar to ipatasertib.  Every effort 
should be made to determine the etiology of dyspnea and changes in pulmonary 
function (see Table 8). 


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Table 8 
Pneumonitis Management Guidelines 
Severity of 
Pneumonitis 
Management Guideline 
Grade 1 
 
Continue study drugs. 
 
Perform CT scan and PFTs.  Repeat CT scan every 8 weeks until a 
return to baseline. 
Grade 2 
 
If infectious etiology is ruled out or if improvement is not evident with 
broad spectrum antibiotics, prescribe corticosteroids as clinically 
indicated. 
 
Interrupt ipatasertib treatment until improvement to Grade 1 or better.  
Consider resuming ipatasertib at same dose level or one dose level 
below (see Table 1) per investigator's assessment. 
 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a 
return to baseline. 
 
For recurrent Grade 2 pneumonitis, ipatasertib must be resumed at one 
dose level below the previous dose (see Table 1).   
 
Discontinue ipatasertib if recovery to Grade 1 or better is not evident 
within 28 days. 
Grade 3 
 
If infectious etiology is ruled out or if improvement is not evident with 
broad spectrum antibiotics, prescribe corticosteroids as clinically 
indicated. 
 
Interrupt ipatasertib treatment until improvement to Grade 1 or better.  
Resume ipatasertib at one dose level below previous dose (see Table 1) 
per investigator’s assessment.  If recovery to Grade 1 or better is not 
evident within 28 days, discontinue study treatments.   
 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a 
return to baseline.  Bronchoscopy is recommended. 
 
For recurrent non-infectious Grade 3 pneumonitis events, ipatasertib 
should be permanently discontinued. 
Grade 4 
 
If infectious etiology is ruled out or if improvement is not evident with 
broad spectrum antibiotics, prescribe corticosteroids as clinically 
indicated. 
 
Permanently discontinue ipatasertib. 
 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a 
return to baseline.  Bronchoscopy is recommended. 
CT  computed tomography; PFT  pulmonary function test. 
 
D.5.2.2.8 
Mucositis 
Mouthwash such as magic mouthwash (if inaccessible, warm salt or bicarbonate water) 
should be used as supportive care per institution guidelines.  Brushing teeth after meals, 
keeping lips moisturized with non-Vaseline products, and avoiding alcohol, spicy food, 
and smoking have all been shown to reduce pain and infection related to mucositis.  
Ranitidine or omeprazole may be helpful if patients have epigastric pain.  Dosage 


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modification guidelines for mucositis attributable to study treatment are outlined in 
Table 9. 
Table 9 
Mucositis Management Guidelines 
Severity of 
Mucositis 
Management Guidelines 
Grade 1 or 2 
 
Manage with maximum supportive care.   
 
If Grade  2 mucositis recurs in subsequent 4 week cycles, despite 
maximal supportive care, the dose of ipatasertib should be reduced by one 
dose level (see Table 1).   
Grade  3 
 
Hold ipatasertib until recovery to Grade 2 or better.  If the mucositis 
resolves to Grade 2 or better during the current cycle, the dose of 
ipatasertib should be reduced by one dose level (see Table 1).   
 
If recovery of mucositis to Grade 2 or better does not occur within a 
maximum of 4 weeks, the patient will permanently ipatasertib. 
 
D.5.2.2.9 
Dyslipidemia 
Use of lipid-lowering therapy for patients experiencing Grade  2 elevations may be 
initiated per institutional standard of care. 
D.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients taking ipatasertib: 
 
Grade  3 fasting hyperglycemia  
 
Grade  3 hepatotoxicity 
 
Grade  3 ALT/AST elevations 
 
Grade  2 colitis/enterocolitis 
 
Grade  3 diarrhea 
 
Grade  3 rash 
 
Grade  2 pneumonitis 
 
D.5.4 
Selected Adverse Events 
Additional data may be analyzed for the following selected adverse events: 
 
Diarrhea 


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 
Asthenia (fatigue) 
 
Nausea 
 
Neutropenia (neutrophil count decreased, febrile neutropenia) 
 
Rash (e.g., maculopapular, erythema, urticarial, dermatitis, rash popular, skin 
exfoliation, toxic skin eruption) 
 
Erythema multiforme 
 
Vomiting 
 
Oral mucositis (stomatitis, mucosal inflammation, mouth inflammation, mouth 
ulceration) 
 
Hyperlipidemia (hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, blood 
cholesterol increased, blood triglycerides increased) 
 
Hepatotoxicity (ALT, AST increased) 
 
Hyperglycemia (blood glucose increased) 
 
Pneumonitis (interstitial lung diseases) 
 
 


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D.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-Treatment 
Screening 
Treatment Period  
End Of Treatment 
Visit b 
Day And Study Cycle 
 
Day 1 Of Each Cycle 
Other Days As 
Specified 
 
Day (Window) 
28 to 1 a 
(3) 
(3) 
 28 Days After 
Last Study Dose 
Informed consent d 
x 
 
 
 
Documentation of positive AKT 
activating mutation or PTEN loss/loss 
of function status by local test e 
x 
 
 
 
Medical history and baseline conditions 
f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
ECOG Performance Status h 
x 
x 
 
x 
Pregnancy test i 
x 
x 
 
x 
Chemistry j  
x 
x 
 
x c 
Hematology/CBC with differential k 
x 
x 
 
x c 
Coagulation panel l 
x 
 
 
x 
Fasting lipid panel, amylase, lipase m 
x 
x 
 
x 
Fasting HbA1C m 
x 
x 
 
x 
Fasting blood glucose n 
x 
x 
Weekly during C1 
x 
ECHO or MUGA o 
x 
As clinically indicated 
Response assessments p, q 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) r 
 
Submit within 21 days of C1, D1 
 
 
Whole blood samples s 
x 
 
See footnote s 
 
Study drug compliance assessment t 
 
x 
 
x 


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Assessments 
Pre-Treatment 
Screening 
Treatment Period  
End Of Treatment 
Visit b 
Day And Study Cycle 
 
Day 1 Of Each Cycle 
Other Days As 
Specified 
 
Day (Window) 
28 to 1 a 
(3) 
(3) 
 28 Days After 
Last Study Dose 
Study drug dispensing 
 
x 
 
 
Prophylaxis anti-diarrheal u 
 
Every day of cycle 1 and as clinically indicated 
 
Adverse events v 
x 
Collected on an ongoing basis 
x v 
Concomitant Medications w 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic Case Report Form; 
FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection fraction; MRImagnetic resonance 
imaging; MUGA  multiple-gated acquisition; PDprogressive disease; RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response 
Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious adverse event. 
Note: Cycle28 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if the 
hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1, with the exception 
of glucose, which should be drawn within 3 days prior.  Scans to document measurable or evaluable disease (i.e., tumor measurement) should be 
performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment follow-
up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  If the 
patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may take place by telephone to 
include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to collect AE data and any standard of care laboratory 
and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive AKT gene activating mutations or PTEN loss or loss of function status should occur prior to performing other trial-related 
eligibility assessments. 


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f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a serum 
pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who have a 
positive pregnancy test must not receive study drug.   
j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, total 
bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first dose of 
study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1, with the exception of 
glucose, which should be drawn within 3 days prior.  Subsequent chemistry evaluations should be completed prior to dosing on Day 1 of each 
indicated cycle (or up to 3 days before). 
k Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  
l Coagulation includes aPTT and INR. 
m Fasting lipid panel (cholesterol, triglyceride, HDL, and LDL), amylase, lipase and HbA1c will be assessed after ≥8 hours of fasting.  If results are 
obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.   
n Samples should be assessed weekly during the first Cycle and D1 at every other cycle.  Mid-cycle fasting glucose levels may be obtained by 
glucometer (fingerstick). If measurements are done at home, phone visits with site staff should be conducted to review results and assess any 
potential signs or symptoms of hyperglycemia.  
o LVEF assessment by ECHO or MUGA to be performed at screening and as clinically indicated.  Evaluation of LVEF must be performed by the 
same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and operator perform ECHO/MUGA scan 
for each individual patient. 


Arm D:  Ipatasertib in Patients with PTEN Loss/Loss-of-Function or AKT Activating Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
254/Protocol ML42439, Version 5 
p All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), 
a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  A CT or MRI scan 
of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or refute the diagnosis of 
CNS metastases at baseline in the event of an equivocal scan.   
q At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, termination 
of an individual study arm by the Sponsor, or death, whichever occurs first.   
r For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
s Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.  
t Study drug compliance will be reviewed with the patient.  
u Loperamide 2 mg BID or equivalent or per local institutional guideline for the first cycle.  If loose watery stools occur, take additional 2 mg after 
each loose watery stool and up to 16 mg per day. 
v After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation. All patients will be 
followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all deaths, regardless of 
cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior study drug treatment (see Section 5.6). 
w Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient 
in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study drug. 


Arm D:  Ipatasertib in Patients with AKT1/2/3 Mutant-Positive Tumors 
MyTACTIC Study—Genentech, Inc. 
255/Protocol ML42439, Version 5 
D.7 
REFERENCES 
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the 
use of granulocyte-colony stimulating factor to reduce the incidence of 
chemotherapy-induced febrile neutropenia in adult patients with 
lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47:832. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for 
the use of white blood cell growth factors: an evidence-based clinical practice 
guideline. J Clin Oncol 2006;24:3187205. 
 
 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
256/Protocol ML42439, Version 5 
Appendix 14  
Arm E:  Atezolizumab plus Chemotherapy in Patients 
with TMB-H/MSI-H/dMMR-Positive Tumors 
15. 
ARM E:  ATEZOLIZUMAB PLUS CHEMOTHERAPY IN 
PATIENTS WITH TMB-H/MSI-H/DMMR-POSITIVE TUMORS 
TABLE OF CONTENTS 
 
E.4 
Materials and Methods .................................................. 257 
E.4.1 
Patients ......................................................................... 257 
E.4.1.1 
Additional Inclusion Criteria ........................................... 257 
E.4.1.2 
Additional Exclusion Criteria .......................................... 257 
E.4.2 
Study Treatment ............................................................ 260 
E.4.2.1 
Formulation and Packaging........................................... 260 
E.4.2.2 
Study Treatment Dosage, Administration, and 
Compliance ................................................................... 260 
E.4.3 
Concomitant Therapy .................................................... 262 
E.4.3.1 
Permitted Therapy ......................................................... 262 
E.4.3.2 
Cautionary Therapy ....................................................... 263 
E.4.3.3 
Prohibited Therapies ..................................................... 263 
E.4.4 
Arm-specific Assessments ............................................ 264 
E.5 
Safety Plan .................................................................... 264 
E.5.1 
Risks Associated with Atezolizumab plus 
Chemotherapy ............................................................... 264 
E.5.1.1 
Risks Associated with Atezolizumab ............................. 264 
E.5.1.2 
Risks Associated with Docetaxel, Paclitaxel, and 
Capecitabine ................................................................. 265 
E.5.2 
Guidelines for Management of Adverse Events ............ 265 
E.5.2.1 
Dose Modifications and Interruptions ............................ 265 
E.5.2.2 
Guidelines for Management of Specific Adverse 
Events Associated with Atezolizumab ........................... 266 
E.5.2.3 
Guidelines for Management of Adverse Events 
Associated with Chemotherapy ..................................... 296 
E.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ........................................... 296 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
257/Protocol ML42439, Version 5 
E.6 
Schedule of Activities .................................................... 298 
E.7 
References .................................................................... 302 
 
E.4 
MATERIALS AND METHODS 
E.4.1 
Patients 
To be enrolled in Arm E:  atezolizumab plus chemotherapy treatment, patients must 
have met and continue to meet all general eligibility criteria (see Section 4.1), in addition 
to the arm-specific criteria below. 
E.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm E: 
atezolizumab plus chemotherapy treatment: 
 
Documentation of one of the following biomarkers, as determined by a Clinical 
Laboratory Improvement Amendments (CLIA) or equivalently certified assay (tissue 
or blood): 
– 
Tumor mutational burden-high (TMB-H), defined as  10 mutations per 
megabase as determined by a tissue-based NGS assay 
– 
Microsatellite instability high (MSI-H) 
– 
Deficient mismatch repair (dMMR) 
 
ANC  1500/L within 14 days prior to initiation of study treatment 
 
Lymphocyte count  500/L 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
5 months after the last dose of atezolizumab or 6 months after the last dose of 
chemotherapy, whichever is later; and agreement to refrain from donating eggs 
during this same period.  Please see Appendix 2 for complete details on 
contraception requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of  1% per year during the treatment period and for 3 months after the 
last dose of chemotherapy and agreement to refrain from donating sperm during this 
same period.  See detailed contraception requirements in Appendix 2. 
 
E.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm E: atezolizumab plus chemotherapy treatment: 
 
Primary CNS tumors with any of the following characteristics: 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
258/Protocol ML42439, Version 5 
– 
History of intracranial hemorrhage or spinal cord hemorrhage  
– 
Neurosurgical resection or brain biopsy to the primary brain tumor within 
28 days of Cycle 1, Day 1 
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium  upper limit of normal  [ULN]) 
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
Patients with a history of HCV infection but who are negative for HCV RNA by 
PCR will be considered non-infected with HCV. 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid replacement hormone are eligible for the study 
– 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
259/Protocol ML42439, Version 5 
o Rash must cover  10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids 
within the previous 12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study   
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the final dose of atezolizumab 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including antiPD-1, and antiPD-L1 therapeutic antibodies  
Patients who have had prior anti-CTLA-4 treatment may be enrolled, 
provided the following requirements are met: 
– 
Last dose of anti-CTLA-4 at least 6 weeks prior to enrollment 
– 
No history of severe immune-related adverse events from the anti-CTLA-4 
(National Cancer Institute Common Terminology Criteria for Research 
Adverse Events [NCI CTCAE] Grade 3 and 4)  
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives 
(whichever is longer) prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
260/Protocol ML42439, Version 5 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation  
 
E.4.2 
Study Treatment 
Study treatment in this arm will consist of atezolizumab in combination with either 
docetaxel, paclitaxel, or capecitabine chemotherapy, as determined by the investigator.  
E.4.2.1 
Formulation and Packaging 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
Chemotherapy will consist of either docetaxel, paclitaxel, or capecitabine, as determined 
by the investigator and will be used in commercially available formulations.  
For information on the formulation and handling of docetaxel, paclitaxel, and 
capecitabine, refer to the respective package insert.  
E.4.2.2 
Study Treatment Dosage, Administration, and Compliance 
Study treatment will be administered in 21-day cycles.  Atezolizumab should be 
administered prior to chemotherapy on days when both are administered. 
If a delay in administration of either agent is necessary, reasonable effort should be 
made to keep the administration synced if clinically feasible (e.g., briefly delay 
administration of the other agent).  A cycle should be considered to start when any drug 
is administered.   
If atezolizumab is discontinued, chemotherapy can be continued if the patient is likely to 
derive clinical benefit, as determined by the investigator.  If chemotherapy is 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
261/Protocol ML42439, Version 5 
discontinued, atezolizumab can be continued if the patient is likely to derive clinical 
benefit, as determined by the investigator. 
E.4.2.2.1 
Dosage, Administration, and Compliance for Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients 
on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss 
of clinical benefit in consultation with the Medical Monitor, see Section 3.1.2 for 
treatment beyond disease progression).  
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.   
Administration of atezolizumab will be performed in a monitored setting where there is 
access to trained personnel and adequate equipment/medicine to manage potentially 
serious reactions.  For anaphylaxis precautions, see Appendix 6.  Atezolizumab 
infusions will be administered per the instructions outlined in Table 1. 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 No premedication is permitted prior to 
the atezolizumab infusion. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) 
should be measured within 60 minutes 
prior to the infusion a 
 Atezolizumab should be infused over 
60 (15) minutes. 
 If clinically indicated, vital signs should 
be measured every 15 (5) minutes 
during the infusion and at 
30 (10) minutes after the infusion. a 
 Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact 
their study physician if they develop 
such symptoms. 
 If the patient experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, antipyretics, 
and/or analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 Vital signs should be measured within 
60 minutes prior to the infusion. a 
 Atezolizumab should be infused over 30 (10) 
minutes if the previous infusion was tolerated 
without an infusion-related reaction, or 60 
(15) minutes if the patient experienced an 
infusion-related reaction with the previous 
infusion. 
 If the patient experienced an infusion-related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
measured during the infusion and at 
30 (10) minutes after the infusion. a 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  Record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Section E.5.2.2.7. 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
262/Protocol ML42439, Version 5 
No dose reductions for atezolizumab are allowed.  See Section E.5.2 for management 
guidelines. 
E.4.2.2.2 
Dosage, Administration, and Compliance for Docetaxel, 
Paclitaxel, and Capecitabine 
Docetaxel, paclitaxel, or capecitabine will be administered per package insert and 
institutional guidelines, including considerations for premedication, supportive 
medications, infusion times, infusion frequency, and total cycle count. 
E.4.3 
Concomitant Therapy 
E.4.3.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives  
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section E.4.3.3) 
 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for COPD or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab may be 
continued during palliative radiotherapy. 
 
Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency 
ablation) as outlined below: 
Patients experiencing a mixed response requiring local therapy for control of 
three or fewer lesions may still be eligible to continue study treatment in 
consultation with the Medical Monitor.  Patients who receive local therapy 
directed at a target lesion will no longer be evaluable for radiographic response 
but will remain evaluable for progression. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, at the 
discretion of the investigator. 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
263/Protocol ML42439, Version 5 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Section E.4.3.2 and Section E.4.3.3) as clinically indicated, per 
local standard practice.  Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-
receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion associated-events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 6). 
E.4.3.2 
Cautionary Therapy  
E.4.3.2.1 
Corticosteroids and TNF- Inhibitors 
Systemic corticosteroids and TNF- inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in which 
systemic corticosteroids or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids and TNF- inhibitors may be administered at the 
discretion of the investigator. 
Patients with primary CNS tumors can be receiving concurrent treatment with 
corticosteroids in consultation with the Medical Monitor.  Patients must be receiving a 
stable or decreasing dose for  5 days prior to the baseline magnetic resonance imaging 
(MRI) scan and at the time of drug initiation. 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy (refer 
to Section E.5.2 for details). 
E.4.3.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions (DDIs) are 
generally unknown.  However, herbal therapies not intended for the treatment of cancer 
may be used during the study at the discretion of the investigator. 
E.4.3.3 
Prohibited Therapies 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited within 
3 weeks prior to starting study treatment and during study treatment, until disease 
progression is documented and the patient has discontinued study treatment, with 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
264/Protocol ML42439, Version 5 
the exception of palliative radiotherapy and local therapy under certain 
circumstances (see Section E.4.3.1 for details). 
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after 
the final dose of atezolizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab. 
 
Any prohibited therapies in accordance with the local label for applicable 
chemotherapy 
 
E.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients receiving atezolizumab.  Refer to the schedule of 
activities (Section E.6) for arm-specific assessment timepoints. 
Local Laboratory Assessments  
 
Coagulation:  INR and aPTT 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (T4) 
 
Functional Assessments 
 
LVEF assessment:  echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
 
E.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm E: atezolizumab plus 
chemotherapy treatment.  
E.5.1 
Risks Associated with Atezolizumab plus Chemotherapy 
E.5.1.1 
Risks Associated with Atezolizumab  
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
265/Protocol ML42439, Version 5 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, 
myelitis, meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, 
and severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 
involve any organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer 
to the Atezolizumab Investigator's Brochure for a detailed description of anticipated 
safety risks for atezolizumab.   
E.5.1.2 
Risks Associated with Docetaxel, Paclitaxel, and Capecitabine  
Docetaxel has been associated with risks such as the following: infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, 
dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, 
diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia.  For more details 
regarding the safety profile of docetaxel, refer to the prescribing information for 
docetaxel. 
Paclitaxel has been associated with risks such as the following: Bone marrow 
suppression, neutropenia, alopecia, peripheral neuropathy, myalgia, arthralgia, nausea, 
and vomiting.  Additionally reported adverse events which were less common are 
hypersensitivity reactions, infections, bleeding, diarrhea, mucositis, liver function test 
(LFT) elevations, injection-site reactions, and cardiovascular effects such as 
hypotension, bradycardia, hypertension, arrhythmias, other ECG abnormalities, 
syncope, and venous thrombosis.  For more details regarding the safety profile of 
paclitaxel, refer to the prescribing information for paclitaxel. 
Capecitabine has been associated with risks such as the following: diarrhea, 
hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and 
hyperbilirubinemia.  For more details regarding the safety profile of capecitabine, refer to 
the prescribing information for capecitabine. 
E.5.2 
Guidelines for Management of Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
E.5.2.1 
Dose Modifications and Interruptions 
E.5.2.1.1 
Dose Modifications and Interruptions for Atezolizumab 
No dose reductions for atezolizumab are allowed.   
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to the equivalent of  10 mg/day oral 


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prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for  12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for  12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).  The acceptable length of treatment 
interruption must be based on the investigator's benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
E.5.2.1.2 
Dose Modifications and Interruptions for Chemotherapy 
Dose modifications and interruptions for docetaxel, paclitaxel, and capecitabine should 
be done according to standard medical practice and in accordance with the respective 
packaging insert.  
E.5.2.2 
Guidelines for Management of Specific Adverse Events 
Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents.  
The following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections.  
 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment.  There should be a high level of suspicion that new symptoms are 
treatment related. 
 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 


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 
Consider holding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids 
(initial dose of 0.51 mg/kg/day of prednisone or equivalent) may be administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (12 mg/kg/day prednisone or equivalent).  Corticosteroids should 
be tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed.  If symptoms do not improve within 48 to 72 hours 
of high-dose corticosteroid use, other immunosuppressants may be offered for some 
toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 
hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance for a given patient prior 
to further administration of atezolizumab.  Resumption of atezolizumab may be 
considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with atezolizumab 
should be based on the investigator's assessment of the benefits and risks and 
documented by the Investigator.  The Medical Monitor is available to advise as 
needed.  
  
E.5.2.2.1 
Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in Table 2. 


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Table 2 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
 For recurrent events or events with no improvement after 48–72 hours 
of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c,d 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 Bronchoscopy or BAL is recommended. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/ IV 
methylprednisolone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
BAL  bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator's benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.  
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 








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Table 4 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start 
empiric IV steroids while waiting for definitive diagnosis. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist 5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone.  If 
the event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
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Table 4 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.  If event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
GI  gastrointestinal; IVintravenous. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 
E.5.2.2.4 
Endocrine Events 
Management guidelines for endocrine events are provided in Table 5. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 


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endocrinologist if an endocrinopathy is suspected.  Thyroidstimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
MRI of the brain (with detailed pituitary sections) may help to differentiate primary 
pituitary insufficiency from primary adrenal insufficiency. 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
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MyTACTIC Study—Genentech, Inc. 
275/Protocol ML42439, Version 5 
Table 5 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
Grade 3 and 4 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hypothyroidism. c. 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism. 
 Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 


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Table 5  
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Grade 3 and 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
 Refer to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c 
Symptomatic adrenal 
insufficiency, 
Grades 24  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Investigate for diabetes.  If patient has Type 1 diabetes, treat as 
a Grade 3 event.  If patient does not have Type 1 diabetes, treat 
as per institutional guidelines. 
 Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
 Withhold atezolizumab. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
 Monitor for glucose control. 
 Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 


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Table 5 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 


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E.5.2.2.5 
Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 6. 
Table 6 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.   
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 


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E.5.2.2.6 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 7. 
Immune-Mediated Myocarditis 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-
type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis and should be managed accordingly.  Immune-
mediated myocarditis needs to be distinguished from myocarditis or associated with 
pericarditis (see section on pericardial disorders below)  resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram (ECHO), and a cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 7. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, 
and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  


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Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 7.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
Table 7 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 
24 
 
Immune-mediated 
pericardial disorders, 
Grades 24 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD or 
pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
 
E.5.2.2.7 
Infusion-Related Reactions and Cytokine-Release Syndrome 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an IRR or cytokine-release syndrome (CRS) with 
atezolizumab may receive premedication with antihistamines, antipyretic medications, 
and/or analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole 
(dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential 
for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 


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onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 8. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  
If a patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator’s judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 
 


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Table 8 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms  
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per Grade 
2. 
 For subsequent infusions, consider administration of oral premedication with 
antihistamines, antipyretic medications, and/or analgesics, and monitor 
closely for IRRs and/or CRS. 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygen d 
by nasal cannula 
or blowby 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  If 
no improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS as described in this appendix. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab, and contact the Medical Monitor. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
antipyretic medications, and/or analgesics and monitor closely for IRRs 
and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Medical Monitor. 


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Table 8 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
 
Event 
Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
nonrebreather 
mask, or Venturi 
mask 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor.e 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ toxicities 
as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy. 
 Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
Grade 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. e 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor. 
 Hospitalize patient until complete resolution of symptoms. 


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Table 8 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive 
airway pressure; CAR  chimeric antigen receptor; CPAP  continuous positive airway 
pressure; CRS  cytokine-release syndrome; CTCAE  Common Terminology Criteria for 
Adverse Events; eCRF  electronic Case Report Form; HLH  hemophagocytic 
lymphohistiocytosis; ICU  intensive care unit; IRR  infusion-related reaction; 
MAS  macrophage activation syndrome; NCCN  National Cancer Comprehensive Network; 
NCI  National Cancer Institute. 
Note:  The management guidelines have been adapted from the NCCN guidelines for  the 
management of CAR T-cellrelated toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities associated 
with CRS should not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at  6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.  
For subsequent infusions, administer oral premedication with antihistamines, antipyretic 
medications, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication 
with corticosteroids and extending the infusion time may also be considered after assessing 
the benefitrisk ratio. 
f Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 
E.5.2.2.8 
Pancreatic Events 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 9. 


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Table 9 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c 
GI  gastrointestinal; ULNupper limit of normal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 


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Table 9 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
E.5.2.2.9 
Dermatologic Events 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self limited, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 


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persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 10. 
Table 10 Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, 
Grade 1  
 Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event, 
Grade 2  
 Continue atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
 If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day. 
Dermatologic event, 
Grade 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 12 mg/kg/day if event does not 
improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 


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Table 10 Management Guidelines for Dermatologic Events (cont.) 
Dermatologic event, 
Grade 4 
 Permanently discontinue atezolizumab and contact Medical 
Monitor.  c 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
 Withhold atezolizumab for suspected Stevens-Johnson syndrome 
or toxic epidermal necrolysis. 
 Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy. 
 Follow the applicable treatment and management guidelines above. 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
E.5.2.2.10 
Neurologic Disorders 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 11, with specific guidelines for myelitis provided in Table 12. 


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Table 11 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
 Continue atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2  
 For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume atezolizumab. b 
– 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
 For facial paresis: 
– 
If event resolves fully, resume atezolizumab b 
– 
If event does not resolve fully while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 
4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c  
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of corticosteroids equivalent to 12 mg/kg/day oral 
or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 


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Table 12 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
E.5.2.2.11 
Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 13. 


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Table 13 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor.  
 Refer patient to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 
 
E.5.2.2.12 
Renal Events 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
nonsteroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 


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Table 14 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine and urine protein, closely 
until values resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
E.5.2.2.13 
Immune-Mediated Myositis 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
293/Protocol ML42439, Version 5 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 15. 
Table 15 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
 
Continue atezolizumab. 
 
Refer patient to rheumatologist or neurologist.  
 
Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset a and 
contact the Medical Monitor. 
 
Refer patient to rheumatologist or neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
Consider treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If corticosteroids are initiated and event does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
294/Protocol ML42439, Version 5 
Table 15 Management Guidelines for Immune-Mediated Myositis (cont.) 
Immune-mediated 
myositis, Grade 3 
 
Withhold atezolizumab for up to 12 weeks after event onset a and 
contact the Medical Monitor. 
 
Refer patient to rheumatologist or neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
Respiratory support may be required in more severe cases. 
 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 
For recurrent events, treat as a Grade 4 event.  Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 
Immune-mediated 
myositis, Grade 4 
 
Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 
Refer patient to rheumatologist or neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
Respiratory support may be required in more severe cases. 
 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
295/Protocol ML42439, Version 5 
E.5.2.2.14 
Hemophagocytic Lymphohistiocytosis and Macrophage 
Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).   
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  9 g/dL ( 10 g/dL for infants  4 weeks old) 
– 
Platelet count  100  109/L 
– 
ANC  1000/L 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
– 
Platelet count  181  109/L  
– 
AST  48 U/L 
– 
Triglycerides  1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L (360 mg/dL) 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 16. 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
296/Protocol ML42439, Version 5 
Table 16 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab and contact the Medical Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if indicated 
per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
E.5.2.3 
Guidelines for Management of Adverse Events Associated with 
Chemotherapy 
Toxicities associated or possibly associated with docetaxel, paclitaxel, or capecitabine 
treatment should be managed according to standard medical practice and in accordance 
with the respective packaging insert.   
E.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients receiving atezolizumab: 
 
Systemic lupus erythematosus 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade  2 cardiac disorders  
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
297/Protocol ML42439, Version 5 
 
Myelitis 
 
Facial paresis  
 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
298/Protocol ML42439, Version 5 
E.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 TO 1 A 
(3) 
(3) 
28 days after last 
study dose 
Informed consent d 
x 
 
 
 
Documentation of TMB-H/ MSI-H/dMMR 
status by local test e 
x 
 
 
 
Medical history and baseline conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
Weight h 
x 
x 
 
 
ECOG Performance Status i 
x 
x 
 
x 
Pregnancy test j 
x 
x 
 
x 
Chemistry k 
x 
x 
 
x c 
Hematology/CBC with differential l 
x 
x 
 
x c 
Coagulation panel m 
x 
 
 
x 
Thyroid function test (TSH, free T3 [or 
total T3], free T4) 
x 
x 
 
x 
ECHO/MUGA n 
x 
As clinically indicated 
x  
Atezolizumab administration o 
 
x 
 
 
Chemotherapy administration p 
 
x 
see footnote p 
 
Response Assessment q, r 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) s 
 
Submit within 21 days of Cycle 1 Day 1 
 
 
Whole blood samples t 
x 
 
See footnote t 
 
Adverse events u  
x 
Collected on an ongoing basis 
x u 
Concomitant medications v 
x 
Collected on an ongoing basis 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
299/Protocol ML42439, Version 5 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; dMMRdeficient mismatch repair; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; 
eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular 
ejection fraction; MSI-Hmicrosatellite-high; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease;; 
RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious 
adverse event; TMB-Htumor mutational burden-high; TSH  thyroid-stimulating hormone. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if 
the chemistry panel and thyroid function test are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1.  Scans 
to document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post- chemotherapy 
discontinuation or 90 days post-atezolizumab discontinuation.  If the patient’s worsening disease combined with travel distance makes this 
visit too difficult, follow-up with the patient may take place by telephone to include an assessment of AEs.  Alternatively, the patient's local 
physician may be contacted to collect AE data and any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of TMB-H/MSI-H/dMMR status should occur prior to performing other trial-related eligibility assessments.  TMB-H should be 
determined using a tissue-based NGS assay.  
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), 
reproductive status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional 
supplements) used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any 
abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-
directed physical examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in 
patient notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline. 
i All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that 
a patient’s performance status be assessed by the same person throughout the study. 
 j Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
300/Protocol ML42439, Version 5 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients 
who have a positive pregnancy test must not receive study drug.   
k Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the 
first dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  
Subsequent chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
l Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). If results are obtained within 3 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.   
m Coagulation includes aPTT and INR. 
n LVEF assessment by ECHO or MUGA to be performed at screening, at end of treatment, and as clinically indicated.  Evaluation of LVEF 
must be performed by the same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and 
operator perform ECHO/MUGA scan for each individual patient. 
o The initial infusion of atezolizumab will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if 
the previous infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-
associated adverse event with the previous infusion. 
p Docetaxel, paclitaxel, or capecitabine will be administered per package insert and institutional guidelines, including considerations for 
premedication, supportive medications, infusion times, infusion frequency, and total cycle count. 
q All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do 
not have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
r At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic 
procedures every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, 
until investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors) or loss of clinical benefit 
(with Medical Monitor consultation; see Section 3.1.2), withdrawal of consent, termination of an individual study arm by the Sponsor, or 
death, whichever occurs first.   
s For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing. If both archival and 
recent tissue is available, the recent tissue should be preferentially submitted.   
t Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
301/Protocol ML42439, Version 5 
u After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of 
chemotherapy or 90 days after the final dose of atezolizumab, whichever is longer.  All patients will be followed until treatment-related 
toxicities resolve or for at least 28 days post-chemotherapy discontinuation or 90 days post-atezolizumab discontinuation, whichever is 
longer. After this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
 v Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the last dose of study 
treatment. 
 


Arm E:  Atezolizumab plus Chemotherapy in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
302/Protocol ML42439, Version 5 
E.7 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc 
Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. 
Up to Date [resource on the Internet]. 2014 [updated 29 October 2018; cited: 17 May 
2019]. Available from: https://www.uptodate.com/contents/clinical-features-and-diagnosis-
of-hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine 
release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag 
2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving PD-1-
directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. 
Blood 2015;125:290814. 
 


 
MyTACTIC Study—Genentech, Inc. 
303/Protocol ML42439, Version 5 
Appendix 15  
Arm F:  Trastuzumab Emtansine Plus Atezolizumab in Patients 
with ERBB2 Gene Amplification- or Mutation-Positive Tumors 
16. 
ARM F:  TRASTUZUMAB EMTANSINE PLUS ATEZOLIZUMAB IN 
PATIENTS WITH ERBB2 GENE AMPLIFICATION- OR 
MUTATION-POSITIVE TUMORS 
TABLE OF CONTENTS 
 
F.4 
Materials and Methods .................................................. 304 
F.4.1 
Patients ......................................................................... 304 
F.4.1.1 
Additional Inclusion Criteria ........................................... 304 
F.4.1.2 
Additional Exclusion Criteria .......................................... 305 
F.4.2 
Study Treatment ............................................................ 308 
F.4.2.1 
Formulation and Packaging........................................... 308 
F.4.2.2 
Dosage, Administration, and Compliance ..................... 309 
F.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ................................................................... 311 
F.4.3.1 
Permitted Therapy ......................................................... 311 
F.4.3.2 
Prohibited Therapy ........................................................ 312 
F.4.4 
Arm-specific Assessments ............................................ 313 
F.5 
Safety Plan .................................................................... 313 
F.5.1 
Risks Associated with Trastuzumab Emtansine plus 
Atezolizumab ................................................................. 314 
F.5.1.1 
Risks Associated with Trastuzumab Emtansine ............ 314 
F.5.1.2 
Risks Associated with Atezolizumab ............................. 314 
F.5.2 
Guidelines for Management of Adverse Events ............ 314 
F.5.2.1 
Dose Modifications and Interruptions ............................ 314 
F.5.2.2 
Guidelines for Management of Specific Adverse Events for 
Trastuzumab Emtansine ............................................... 315 
F.5.2.3 
Guidelines for Management of Specific Adverse Events 
Associated with Atezolizumab ....................................... 319 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
304/Protocol ML42439, Version 5 
F.5.2.4 
Guidelines for Management of Adverse Events that are 
Potential Overlapping Toxicities Associated with 
Trastuzumab Emtansine in Combination with Atezolizumab
 ...................................................................................... 320 
F.5.3 
Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor) .............................................................. 325 
F.6 
Schedule of Activities .................................................... 326 
F.7 
References .................................................................... 330 
  
F.4 
MATERIALS AND METHODS 
F.4.1 
Patients 
To be enrolled in Arm F:  trastuzumab emtansine plus atezolizumab treatment, patients 
must have met and continue to meet all general eligibility criteria (see Section 4.1), in 
addition to the arm-specific criteria below. 
F.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm F:  
trastuzumab emtansine plus atezolizumab treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants 
listed below: 
– 
Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; 
S310F/Y; C311R/S; E321G; C334S 
– 
Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; 
D769H/N/Y; Y772_A775dup; 
A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; 
V842I; N857S; T862A; L869R; H878Y; R896C 
– 
Transmembrane domain:  S653C; V659E; G660D; R678Q 
– 
GFR domain IV:  P551L; R552S 
– 
Receptor L:  S418T; A440T 
– 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently 
certified in-situ hybridization or NGS assay. Amplification is defined as a copy 
number of  6 for NGS assays or, for in-situ hybridization assays, as a 
HER2:CEP17 ratio  2.0 and average HER2 copy number/cell  4.0 signals/cell  


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
305/Protocol ML42439, Version 5 
 
ANC  1200/l within 14 days prior to initiation of study treatment 
 
For females of childbearing potential:  Negative serum pregnancy test 7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
7 months after the last dose of trastuzumab emtansine or 5 months after the last 
dose of atezolizuamb, whichever is longer; and agreement to refrain from donating 
eggs during this same period.  See Appendix 2 for details regarding requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of 1% per year during the treatment period and for at least 7 months 
after the last dose of trastuzumab emtansine and agreement to refrain from 
donating sperm during this same period.  See Appendix 2 for details regarding 
contraception requirements. 
 
F.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm F: trastuzumab emtansine plus atezolizumab treatment: 
 
Breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS 
assay, microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) 
status 
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
History of exposure to the following cumulative doses of anthracyclines as specified 
below: 
– 
Doxorubicin  500 mg/m2 
– 
Liposomal doxorubicin  500 mg/m2 
– 
Epirubicin  720 mg/m2 
– 
Mitoxantrone  120 mg/m2 
– 
Idarubicin  90 mg/m2 
If another anthracycline or more than one anthracycline has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
 
History of severe hypersensitivity to components of the trastuzumab emtansine 
formulation 
 
Cardiopulmonary dysfunction as defined by any of the following: 
– 
Uncontrolled hypertension (systolic 150 mmHg and/or diastolic 100 mmHg) 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
306/Protocol ML42439, Version 5 
– 
Inadequate left ventricular ejection fraction at baseline,  50% by 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
– 
History of symptomatic congestive heart failure Grade  3 per National Cancer 
Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI 
CTCAE v5.0)  
– 
History of decrease in left ventricular ejection function to  40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of enrollment 
– 
Current dyspnea at rest due to complications of advanced malignancy, or other 
disease requiring continuous oxygen therapy  
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade  2) relating to left ventricular ejection fraction 
(LVEF), cardiac arrhythmia, or cardiac ischemia  
– 
Serious cardiac arrhythmia not controlled by adequate medication 
 
Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, autoimmune hepatic disorders, or sclerosis cholangitis  
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium  upper limit of normal [ULN]) 
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
– 
Patients with a history of HCV infection but who are negative for HCV RNA by 
PCR will be considered non-infected with HCV 
 
Grade  3 peripheral neuropathy, as defined by NCI CTCAE v5.0 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid replacement hormone are eligible for the study 
– 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
307/Protocol ML42439, Version 5 
o Rash must cover  10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids 
within the previous 12 months 
 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
 
Uncontrolled tumor-related pain 
– 
Patients requiring pain medication must be on a stable regimen at study entry 
– 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated  14 days 
prior to Cycle 1, Day 1.  The patient must have recovered from any resulting 
acute toxicity (to Grade  1) prior to study treatment initiation 
– 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment 
 
Symptomatic pleural effusion, pericardial effusion, or ascites.  History of idiopathic 
pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography (CT) 
scan.  Patients with a history of radiation pneumonitis in the radiation field (fibrosis) 
are eligible.  
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible 
for the study 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the final dose of atezolizumab 
 
Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of study treatment 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
308/Protocol ML42439, Version 5 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor-alpha (TNF-α) agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 
80 or 20 or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
 
F.4.2 
Study Treatment 
Study treatment in this arm will consist of atezolizumab in combination with trastuzumab 
emtansine.  
F.4.2.1 
Formulation and Packaging 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
Trastuzumab emtansine is provided as a lyophilized product in either 15-mL or 20-mL 
single-use vials which contain enough product to deliver 100 mg or 160 mg, respectively, 
of trastuzumab emtansine.  The lyophilized form of the product is provided for 
reconstitution to a liquid concentrate using sterile water for injection.  After reconstitution, 
both the 15-mL and 20-mL vials contain 20 mg/mL trastuzumab emtansine, 10 mM 
sodium succinate, pH 5.0, 6% w/v sucrose, and 0.02% (w/v) polysorbate 20.  The 
reconstituted product contains no preservative and is intended for single use only.  The 
density of the drug product after reconstitution is 1.026 g/mL.  


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
309/Protocol ML42439, Version 5 
For information on the formulation and handling of trastuzumab emtansine, see the 
pharmacy manual and the Trastuzumab Emtansine Investigator's Brochure. 
F.4.2.2 
Dosage, Administration, and Compliance 
Atezolizumab will be administered first followed by trastuzumab emtansine.  
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical 
benefit with Medical Monitor consultation, see Section 3.1.2 for treatment beyond 
disease progression).   
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.  The size of 
the infusion bag for each dose is listed below and will accommodate fluid restrictions 
needed for smaller patients. 
Administration of atezolizumab will be performed in a monitored setting where there is 
access to trained personnel and adequate equipment/medicine to manage potentially 
serious reactions.  For anaphylaxis precautions, see Appendix 6.  Atezolizumab 
infusions will be administered per the instructions outlined in Table 1. 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
310/Protocol ML42439, Version 5 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 No premedication is permitted prior to 
the atezolizumab infusion. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) 
should be measured within 60 minutes 
prior to the infusion a 
 Atezolizumab should be infused over 
60 (15) minutes. 
 If clinically indicated, vital signs should 
be measured every 15 (5) minutes 
during the infusion and at 
30 (10) minutes after the infusion. a 
 Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact 
their study physician if they develop 
such symptoms. 
 If the patient experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, antipyretics, 
and/or analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 Vital signs should be measured within 
60 minutes prior to the infusion. a 
 Atezolizumab should be infused over 30 (10) 
minutes if the previous infusion was tolerated 
without an infusion-related reaction, or 60 
(15) minutes if the patient experienced an 
infusion-related reaction with the previous 
infusion. 
 If the patient experienced an infusion-related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
measured during the infusion and at 
30 (10) minutes after the infusion. a 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  Record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Section E.5.2.2.7 for atezolizumab. 
No dose modification for atezolizumab is allowed. 
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 
21 days (unless dose reduction and/or dose delays are required) until disease 
progression or unacceptable toxicity (or loss of clinical benefit with Medical Monitor 
consultation when given in combination with atezolizumab; Section 3.1.2 for treatment 
beyond disease progression).  The dose of trastuzumab emtansine will be administered 
on the basis of the patient’s baseline weight.  Weight will be measured at each visit and 
dose must be re-adjusted for weight changes  10% compared to the previous visit or 
baseline.  The investigator may choose to recalculate the dose at every cycle using 
actual weight at that time, according to their local practice.  The calculated total dose 
may be rounded to the nearest milligram.   
Trastuzumab emtansine infusions will be administered per the instructions outlined in 
Table 2.The initial dose will be administered over 90 minutes.  Infusions may be slowed 
or interrupted for patients experiencing infusion-associated symptoms.  Vital signs must 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
311/Protocol ML42439, Version 5 
be assessed predose and postdose.  Following the initial dose, patients will be observed 
for at least 90 minutes.  Subsequent doses of trastuzumab emtansine may be 
administered over 30 minutes. Guidelines for medical management of infusion-related 
reactions (IRRs) are provided in Section F.5.2.2.4. 
If a delay in administration of either agent is necessary, reasonable effort should be 
made to keep the administration synced if clinically feasible (e.g., briefly delay 
administration of the other agent). A cycle should be considered to start when any drug 
is administered.   
Table 2 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine 
First Infusion 
Subsequent Infusions 
 No premedication is administered. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured a 
 Administer the initial dose as a 90-
minute intravenous infusion.  
 Patients should be observed during the 
infusion and for at least 90 minutes 
following the initial dose for fever, chills, 
or other infusion related reactions. 
 The infusion rate should be slowed or 
interrupted if the patient develops 
infusion-related symptoms 
 The infusion site should be closely 
monitored for possible subcutaneous 
infiltration during drug administration. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured a 
 If prior infusions were well tolerated, 
subsequent doses may be administered 
as 30-minute infusions  
 Patient should be observed during the 
infusions and for at least 30 minutes after 
infusion. 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  Record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF 
 
F.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
F.4.3.1 
Permitted Therapy 
Use of the following therapies is permitted during the study: 
 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
312/Protocol ML42439, Version 5 
 
Patients on anti-coagulant treatment should have their platelet count monitored 
closely during treatment with trastuzumab emtansine. 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section F.4.3.2) 
 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for COPD or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Bisphosphonates for the prevention or delay of skeletal complications, and palliation 
of bone pain in patients with documented bone metastases.  Use bisphosphonates 
or other agents for hypercalcemia or malignancy is prohibited and patients requiring 
such treatment should be evaluated for progressive disease.   
 
Erythropoiesis-stimulating agents or granulocyte colony-stimulating factors 
 
Radiation therapy for the treatment of bone pain for bone metastases in the 
absence of progressive disease  
 
Premedication with antihistamines, antipyretics, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, as 
clinically indicated.  
Other medications considered necessary for the patient’s safety and well-being may be 
given at the discretion of the investigator. 
F.4.3.2 
Prohibited Therapy 
Use of the following therapy is prohibited during study treatment: 
 
Any systemic therapy intended for the treatment of the disease under study, 
including any other investigational agent 
 
Concomitant use of potent cytochrome (CYP) P450 3A4/5 inhibitors (such as 
ketoconazole and itraconazole) with trastuzumab emtansine should be avoided.  
Consider an alternate medication with no or minimal potential to inhibit CYP3A4/5.  
If a strong CYP3A4/5 inhibitor needs to be co-administered with trastuzumab 
emtansine, patients should be closely monitored for adverse reactions. 
 
Any hormonal therapy used for the treatment of the disease under study.  Patients 
who require the use of these agents will be discontinued from study treatment. 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
313/Protocol ML42439, Version 5 
Section 4.1.2), and during study treatment, until disease progression is documented 
and the patient has discontinued study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after 
the final dose of atezolizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-
2) are prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
within 2 weeks prior to the initiation of study treatment and during study treatment 
because these agents could potentially alter the efficacy and safety of atezolizumab. 
 
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, magnetic resonance imaging (MRI) scans of the chest, abdomen, and 
pelvis with a non-contrast CT scan of the chest must be performed. 
 
F.4.4 
Arm-specific Assessments
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients receiving trastuzumab emtansine plus 
atezolizumab.  Refer to the schedule of activities (Section F.6) for arm-specific 
assessment timepoints.
Local Laboratory Assessments
 
Coagulation:  INR and aPTT
 
Thyroid function test (thyroid-stimulating hormone [TSH], free triiodothyronine (T3)
(or total T3 for sites where free T3 is not performed), and free thyroxine (T4)
 
Functional Assessments 
 
LVEF assessment:  echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
 
F.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm F: trastuzumab emtansine 
plus atezolizumab treatment. 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
314/Protocol ML42439, Version 5 
F.5.1 
Risks Associated with Trastuzumab Emtansine plus 
Atezolizumab 
F.5.1.1 
Risks Associated with Trastuzumab Emtansine 
Trastuzumab emtansine has been associated with risks such as the following: 
hepatotoxicity, (predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases; serious hepatobiliary disorders, including 
nodular regenerative hyperplasia (NRH) of the liver), left ventricular dysfunction, 
infusion-related reaction (IRR), hypersensitivity, hemorrhagic events, (including CNS, 
respiratory, and gastrointestinal hemorrhage), thrombocytopenia, peripheral neuropathy, 
reactions secondary to extravasation, and interstitial lung disease (including 
pneumonitis).  Refer to the Trastuzumab Emtansine Investigator’s Brochure for a 
description of all anticipated safety risks for trastuzumab emtansine. 
F.5.1.2 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to the 
Atezolizumab Investigator's Brochure for a detailed description of anticipated safety risks 
for atezolizumab.  
Suggested workup and management guidelines for overlapping toxicities between 
atezolizumab and trastuzumab emtansine, pulmonary and hepatic events, are provided 
in Section F.5.2.4. 
F.5.2 
Guidelines for Management of Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
F.5.2.1 
Dose Modifications and Interruptions 
F.5.2.1.1 
Dose Modifications and Interruptions for Trastuzumab 
Emtansine 
For adverse events not listed below in Section F.5.2.2 the following guidance should be 
used with regards to dose delays and modifications: 
 
For Grade 3 non-hematologic adverse events not adequately managed by standard 
medical intervention or for any Grade 4 non-hematologic adverse event, study 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
315/Protocol ML42439, Version 5 
treatment should be held until recovery to Grade  1.  A maximum dose delay of 
42 days for the last administered dose of study drug will be allowed.  
 
If withheld for 42 days, trastuzumab emtansine may be resumed at either the same 
dose level as before or at one dose level lower (see Table 3), at the discretion of the 
investigator.  Subsequent cycles should remain every 21 days. 
 
Dose re-escalation is not permitted for trastuzumab emtansine. 
 
Resuming trastuzumab emtanzine after 42 days may be considered in exceptional 
circumstances and should be done in consultation with the Medical Monitor. 
 
Table 3 
Recommended Dose Reduction Schedule for Trastuzumab 
Emtansine 
Dose Reduction Schedule 
Dose Level 
Starting dose 
3.6 mg/kg 
First dose reduction 
3 mg/kg 
Second dose reduction 
2.4 mg/kg 
Requirement for further dose reduction 
Permanently discontinue 
 
F.5.2.1.2 
Dose Modifications and Interruptions for Atezolizumab 
No dose reductions for atezolizumab are allowed.  Interruptions to atezolizumab 
treatment are described in Section E.5.2.1.1. 
F.5.2.2 
Guidelines for Management of Specific Adverse Events for 
Trastuzumab Emtansine 
F.5.2.2.1 
Hepatotoxicity  
Hepatotoxicity is an overlapping toxicity for trastuzumab emtansine and atezolizumab.  
Management guidelines are provided in, Section F.5.2.4.2. 
F.5.2.2.2 
Pulmonary Toxicity 
Pulmonary Toxicity is an overlapping toxicity for trastuzumab emtansine and 
atezolizumab.  Management guidelines are provided in Section F.5.2.4.1. 
F.5.2.2.3 
Cardiotoxicity  
Patients without significant cardiac history and with a baseline LVEF of  50% as 
determined by ECHO or MUGA scan are eligible for arm participation.  Cardiac 
monitoring (ECHO/MUGA) will be performed in all patients enrolled in this arm.  
Assessments will occur during the screening period, and on Day 15 of Cycle 1, and 
every fourth cycle thereafter.  ECHO or MUGA will be performed following study 
treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
316/Protocol ML42439, Version 5 
28 days before last study treatment administration and if no post-treatment evaluation 
was performed (see Section F.6).
Figure 1 summarizes the management of trastuzumab emtansine on the basis of LVEF 
measurements and changes in LVEF from baseline in patients.  If an investigator is 
concerned that an adverse event may be related to cardiac dysfunction, an additional 
LVEF measurement may be performed.  Trastuzumab emtansine will be discontinued in 
any patient who develops symptomatic CHF.  CHF should be treated and monitored 
according to standard medical practice.
The decision to stop or continue trastuzumab emtansine treatment should be on the 
basis of the algorithm shown in Figure 1 or asymptomatic declines in LVEF. 
Trastuzumab emtansine must be discontinued in all patients for whom a confirmed 
decrease of LVEF to   40% is documented (with a confirmation assessment carried out 
within 21 days).  For patients whose LVEF decreases to values of 40%45% with an 
absolute decrease in LVEF of  10% points from baseline, trastuzumab emtansine dose 
should be held.  For these patients, the LVEF measurement should be repeated within 
21 days, and trastuzumab emtansine treatment should be discontinued if the LVEF has 
not recovered to within a 10% absolute difference below baseline.  If clinically significant 
cardiac dysfunction or cardiac failure develops or persists or if significant medical 
management is required to maintain LVEF, the patient should be discontinued from all 
study treatment.




Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
318/Protocol ML42439, Version 5 
Table 4 
Management Guidelines for Trastuzumab Emtansine Infusion-
Related Reactions (Caused by Cytokine Release) or 
Hypersensitivity (Allergic) Reaction 
Event 
Action to Be Taken  
Grade 2 reaction  
Decrease trastuzumab emtansine infusion rate or interrupt infusion.  
Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s 
discretion.  Monitor patient until complete resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at the 
investigator’s discretion.  In the event of a true hypersensitivity reaction 
(in which severity of reaction increases with subsequent infusions), 
discontinue trastuzumab emtansine. 
Premedication for infusion reactions (e.g., antihistamines such as 
diphenhydramine or corticosteroids) may be given at the investigator’s 
discretion. 
Grade 3 reaction  
Stop trastuzumab emtansine infusion.  Administer supportive care with 
oxygen, -agonists, antihistamines, antipyretics, or corticosteroids, 
as appropriate, at the investigator’s discretion.  Monitor patient until 
complete resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at the 
investigator’s discretion.  In the event of a true hypersensitivity reaction 
(in which severity of reaction increases with subsequent infusions), 
discontinue trastuzumab emtansine.   
Premedication for infusion reactions (e.g., antihistamines such as 
diphenhydramine or corticosteroids) may be given at the investigator’s 
discretion.  
Grade 4 reaction 
Stop trastuzumab emtansine infusion.  Administer supportive care with 
oxygen, β-agonists, antihistamines, antipyretics, or corticosteroids, as 
appropriate, at the investigator’s discretion.  Monitor patient until 
complete resolution of symptoms. 
Discontinue trastuzumab emtansine. 
 
F.5.2.2.5 
Hematologic Toxicities 
See Table 5 for trastuzumab emtansine dose modification guidelines for hematological 
toxicities, including thrombocytopenia. 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
319/Protocol ML42439, Version 5 
Table 5 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hematological Toxicity 
Event 
Action to Be Taken 
Grade 2 thrombocytopenia 
(50,000 to 75,0000/L) 
Assess platelet counts weekly or as medically indicated until 
recovery.  Withhold study treatment until Grade  1.  Resume 
treatment without dose reduction.   
Grade 3 thrombocytopenia 
(25,000 to < 50,000/μL) 
Withhold trastuzumab emtansine until recovery to Grade  1 
(≥ 75,000/μL).  Following recovery, resume trastuzumab 
emtansine at the same dose level.  Discontinue trastuzumab 
emtansine if the event has not resolved to Grade   1 within 
42 days after the last dose received. 
Grade 4 thrombocytopenia 
(< 25,000/μL) at any time 
Withhold trastuzumab emtansine until recovery to Grade  1 
(≥ 75,000/μL).  Following recovery, resume trastuzumab 
emtansine with one dose level reduction.  Discontinue 
trastuzumab emtansine if the event has not resolved to 
Grade ≤ 1 within 42 days after the last dose received. 
Grade ≥ 3 hematologic toxicity 
other than thrombocytopenia 
Withhold trastuzumab emtansine until recovery to Grade  2.  
Following recovery, resume trastuzumab emtansine at the 
same dose level.  Discontinue trastuzumab emtansine if the 
event has not resolved to Grade  2 within 42 days after the 
last dose received. 
 
F.5.2.2.6 
Neuropathy 
See Table 6 for trastuzumab emtansine dose modification guidelines for neuropathy. 
Table 6 
Trastuzumab Emtansine Dose Modification Guidelines for 
Neuropathy 
Event 
Action to Be Taken 
Grade ≥ 3 peripheral 
neuropathy 
Withhold trastuzumab emtansine until recovery to Grade ≤ 2.  
Following recovery, resume trastuzumab emtansine at the 
same dose level or with one dose level reduction, at the 
investigator's discretion.  Discontinue trastuzumab emtansine 
if the event has not resolved to Grade ≤ 2 within 42 days after 
the last dose received. 
 
F.5.2.3 
Guidelines for Management of Specific Adverse Events 
Associated with Atezolizumab 
Guidelines for management of specific adverse events associated with atezolizumab can 
be found in Section E.5.2.2.  


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
320/Protocol ML42439, Version 5 
F.5.2.4 
Guidelines for Management of Adverse Events that are 
Potential Overlapping Toxicities Associated with Trastuzumab 
Emtansine in Combination with Atezolizumab  
The following adverse events are potential overlapping toxicities associated with 
combination use of trastuzumab emtansine and atezolizumab:  pulmonary and 
hepatic events.   
F.5.2.4.1 
Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (diffusion capacity of the lung for carbon monoxide) 
 
Pulmonary function testing with a pulmonary embolism protocol 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study, and 
will also have CT scans of the chest at every tumor assessment.  COVID-19 evaluation 
should be performed per institutional guidelines where relevant.  See Table 7 for 
management guidelines for pulmonary events and pneumonitis.  
In this study, atezolizumab and trastuzumab emtansine are discontinued for all grades of 
interstitial lung disease and pneumonitis. 
Table 7 
Management Guidelines for Interstitial Lung Disease and 
Pneumonitis 
Severity 
Trastuzumab Emtansine 
Atezolizumab 
Grade 1  4 
Discontinue trastuzumab 
emtansine treatment. 
Discontinue atezolizumab 
treatment 
 
F.5.2.4.2 
Hepatic Events 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases.  Liver function will be monitored throughout 
study treatment. 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
321/Protocol ML42439, Version 5 
While on this study, patients who present with right upper-quadrant abdominal pain 
and/or unexplained nausea or vomiting should have liver function tests (LFTs) performed 
immediately and reviewed before administration of the next dose of study drug. 
If outcome of LFTs is worsening, concurrent medications, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.  Imaging of 
the liver, gall bladder, and biliary tree should be performed to rule out neoplastic or other 
causes for worsening outcome of LFTs.  Antinuclear antibody, perinuclear antineutrophil 
cytoplasmic antibody, anti-liver kidney microsomal antibodies, and anti-smooth muscle 
antibody tests should be performed if an autoimmune etiology is considered.  See 
Table 8 for management guidelines for atezolizumab and trastuzumab emtansine 
hepatic events. 
See Table 8 for Management Guidelines for Increased Transaminases (AST/ALT) and 
Hepatic Events.  See Table 9 for dose modifications of trastuzumab emtansine for 
hyperbilirubinemia. 
Note:  No dose modification for atezolizumab is indicated on the basis of 
hyperbilirubinemia alone. 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
322/Protocol ML42439, Version 5 
Table 8 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events 
Severity 
Atezolizumab 
Trastuzumab 
Emtansine 
ALT or AST increase that 
meets Hy's law criteria:  ALT 
or AST  3  ULN, in 
combination with TBILI 
 2  ULN or clinical jaundice 
Discontinue atezolizumab 
treatment. 
Discontinue 
trastuzumab emtansine 
treatment. 
Grade 1  
AST or ALT 
 ULN3.0  ULN if 
baseline was normal; 
1.53.0  baseline if baseline 
was abnormal  
 
Treat at the same dose level. 
Continue LFT monitoring. 
Treat at the same dose 
level. 
Grade 2  
AST or ALT 
 3.05.0  ULN if baseline 
was normal; 
 3.05.0  baseline if 
baseline was abnormal 
 
Withhold atezolizumab dose. 
If persists  57 days:  Consider 
starting 12 mg/kg/day 
prednisone or equivalent per 
day; when recover to Grade  1, 
taper steroids over  1 month. 
Resume therapy when systemic 
steroid dose is  10mg oral 
prednisone equivalent per day 
and resume when recovery to 
Grade  1 at same dose within 
12 weeks. 
Permanently discontinue 
atezolizumab and contact the 
Medical Monitor if event does not 
resolve to Grade 1 or better 
within 12 weeks. 
Treat at the same dose 
level. 
GI   gastrointestinal; LFT  liver function test; NRH    Nodular Regenerative 
Hyperplasia; TNF    tumor necrosis factor; ULN    upper limit of normal.  
 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
323/Protocol ML42439, Version 5 
Table 8 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Atezolizumab 
Trastuzumab 
Emtansine 
Grade 3  
AST or ALT 
 5.020.0  ULN if baseline 
was normal; 
 5.020.0  baseline if 
baseline was abnormal  
 
Discontinue atezolizumab dose. 
Consider GI consult and liver 
biopsy to establish etiology of 
hepatic injury if necessary. 
Start 60 mg prednisone or 
equivalent per day. 
If LFT results do not decrease 
within 48 hours after initiation of 
systemic steroids, addition of an 
alternative immunosuppressive 
agent (e.g., mycophenolate or 
TNF- antagonist) may be 
considered. 
Taper steroids over  1 month, 
when symptoms improve to Grade 
0 or Grade 1. 
Contact the Medical Monitor if 
atezolizumab treatment is 
discontinued. 
Withhold trastuzumab 
emtansine dose. 
Do not administer 
trastuzumab emtansine 
until recovery to Grade  2, 
and then resume with dose 
reduction by one level.  
Discontinue trastuzumab 
emtansine treatment if the 
event has not resolved to 
Grade  2 within 42 days 
after the last dose 
received. 
Grade 4 
AST or ALT  20.0  ULN if 
baseline was normal; 
 20.0  baseline if baseline 
was abnormal  
 
Discontinue atezolizumab 
treatment. 
Consider GI consult and liver 
biopsy to establish etiology of 
hepatic injury if necessary. 
Start 60 mg prednisone or 
equivalent per day. 
If LFT results do not decrease 
within 48 hours after initiation of 
systemic steroids, addition of an 
alternative immunosuppressive 
agent (e.g., mycophenolate or 
TNF- antagonist) may be 
considered. 
Taper steroids over  1 month, 
when symptoms improve to Grade 
0 or Grade 1.  
Contact the Medical Monitor if 
atezolizumab treatment is 
discontinued. 
Discontinue trastuzumab 
emtansine treatment. 
Laboratory tests may be 
repeated (within 24 hours) 
to exclude laboratory error 
prior to discontinuing 
trastuzumab emtansine. 
GI   gastrointestinal; LFT  liver function test; NRH    Nodular Regenerative Hyperplasia; 
TNF    tumor necrosis factor; ULN    upper limit of normal.  
 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
324/Protocol ML42439, Version 5 
Table 8 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Atezolizumab 
Trastuzumab 
Emtansine 
NRH 
If there are signs of 
portal hypertension 
(e.g., ascites and/or 
varices) and/or a 
cirrhosis-like pattern 
is seen on a CT 
scan of the liver, the 
possibility of NRH 
should be 
considered.   
Discontinue atezolizumab treatment 
Discontinue trastuzumab 
emtansine treatment and have 
the patient evaluated by a 
hepatologist. 
GI   gastrointestinal; LFT  liver function test; NRH    Nodular Regenerative 
Hyperplasia; TNF    tumor necrosis factor; ULN    upper limit of normal.  
 
Table 9 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hyperbilirubinemia  
Severity 
Action to be Taken 
Grade 2 
Total bilirubin 
 1.53.0  ULN if baseline 
was normal; 
 1.53.0  baseline if 
baseline was abnormal 
 
Withhold until total bilirubin recovers to Grade  1 and then 
resume at the same dose level. 
Grade 3 
Total bilirubin 
 3.0 - 10.0  ULN if 
baseline was normal; 
 3.010.0  baseline if 
baseline was abnormal 
Withhold until total bilirubin recovers to Grade  1 and then 
resume by one dose level reduction.   
Grade 4 
Total bilirubin  10.0  ULN 
if baseline was normal; 
 10.0  baseline if baseline 
was abnormal 
Discontinue trastuzumab emtansine treatment. 
ULN   upper limit of normal. 
 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification- 
or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
325/Protocol ML42439, Version 5 
F.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, for Arm F, the following adverse events are required 
to be reported by the investigator immediately:   
Atezolizumab 
 
Systemic lupus erythematosus 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade 2 cardiac disorders  
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  
 
Trastuzumab Emtansine 
 
Not Applicable 
 
 


 
MyTACTIC Study—Genentech, Inc. 
326/Protocol ML42439, Version 5 
F.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 a 
(3) 
(3) 
≤ 28 days after last 
study dose 
Informed consent d 
x 
 
 
 
Documentation of positive ERBB2 gene mutation 
or amplification by local test e 
x 
 
 
 
Medical history and baseline conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
Weight h 
x 
x 
 
 
ECOG Performance Status i 
x 
x 
 
x 
Pregnancy test j 
x 
x 
 
x 
Chemistry k  
x 
x 
 
 x c 
Hematology/CBC with differential l 
x 
x 
 
x c 
Coagulation Panel m 
x 
 
 
x 
Thyroid function test (TSH, free T3 [or total], and 
free T4) n 
x 
C1, D1 and every 4 cycles 
thereafter 
 
 
ECHO or MUGA o 
x 
As clinically indicated  
C1, D15 and every 4 
cycles thereafter  
x o 
Atezolizumab administration p 
 
x 
 
 
Trastuzumab emtansine administration q 
 
x 
 
 
Response Assessments r, s 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 
(2) weeks 
 
Pre-treatment tumor tissue sample for central 
testing (if applicable) t 
 
Submit within 21 days  
of C1, D1 
 
 
Whole blood samples u  
x 
 
see footnote u 
 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
327/Protocol ML42439, Version 5 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 a 
(3) 
(3) 
≤ 28 days after last 
study dose 
Adverse events v 
x  
Collected on an ongoing basis 
x v 
Concomitant Medications w 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; dMMRdeficient mismatch repair; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; 
eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection 
fraction; MSI-Hmicrosatellite-high; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; 
PETpositron emission tomography; RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid 
Tumors, Version 1.1; SAEserious adverse event; TMB-Htumor mutational burden-high; TSH  thyroid-stimulating hormone. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done  28 days prior to initiation of treatment.  However, if the 
hematology/CBC, chemistry panel, and thyroid function test are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 
1.  Scans to document measurable or evaluable disease (i.e., tumor measurement) should be performed  4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment follow-
up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-trastuzumab emtansine 
discontinuation or 90 days post-atezolizumab discontinuation, whichever is longer.  If the patient’s worsening disease combined with travel 
distance makes this visit too difficult, follow-up with the patient may take place by telephone to include an assessment of AEs.  Alternatively, the 
patient's local physician may be contacted to collect AE data and any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive ERBB2 gene mutation or amplification without known TMB-H/MSI-H/dMMR status should occur prior to performing other 
trial-related eligibility assessments. 
f  Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
328/Protocol ML42439, Version 5 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline. 
i  All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
j  Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a serum 
pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who have a 
positive pregnancy test must not receive study drug.   
k Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, total 
bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first dose of 
study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent chemistry 
evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
l  Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.   
m Coagulation includes INR and aPTT. 
n TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every four cycles 
thereafter (i.e., Cycles 5, 9, 13, etc.). 
o LVEF assessments will occur during the screening period, and on Day 15 of Cycle 1, every fourth cycle thereafter (e.g. C5D15, C9D15, etc.).  
ECHO or MUGA will be performed following study treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed 28 
days before last study treatment administration and if no post-treatment evaluation was performed.  Evaluation of LVEF must be performed by the 
same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and operator perform ECHO/MUGA scan 
for each individual patient. 
p Atezolizumab will be administered first by IV infusion at a dose of 1200 mg on Cycle 1, and on Day 1 of each 21-day cycle thereafter.  For the first 
infusion of atezolizumab, vital signs should be determined within 60 minutes before, every 15 ( 5) minutes during, and 30 ( 10) minutes after the 
infusion, if clinically indicated.  For subsequent infusions, vital signs do not need to be obtained during the infusion if the prior infusion was 
tolerated without symptoms.   
q Trastuzumab emtansine will be administered second by IV infusion at a dose of 3.6 mg/kg on Day 1 of Cycle 1, and on Day 1 of each 21-day 
cycle thereafter.  Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
329/Protocol ML42439, Version 5 
related adverse events, over approximately 30 minutes in subsequent doses.  Vital signs should be taken before and after the trastuzumab 
emtansine infusion.  Patients will be monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine 
infusion and, in the absence of infusion-related events, for a minimum of 30 minutes at subsequent infusions. 
r  All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), 
a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  A CT or MRI scan 
of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or refute the diagnosis of 
CNS metastases at baseline in the event of an equivocal scan.   
s At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 ( 1) weeks for 3 evaluations, then every 12 ( 2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors)(or loss of clinical benefit with 
Medical Monitor consultation, see Section 3.1.2), withdrawal of consent, termination of an individual study arm by the Sponsor, or death, 
whichever occurs first.   
t  For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
u Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   
v After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of trastuzumab 
emtansine or 90 days after the final dose of atezolizumab, whichever is longer.  All patients will be followed until treatment-related toxicities 
resolve or for at least 28 days post-trastuzumab emtansine discontinuation or 90 days post-atezolizumab discontinuation, whichever is longer.  
After this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
w Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the last dose of study treatment. 


Arm F:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Mutant-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
330/Protocol ML42439, Version 5 
F.7 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc 
Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. 
Up to Date [resource on the Internet]. 2014 [updated 29 October 2018; cited: 17 May 
2019]. Available from: https://www.uptodate.com/contents/clinical-features-and-diagnosis-
of-hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine 
release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag 
2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving 
PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. 
Blood 2015;125:290814. 
 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
331/Protocol ML42439, Version 5 
Appendix 16  
Arm G:  PH FDC SC in Patients with ERBB2 Gene 
Amplification- or Mutation-Positive Tumors 
17. 
ARM G:  PH FDC SC IN PATIENTS WITH ERBB2 GENE 
AMPLIFICATION- OR MUTATION-POSITIVE TUMORS 
TABLE OF CONTENTS 
 
G.4 
Materials and Methods .................................................. 332 
G.4.1 
Patients ......................................................................... 332 
G.4.1.1 
Additional Inclusion Criteria ........................................... 332 
G.4.1.2 
Additional Exclusion Criteria .......................................... 333 
G.4.2 
Study Treatment ............................................................ 334 
G.4.2.1 
Formulation and Packaging........................................... 334 
G.4.2.2 
Dosage, Administration, and Compliance ..................... 334 
G.4.3 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ................................................... 335 
G.4.3.1 
Permitted Therapy ......................................................... 335 
G.4.3.2 
Cautionary Therapy ....................................................... 336 
G.4.3.3 
Prohibited Therapy ........................................................ 336 
G.4.4 
Arm-specific Assessments ............................................ 337 
G.5 
Safety Plan .................................................................... 337 
G.5.1 
Risks Associated with PH FDC SC ............................... 337 
G.5.2 
Management of Patients Who Experience Adverse 
Events ........................................................................... 338 
G.5.2.1 
Dose Modifications and Interruptions for PH FDC SC ... 338 
G.5.2.2 
Guidelines for Management of Specific Adverse 
Events Associated with PH FDC SC ............................. 338 
G.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ........................................... 340 
G.5.4 
Reporting for Selected Adverse Events ........................ 341 
G.5.4.1 
Heart Failure ................................................................. 341 
G.5.4.2 
Asymptomatic Declines in Left Ventricular Ejection 
Fraction ......................................................................... 341 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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G.5.4.3 
Administration-Related Reactions: Injection-Related 
Reactions and Injection-Site Reactions ......................... 342 
G.6 
Schedule of Activities .................................................... 344 
 
G.4 
MATERIALS AND METHODS 
G.4.1 
Patients 
To be enrolled in Arm G:  fixed dose combination of trastuzumab and pertuzumab 
administered subcutaneously (PH FDC SC) treatment, patients must have met and 
continue to meet all general eligibility criteria (see Section 4.1), in addition to the arm-
specific criteria below. 
G.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm G:  PH 
FDC SC treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants 
listed below: 
– 
Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; 
S310F/Y; C311R/S; E321G; C334S 
– 
Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; 
D769H/N/Y; Y772_A775dup; 
A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; 
V842I; N857S; T862A; L869R; H878Y; R896C 
– 
Transmembrane domain:  S653C; V659E; G660D; R678Q 
– 
GFR domain IV:  P551L; R552S 
– 
Receptor L:  S418T; A440T 
– 
Other applicable mutations are eligible with Medical Monitor approval 
 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently 
certified in-situ hybridization or NGS assay. Amplification is defined as a copy 
number of  6 for NGS assays or, for in-situ hybridization assays, as a 
HER2:CEP17 ratio  2.0 and average HER2 copy number/cell  4.0 signals/cell  
 
Intact skin at planned site of subcutaneous (SC) injections (thigh) 
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Baseline and most recent (within 3 months) left ventricular ejection fraction (LVEF) 
 50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan 
(MUGA)  


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 7 
months after the last dose of PH FDC SC; and agreement to refrain from donating 
eggs during this same period.  See Appendix 2 for details regarding contraception 
requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of 1% per year during the treatment period and for at least 7 months 
after the last dose of PH FDC SC, and agreement to refrain from donating sperm 
during this same period.  See Appendix 2 for details regarding contraception 
requirements. 
 
G.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm G: PH FDC SC treatment:  
 
Breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS 
assay, microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) 
status 
 
History of National Cancer Institute Common Terminology Criteria for Adverse 
Events version 5.0 (NCI CTCAE v5.0) Grade  3 symptomatic congestive heart 
failure (CHF)  
 
In addition to the core exclusion criterion for significant cardiovascular disease (see 
Section 4.1.2), patients will be excluded if they have any of the following:  
– 
High-risk arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at rest, 
significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz 
type II] or third-degree AV-block) not controlled by adequate medication 
– 
Evidence of transmural infarction on ECG 
– 
Evidence of myocardial infarction within 12 months prior to enrollment, 
cerebrovascular accident within 3 months prior to enrollment 
– 
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 
mmHg) 
– 
Angina pectoris requiring anti-angina medication 
– 
Clinically significant valvular heart disease 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], 
left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 


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demonstrated by diagnostic testing), clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome 
 
Known active liver disease, for example, autoimmune hepatic disorders, or 
sclerosing cholangitis 
 
Current treatment with anti-viral therapy for HBV 
 
Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins 
 
Previously experienced severe injection related reactions with pertuzumab plus 
trastuzumab IV and/or PH FDC SC 
 
Current chronic daily treatment with corticosteroids (dose  10 mg 
methylprednisolone or equivalent excluding inhaled steroids) 
 
G.4.2 
Study Treatment  
Study treatment in this arm will consist of PH FDC SC. 
G.4.2.1 
Formulation and Packaging 
PH FDC SC will be provided in two configurations:  a loading dose configuration and 
maintenance dose configuration as single vials:  
 
Loading dose: a sterile solution for injection containing L-histidine hydrochloride, 
trehalose, sucrose, polysorbate 20, methionine, and rHuPH20 (2,000 U/mL).  Each 
single use 20 mL glass colourless vial contains 1200 mg of pertuzumab and 600 mg 
of trastuzumab in 15 mL of solution. 
 
Maintenance dose: a sterile solution for injection containing L-histidine 
hydrochloride, trehalose, sucrose, polysorbate 20, methionine, and rHuPH20 
(2,000 U/mL).  Each single use 15 mL colourless glass vial contains 600 mg of 
pertuzumab and 600 mg of trastuzumab in 10 mL of solution. 
 
For information on the packaging, handling and storage of PH FDC SC, see the 
Pharmacy Manual and PH FDC SC Investigator's Brochure. 
G.4.2.2 
Dosage, Administration, and Compliance 
Study treatment will be administered in 21-day cycles.   
PH FDC SC is given as a fixed dose (i.e. non-weight based).  Two doses of PH FDC SC 
may be administered in the study:  a 15 mL loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab and a 10 mL maintenance dose consisting of 
600 mg pertuzumab and 600 mg trastuzumab.  Patients who have had  6 weeks since a 
prior dose of Perjeta and Herceptin intravenous (IV) or PH FDC subcutaneous (SC) at 
study entry, or have had  6 weeks since their last study treatment during the study 
treatment periods, must receive a loading dose before continuing with maintenance 
doses for subsequent administrations.  


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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All PH FDC SC doses will be administered by SC injection by the investigator or their 
designee over 58 minutes at a rate of  2 mL/min with hand-held syringe to the thigh on 
Day 1 of each 3-week treatment cycle.  Patients should be monitored for 30 minutes 
after their first PH FDC SC dose administration regardless of whether a loading dose is 
required.  Patients should be monitored for 1015 minutes following subsequent 
administrations.  Patients can be observed for longer periods at the discretion of the 
investigator or if necessary, as per local requirements. 
No dose reductions are allowed for PH FDC SC.  If an accidental overdose or 
medication error occurs, it should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should also be reported as described in 
Section 5.3.5.12. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section G.5.2. 
G.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
Concomitant therapy consists of any medication (e.g., prescription drugs, over the 
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from seven days prior to initiation of study drug until 28 days after the final 
dose of study treatment.  After this period until the end of the study, only medications 
used for the treatment of cancer will be reported.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
G.4.3.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
H1-receptor or H2-receptor antagonists (e.g., diphenhydramine, cimetidine) 
 
Cardiovascular medications including angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers 
and diuretics, beta blockers, calcium channel blockers, digoxin, thrombocyte 
aggregation inhibitors 
 
Analgesics / anti-inflammatories (e.g., paracetamol / acetaminophen, meperidine, 
opioids) 
 
Standard therapies for pre-existing medical conditions and medical or surgical 
complications 
 
Any medication intended solely for supportive care (e.g., analgesics, antidiarrheals, 
antidepressants) at the investigator’s discretion 
 
Blood transfusions at the investigator’s discretion 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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 
Gonadotropin-releasing hormone agonists for fertility preservation 
 
Vitamin and mineral supplements 
 
Bone density modifying agents (to be used in accordance with the approved labelled 
indication and/or nationally recognized treatment guidelines) 
 
Any other medication not included in the list of prohibited medications 
 
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per institutional standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per institutional standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists,see Appendix 6 ). 
G.4.3.2 
Cautionary Therapy 
Concomitant use of herbal therapies is not recommended because their pharmacokinetic 
profiles, safety profiles, and potential drug-drug interactions are generally unknown.  
However, herbal therapies not intended for the treatment of cancer may be used during 
the study at the discretion of the investigator. 
G.4.3.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Any investigational therapy or agent (other than protocol-mandated study treatment) 
is prohibited within 28 days prior to initiation of study treatment and during study 
treatment 
 
Any targeted anti-cancer treatment other than adjuvant hormone treatment, adjuvant 
radiotherapy or bone density modifying treatment (e.g., lapatinib, neratinib) 
 
Regular systemic treatment with steroids 
Short-term corticosteroid to treat and prevent allergic or infusion reactions are 
allowed however the dose must not exceed  20 mg/day of dexamethasone (or 
equivalent) for  7 consecutive days. 
 
Hormone-replacement therapy 
 
Use of erythropoiesis-stimulating agents (e.g., erythropoietin) 
 
Herbal remedies initiated for cancer treatment.  Other herbal remedies are 
discouraged but permitted and must be reported on the appropriate eCRF. 
 
Topical estrogens (including any intra-vaginal preparations), megestrol acetate, and 
selective ER modulators used with prophylactic intent are prohibited 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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Postmenopausal women with significant vaginal discomfort associated with 
anti-estrogen therapy may be considered for intermittent use of low-dose topical 
estrogens if non-prescription methods are unsuccessful at ameliorating symptoms. 
G.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in Arm G: PH FDC SC.  Refer to the schedule of 
activities (Section G.6) for arm-specific assessment timepoints. 
Cardiac Function 
Prior to study enrolment, patients must have an assessment for history of cardiac 
events, a physical examination, and an LVEF assessment (by ECHO or MUGA) to 
exclude any cardiac condition that would render them ineligible for participation in this 
trial.  Cardiac function will be assessed locally according to the schedule of activities 
(Section G.6).  
All patients must have an LVEF  50% by ECHO or MUGA scan in order to be eligible for 
the study.  The same LVEF evaluation method should be used throughout the study for 
each patient and should be performed and assessed by the same assessor if possible.  
Results of LVEF assessments must be reviewed prior to study treatment administration 
on the scheduled visit day. 
Investigators must be aware of local institutional regulations regarding the maximum 
allowable frequency of repeat MUGA scans.  The repeated administration of 
radioisotopes is limited in some nuclear medicine laboratories, and patients in this study 
require LVEF assessment on more than four occasions within one year. 
G.5 
SAFETY PLAN  
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm G: PH FDC SC treatment. 
G.5.1 
Risks Associated with PH FDC SC  
PH FDC SC has been associated with risks such as the following: cardiomyopathy, 
embryo-fetal toxicity, pulmonary toxicity, alopecia, dry skin, rash, nausea, diarrhea, 
stomatitis, constipation, vomiting, dyspepsia, anemia, neutropenia, fatigue, mucosal 
inflammation, injection site reaction, pyrexia, dysgeusia, peripheral sensory neuropathy, 
headache, neuropathy peripheral, paresthesia, dizziness, weight decreased, myalgia, 
arthralgia, back pain, cough, epistaxis, dyspnea, upper respiratory tract infection, 
procedural pain, radiation skin injury, decreased appetite, insomnia, and hot flush. Refer 
to the PH FDC SC Investigator's Brochure for a detailed description of anticipated safety 
risks for PH FDC SC. 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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G.5.2 
Management of Patients Who Experience Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
G.5.2.1 
Dose Modifications and Interruptions for PH FDC SC 
Dose modification of PH FDC SC is not permitted.  The administration of PH FDC SC 
may be delayed to assess or treat adverse events, such as cardiac adverse events.   
During the study treatment period, a dose delay of up to (and including) six weeks (i.e., 
up to and including nine weeks between doses) will be permitted to allow adverse event 
recovery to baseline.  Following a dose delay of less than 3 weeks (i.e.,  6 weeks 
between doses), study treatment does not need to be reloaded (only the maintenance 
doses needs to be given).    
Patients receiving PH FDC SC with  6 weeks since their last PH FDC SC or Perjeta and 
Herceptin intravenous (IV) treatment must receive a loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab FDC SC before continuing with maintenance 
doses for subsequent administrations.  Patients should be monitored for 30 minutes after 
their first PH FDC SC dose administration in the study and if a loading dose is required 
during the study.  Patients should be monitored for 1015 minutes following 
maintenance dose administrations. 
If study treatment is withheld for more than two cycles ( 9 weeks) because of toxicity, 
the patient should be discontinued from study treatment, unless resumption of treatment 
is approved following investigator discussion with the Medical Monitor.  Study treatment 
may be suspended for reasons other than toxicity (e.g., surgical procedures) with 
Medical Monitor consultation.  The investigator and the Medical Monitor will determine 
the acceptable length of treatment interruption. 
G.5.2.2 
Guidelines for Management of Specific Adverse Events 
Associated with PH FDC SC 
Supportive care and medical management of adverse events are at the discretion of the 
investigator, unless specifically listed below. 
G.5.2.2.1 
Symptomatic LVSD and/or LVEF Decline 
All patients must have a baseline LVEF  50%.  LVEF will be monitored regularly 
according to the Schedule of Activities (see Section G.6).  If an investigator is concerned 
that an adverse event may be related to LVSD, an additional LVEF measurement should 
be performed as soon as possible and within three weeks.  Symptomatic LVSD (CHF) 
should be assessed as “heart failure” on the basis of NCI CTCAE v5.0 and NYHA 
classification (see Appendix 9).  Symptomatic LVSD (CHF) should be treated and 


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monitored according to standard medical practice.  These patients should be evaluated 
by a certified cardiologist locally, 
Figure 1 summarizes the management of study medication in patients who develop an 
asymptomatic decrease in LVEF.  The decision to initiate study treatment and whether to 
continue or stop therapy should be based on two factors: measured LVEF and changes 
in LVEF from baseline.  If a significant LVEF decrease occurs, this decrease should be 
confirmed by a second assessment within approximately 3 weeks showing also a 
significant decrease.  
Heart failure and asymptomatic LVEF decline adverse events must be graded per NCI 
CTCAE v5.0 (see Appendix 9) and reported in the eCRF as described Section G.5.4.2. 
Figure 1 Asymptomatic Decline in LVEF:  Algorithm for Continuation and 
Discontinuation of Study Treatment 
 
LVEFleft ventricular ejection fraction 
Patients must have an LVEF  50% measured by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) to be eligible for the study. 
 
G.5.2.2.2 
Hypersensitivity / Anaphylaxis and Administration-Related 
Reactions 
Patients should be observed closely for hypersensitivity reactions.  Although severe 
hypersensitivity reactions, including anaphylaxis and events with fatal outcomes, have 
not been observed in patients treated with PH FDC SC, caution should be exercised as 
these have been associated with Perjeta IV in combination with Herceptin IV. 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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Study treatment administration should be stopped in subjects who develop dyspnea or 
clinically significant hypotension (defined per investigator’s discretion). 
Patients who experience any of the following events will be discontinued from study 
treatment: 
 
Grade 4 allergic reaction 
 
Grade 3 or 4 hypersensitivity reaction 
 
Acute respiratory distress syndrome (ARDS) 
 
Bronchospasm 
Patients who experience administration-related reactions (ARRs) may be managed by: 
 
Stopping the injection of PH FDC SC 
 
Supportive care with antihistamines, antipyretics, corticosteroids or epinephrine as 
appropriate at the investigator's discretion, as per institutional practice 
 
Subsequently pre-medicating with analgesia and antihistamines as per institutional 
practice 
 
Patients should be monitored until complete resolution of signs and symptoms of any 
systemic reactions. 
In order to be able to calculate time to onset of such reactions, the occurrence of 
associated adverse events must be documented with the date and time of the onset and 
duration of the event (i.e., resolution of the event).  
All ARRs should be recorded as described in Section G.5.4.3. 
G.5.2.2.3 
Diarrhea 
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication 
(e.g. loperamide) should be considered, and patients should be treated with fluids and 
electrolyte replacement, as clinically indicated. 
G.5.2.2.4 
Rash / Skin Reactions 
Treatment recommendations for rash / skin reactions include topical or oral antibiotics, 
topical pimecrolimus, and topical steroids or systemic steroids (for severe reactions).  
These agents may be used in patients experiencing pertuzumab-related rash / skin 
reactions, as clinically indicated, although they have not been studied in this context. 
G.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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341/Protocol ML42439, Version 5 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients in the Arm G:  PH FDC SC. 
 
An asymptomatic decline in LVEF that requires treatment or that leads to 
discontinuation of study treatment  
 
G.5.4 
Reporting for Selected Adverse Events 
Additional data will be collected for the selected adverse events described below. 
G.5.4.1 
Heart Failure 
Symptomatic LVSD (referred to as heart failure) should be reported as an SAE.  If the 
diagnosis is heart failure, it should be reported as such, and not as individual signs and 
symptoms of heart failure.  Heart failure should be graded according to both NCI CTCAE 
and NYHA Class (see Appendix 9).  Left ventricular ejection fraction results must also be 
reported.  
Heart failure occurring during the study must be reported irrespective of causal 
relationship and followed until one of the following occurs: resolution or improvement to 
baseline status, no further improvement can be expected, or death. 
G.5.4.2 
Asymptomatic Declines in Left Ventricular Ejection Fraction 
Asymptomatic declines in LVEF should not be reported as adverse events because 
LVEF data are collected separately in the eCRF.  Exceptions to this rule are as follows: 
 
An asymptomatic decline in LVEF of  10 percentage-points from baseline to an 
LVEF  50% must be reported as an adverse event with the term of “ejection 
fraction decreased,” as per NCI CTCAE v5.0 (see Appendix 9).  In addition, a 
comment in the adverse events comments field should confirm that the event was 
asymptomatic. 
 
An asymptomatic decline in LVEF requiring treatment or leading to discontinuation 
of study treatment is an adverse event of special interest and must be reported in an 
expedited manner (see Section 5.7).  The event must be reported as an adverse 
event with the term of “ejection fraction decreased,” as per NCI CTCAE v5.0 (see 
Appendix 9) and a comment should be added to the adverse events comments field 
confirming that the event was asymptomatic. 
 
Table 1 summarizes the reporting conventions for LVSD and heart failure. 


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Table 1 
Reporting Conventions for Left Ventricular Systolic 
Dysfunction / Congestive Heart Failure 
Observation 
How to Report 
Term to be 
Reported 
Grading 
Asymptomatic decline in 
LVEF of  10 percentage 
points from baseline or 
to an LVEF of  50% 
No additional 
reporting required; 
LVEF results to be 
reported on eCRFs 
NA 
NA 
Asymptomatic decline in 
LVEF of  10 percentage 
points from baseline [c] 
to an LVEF of  50% 
AE [a] (AE eCRF) 
Ejection fraction 
decreased [a] 
NCI CTCAE for 
“ejection fraction 
decreased” 
Asymptomatic decline in 
LVEF requiring 
treatment or leading to 
study treatment 
discontinuation 
AE (AE eCRF) and 
report as a non-
serious AEs of 
special interest on 
an SAE eCRF 
Ejection fraction 
decreased [a] 
NCI CTCAE for 
“ejection fraction 
decreased” 
Heart failure / CHF 
(symptomatic LVSD) [b] 
AE (AE eCRF) and 
SAE (SAE eCRF) 
“Heart failure” 
NCI CTCAE for 
"heart failure" and 
NYHA class 
AEadverse event; CHFcongestive heart failure; eCRFelectronic case report form; 
LVEFleft ventricular ejection fraction; LVSDleft ventricular systolic dysfunction; NAnot 
applicable; NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse 
Events; NYHANew York Heart Association; SAEserious adverse event. 
a Report the status as asymptomatic and provide the LVEF value in the comments field as 
appropriate. 
b Any symptomatic LVSD event must be reported as “heart failure.” 
c Baseline is considered the last LVEF prior to enrolling in study. 
 
G.5.4.3 
Administration-Related Reactions: Injection-Related Reactions 
and Injection-Site Reactions  
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug injection should be captured as a specific 
diagnosis (e.g.,  “injection-related reaction”, "injection-site reaction", "anaphylactic 
reaction") on the Adverse Event eCRF in the EDC system.  If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded 
on the dedicated Injection Reaction eCRF.  If a patient experiences both a local and 
systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Injection Reaction eCRF. 
See Table 2 for the reporting conventions for injection-related reactions and injection-site 
reactions. 


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Table 2 
Reporting Conventions for Administration-Related Reactions 
Adverse Event 
Term to Be Used on 
Adverse Event eCRF Form 
Symptoms to Be Entered on 
eCRF Form 
Systemic Injection Reaction 
“Injection-related reaction” 
Injection reaction 
Local Injection Reaction 
“Injection-site reaction” 
Injection reaction 
 
 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
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G.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit 
b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 A 
(3) 
 (3) 
28 days after 
last study dose 
Informed consent d 
x 
 
 
 
Documentation of positive ERBB2 gene 
mutation or amplification by local test e 
x 
 
 
 
Medical history and baseline conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
ECOG Performance Status h 
x 
x 
 
x 
Pregnancy test i 
x 
x 
 
x 
Chemistry j 
x 
x 
 
x c 
Hematology/CBC with differential k 
x 
x 
 
x c 
ECHO or MUGA l 
x 
As clinically indicated 
C1, D15 and every 4 
cycles thereafter  
x l 
PH FDC SC administration m 
 
x 
 
 
Response Assessment n, o 
x 
Every 8 (1) weeks for 3 evaluations,  
then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) p 
 
Submit within 21 days  
of C1, D1 
 
 
Whole blood samples q 
x 
 
see footnote q  
 
Adverse events r 
x 
Collected on an ongoing basis 
x r 
Concomitant Medications s 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; dMMRdeficient mismatch repair; ECHO  echocardiogram; eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; 
ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection fraction; MSI-Hmicrosatellite-high; MRImagnetic resonance 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
345/Protocol ML42439, Version 5 
imaging; MUGA  multiple-gated acquisition; PDprogressive disease; PH FDC SCfixed dose combination of trastuzumab and pertuzumab 
administered subcutaneously; RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, 
Version 1.1; SAEserious adverse event; TMB-Htumor mutational burden-high. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done  28 days prior to initiation of treatment.  However, if the 
hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1.  Scans to 
document measurable or evaluable disease (i.e., tumor measurement) should be performed  4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may take 
place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to collect AE data and any 
standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated  
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive ERBB2 gene mutation or amplification status without known TMB-high/MSI-high/dMMR should occur prior to performing 
other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.   
j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent 
chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 


Arm G:  PH FDC SC in Patients with ERBB2 Amplification or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
346/Protocol ML42439, Version 5 
k Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.   
l LVEF assessments will occur during the screening period, and on Day 15 of Cycle 1, and every fourth cycle thereafter (e.g. C5D15, C9D15, 
etc.).  ECHO or MUGA will be performed following study treatment discontinuation only if the most recent follow-up ECHO/MUGA was 
performed  28 days before last study treatment administration and if no post-treatment evaluation was performed.  Evaluation of LVEF must be 
performed by the same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and operator perform 
ECHO/MUGA scan for each individual patient. 
m Patients who have had  6 weeks since their last PH FDC SC (or pertuzumab plus trastuzumab IV) treatment must receive a loading dose 
before continuing with maintenance doses for subsequent administrations 
n All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
o At each subsequent tumor assessment, all measurable, and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 ( 1) weeks for 3 evaluations, then every 12 ( 2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
p For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
q Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   
r After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all 
deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
s Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study 
treatment. 
 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
347/Protocol ML42439, Version 5 
Appendix 17  
Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 
Amplification- or Mutation-Positive Tumors 
18. 
ARM H:  PH FDC SC PLUS CHEMOTHERAPY IN PATIENTS 
WITH ERBB2 AMPLIFICATION OR MUTATION-POSITIVE 
TUMORS 
TABLE OF CONTENTS 
 
H.4 
Materials and Methods .......................................................... 348 
H.4.1 
Patients .................................................................................. 348 
H.4.1.1 
Additional Inclusion Criteria ................................................... 348 
H.4.1.2 
Additional Exclusion Criteria .................................................. 349 
H.4.2 
Study Treatment .................................................................... 350 
H.4.2.1 
Formulation and Packaging ................................................... 350 
H.4.2.2 
Study Treatment Dosage, Administration, and Compliance .. 351 
H.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 352 
H.4.3.1 
Permitted Therapy ................................................................. 352 
H.4.3.2 
Cautionary Therapy ............................................................... 353 
H.4.3.3 
Prohibited Therapy ................................................................ 353 
H.4.4 
Arm-specific Assessments ..................................................... 354 
H.5 
Safety Plan ............................................................................ 354 
H.5.1 
Risks Associated with PH FDC SC plus Chemotherapy ........ 354 
H.5.1.1 
Risks Associated with PH FDC SC ........................................ 354 
H.5.1.2 
Risks Associated with Docetaxel, Paclitaxel, and 
Capecitabine .......................................................................... 355 
H.5.2 
Management of Patients Who Experience Adverse Events ... 355 
H.5.2.1 
Dose Modifications and Interruptions ..................................... 355 
H.5.2.2 
Guidelines for Management of Specific Adverse Events 
Associated with PH FDC SC.................................................. 356 
H.5.2.3 
Guidelines for Management of Adverse Events Associated 
with Chemotherapy ................................................................ 358 
H.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 358 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
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348/Protocol ML42439, Version 5 
H.5.4 
Additional Reporting for Selected Adverse Events ................ 359 
H.5.4.1 
Heart Failure .......................................................................... 359 
H.5.4.2 
Asymptomatic Declines in Left Ventricular Ejection 
Fraction .................................................................................. 359 
H.5.4.3 
Administration-Related Reactions: Injection-Related 
Reactions and Injection-Site Reactions ................................. 360 
H.6 
Schedule of Activities ............................................................. 362 
 
H.4 
MATERIALS AND METHODS 
H.4.1 
Patients 
To be enrolled in Arm H:  fixed dose combination of trastuzumab and pertuzumab 
administered subcutaneously (PH FDC SC) plus chemotherapy treatment, patients must 
have met and continue to meet all general eligibility criteria (see Section 4.1), in addition 
to the arm-specific criteria below. 
H.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm H:  PH 
FDC SC plus chemotherapy treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below: 
– 
Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; 
S310F/Y; C311R/S; E321G; C334S 
– 
Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; 
D769H/N/Y; Y772_A775dup; 
A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; 
V842I; N857S; T862A; L869R; H878Y; R896C 
– 
Transmembrane domain:  S653C; V659E; G660D; R678Q 
– 
GFR domain IV:  P551L; R552S 
– 
Receptor L:  S418T; A440T 
– 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplificationdetermined by CLIA or equivalently 
certified in-situ hybridization or NGS assay.  Amplification is defined as a copy 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
349/Protocol ML42439, Version 5 
number of  6 for NGS assays or, for in-situ hybridization assays, as a 
HER2:CEP17 ratio  2.0 and average HER2 copy number/cell  4.0 signals/cell 
 
Intact skin at planned site of subcutaneous (SC) injections (thigh) 
 
ANC  1500/L within 14 days prior to initiation of study treatment 
 
Baseline and most recent (witin 3 months) left ventricular ejection fraction (LVEF) 
 50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan 
(MUGA)  
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
7 months after the last dose of PH FDC SC or 6 months after the last dose of 
chemotherapy, whichever is later; and agreement to refrain from donating eggs 
during this same period.  See Appendix 2 for details regarding contraception 
requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of 1% per year during the treatment period and for at least 7 months 
after the last dose of PH FDC SC or 3 months after the last dose of chemotherapy, 
whichever is later, and agreement to refrain from donating sperm during this same 
period.  See Appendix 2 for details regarding contraception requirements. 
 
H.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm H: PH FDC SC plus chemotherapy treatment:  
 
Diagnosed with breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS 
assay, microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) 
status 
 
History of National Cancer Institute Common Terminology Criteria for Adverse 
Events, version 5.0 (NCI CTCAE v5.0) Grade  3 symptomatic congestive heart 
failure (CHF)  
 
In addition to the core exclusion criterion for significant cardiovascular disease (see 
Section 4.1.2), patients will be excluded if they meet any of the following criteria:  
– 
High-risk arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at rest, 
significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz 
type II] or third-degree AV-block) not controlled by adequate medication 
– 
Evidence of transmural infarction on ECG 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
350/Protocol ML42439, Version 5 
– 
Evidence of myocardial infarction within 12 months prior to enrollment, 
cerebrovascular accident within 3 months prior to enrollment 
– 
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 
mmHg) 
– 
Angina pectoris requiring anti-angina medication 
– 
Clinically significant valvular heart disease 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], 
left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome 
 
Known active liver disease, for example, autoimmune hepatic disorders, or 
sclerosing cholangitis 
 
Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
 
Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins 
 
Previously experienced severe injection related reactions with pertuzumab plus 
trastuzumab IV and/or PH FDC SC 
 
Current chronic daily treatment with corticosteroids (dose  10 mg 
methylprednisolone or equivalent excluding inhaled steroids) 
 
H.4.2 
Study Treatment  
Study treatment in this arm will consist of PH FDC SC in combination with either 
docetaxel, paclitaxel, or capecitabine chemotherapy, as determined by the investigator. 
H.4.2.1 
Formulation and Packaging 
PH FDC SC will be provided in two configurations:  a loading dose configuration and 
maintenance dose configuration as single vials:  
 
Loading dose:  a sterile solution for injection containing L-histidine hydrochloride, 
trehalose, sucrose, polysorbate 20, methionine, and rHuPH20 (2,000 U/mL).  Each 
single use 20 mL glass colourless vial contains 1200 mg of pertuzumab and 600 mg 
of trastuzumab in 15 mL of solution. 
 
Maintenance dose: a sterile solution for injection containing L-histidine 
hydrochloride, trehalose, sucrose, polysorbate 20, methionine, and rHuPH20 
(2,000 U/mL).  Each single use 15 mL colourless glass vial contains 600 mg of 
pertuzumab and 600 mg of trastuzumab in 10 mL of solution. 
 
For information on the packaging, handling and storage of PH FDC SC, see the 
Pharmacy Manual and PH FDC SC Investigator's Brochure. 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
351/Protocol ML42439, Version 5 
Chemotherapy will consist of either docetaxel, paclitaxel, or capecitabine, as determined 
by the investigator and will be used in commercially available formulations. 
For information on the formulation and handling of docetaxel, paclitaxel, and 
capecitabine, refer to the respective package insert.  
H.4.2.2 
Study Treatment Dosage, Administration, and Compliance 
Study treatment will be administered in 21 day cycles.  PH FDC SC should be 
administered prior to chemotherapy on days when both are administered. 
If a delay in administration of either agent is necessary, reasonable effort should be 
made to keep the administration synced if clinically feasible (e.g., briefly delay 
administration of the other agent).  A cycle should be considered to start when any drug 
is administered.   
If PH FDC SC is discontinued, chemotherapy can be continued if the patient is likely to 
derive clinical benefit, as determined by the investigator.  If chemotherapy is 
discontinued, PH FDC SC can be continued if the patient is likely to derive clinical 
benefit, as determined by the investigator. 
H.4.2.2.1 
PH FDC SC 
PH FDC SC is given as a fixed dose (i.e. non-weight based).  Two doses of PH FDC SC 
may be administered in the study:  a 15 mL loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab and a 10 mL maintenance dose consisting of 
600 mg pertuzumab and 600 mg trastuzumab.  Patients who have had  6 weeks since a 
prior dose of Perjeta and Herceptin intravenous (IV) or PH FDC SC at study entry, or 
have had  6 weeks since their last study treatment during the study treatment period, 
must receive a loading dose before continuing with maintenance doses for subsequent 
administrations.  
All PH FDC SC doses will be administered by SC injection by the investigator or their 
designee over 58 minutes at a rate of  2 mL/min with hand-held syringe to the thigh on 
Day 1 of each 3-week treatment cycle.  Patients should be monitored for 30 minutes 
after their first PH FDC SC dose administration regardless of whether a loading dose is 
required.  Patients should be monitored for 1015 minutes following subsequent 
administrations.  Patients can be observed for longer periods at the discretion of the 
investigator or if necessary, as per local requirements. 
No dose reductions are allowed for PH FDC SC.  If an accidental overdose or 
medication error occurs, it should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
352/Protocol ML42439, Version 5 
with any associated adverse events, should also be reported as described in 
Section 5.3.5.12. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided Section H.5.2.1. 
H.4.2.2.2 
Chemotherapy 
Docetaxel, paclitaxel, or capecitabine will be administered per package insert and 
institutional guidelines, including considerations for premedication, supportive 
medications, infusion times, infusion frequency, and total cycle count. 
H.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
Concomitant therapy consists of any medication (e.g., prescription drugs, over the 
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from seven days prior to initiation of study drug until 28 days after the final 
dose of study treatment.  After this period until the end of the study, only medications 
used for the treatment of cancer will be reported.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
H.4.3.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
H1-receptor or H2-receptor antagonists (e.g., diphenhydramine, cimetidine) 
 
Cardiovascular medications including angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers 
and diuretics, beta blockers, calcium channel blockers, digoxin, thrombocyte 
aggregation inhibitors 
 
Analgesics / anti-inflammatories (e.g., paracetamol / acetaminophen, meperidine, 
opioids) 
 
Standard therapies for pre-existing medical conditions and medical or surgical 
complications 
 
Any medication intended solely for supportive care (e.g., analgesics, antidiarrheals, 
antidepressants) at the investigator’s discretion 
 
Blood transfusions at the investigator’s discretion 
 
Gonadotropin-releasing hormone agonists for fertility preservation 
 
Vitamin and mineral supplements 
 
Bone density modifying agents (to be used in accordance with the approved labelled 
indication and/or nationally recognized treatment guidelines) 
 
Any other medication not included in the list of prohibited medications 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
353/Protocol ML42439, Version 5 
 
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per institutional standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per institutional standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists). 
H.4.3.2 
Cautionary Therapy 
Concomitant use of herbal therapies is not recommended because their PK, safety 
profiles, and potential drug-drug interactions are generally unknown.  However, herbal 
therapies not intended for the treatment of cancer may be used during the study at the 
discretion of the investigator. 
H.4.3.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Any investigational therapy or agent (other than protocol-mandated study treatment) 
is prohibited within 28 days prior to initiation of study treatment and during study 
treatment 
 
Any targeted anti-cancer treatment other than adjuvant hormone treatment, adjuvant 
radiotherapy or bone density modifying treatment (e.g. lapatinib, neratinib) 
 
Regular systemic treatment with steroids 
Short-term corticosteroid to treat and prevent allergic or infusion reactions are 
allowed however the dose must not exceed  20 mg/day of dexamethasone (or 
equivalent) for  7 consecutive days. 
 
Hormone-replacement therapy 
 
Use of erythropoiesis-stimulating agents (e.g., erythropoietin) 
 
Herbal remedies initiated for cancer treatment.  Other herbal remedies are 
discouraged but permitted and must be reported on the appropriate eCRF. 
 
Topical estrogens (including any intra-vaginal preparations), megestrol acetate, and 
selective estrogen receptor (ER) modulators used with prophylactic intent are 
prohibited 
Postmenopausal women with significant vaginal discomfort associated with 
anti-estrogen therapy may be considered for intermittent use of low-dose topical 
estrogens if non-prescription methods are unsuccessful at ameliorating symptoms. 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
354/Protocol ML42439, Version 5 
H.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in Arm H:  PH FDC SC plus chemotherapy.  Refer 
to the schedule of activities (Section H.6) for arm-specific assessment timepoints. 
Cardiac Function 
Prior to study enrolment, patients must have an assessment for history of cardiac 
events, a physical examination, and an LVEF assessment (by ECHO or MUGA) to 
exclude any cardiac condition that would render them ineligible for participation in this 
trial.  Cardiac function will be assessed locally according to the schedule of activities 
(see Section H.6).  
All patients must have an LVEF  50% by ECHO or MUGA scan in order to be eligible for 
the study.  The same LVEF evaluation method should be used throughout the study for 
each patient and should be performed and assessed by the same assessor if possible.  
Results of LVEF assessments must be reviewed prior to study treatment administration 
on the scheduled visit day. 
Investigators must be aware of local institutional regulations regarding the maximum 
allowable frequency of repeat MUGA scans.  The repeated administration of 
radioisotopes is limited in some nuclear medicine laboratories, and patients in this study 
require LVEF assessment on more than four occasions within one year. 
H.5 
SAFETY PLAN  
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm H:  PH FDC SC plus 
chemotherapy treatment. 
H.5.1 
Risks Associated with PH FDC SC plus Chemotherapy 
H.5.1.1 
Risks Associated with PH FDC SC  
PH FDC SC has been associated with risks such as the following:  cardiomyopathy, 
embryo-fetal toxicity, pulmonary toxicity, alopecia, dry skin, rash, nausea, diarrhea, 
stomatitis, constipation, vomiting, dyspepsia, anemia, neutropenia, fatigue, mucosal 
inflammation, injection site reaction, pyrexia, dysgeusia, peripheral sensory neuropathy, 
headache, neuropathy peripheral, paresthesia, dizziness, weight decreased, myalgia, 
arthralgia, back pain, cough, epistaxis, dyspnea, upper respiratory tract infection, 
procedural pain, radiation skin injury, decreased appetite, insomnia, and hot flush.  Refer 
to the PH FDC SC Investigator's Brochure for a detailed description of anticipated safety 
risks for PH FDC SC. 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
355/Protocol ML42439, Version 5 
H.5.1.2 
Risks Associated with Docetaxel, Paclitaxel, and Capecitabine  
Docetaxel has been associated with risks such as the following:  infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, 
dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, 
diarrhea, vomiting, mucositis, alopecia, skin reactions and myalgia.For more details 
regarding the safety profile of docetaxel, refer to the prescribing information for 
docetaxel. 
Paclitaxel has been associated with risks such as the following:  Bone marrow 
suppression, neutropenia, alopecia, peripheral neuropathy, myalgia, arthralgia, nausea, 
and vomiting.  Additionally reported adverse events which were less common are 
hypersensitivity reactions, infections, bleeding, diarrhea, mucositis, liver function test 
(LFT) elevations, injection-site reactions, and cardiovascular effects such as 
hypotension, bradycardia, hypertension, arrhythmias, other ECG abnormalities, 
syncope, and venous thrombosis.For more details regarding the safety profile of 
paclitaxel, refer to the prescribing information for paclitaxel. 
Capecitabine has been associated with risks such as the following:  diarrhea, 
hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness and 
hyperbilirubinemia.  For more details regarding the safety profile of capecitabine, refer to 
the prescribing information for capecitabine. 
H.5.2 
Management of Patients Who Experience Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
H.5.2.1 
Dose Modifications and Interruptions 
H.5.2.1.1 
Dose Modifications and Interruptions for PH FDC SC 
Dose modification of PH FDC SC is not permitted.  The administration of PH FDC SC 
may be delayed to assess or treat adverse events, such as cardiac adverse events.   
During the study treatment period, a dose delay of up to (and including) 6 weeks (i.e., up 
to and including nine weeks between doses) will be permitted to allow adverse event 
recovery to baseline.  Following a dose delay of less than 3 weeks (i.e.,  6 weeks 
between doses), study treatment does not need to be reloaded (only the maintenance 
doses needs to be given).    
Patients receiving PH FDC SC with  6 weeks since their last PH FDC SC treatment or 
pertuzumab plus trastuzumab IV must receive a loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab FDC SC before continuing with maintenance 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
356/Protocol ML42439, Version 5 
doses for subsequent administrations.  Patients should be monitored for 30 minutes after 
their first PH FDC SC dose administration in the study and if a loading dose is required 
during the study.  Patients should be monitored for 1015 minutes following 
maintenance dose administrations. 
If study treatment is withheld for more than two cycles ( 9 weeks) because of toxicity, 
the patient should be discontinued from study treatment, unless resumption of treatment 
is approved following investigator discussion with the Medical Monitor.  Study treatment 
may be suspended for reasons other than toxicity (e.g., surgical procedures) with 
Medical Monitor consultation.  The investigator and the Medical Monitor will determine 
the acceptable length of treatment interruption. 
Patients who are permanently discontinued from study treatment should be treated at 
the discretion of the investigator as clinically indicated.   
H.5.2.1.2 
Dose Modifications and Interruptions for Chemotherapy 
Dose modifications and interruptions for docetaxel, paclitaxel, and capecitabine should 
be done according to standard medical practice and in accordance with the respective 
packaging insert.  
H.5.2.2 
Guidelines for Management of Specific Adverse Events 
Associated with PH FDC SC 
Supportive care and medical management of adverse events are at the discretion of the 
investigator, unless specifically listed below. 
H.5.2.2.1 
Symptomatic LVSD and/or LVEF Decline 
All patients must have a baseline LVEF  50%.  LVEF will be monitored regularly 
according to the Schedule of Activities (Section H.6).  If an investigator is concerned that 
an adverse event may be related to LVSD, an additional LVEF measurement should be 
performed as soon as possible and within 3 weeks.  Symptomatic LVSD (CHF) should 
be assessed as “heart failure” on the basis of NCI CTCAE v5.0 and New York Heart 
Association (NYHA) classification (see Appendix 9).  Symptomatic LVSD (CHF) should 
be treated and monitored according to standard medical practice.  These patients should 
be evaluated by a certified cardiologist locally, 
Figure 1 summarizes the management of study medication in patients who develop an 
asymptomatic decrease in LVEF.  The decision to initiate study treatment and whether to 
continue or stop therapy should be based on two factors: measured LVEF and changes 
in LVEF from baseline.  If a significant LVEF decrease occurs, this decrease should be 
confirmed by a second assessment within approximately 3 weeks showing also a 
significant decrease.  


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
357/Protocol ML42439, Version 5 
Heart failure and asymptomatic LVEF decline adverse events must be graded per NCI 
CTCAE v5.0 (see Appendix 9) and reported in the eCRF as described in Table 2. 
Figure 1 Asymptomatic Decline in LVEF:  Algorithm for Continuation and 
Discontinuation of Study Treatment 
 
 
 
LVEFleft ventricular ejection fraction. 
Patients must have an LVEF  50% measured by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) to be eligible for the study. 
 
H.5.2.2.2 
Hypersensitivity / Anaphylaxis and Administration-Related 
Reactions 
Patients should be observed closely for hypersensitivity reactions.  Although severe 
hypersensitivity reactions, including anaphylaxis and events with fatal outcomes, have 
not been observed in patients treated with PH FDC SC, caution should be exercised as 
these have been associated with Perjeta IV in combination with Herceptin IV and 
chemotherapy. 
Study treatment administration should be stopped in subjects who develop dyspnea or 
clinically significant hypotension (defined per investigator’s discretion). 
Patients who experience any of the following events will be discontinued from study 
treatment: 
 
Grade 4 allergic reaction 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
358/Protocol ML42439, Version 5 
 
Grade 3 or 4 hypersensitivity reaction 
 
Acute respiratory distress syndrome (ARDS) 
 
Bronchospasm 
 
Patients who experience administration-related reactions (ARRs) may be managed 
by: 
– 
Stopping the injection of PH FDC SC 
– 
Supportive care with antihistamines, antipyretics, corticosteroids or epinephrine 
as appropriate at the investigator's discretion, as per institutional practice 
– 
Subsequently pre-medicating with analgesia and antihistamines as per 
institutional practice 
 
Patients should be monitored until complete resolution of signs and symptoms of any 
systemic reactions. 
In order to be able to calculate time to onset of such reactions, the occurrence of 
associated adverse events must be documented with the date and time of the onset and 
duration of the event (i.e., resolution of the event).  
All ARRs should be recorded as described in Table 2. 
H.5.2.2.3 
Diarrhea 
To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication 
(e.g., loperamide) should be considered, and patients should be treated with fluids and 
electrolyte replacement, as clinically indicated. 
H.5.2.2.4 
Rash / Skin Reactions 
Treatment recommendations for rash / skin reactions include topical or oral antibiotics, 
topical pimecrolimus, and topical steroids or systemic steroids (for severe reactions).  
These agents may be used in patients experiencing pertuzumab-related rash / skin 
reactions, as clinically indicated, although they have not been studied in this context. 
H.5.2.3 
Guidelines for Management of Adverse Events Associated with 
Chemotherapy 
Toxicities associated or possibly associated with docetaxel, paclitaxel, or capecitabine 
treatment should be managed according to standard medical practice and in accordance 
with the respective packaging insert.   
H.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
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359/Protocol ML42439, Version 5 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients in the Arm H:  PH FDC SC plus 
chemotherapy. 
 
An asymptomatic decline in LVEF that requires treatment or that leads to 
discontinuation of study treatment  
 
H.5.4 
Additional Reporting for Selected Adverse Events 
Additional data will be collected for the selected adverse events described below. 
H.5.4.1 
Heart Failure 
Symptomatic LVSD (referred to as heart failure) should be reported as a serious adverse 
event.  If the diagnosis is heart failure, it should be reported as such, and not as 
individual signs and symptoms of heart failure.  Heart failure should be graded according 
to both NCI CTCAE and NYHA Class (see Appendix 9).  LVEF fraction results must also 
be reported.  
Heart failure occurring during the study must be reported irrespective of causal 
relationship and followed until one of the following occurs:  resolution or improvement to 
baseline status, no further improvement can be expected, or death. 
H.5.4.2 
Asymptomatic Declines in Left Ventricular Ejection Fraction 
Asymptomatic declines in LVEF should not be reported as adverse events because 
LVEF data are collected separately in the eCRF.  Exceptions to this rule are as follows:  
An asymptomatic decline in LVEF of  10 percentage-points from baseline to an LVEF 
 50% must be reported as an adverse event with the term of “ejection fraction 
decreased,” as per NCI CTCAE v5.0 (see Appendix 9).  In addition, a comment in the 
adverse events comments field should confirm that the event was asymptomatic. 
An asymptomatic decline in LVEF requiring treatment or leading to discontinuation of 
study treatment is an adverse event of special interest and must be reported in an 
expedited manner (see Section 5.7).  The event must be reported as an adverse event 
with the term of “ejection fraction decreased,” as per NCI CTCAE v5.0 (see Appendix 9) 
and a comment should be added to the adverse events comments field confirming that 
the event was asymptomatic. 
Table 1 summarizes the reporting conventions for LVSD and heart failure.   


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
360/Protocol ML42439, Version 5 
Table 1 
Reporting Conventions for Left Ventricular Systolic 
Dysfunction / Congestive Heart Failure 
Observation 
How to Report 
Term to be 
Reported 
Grading 
Asymptomatic decline in 
LVEF of  10 percentage 
points from baseline or to 
an LVEF of  50% 
No additional 
reporting required; 
LVEF results to be 
reported on eCRFs 
NA 
NA 
Asymptomatic decline in 
LVEF of  10 percentage 
points from baseline [c] to 
an LVEF of  50% 
AE [a] (AE eCRF)  
Ejection fraction 
decreased [a]  
NCI CTCAE v5.0 for 
“ejection fraction 
decreased” 
Asymptomatic decline in 
LVEF requiring treatment 
or leading to study 
treatment discontinuation  
AE (AE eCRF) and 
report as a 
non-serious AEs of 
special interest on 
an SAE eCRF 
Ejection fraction 
decreased [a]  
NCI CTCAE v5.0 for 
“ejection fraction 
decreased” 
Heart failure / CHF 
(symptomatic LVSD) [b]  
AE (AE eCRF) and 
SAE (SAE eCRF) 
“Heart failure” 
NCI CTCAE v5.0 for 
"heart failure" and 
NYHA class 
AEadverse event; CHFcongestive heart failure; eCRFelectronic case report form; 
LVEFleft ventricular ejection fraction; LVSDleft ventricular systolic dysfunction; NAnot 
applicable; NCI CTCAE v5.0National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 5.0; NYHANew York Heart Association; SAEserious adverse event. 
a Report the status as asymptomatic and provide the LVEF value in the comments field as 
appropriate. 
b Any symptomatic LVSD event must be reported as “heart failure.” 
c Baseline is considered the last LVEF prior to enrolling in study. 
 
H.5.4.3 
Administration-Related Reactions: Injection-Related Reactions 
and Injection-Site Reactions  
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug injection should be captured as a specific 
diagnosis (e.g.,  “injection-related reaction,” "injection-site reaction", "anaphylactic 
reaction") on the Adverse Event eCRF in the EDC system.  If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded 
on the dedicated Injection Reaction eCRF.  If a patient experiences both a local and 
systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Injection Reaction eCRF. 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
361/Protocol ML42439, Version 5 
See Table 2 for the reporting conventions for injection-related reactions and injection-site 
reactions. 
Table 2 
Reporting Conventions for Administration-Related Reactions 
Adverse Event 
Term to Be Used on 
Adverse Event eCRF Form 
Symptoms to Be Entered on 
eCRF Form 
Systemic Injection Reaction 
“Injection-related reaction” 
Injection reaction 
Local Injection Reaction 
“Injection-site reaction” 
Injection reaction 
 
 
 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
362/Protocol ML42439, Version 5 
H.6 
SCHEDULE OF ACTIVITIES  
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit 
b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 A 
(3) 
 (3) 
≤ 28 days after 
last study dose 
Informed consent d 
x 
 
 
 
Documentation of positive ERBB2 gene 
mutation or amplification by local test e 
x 
 
 
 
Medical history and baseline conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
Weight h 
x 
x 
 
 
ECOG Performance Status i 
x 
x 
 
x 
Pregnancy test j 
x 
x 
 
x 
Chemistry k  
x 
x 
 
x c 
Hematology/CBC with differential l 
x 
x 
 
x c 
ECHO or MUGA m 
x 
As clinically indicated 
C1, D15 and every 4 
cycles thereafter  
x 
PH FDC SC administration n 
 
x 
 
 
Chemotherapy administration o 
 
x 
 
 
Response Assessment p, q 
x 
Every 8 (1) weeks for 3 evaluations,  
then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) r 
 
Submit within 21 days  
of C1, D1 
 
 
Whole blood samples s 
x 
 
see footnote s  
 
Adverse events t 
x 
Collected on an ongoing basis 
x t 
Concomitant Medications u 
x 
Collected on an ongoing basis 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or Mutation-Positive Tumors 
 
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AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; dMMRdeficient mismatch repair; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; 
eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection 
fraction; MSI-Hmicrosatellite-high; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; PH FDC SC 
fixed dose combination of pertuzumab trastuzumab administered subcutaneously; PETpositron emission tomography; RANOResponse 
Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious adverse event; TMB-
Htumor mutational burden-high; TSH  thyroid-stimulating hormone. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if 
the hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1.  Scans to 
document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may 
take place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to collect AE data and 
any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive ERBB2 gene mutation or amplification status without known TMB-high/MSI-high/dMMR should occur prior to 
performing other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) 
used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline. 
i All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
j Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
364/Protocol ML42439, Version 5 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who 
have a positive pregnancy test must not receive study drug.  
k Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent 
chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
l Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  
m LVEF assessments will occur during the screening period, and on Day 15 of Cycle 1, and every fourth cycle thereafter (e.g. C5D15, C9D15, 
etc.).  ECHO or MUGA will be performed following study treatment discontinuation only if the most recent follow-up ECHO/MUGA was 
performed 28 days before last study treatment administration and if no post-treatment evaluation was performed.  Evaluation of LVEF must be 
performed by the same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and operator perform 
ECHO/MUGA scan for each individual patient. 
n Patients who have had ≥ 6 weeks since their last PH FDC SC or pertuzumab plus trastuzumab IV treatment must receive a loading dose before 
continuing with maintenance doses for subsequent administrations 
o Docetaxel, paclitaxel, or capecitabine will be administered per package insert and institutional guidelines, including considerations for 
premedication, supportive medications, infusion times, infusion frequency, and total cycle count.  
p All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
q At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
r For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing. If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
s Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   
t After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  


Arm H:  PH FDC SC Plus Chemotherapy In Patients With ERBB2 Amplification- or Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
365/Protocol ML42439, Version 5 
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all 
deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
u Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study 
treatment. 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
366/Protocol ML42439, Version 5 
Appendix 18  
Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients with ERBB2 
Amplification- or Mutation-Positive Tumors 
19. 
ARM I:  TRASTUZUMAB EMTANSINE PLUS TUCATINIB IN PATIENTS 
WITH ERBB2 AMPLIFICATION- OR MUTATION-POSITIVE TUMORS 
Table of Contents 
I.4 
Materials and Methods .......................................................... 367 
I.4.1 
Patients .................................................................................. 367 
I.4.1.1 
Additional Inclusion Criteria ................................................... 367 
I.4.1.2 
Additional Exclusion Criteria .................................................. 368 
I.4.2 
Study Treatment .................................................................... 369 
I.4.2.1 
Formulation and Packaging ................................................... 369 
I.4.2.2 
Dosage, Administration, and Compliance .............................. 369 
I.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 371 
I.4.3.1 
Permitted Therapy ................................................................. 371 
I.4.3.2 
Prohibited Therapy ................................................................ 371 
I.4.4 
Arm-specific Assessments ..................................................... 372 
I.5 
Safety Plan ............................................................................ 373 
I.5.1 
Risks Associated with Trastuzumab Emtansine plus Tucatinib373 
I.5.1.1 
Risks Associated with Trastuzumab Emtansine .................... 373 
I.5.1.2 
Risks Associated with Tucatinib ............................................. 373 
I.5.2 
Management of Patients Who Experience Adverse Events ... 373 
I.5.2.1 
Dose Modications and Interruptions ...................................... 373 
I.5.2.2 
Guidelines for Management of Specific Adverse Events for 
Trastuzumab Emtansine ........................................................ 374 
I.5.2.3 
Guidelines for Management of Specific Adverse Events for 
Tucatinib ................................................................................ 381 
I.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) .......................................................................... 382 
I.6 
Schedule of Activities ............................................................. 384 
I.7 
References ............................................................................ 388 
 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
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367/Protocol ML42439, Version 5 
I.4 
MATERIALS AND METHODS 
I.4.1 
Patients 
To be enrolled in Arm I:  trastuzumab emtansine plus tucatinib treatment, patients must 
have met and continue to meet all general eligibility criteria (see Section 4.1), in addition 
to the arm-specific criteria below. 
I.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm I:  
trastuzumab emtansine plus tucatinib treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide 
variants listed below: 
– 
Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; 
S310F/Y; C311R/S; E321G; C334S 
– 
Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; 
D769H/N/Y; Y772_A775dup; 
A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; 
V842I; N857S; T862A; L869R; H878Y; R896C 
– 
Transmembrane domain:  S653C; V659E; G660D; R678Q 
– 
GFR domain IV:  P551L; R552S 
– 
Receptor L:  S418T; A440T 
– 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently 
certified in-situ hybridization or NGS assay. Amplification is defined as a copy 
number of  6 for NGS assays or, for in-situ hybridization assays, as a 
HER2:CEP17 ratio  2.0 and average HER2 copy number/cell  4.0 signals/cell  
 
ANC  1200/l within 14 days prior to initiation of study treatment 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
7 months after the last dose of trastuzumab emtansine or at least 1 week after last 
administration of tucatinib, whichever is longer; and agreement to refrain from 
donating eggs during this same period.  See Appendix 2 for details regarding 
requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
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MyTACTIC Study—Genentech, Inc. 
368/Protocol ML42439, Version 5 
failure rate of  1% per year during the treatment period and for at least 7 months 
after the last dose of trastuzumab emtansine or at least 1 week after last dose of 
tucatinib, whichever is longer, and agreement to refrain from donating sperm during 
this same period.  See Appendix 2 for details regarding contraception requirements. 
 
I.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm I:  trastuzumab emtansine plus tucatinib treatment: 
 
Breast cancer  
 
Known tumor mutational burden (TMB)  10 as determined by a tissue-based NGS 
assay, microsatellite instability high (MSI-H), deficient mismatch repair (dMMR) 
status 
 
History of exposure to the following cumulative doses of anthracyclines as specified 
below: 
– 
Doxorubicin  500 mg/m2 
– 
Liposomal doxorubicin  500 mg/m2 
– 
Epirubicin  720 mg/m2 
– 
Mitoxantrone  120 mg/m2 
– 
Idarubicin  90 mg/m2 
If another anthracycline or more than one anthracycline has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
 
History of severe hypersensitivity to components of the trastuzumab emtansine or 
tucatinib formulations 
 
Cardiopulmonary dysfunction as defined by any of the following: 
– 
Uncontrolled hypertension (systolic  150 mmHg and/or diastolic  100 mmHg) 
– 
Inadequate left ventricular ejection fraction at baseline,  50% by 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
– 
History of symptomatic congestive heart failure Grade  3 per National Cancer 
Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI 
CTCAE v5.0)  
– 
History of decrease in left ventricular ejection function to  40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of enrollment 
– 
Current dyspnea at rest due to complications of advanced malignancy, or other 
disease requiring continuous oxygen therapy  
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade  2) relating to left ventricular ejection fraction 
(LVEF), cardiac arrhythmia, or cardiac ischemia  


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
369/Protocol ML42439, Version 5 
– 
Serious cardiac arrhythmia not controlled by adequate medication 
 
Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, autoimmune hepatic disorders, or sclerosis cholangitis  
 
Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the 
inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 day prior to 
start of treatment 
 
Grade  3 peripheral neuropathy, as defined by CTCAE v5.0 
 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
 
I.4.2 
Study Treatment 
Study treatment in this arm will consist of trastuzumab emtansine in combination with 
tucatinib.  
I.4.2.1 
Formulation and Packaging 
Trastuzumab emtansine is provided as a lyophilized product in either 15-mL or 20-mL 
single-use vials which contain enough product to deliver 100 mg or 160 mg, respectively, 
of trastuzumab emtansine.  The lyophilized form of the product is provided for 
reconstitution to a liquid concentrate using sterile water for injection.  After reconstitution, 
both the 15-mL and 20-mL vials contain 20 mg/mL trastuzumab emtansine, 10 mM 
sodium succinate, pH 5.0, 6% w/v sucrose, and 0.02% (w/v) polysorbate 20.  The 
reconstituted product contains no preservative and is intended for single use only.  The 
density of the drug product after reconstitution is 1.026 g/mL.  
For information on the formulation and handling of trastuzumab emtansine, see the 
pharmacy manual and the Trastuzumab Emtansine Investigator's Brochure.  
Tucatinib drug product may be supplied as both a coated oval-shaped tablet in a 150 mg 
dosage strength and a coated round convex tablet in a 50 mg dosage strength.  The 
tablets are manufactured from a drug product intermediate amorphous dispersion of 
tucatinib in polyvinylpyrrolidone-vinyl acetate copolymer, which is then combined with 
the pharmaceutical excipients (microcrystalline cellulose, sodium chloride, potassium 
chloride, sodium bicarbonate, silicon dioxide, crospovidone, and magnesium stearate), 
and compressed into tablets. 
For information on the formulation and handling of tucatinib, see the pharmacy manual 
and the Tucatinib Investigator's Brochure. 
I.4.2.2 
Dosage, Administration, and Compliance 
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 
21 days (unless dose reduction and/or dose delays are required) until disease 
progression or unacceptable toxicity.  The dose of trastuzumab emtansine will be 
administered on the basis of the patient’s baseline weight.  Weight will be measured at 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
370/Protocol ML42439, Version 5 
each visit and dose must be re-adjusted for weight changes  10% compared to the 
previous visit or baseline.  The investigator may choose to recalculate the dose at every 
cycle using actual weight at that time, according to their local practice.  The calculated 
total dose may be rounded to the nearest milligram.   
Trastuzumab emtansine should be administered as described in Table 1.  The initial 
dose will be administered over 90 minutes.  Infusions may be slowed or interrupted for 
patients experiencing infusion-associated symptoms.  Vital signs must be assessed 
predose and postdose.  Following the initial dose, patients will be observed for at least 
90 minutes.  Subsequent doses of trastuzumab emtansine may be administered over 
30 minutes. 
Table 1 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine 
First Infusion 
Subsequent Infusions 
 No premedication is administered. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured a 
 Administer the initial dose as a 90-minute 
intravenous infusion.  
 Patients should be observed during the 
infusion and for at least 90 minutes 
following the initial dose for fever, chills, 
or other infusion related reactions. 
 The infusion rate should be slowed or 
interrupted if the patient develops 
infusion-related symptoms 
 The infusion site should be closely 
monitored for possible subcutaneous 
infiltration during drug administration. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured a 
 If prior infusions were well tolerated, 
subsequent doses may be administered 
as 30-minute infusions  
 Patient should be observed during the 
infusions and for at least 30 minutes after 
infusion. 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF 
 
Tucatinib 300 mg will be administered PO BID continuously starting from Cycle 1 Day 1 
onwards.  Tucatinib should be taken once in the morning and once in the evening, with 
approximately 8 to 12 hours between doses in the same calendar day.  
It is recommended that if a subject misses a scheduled dose of tucatinib and less than 6 
hours have passed since the scheduled dosing time, the dose should be immediately 
taken.  It is recommended that if more than 6 hours have passed since the scheduled 
dosing time, the subject should not take the missed dose but should wait and take the 
next regularly scheduled dose.   


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
371/Protocol ML42439, Version 5 
Tablets may be taken with or without food.  Tablets must be swallowed whole and may 
not be crushed, chewed, cut or dissolved in liquid.  On the day of dosing, the individual 
unit dose of the tucatinib tablet may be exposed to ambient temperature for up to 6 
hours prior to dose. 
Guidelines for trastuzumab emtansine dosage modification and treatment interruption or 
discontinuation are provided in Section I.5.2.1.1 
Guidelines for tucatinib dosage modification and treatment interruption or discontinuation 
are provided in Section I.5.2.1.2 
See Section 4.3.2 for details on assessment of compliance for self-administered oral 
study drugs. 
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
I.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
I.4.3.1 
Permitted Therapy 
Use of the following therapies is permitted during the study: 
 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Patients on anti-coagulant treatment should have their platelet count monitored 
closely during treatment with trastuzumab emtansine. 
 
Erythropoiesis-stimulating agents or granulocyte colony-stimulating factors 
Other medications considered necessary for the patient’s safety and well-being may be 
given at the discretion of the investigator. 
I.4.3.2 
Prohibited Therapy 
Use of the following therapy is prohibited during study treatment: 
 
Any systemic therapy intended for the treatment of the disease under study, 
including any other investigational agent 
 
Strong inducers of CYP3A4 are prohibited as concomitant medications during study 
treatment and within 1 week of discontinuation of tucatinib.  Concomitant use of 
potent CYP P450 3A4/5 inhibitors (such as ketoconazole and itraconazole) with 
trastuzumab emtansine should be avoided.  Consider an alternate medication with 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
372/Protocol ML42439, Version 5 
no or minimal potential to inhibit CYP3A4/5.  If a strong CYP3A4/5 inhibitor needs to 
be co-administered with trastuzumab emtansine, patients should be closely 
monitored for adverse reactions. 
 
Strong inhibitors or inducers of CYP2C8 are prohibited as concomitant medications 
during study treatment; Strong inhibitors of CYP2C8 are also prohibited within 1 
week of discontinuation of tucatinib (see Appendix 7).  Moderate inhibitors of 
CYP2C8 should be used with caution. 
 
Use of sensitive CYP3A substrates should be avoided 1 week prior to first dose of 
study treatment and during study treatment (see Appendix 7).  Consider using an 
alternate medication which is not a sensitive CYP3A substrate.  If unavoidable, 
consider dose reduction of CYP3A substrates with narrow therapeutic indices and/or 
increased monitoring for potential adverse reactions as described in the 
medication’s prescribing information. 
 
Concomitant use of tucatinib with digoxin, a P-glycoprotein (P-gp) substrate, 
increases digoxin concentrations, which may increase the risk for digoxin related 
adverse reactions.  Concomitant use of tucatinib with digoxin or P-gp substrates 
with a narrow therapeutic index (such as, but not limited to, dabigatran, 
fexofenadine, and cyclosporine) should be used with caution.  Refer to the 
prescribing information of digoxin or other P-gp substrates for dosage adjustment 
recommendations due to drug interactions. 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment and during study treatment 
(See Section 4.1.2), until disease progression is documented and the patient has 
discontinued study treatment. 
– 
Palliative radiation therapy for the treatment of bone pain for bone metastases 
in the absence of progressive disease is permitted, however tucatinib should be 
held during and for 7 days following radiation therapy.  
 
I.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients receiving trastuzumab emtansine plus tucatinib.  
Refer to the schedule of activities (Section I.6) for arm-specific assessment timepoints. 
Local Laboratory Assessments 
 
Coagulation:  INR and aPTT 
 
Liver function test: ALT/AST, total bilirubin 
 
Functional Assessments 
 
ECHO/MUGA 
 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
373/Protocol ML42439, Version 5 
I.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm I: trastuzumab emtansine 
plus tucatinib treatment. 
I.5.1 
Risks Associated with Trastuzumab Emtansine plus Tucatinib 
I.5.1.1 
Risks Associated with Trastuzumab Emtansine 
Trastuzumab emtansine has been associated with risks such as the following: 
hepatotoxicity, (predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases; serious hepatobiliary disorders, including 
nodular regenerative hyperplasia (NRH) of the liver), left ventricular dysfunction, 
infusion-related reaction (IRR), hypersensitivity, hemorrhagic events, (including CNS, 
respiratory, and gastrointestinal hemorrhage), thrombocytopenia, peripheral neuropathy, 
reactions secondary to extravasation, interstitial lung disease (including pneumonitis).  
Refer to the Trastuzumab Emtansine Investigator’s Brochure for a description of all 
anticipated safety risks for trastuzumab emtansine. 
I.5.1.2 
Risks Associated with Tucatinib 
Tucatinib has been associated with risks such as the following: diarrhea, palmar-plantar 
erythrodysesthesia (PPE) syndrome, nausea, fatigue, hepatotoxicity, vomiting, 
stomatitis, decreased appetite, abdominal pain, headache, anemia, rash, arthralgia, 
creatinine increased, weight decreased, peripheral neuropathy, and epistaxis.  Refer to 
the Tucatinib USPI for a detailed description of anticipated safety risks for tucatinib.  
Guidelines for Management of Adverse Events. 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
I.5.2 
Management of Patients Who Experience Adverse Events 
I.5.2.1 
Dose Modications and Interruptions 
I.5.2.1.1 
Dose Modifications and Interruptions for Trastuzumab 
Emtansine 
For adverse events not listed below in Section I.5.2.2 the following guidance should be 
used with regards to dose delays and modifications: 
 
For Grade 3 non-hematologic adverse events not adequately managed by standard 
medical intervention or for any Grade 4 non-hematologic adverse event, study 
treatment should be held until recovery to Grade  1.  A maximum dose delay of 42 
days for the last administered dose of study drug will be allowed.  


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
374/Protocol ML42439, Version 5 
 
If withheld for 42 days, trastuzumab emtansine may be resumed at either the same 
dose level as before or at one dose level lower (see Table 2), at the discretion of the 
investigator.  Subsequent cycles should remain every 21 days. 
 
Dose re-escalation is not permitted for trastuzumab emtasine.   
 
Resuming trastuzumab emtanzine after 42 days may be considered in exceptional 
circumstances and should be done in consultation with the Medical Monitor. 
 
Table 2 
Recommended Dose Reduction Schedule for Trastuzumab 
Emtansine 
Dose Reduction Schedule 
Dose Level 
Starting dose 
3.6 mg/kg 
First dose reduction 
3 mg/kg 
Second dose reduction 
2.4 mg/kg 
Requirement for further dose reduction 
Permanently discontinue 
 
I.5.2.1.2 
Dose Modifications and Interruptions for Tucatinib 
Up to three dose reductions of tucatinib are allowed.  Dose reductions of larger intervals 
than those described in Table 3.  Dose re-escalation is not permitted for tucatinib.   
Table 3 
Tucatinib: Recommended Dose Reduction Schedule for Adverse 
Events 
Dose Reduction Schedule 
Tucatinib Dose Level 
Starting dose 
300 mg PO BID a 
1st dose reduction 
250 mg PO BID 
2nd dose reduction 
200 mg PO BID 
3rd dose reduction 
150 mg PO BID 
Requirement for further dose reduction 
Discontinue tucatinib 
a Dose reductions of greater intervals than those recommended in this table (i.e., more than 50 
mg per dose reduction) may be made if considered clinically appropriate by the investigator in 
consultation with the Medical Monitor.  However, tucatinib may not be dose reduced below 150 
mg BID. 
 
I.5.2.2 
Guidelines for Management of Specific Adverse Events for 
Trastuzumab Emtansine 
I.5.2.2.1 
Cardiotoxicity  
Patients without significant cardiac history and with a baseline LVEF of  50% as 
determined by ECHO or MUGA scan are eligible for arm participation.  Cardiac 
monitoring (ECHO/MUGA) will be performed in all patients enrolled in this arm.  


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
375/Protocol ML42439, Version 5 
Assessments will occur during the screening period, and on Day 15 of Cycle 1, and 
every fourth cycle thereafter.  ECHO or MUGA will be performed following study 
treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed 
 28 days before last study treatment administration and if no post-treatment evaluation 
was performed (Section I.6). 
Figure 1 summarizes the management of trastuzumab emtansine on the basis of LVEF 
measurements and changes in LVEF from baseline in patients.  If an investigator is 
concerned that an adverse event may be related to cardiac dysfunction, an additional 
LVEF measurement may be performed.  Trastuzumab emtansine will be discontinued in 
any patient who develops symptomatic CHF.  CHF should be treated and monitored 
according to standard medical practice. 
The decision to stop or continue trastuzumab emtansine treatment should be on the 
basis of the algorithm shown in Figure 1 or asymptomatic declines in LVEF.  
Trastuzumab emtansine must be discontinued in all patients for whom a confirmed 
decrease of LVEF to  40% is documented (with a confirmation assessment carried out 
within 21 days).  For patients whose LVEF decreases to values of 40%45% with an 
absolute decrease in LVEF of ≥ 10% points from baseline, trastuzumab emtansine dose 
should be held.  For these patients, the LVEF measurement should be repeated within 
21 days, and trastuzumab emtansine treatment should be discontinued if the LVEF has 
not recovered to within a 10% absolute difference below baseline.  If clinically significant 
cardiac dysfunction or cardiac failure develops or persists or if significant medical 
management is required to maintain LVEF, the patient should be discontinued from all 
study treatment. 




Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
377/Protocol ML42439, Version 5 
Table 4 
Management Guidelines for Trastuzumab Emtansine Infusion-
Related Reactions (Caused by Cytokine Release) or 
Hypersensitivity (Allergic) Reaction 
Event 
Action to Be Taken  
Grade 2 
reaction  
Decrease trastuzumab emtansine infusion rate or interrupt 
infusion.  Administer supportive care with oxygen, -agonists, 
antihistamines, antipyretics, or corticosteroids, as appropriate, at 
the investigator’s discretion.  Monitor patient until complete 
resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at 
the investigator’s discretion.  In the event of a true 
hypersensitivity reaction (in which severity of reaction increases 
with subsequent infusions), discontinue trastuzumab emtansine. 
Premedication for infusion reactions (e.g., antihistamines such 
as diphenhydramine or corticosteroids) may be given at the 
investigator’s discretion. 
Grade 3 
reaction  
Stop trastuzumab emtansine infusion.  Administer supportive 
care with oxygen, -agonists, antihistamines, antipyretics, 
or corticosteroids, as appropriate, at the investigator’s discretion.  
Monitor patient until complete resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at 
the investigator’s discretion.  In the event of a true 
hypersensitivity reaction (in which severity of reaction increases 
with subsequent infusions), discontinue trastuzumab 
emtansine.   
Premedication for infusion reactions (e.g., antihistamines such 
as diphenhydramine or corticosteroids) may be given at the 
investigator’s discretion.  
Grade 4 
reaction 
Stop trastuzumab emtansine infusion.  Administer supportive 
care with oxygen, β-agonists, antihistamines, antipyretics, or 
corticosteroids, as appropriate, at the investigator’s discretion.  
Monitor patient until complete resolution of symptoms. 
Discontinue trastuzumab emtansine. 
 
I.5.2.2.3 
Hematologic Toxicities 
See Table 5 for trastuzumab emtansine dose modification guidelines for hematological 
toxicities, including thrombocytopenia. 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
378/Protocol ML42439, Version 5 
Table 5 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hematological Toxicity 
Event 
Action to Be Taken 
Grade 2 
thrombocytopenia 
(50,000 to 75,0000/L) 
Assess platelet counts weekly or as medically 
indicated until recovery.  Withhold study treatment 
until Grade  1.  Resume treatment without dose 
reduction.   
Grade 3 
thrombocytopenia 
(25,000 to  50,000/μL
) 
Withhold trastuzumab emtansine until recovery to 
Grade  1 (≥ 75,000/μL).  Following recovery, 
resume trastuzumab emtansine at the same dose 
level.  Discontinue trastuzumab emtansine if the 
event has not resolved to Grade  1 within 42 days 
after the last dose received. 
Grade 4 
thrombocytopenia 
( 25,000/μL) at any 
time 
Withhold trastuzumab emtansine until recovery to 
Grade  1 ( 75,000/μL).  Following recovery, 
resume trastuzumab emtansine with one dose level 
reduction.  Discontinue trastuzumab emtansine if the 
event has not resolved to Grade  1 within 42 days 
after the last dose received. 
Grade  3 hematologic 
toxicity other than 
thrombocytopenia 
Withhold trastuzumab emtansine until recovery to 
Grade  2.  Following recovery, resume trastuzumab 
emtansine at the same dose level.  Discontinue 
trastuzumab emtansine if the event has not resolved 
to Grade  2 within 42 days after the last dose 
received. 
 
I.5.2.2.4 
Neuropathy 
See Table 6 for trastuzumab emtansine dose modification guidelines for neuropathy. 
Table 6 
Trastuzumab Emtansine Dose Modification Guidelines for 
Neuropathy 
Event 
Action to Be Taken 
Grade  3 peripheral 
neuropathy 
Withhold trastuzumab emtansine until recovery to 
Grade  2.  Following recovery, resume trastuzumab 
emtansine at the same dose level or with one dose 
level reduction, at the investigator's discretion.  
Discontinue trastuzumab emtansine if the event has 
not resolved to Grade  2 within 42 days after the last 
dose received. 
 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
379/Protocol ML42439, Version 5 
I.5.2.2.5 
Hepatotoxicity 
Dose modification guidelines for trastuzumab emtansine and elevated liver function tests 
are provided in Table 7 and Table 8.  For dose modifications for tucatinib, see 
Section I.5.2.3. 
Trastuzumab emtansine must be permanently discontinued in patients with either 
Grade 4 transaminase elevations or Grade 4 total bilirubin elevations. 
Dose reductions are recommended for Grade 3 hepatic events (e.g., liver dysfunction, 
elevated AST, ALT, and/or total bilirubin).  The dose should be held in accordance with 
the dose delay guidance described in Table 7.  Dosage Modification for Toxicity to allow 
for recovery to Grade  2 (transaminase levels) and/or Grade  1 (total bilirubin level) 
prior to resuming trastuzumab emtansine at a lower dose level.  Patients who 
experience a Grade 2 total bilirubin elevation should have the dose held to allow for 
recovery to Grade  1 prior to resuming trastuzumab emtansine.  Patients who 
experience a Grade 3 hepatic event at the lowest dose level will be discontinued from 
study treatment.  No reescalation of the trastuzumab emtansine dose will be allowed. 
Patients with ALT and/or AST 3  the ULN concurrent with total bilirubin  2  ULN and/or 
clinical jaundice should discontinue trastuzumab emtansine. 
Trastuzumab emtansine must be permanently discontinued in patients who are 
diagnosed with NRH. 
Patients with increased total bilirubin because of Gilbert syndrome are allowed to 
continue trastuzumab emtansine dosing without a dose hold or dose modification if the 
direct (conjugated) bilirubin level is within the normal reference range.  


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
380/Protocol ML42439, Version 5 
Table 7 
Dose Modification Guidelines for Hypertransaminasemia 
(AST/ALT) 
 
Grade 4 
( 20  the ULN if 
baseline was normal; 
 20.0  baseline if 
baseline was abnormal) 
Grade 3 
( 5 to 20 the ULN if 
baseline was normal; 
 5.020.0  baseline if 
baseline was abnormal) 
Grade 2 
( 3.0 to 5.0  the ULN 
if baseline was normal; 
 3.05.0  baseline if 
baseline was abnormal) 
Trastuzumab 
emtansine 
Discontinue 
Hold dose; reduce 
one dose level when 
recovered to 
Grade  2. 
Discontinue if 
concurrent with a 
bilirubin  2  the ULN 
or clinical jaundice.  
Treat at the same 
dose level. 
Discontinue if 
concurrent a with a 
bilirubin  2  the ULN 
or clinical jaundice. 
ALTalanine transaminase; ASTaspartate transaminase; ULNupper limit of normal. 
Note:  A maximum of two dose reductions of trastuzumab emtansine is allowed.  A patient 
requiring more than two dose reductions must discontinue study treatment. 
a 
Within 21 days. 
 
Table 8 
Dose Modification Guidelines for Hyperbilirubinemia 
 
Grade 4 
( 10.0  the 
ULN if baseline 
was normal; 
 10.0  baseline 
if baseline was 
abnormal) 
Grade 3 
( 3.0 to 10.0  the 
ULN if baseline was 
normal; 
 3.010.0  baseline if 
baseline was abnormal) 
Grade 2 
( 1.5 to 3.0  the 
ULN if baseline was 
normal; 
 1.53.0  baseline if 
baseline was 
abnormal) 
Grade 1 
( ULN1.5  
ULN if baseline 
was normal; 
1.01.5  baseli
ne if baseline 
was abnormal) 
Trastuzumab 
emtansine 
Discontinue 
Hold dose; reduce 
one dose level when 
recovered to 
Grade  1 or 
baseline. 
Discontinue if 
concurrent a with ALT 
or AST  3  the 
ULN. 
Hold dose; treat at 
same dose level 
when recovered to 
Grade  1. 
Discontinue if 
 2  the ULN and 
concurrent a with 
ALT or AST  3  
the ULN.  
Treat at same 
dose level. 
ALTalanine transaminase; ASTaspartate transaminase; ULNupper limit of normal. 
Note:  A maximum of two dose reductions of trastuzumab emtansine is allowed.  A 
patient requiring more than two dose reductions must discontinue study treatment.   
a 
Within 21 days. 
 
 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
381/Protocol ML42439, Version 5 
I.5.2.2.6 
Pulmonary Toxicity 
It is recommended that treatment with trastuzumab emtansine be permanently 
discontinued in patients who are diagnosed with ILD or pneumonitis due to trastuzumab 
emtansine. 
 
I.5.2.3 
Guidelines for Management of Specific Adverse Events for 
Tucatinib 
General dose modification guidelines for clinical adverse events related tucatinib are 
provided Table 9 and Table 10.  For subjects with documented Gilbert’s disease, contact 
the medical monitor for guidance regarding dose modifications for LFT abnormalities.  
For dose modifications for trastuzumab emtansine, see Section I.5.2.2. 
Table 9  
Dose Modifications for Clinical Adverse Events Related to 
Tucatinib 
Adverse Reactions 
Tucatinib Dose Modification 
Diarrhea 
 
Grade 3 without anti-diarrheal treatment 
Initiate or intensify appropriate medical therapy.  
Hold tucatinib until recovery to Grade  1 or 
baseline 
Resume tucatinib at same dose level 
Grade 3 with anti-diarrheal treatment 
Initiate or intensify appropriate medical therapy.  
Hold tucatinib until recovery to Grade  1 or 
baseline 
Reduce tucatinib dose. 
Grade 4 (life-threatening consequences; 
urgent intervention indicated) 
Permanently discontinue tucatinib treatment. 
Other adverse reactions 
 
Grade 3 
Hold tucatinib until recovery to Grade  1 or 
baseline 
Reduce tucatinib dose 
Grade 4 
Permanently discontinue tucatinib. 
 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
382/Protocol ML42439, Version 5 
Table 10 Dose Modifications of Tucatinib for LFT Abnormalities, 
Regardless of Relationship to Tucatinib 
Laboratory Abnormality 
Tucatinib Dose Modification 
Grade 2 Bilirubin elevation  
 1.5–3 × ULN if baseline was 
normal;  1.53.0  baseline if 
baseline was abnormal 
Hold tucatinib until recovery to 
 1.5 × ULN Resume tucatinib at same 
dose level 
Grade 3 Bilirubin elevation  
 3–10 × ULN if baseline was 
normal;  3.010.0  baseline if 
baseline was abnormal 
Hold tucatinib until recovery to 
 1.5 × ULN 
Reduce tucatinib dose. 
Grade 4 Bilirubin elevation 
 10 × ULN if baseline was normal; 
 10.0  baseline if baseline was 
abnormal 
Permanently discontinue tucatinib. 
Grade 3 ALT or AST elevation  
 5–20 × ULN if baseline was 
normal;  5.020.0  baseline if 
baseline was abnormal 
Hold tucatinib until recovery to  3 × ULN 
or return to baseline level in subjects 
with known liver metastasis  
Reduce tucatinib dose. 
Grade 4 ALT or AST elevation 
 20 × ULN if baseline was normal; 
 20.0  baseline if baseline was 
abnormal 
Permanently discontinue tucatinib. 
ALT or AST  3 × ULN if baseline 
was normal;  3  baseline if 
baseline was abnormal AND 
bilirubin  2 × ULN if baseline was 
normal;  2  baseline if baseline 
was abnormal 
Permanently discontinue tucatinib. 
 
I.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately:   
Tucatinib 
Hepatotoxicity 
 
AST or ALT elevations that are >3 x ULN with concurrent elevation (within 21 days 
of AST and/or ALT elevations) of total bilirubin >2 x ULN, except in subjects with 
documented Gilbert’s syndrome  


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or 
Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
383/Protocol ML42439, Version 5 
 
Grade 4 AST, ALT, or bilirubin elevations  
 
Measurement of direct and indirect bilirubin should be considered in cases of 
hyperbilirubinemia to assist in determination of its etiology.  The sponsor will 
subsequently determine whether the elevations are associated with other possible 
causes of aminotransferase elevation and hyperbilirubinemia, such as viral hepatitis, 
pre-existing chronic or acute liver disease, or the administration of other drug(s) known 
to be hepatotoxic. 
Trastuzumab Emtansine 
 
N/A 
 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
384/Protocol ML42439, Version 5 
I.6 
SCHEDULE OF ACTIVITIES  
Assessments 
Pre-
treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study 
Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 a 
(3) 
 (3) 
 28 days after last 
study dose 
Informed consent d 
x 
 
 
 
Documentation of positive 
ERBB2 gene mutation or 
amplification by local test e 
x 
 
 
 
Medical history and baseline 
conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
Weight h 
x 
x 
 
 
ECOG Performance Status ii 
x 
x 
 
x 
Pregnancy test j 
x 
x 
 
x 
Chemistry k  
x 
x 
 
x c 
Hematology/CBC with differential 
l 
x 
x 
 
x c 
Coagulation Panel m 
x 
 
 
x 
Liver function test n 
 
 
C1, D15 and C2, D15 
 
ECHO or MUGA o 
x 
As clinically indicated 
C1, D15 and every  
4 cycles thereafter  
x o 
Trastuzumab emtansine 
administration p 
 
x 
 
 
Tucatinib compliance 
assessment q 
 
x 
 
x 
Tucatinib dispensing 
 
x 
 
 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
385/Protocol ML42439, Version 5 
Assessments 
Pre-
treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study 
Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 a 
(3) 
 (3) 
 28 days after last 
study dose 
Response Assessment r, s 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue 
sample for central testing (if 
applicable) t 
 
Submit within 21 days  
of C1, D1 
 
 
Whole blood samples u  
x 
 
see footnote u 
 
Adverse events v 
x  
Collected on an ongoing basis 
x v 
Concomitant Medications w 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; dMMRdeficient mismatch repair; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; 
eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection 
fraction; MSI-Hmicrosatellite-high; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; PETpositron 
emission tomography; RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 
1.1; SAEserious adverse event; TMB-Htumor mutational burden-high; TSH  thyroid-stimulating hormone. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if the 
hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 1.  Scans to 
document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may take 
place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to collect AE data and any 
standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
386/Protocol ML42439, Version 5 
e Confirmation of positive ERBB2 gene mutation or amplification status without known TMB-high/MSI-high/dMMR should occur prior to performing 
other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline. 
i All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
j Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who 
have a positive pregnancy test must not receive study drug.   
k Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent 
chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
l Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  
m Coagulation includes INR and aPTT. 
n Liver function test includes ALT/AST, total bilirubin. 
o LVEF assessments will occur during the screening period, and on Day 15 of Cycle 1, and every fourth cycle thereafter (e.g. C5D15, C9D15, 
etc.).  ECHO or MUGA will be performed following study treatment discontinuation only if the most recent follow-up ECHO/MUGA was 
performed 28 days before last study treatment administration and if no post-treatment evaluation was performed.  Evaluation of LVEF must be 
performed by the same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and operator perform 
ECHO/MUGA scan for each individual patient. 
p Trastuzumab emtansine will be administered by IV infusion at a dose of 3.6 mg/kg on Day 1 of Cycle 1, and on Day 1 of each 21-day cycle 
thereafter.  Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification or Mutant-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
387/Protocol ML42439, Version 5 
related adverse events, over approximately 30 minutes in subsequent doses.  Vital signs should be taken before and after the trastuzumab 
emtansine infusion.  Patients will be monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab 
emtansine infusion and, in the absence of infusion-related events, for a minimum of 30 minutes at subsequent infusions.  
q Tucatinib is administered PO BID, on a 21-day cycle.  On Day 1 of each cycle, review compliance from previous cycle and dispense tucatinib for 
next cycle. 
r All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
s At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
t For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing. If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
u Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   
v After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all 
deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
w Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the last dose of study treatment. 


Arm I:  Trastuzumab Emtansine plus Tucatinib in Patients With ERBB2 Amplification- or 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
388/Protocol ML42439, Version 5 
I.7 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric 
Rheumatology International Trials Organisation Collaborative Initiative. Ann 
Rheum Dis 2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther 
Clin Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 
 


 
MyTACTIC Study—Genentech, Inc. 
389/Protocol ML42439, Version 5 
Appendix 19  
Arm J:  Trastuzumab Emtansine Plus Atezolizumab in Patients with 
ERBB2 Amplification Or Mutation Plus TMB-H/MSI-H/dMMR-Positive 
Tumors 
20. 
ARM J:  TRASTUZUMAB EMTANSINE PLUS ATEZOLIZUMAB IN 
PATIENTS WITH ERBB2 AMPLIFICATION OR MUTATION PLUS TMB-
H/MSI-H/DMMR-POSITIVE TUMORS 
TABLE OF CONTENTS 
J.4 
Materials and Methods .......................................................... 390 
J.4.1 
Patients .................................................................................. 390 
J.4.1.1 
Additional Inclusion Criteria ................................................... 390 
J.4.1.2 
Additional Exclusion Criteria .................................................. 391 
J.4.2 
Study Treatment .................................................................... 394 
J.4.2.1 
Formulation and Packaging ................................................... 394 
J.4.2.2 
Dosage, Administration, and Compliance .............................. 395 
J.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 397 
J.4.3.1 
Permitted Therapy ................................................................. 397 
J.4.3.2 
Prohibited Therapy ................................................................ 398 
J.4.4 
Arm-specific Assessments ..................................................... 399 
J.5 
Safety Plan ............................................................................ 399 
J.5.1 
Risks Associated with Trastuzumab Emtansine plus 
Atezolizumab ......................................................................... 399 
J.5.1.1 
Risks Associated with Trastuzumab Emtansine .................... 399 
J.5.1.2 
Risks Associated with Atezolizumab ...................................... 400 
J.5.2 
Guidelines for Management of Adverse Events ..................... 400 
J.5.2.1 
Dose Modifications and Interruptions ..................................... 400 
J.5.2.2 
Guidelines for Management of Specific Adverse Events for 
Trastuzumab Emtansine ........................................................ 402 
J.5.2.3 
Guidelines for Management of Adverse Events Associated with 
Atezolizumab ......................................................................... 405 
J.5.2.4 
Guidelines for Management of Adverse Events that are Potential 
Overlapping Toxicities Associated with Trastuzumab Emtansine 
in Combination with Atezolizumab ......................................... 406 
J.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) .......................................................................... 410 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
390/Protocol ML42439, Version 5 
J.6 
Schedule of Activities ............................................................. 412 
J.7 
References ............................................................................ 416 
 
J.4 
MATERIALS AND METHODS 
J.4.1 
Patients 
To be enrolled in Arm J:  trastuzumab emtansine plus atezolizumab treatment, patients 
must have met and continue to meet all general eligibility criteria (see Section 4.1), in 
addition to the arm-specific criteria below. 
J.4.1.1 
 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm J:  
trastuzumab emtansine plus atezolizumab treatment: 
 
ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
ERBB2 mutation positivity is defined by selected single nucleotide variants 
listed below: 
– 
Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; 
S310F/Y; C311R/S; E321G; C334S 
– 
Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; 
D769H/N/Y; Y772_A775dup; 
A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; 
V842I; N857S; T862A; L869R; H878Y; R896C 
– 
Transmembrane domain:  S653C; V659E; G660D; R678Q 
– 
GFR domain IV:  P551L; R552S 
– 
Receptor L:  S418T; A440T 
– 
Other applicable mutations are eligible with Medical Monitor approval 
or evidence of ERBB2 gene amplification determined by CLIA or equivalently 
certified in-situ hybridization or NGS assay. Amplification is defined as a copy 
number of  6 for NGS assays or, for in-situ hybridization assays, as a 
HER2:CEP17 ratio  2.0 and average HER2 copy number/cell  4.0 signals/cell  
 
Documentation of one of the following biomarkers, as determined by a CLIA or 
equivalently certified assay (tissue or blood): 
– 
Tumor mutational burden (TMB) high, defined as  10 mutations per megabase 
as determined by a tissue-based NGS assay 
– 
Microsatellite instability high (MSI-H)  


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
391/Protocol ML42439, Version 5 
– 
Deficient mismatch repair (dMMR)  
 
ANC  1200/l within 14 days prior to initiation of study treatment 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
7 months after the last dose of trastuzumab emtansine or 5 months after the last 
dose of atezolizumab, whichever is longer; and agreement to refrain from donating 
eggs during this same period.  See Appendix 2 for details regarding requirements.  
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of  1% per year during the treatment period and for at least 7 months 
after the last dose of trastuzumab emtansine and agreement to refrain from 
donating sperm during this same period.  See Appendix 2 for details regarding 
contraception requirements. 
 
J.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm J: trastuzumab emtansine plus atezolizumab treatment: 
 
Breast cancer  
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
History of exposure to the following cumulative doses of anthracyclines as specified 
below: 
– 
Doxorubicin  500 mg/m2 
– 
Liposomal doxorubicin  500 mg/m2 
– 
Epirubicin  720 mg/m2 
– 
Mitoxantrone  120 mg/m2 
– 
Idarubicin  90 mg/m2 
If another anthracycline or more than one anthracycline has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 
 
History of severe hypersensitivity to components of the trastuzumab emtansine 
formulation 
 
Cardiopulmonary dysfunction as defined by any of the following: 
– 
Uncontrolled hypertension (systolic  150 mmHg and/or diastolic  100 mmHg) 
– 
Inadequate left ventricular ejection fraction at baseline,  50% by 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
392/Protocol ML42439, Version 5 
– 
History of symptomatic congestive heart failure Grade  3 per National Cancer 
Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI 
CTCAE v5.0) or Class  II New York Heart Association 
– 
History of decrease in left ventricular ejection function to  40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment 
– 
Myocardial infarction or unstable angina within 6 months of enrollment 
– 
Current dyspnea at rest due to complications of advanced malignancy, or other 
disease requiring continuous oxygen therapy  
– 
Evidence of transmural infarction on ECG 
– 
Significant symptoms (Grade  2) relating to left ventricular ejection fraction 
(LVEF), cardiac arrhythmia, or cardiac ischemia  
– 
Serious cardiac arrhythmia not controlled by adequate medication 
 
Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, autoimmune hepatic disorders, or sclerosis cholangitis  
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12  mg/dL, or corrected calcium  upper limit of normal [ULN]) 
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
– 
Patients with a history of HCV infection but who are negative for HCV RNA by 
PCR will be considered non-infected with HCV 
 
Grade  3 peripheral neuropathy, as defined by NCI CTCAE v5.0 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid replacement hormone are eligible for the study 
– 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
393/Protocol ML42439, Version 5 
o Rash must cover  10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids 
within the previous 12 months 
 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated  14 days 
prior to Cycle 1, Day 1.  The patient must have recovered from any resulting 
acute toxicity (to Grade  1) prior to study treatment initiation. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
 
Symptomatic pleural effusion, pericardial effusion, or ascites.  History of idiopathic 
pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography (CT) 
scan.  Patients with a history of radiation pneumonitis in the radiation field (fibrosis) 
are eligible.  
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) are eligible for the study 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the final dose of atezolizumab 
 
Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of study treatment 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
394/Protocol ML42439, Version 5 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-α agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study 
treatment, with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 
80 or 20 or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
 
J.4.2 
Study Treatment 
Study treatment in this arm will consist of atezolizumab in combination with trastuzumab 
emtansine.  
J.4.2.1 
Formulation and Packaging 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
Trastuzumab emtansine is provided as a lyophilized product in either 15-mL or 20-mL 
single-use vials which contain enough product to deliver 100 mg or 160 mg, respectively, 
of trastuzumab emtansine.  The lyophilized form of the product is provided for 
reconstitution to a liquid concentrate using sterile water for injection.  After reconstitution, 
both the 15-mL and 20-mL vials contain 20 mg/mL trastuzumab emtansine, 10 mM 
sodium succinate, pH 5.0, 6% w/v sucrose, and 0.02% (w/v) polysorbate 20.  The 
reconstituted product contains no preservative and is intended for single use only.  The 
density of the drug product after reconstitution is 1.026 g/mL.  
For information on the formulation and handling of trastuzumab emtansine, see the 
pharmacy manual and the Trastuzumab Emtansine Investigator's Brochure. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
395/Protocol ML42439, Version 5 
J.4.2.2 
Dosage, Administration, and Compliance 
Atezolizumab will be administered first followed by trastuzumab emtansine.  
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical 
benefit with Medical Monitor consultation, see Section 3.1.2 for treatment beyond 
disease progression).   
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.  The size of 
the infusion bag for each dose is listed below and will accommodate fluid restrictions 
needed for smaller patients. 
Administration of atezolizumab will be performed in a monitored setting where there is 
access to trained personnel and adequate equipment/medicine to manage potentially 
serious reactions.  For anaphylaxis precautions, see Appendix 6.  Atezolizumab 
infusions will be administered per the instructions outlined in Table 1. 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 No premedication is permitted prior to 
the atezolizumab infusion. 
 Vital signs (pulse rate, respiratory 
rate, blood pressure, and 
temperature) should be measured 
within 60 minutes prior to the infusion 
a. 
 Atezolizumab should be infused over 
60 (15) minutes. 
 If clinically indicated, vital signs 
should be measured every 
15 (5) minutes during the infusion 
and at 30 (10) minutes after the 
infusion. a 
 Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact 
their study physician if they develop 
such symptoms. 
 If the patient experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
 Vital signs should be measured within 
60 minutes prior to the infusion a. 
 Atezolizumab should be infused over 
30 (10) minutes if the previous infusion was 
tolerated without an infusion-related reaction, 
or 60 (15) minutes if the patient 
experienced an infusion-related reaction with 
the previous infusion. 
 If the patient experienced an infusion-related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
measured during the infusion and at 
30 (10) minutes after the infusion. a  
a Vital signs should be obtained as directed but are not required to be reported on the eCRF 
during study treatment.  Record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Section E.5.2.2.6. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
396/Protocol ML42439, Version 5 
No dose modification for atezolizumab is allowed. 
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 
21 days (unless dose reduction and/or dose delays are required) until disease 
progression or unacceptable toxicity (or loss of clinical benefit with Medical Monitor 
consultation when given in combination with atezolizumab; see Section 3.1.2 for 
treatment beyond disease progression).  The dose of trastuzumab emtansine will be 
administered on the basis of the patient’s baseline weight.  Weight will be measured at 
each visit and dose must be re-adjusted for weight changes  10% compared to the 
previous visit or baseline.  The investigator may choose to recalculate the dose at every 
cycle using actual weight at that time, according to their local practice.  The calculated 
total dose may be rounded to the nearest milligram.   
The initial dose will be administered over 90 minutes.  Infusions may be slowed or 
interrupted for patients experiencing infusion-associated symptoms.  Vital signs must be 
assessed predose and postdose.  Following the initial dose, patients will be observed for 
at least 90 minutes.  Subsequent doses of trastuzumab emtansine may be administered 
over 30 minutes. Guidelines for medical management of infusion-related reactions 
(IRRs) are provided in Section J.5.2.2.4. 
If a delay in administration of either agent is necessary, reasonable effort should be 
made to keep the administration synced if clinically feasible (e.g., briefly delay 
administration of the other agent). A cycle should be considered to start when any drug 
is administered. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
397/Protocol ML42439, Version 5 
Table 2 
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine 
First Infusion 
Subsequent Infusions 
 No premedication is administered. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) 
should be measured a 
 Administer the initial dose as a 90-
minute intravenous infusion.  
 Patients should be observed during 
the infusion and for at least 
90 minutes following the initial dose 
for fever, chills, or other infusion 
related reactions. 
 The infusion rate should be slowed or 
interrupted if the patient develops 
infusion-related symptoms 
 The infusion site should be closely 
monitored for possible subcutaneous 
infiltration during drug administration. 
 Vital signs (pulse rate, respiratory rate, blood 
pressure, and temperature) should be 
measured a 
 If prior infusions were well tolerated, 
subsequent doses may be administered as 
30-minute infusions  
 Patient should be observed during the 
infusions and for at least 30 minutes after 
infusion. 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  Record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF 
 
J.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
J.4.3.1 
Permitted Therapy 
Use of the following therapies is permitted during the study: 
 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Patients on anti-coagulant treatment should have their platelet count monitored 
closely during treatment with trastuzumab emtansine. 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section J.4.3.2) 
 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for COPD or asthma 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
398/Protocol ML42439, Version 5 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Bisphosphonates for the prevention or delay of skeletal complications, and palliation 
of bone pain in patients with documented bone metastases.  Use bisphosphonates 
or other agents for hypercalcemia or malignancy is prohibited and patients requiring 
such treatment should be evaluated for progressive disease.   
 
Erythropoiesis-stimulating agents or granulocyte colony-stimulating factors 
 
Radiation therapy for the treatment of bone pain for bone metastases in the 
absence of progressive disease  
 
Premedication with antihistamines, antipyretics, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, as 
clinically indicated.  
Other medications considered necessary for the patient’s safety and well-being may be 
given at the discretion of the investigator. 
J.4.3.2 
Prohibited Therapy 
Use of the following therapy is prohibited during study treatment: 
 
Any systemic therapy intended for the treatment of the disease under study, 
including any other investigational agent 
 
Concomitant use of potent cytochrome (CYP) P450 3A4/5 inhibitors (such as 
ketoconazole and itraconazole) with trastuzumab emtansine should be avoided.  
Consider an alternate medication with no or minimal potential to inhibit CYP3A4/5.  
If a strong CYP3A4/5 inhibitor needs to be co-administered with trastuzumab 
emtansine, patients should be closely monitored for adverse reactions. 
 
Any hormonal therapy used for the treatment of the disease under study.  Patients 
who require the use of these agents will be discontinued from study treatment. 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2), and during study treatment, until disease progression is documented 
and the patient has discontinued study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after 
the final dose of atezolizumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-
2) are prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
399/Protocol ML42439, Version 5 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
within 2 weeks prior to the initiation of study treatment and during study treatment 
because these agents could potentially alter the efficacy and safety of atezolizumab. 
 
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, MRI scans of the chest, abdomen, and pelvis with a non-contrast 
CT scan of the chest must be performed. 
 
J.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients receiving trastuzumab emtansine plus 
atezolizumab.  Refer to the schedule of activities (Section J.6) for arm-specific 
assessment timepoints. 
Local Laboratory Assessments 
 
Coagulation:  INR and aPTT 
 
Thyroid function test (thyroid-stimulating hormone [TSH], free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (T4) 
 
Functional Assessments 
 
ECHO/MUGA 
 
J.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm J: trastuzumab emtansine 
plus atezolizumab treatment. 
J.5.1 
Risks Associated with Trastuzumab Emtansine plus 
Atezolizumab 
J.5.1.1 
Risks Associated with Trastuzumab Emtansine 
Trastuzumab emtansine has been associated with risks such as the following: interstitial 
lung disease, (including pneumonitis), hepatotoxicity, (predominantly in the form of 
asymptomatic increases in the concentrations of serum transaminases; serious 
hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver), 
left ventricular dysfunction, IRR, hypersensitivity, hemorrhagic events, (including CNS, 
respiratory, and gastrointestinal hemorrhage), thrombocytopenia, peripheral neuropathy, 
and reactions secondary to extravasation.  Refer to the Trastuzumab Emtansine 
Investigator’s Brochure for a description of all anticipated safety risks for trastuzumab 
emtansine. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
400/Protocol ML42439, Version 5 
J.5.1.2 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer to the 
Atezolizumab Investigator's Brochure for a detailed description of anticipated safety risks 
for atezolizumab.  
Suggested workup and management guidelines for overlapping toxicities between 
atezolizumab and trastuzumab emtansine, pulmonary and hepatic events, are provided 
in Section J.5.2.4. 
J.5.2 
Guidelines for Management of Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
J.5.2.1 
Dose Modifications and Interruptions 
J.5.2.1.1 
Dose Modifications and Interruptions for Trastuzumab 
Emtansine 
For adverse events not listed below in Section J.5.2.2 the following guidance should be 
used with regards to dose delays and modifications: 
 
For Grade 3 non-hematologic adverse events not adequately managed by standard 
medical intervention or for any Grade 4 non-hematologic adverse event, study 
treatment should be held until recovery to Grade  1.  A maximum dose delay of 42 
days for the last administered dose of study drug will be allowed. 
 
If withheld for 42 days, trastuzumab emtansine may be resumed at either the same 
dose level as before or at one dose level lower (see Table 3), at the discretion of the 
investigator.  Subsequent cycles should remain every 21 days. 
 
Dose re-escalation is not permitted for trastuzumab emtasine.   
 
Resuming trastuzumab emtanzine after 42 days may be considered in exceptional 
circumstances and should be done in consultation with the Medical Monitor. 
 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
401/Protocol ML42439, Version 5 
Table 3 
Recommended Dose Reduction Schedule for Trastuzumab 
Emtansine 
Dose Reduction Schedule 
Dose Level 
Starting dose 
3.6 mg/kg 
First dose reduction 
3 mg/kg 
Second dose reduction 
2.4 mg/kg 
Requirement for further dose reduction 
Permanently discontinue 
 
J.5.2.1.2 
Dose Modifications and Interruptions for Atezolizumab 
No dose reductions for atezolizumab are allowed.  Interruptions to atezolizumab 
treatment are described in Section E.5.2.1.1.


 
MyTACTIC Study—Genentech, Inc. 
402/Protocol ML42439, Version 5 
J.5.2.2 
Guidelines for Management of Specific Adverse Events for 
Trastuzumab Emtansine 
J.5.2.2.1 
Hepatotoxicity  
Hepatotoxicity is an overlapping toxicity for trastuzumab emtansine and atezolizumab.  
Management guidelines are provided in Section J.5.2.4.2. 
J.5.2.2.2 
Pulmonary Toxicity 
Pulmonary Toxicity is an overlapping toxicity for trastuzumab emtansine and 
atezolizumab.  Management guidelines are provided in Section J.5.2.4.1 
J.5.2.2.3 
Cardiotoxicity  
Patients without significant cardiac history and with a baseline LVEF of  50% as 
determined by ECHO or MUGA scan are eligible for arm participation.  Cardiac 
monitoring (ECHO/MUGA) will be performed in all patients enrolled in this arm.  
Assessments will occur during the screening period, and on Day 15 of Cycle 1, and 
every fourth cycle thereafter.  ECHO or MUGA will be performed following study 
treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed 
 28 days before last study treatment administration and if no post-treatment evaluation 
was performed (see Section J.6). 
Figure 1 summarizes the management of trastuzumab emtansine on the basis of LVEF 
measurements and changes in LVEF from baseline in patients.  If an investigator is 
concerned that an adverse event may be related to cardiac dysfunction, an additional 
LVEF measurement may be performed.  Trastuzumab emtansine will be discontinued in 
any patient who develops symptomatic CHF.  CHF should be treated and monitored 
according to standard medical practice. 
The decision to stop or continue trastuzumab emtansine treatment should be on the 
basis of the algorithm shown in Figure 1 or asymptomatic declines in LVEF.  
Trastuzumab emtansine must be discontinued in all patients for whom a confirmed 
decrease of LVEF to  40% is documented (with a confirmation assessment carried out 
within 21 days).  For patients whose LVEF decreases to values of 40%45% with an 
absolute decrease in LVEF of ≥ 10% points from baseline, trastuzumab emtansine dose 
should be held.  For these patients, the LVEF measurement should be repeated within 
21 days, and trastuzumab emtansine treatment should be discontinued if the LVEF has 
not recovered to within a 10% absolute difference below baseline.  If clinically significant 
cardiac dysfunction or cardiac failure develops or persists or if significant medical 
management is required to maintain LVEF, the patient should be discontinued from all 
study treatment. 




 
MyTACTIC Study—Genentech, Inc. 
404/Protocol ML42439, Version 5 
J.5.2.2.4 
Infusion-Related Reactions and Hypersensitivity Reactions 
See Table 4 for management guidelines for trastuzumab emtansine-associated infusion-
related reactions and hypersensitivity reactions. 
Table 4 
Management Guidelines for Trastuzumab Emtansine Infusion-
Related Reactions (Caused by Cytokine Release) or 
Hypersensitivity (Allergic) Reaction 
Event 
Action to Be Taken  
Grade 2 reaction  
Decrease trastuzumab emtansine infusion rate or interrupt infusion.  
Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s 
discretion.  Monitor patient until complete resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at the 
investigator’s discretion.  In the event of a true hypersensitivity reaction 
(in which severity of reaction increases with subsequent infusions), 
discontinue trastuzumab emtansine. 
Premedication for infusion reactions (e.g., antihistamines such as 
diphenhydramine or corticosteroids) may be given at the investigator’s 
discretion. 
Grade 3 reaction  
Stop trastuzumab emtansine infusion.  Administer supportive care with 
oxygen, -agonists, antihistamines, antipyretics, or corticosteroids, 
as appropriate, at the investigator’s discretion.  Monitor patient until 
complete resolution of symptoms.   
May continue trastuzumab emtansine at the same dose level at the 
investigator’s discretion.  In the event of a true hypersensitivity reaction 
(in which severity of reaction increases with subsequent infusions), 
discontinue trastuzumab emtansine.   
Premedication for infusion reactions (e.g., antihistamines such as 
diphenhydramine or corticosteroids) may be given at the investigator’s 
discretion.  
Grade 4 reaction 
Stop trastuzumab emtansine infusion.  Administer supportive care with 
oxygen, β-agonists, antihistamines, antipyretics, or corticosteroids, as 
appropriate, at the investigator’s discretion.  Monitor patient until 
complete resolution of symptoms. 
Discontinue trastuzumab emtansine. 
 
J.5.2.2.5 
Hematologic Toxicities 
See Table 5 for trastuzumab emtansine dose modification guidelines for hematological 
toxicities, including thrombocytopenia. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
405/Protocol ML42439, Version 5 
Table 5 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hematological Toxicity 
Event 
Action to Be Taken 
Grade 2 thrombocytopenia 
(50,000 to 75,0000/L) 
Assess platelet counts weekly or as medically indicated until 
recovery.  Withhold study treatment until Grade  1.  Resume 
treatment without dose reduction.   
Grade 3 thrombocytopenia 
(25,000 to  50,000/μL) 
Withhold trastuzumab emtansine until recovery to Grade  1 
( 75,000/μL).  Following recovery, resume trastuzumab 
emtansine at the same dose level.  Discontinue trastuzumab 
emtansine if the event has not resolved to Grade  1 within 
42 days after the last dose received. 
Grade 4 thrombocytopenia 
( 25,000/μL) at any time 
Withhold trastuzumab emtansine until recovery to Grade  1 
( 75,000/μL).  Following recovery, resume trastuzumab 
emtansine with one dose level reduction.  Discontinue 
trastuzumab emtansine if the event has not resolved to 
Grade  1 within 42 days after the last dose received. 
Grade  3 hematologic toxicity 
other than thrombocytopenia 
Withhold trastuzumab emtansine until recovery to Grade  2.  
Following recovery, resume trastuzumab emtansine at the 
same dose level.  Discontinue trastuzumab emtansine if the 
event has not resolved to Grade  2 within 42 days after the 
last dose received. 
 
J.5.2.2.6 
Neuropathy 
See Table 6 for trastuzumab emtansine dose modification guidelines for neuropathy. 
Table 6 
Trastuzumab Emtansine Dose Modification Guidelines for 
Neuropathy 
Event 
Action to Be Taken 
Grade  3 peripheral 
neuropathy 
Withhold trastuzumab emtansine until recovery to Grade  2.  
Following recovery, resume trastuzumab emtansine at the 
same dose level or with one dose level reduction, at the 
investigator's discretion.  Discontinue trastuzumab emtansine 
if the event has not resolved to Grade  2 within 42 days after 
the last dose received. 
 
J.5.2.3 
Guidelines for Management of Adverse Events Associated with 
Atezolizumab 
Guidelines for management of adverse events associated with atezolizumab can be found in 
Section E.5.2.2  


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
406/Protocol ML42439, Version 5 
J.5.2.4 
Guidelines for Management of Adverse Events that are 
Potential Overlapping Toxicities Associated with Trastuzumab 
Emtansine in Combination with Atezolizumab  
The following adverse events are potential overlapping toxicities associated with 
combination use of trastuzumab emtansine and atezolizumab:  pulmonary and 
hepatic events.   
J.5.2.4.1 
Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (diffusion capacity of the lung for carbon monoxide) 
 
Pulmonary function testing with a pulmonary embolism protocol 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study, and 
will also have CT scans of the chest at every tumor assessment.  COVID-19 evaluation 
should be performed per institutional guidelines where relevant.  See Table 7 for 
management guidelines for pulmonary events and pneumonitis.  
In this study, atezolizumab and trastuzumab emtansine are discontinued for all grades of 
interstitial lung disease and pneumonitis. 
Table 7 
Management Guidelines for Interstitial Lung Disease and 
Pneumonitis 
Severity 
Trastuzumab Emtansine 
Atezolizumab 
Grade 1  4 
Discontinue trastuzumab 
emtansine treatment. 
Discontinue atezolizumab 
treatment 
 
J.5.2.4.2 
Hepatic Events 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases.  Liver function will be monitored throughout 
study treatment. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
407/Protocol ML42439, Version 5 
While on this study, patients who present with right upper-quadrant abdominal pain 
and/or unexplained nausea or vomiting should have liver function tests (LFTs) performed 
immediately and reviewed before administration of the next dose of study drug. 
If outcome of LFTs is worsening, concurrent medications, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.  Imaging of 
the liver, gall bladder, and biliary tree should be performed to rule out neoplastic or other 
causes for worsening outcome of LFTs.  Antinuclear antibody, perinuclear antineutrophil 
cytoplasmic antibody, antiliver kidney microsomal antibodies, and antismooth muscle 
antibody tests should be performed if an autoimmune etiology is considered.  See 
Table 8 for management guidelines for atezolizumab and trastuzumab emtansine 
hepatic events.  
See Table 8 for Management Guidelines for Increased Transaminases (AST/ALT) and 
Hepatic Events.  See Table 9 for dose modifications of trastuzumab emtansine for 
hyperbilirubinemia.  
Note:  No dose modification for atezolizumab is indicated on the basis of 
hyperbilirubinemia alone. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
408/Protocol ML42439, Version 5 
Table 8 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events 
Severity 
Atezolizumab 
Trastuzumab Emtansine 
ALT or AST increase that 
meets Hy's law criteria:  
ALT or AST  3  ULN, in 
combination with TBILI 
 2  ULN or clinical 
jaundice 
Discontinue atezolizumab 
treatment. 
Discontinue trastuzumab 
emtansine treatment. 
Grade 1  
AST or ALT 
 ULN3.0  ULN if 
baseline was normal; 
1.53.0  baseline if 
baseline was abnormal  
 
Treat at the same dose level. 
Continue LFT monitoring. 
Treat at the same dose 
level. 
Grade 2  
AST or ALT 
 3.05.0  ULN if baseline 
was normal; 
 3.05.0  baseline if 
baseline was abnormal 
 
Withhold atezolizumab dose. 
If persists   57 days:  Consider 
starting 12 mg/kg/day 
prednisone or equivalent per day; 
when recover to Grade  1, taper 
steroids over   1 month. 
Resume therapy when systemic 
steroid dose is   10mg oral 
prednisone equivalent per day 
and resume when recovery to 
Grade  1 at same dose within 
12 weeks. 
Permanently discontinue 
atezolizumab and contact the 
Medical Monitor if event does not 
resolve to Grade 1 or better within 
12 weeks. 
Treat at the same dose 
level. 
GIgastrointestinal; LFTliver function test; NRHNodular Regenerative Hyperplasia; 
TNFtumor necrosis factor; ULNupper limit of normal.  
 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
409/Protocol ML42439, Version 5 
Table 8 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Atezolizumab 
Trastuzumab Emtansine 
Grade 3  
AST or ALT 
 5.020.0  ULN if 
baseline was normal; 
 5.020.0  baseline 
if baseline was 
abnormal  
 
Discontinue atezolizumab dose. 
Consider GI consult and liver biopsy 
to establish etiology of hepatic injury if 
necessary. 
Start 60 mg prednisone or equivalent 
per day. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent 
(e.g., mycophenolate or TNF- 
antagonist) may be considered. 
Taper steroids over  1 month, when 
symptoms improve to Grade 0 or 
Grade 1. 
Contact the Medical Monitor if 
atezolizumab treatment is 
discontinued. 
Withhold trastuzumab 
emtansine dose. 
Do not administer 
trastuzumab emtansine until 
recovery to Grade  2, and 
then resume with dose 
reduction by one level. 
Discontinue trastuzumab 
emtansine treatment if the 
event has not resolved to 
Grade  2 within 42 days after 
the last dose received. 
Grade 4 
AST or ALT 
 20.0  ULN if 
baseline was normal; 
 20.0  baseline if 
baseline was 
abnormal  
 
Discontinue atezolizumab treatment. 
Consider GI consult and liver biopsy 
to establish etiology of hepatic injury if 
necessary. 
Start 60 mg prednisone or equivalent 
per day. 
If LFT results do not decrease within 
48 hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent 
(e.g., mycophenolate or TNF- 
antagonist) may be considered. 
Taper steroids over  1 month, when 
symptoms improve to Grade 0 or 
Grade 1.  
Contact the Medical Monitor if 
atezolizumab treatment is 
discontinued. 
Discontinue trastuzumab 
emtansine treatment. 
Laboratory tests may be 
repeated (within 24 hours) to 
exclude laboratory error prior 
to discontinuing trastuzumab 
emtansine. 
GIgastrointestinal; LFTliver function test; NRHNodular Regenerative Hyperplasia; 
TNFtumor necrosis factor; ULNupper limit of normal.  


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
410/Protocol ML42439, Version 5 
Table 8 
Management Guidelines for Increased Transaminases (AST/ALT) 
and Hepatic Events (cont.)  
Severity 
Atezolizumab 
Trastuzumab Emtansine 
NRH 
If there are signs of portal 
hypertension (e.g., ascites 
and/or varices) and/or a 
cirrhosis-like pattern is seen 
on a CT scan of the liver, the 
possibility of NRH should be 
considered.   
Discontinue atezolizumab 
treatment 
Discontinue trastuzumab 
emtansine treatment and 
have the patient evaluated 
by a hepatologist. 
GIgastrointestinal; LFTliver function test; NRHNodular Regenerative Hyperplasia; 
TNFtumor necrosis factor; ULNupper limit of normal.  
 
Table 9 
Trastuzumab Emtansine Dose Modification Guidelines for 
Hyperbilirubinemia  
Severity 
Action to be Taken 
Grade 2 
Total bilirubin 
 1.53.0  ULN if 
baseline was normal; 
 1.53.0  baseline if 
baseline was abnormal 
Withhold until total bilirubin recovers to Grade   1 and then 
resume at the same dose level. 
Grade 3 
Total bilirubin 
 3.0 - 10.0  ULN if 
baseline was normal; 
 3.010.0  baseline if 
baseline was abnormal 
Withhold until total bilirubin recovers to Grade   1 and then 
resume by one dose level reduction.   
Grade 4 
Total bilirubin 
 10.0  ULN if 
baseline was normal; 
 10.0  baseline if 
baseline was abnormal 
Discontinue trastuzumab emtansine treatment. 
ULN   upper limit of normal. 
 
J.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification 
or Mutation plus TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
411/Protocol ML42439, Version 5 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately:   
Atezolizumab 
 
Systemic lupus erythematosus 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade 2 cardiac disorders  
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  
 
Trastuzumab Emtansine 
 
Not Applicable 
  


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2 Amplification or Mutation plus TMB-H/MSI-H/dMMR-Positive 
Tumors 
MyTACTIC Study—Genentech, Inc. 
412/Protocol ML42439, Version 5 
J.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment  
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 A 
(3) 
 (3) 
≤ 28 days after 
last study dose 
Informed consent d 
x 
 
 
 
Documentation of positive ERBB2 gene 
mutation or amplification plus TMB-H/MSI-
H/dMMR by local test e 
x 
 
 
 
Medical history and baseline conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
Weight h 
x 
x 
 
 
ECOG Performance Status i 
x 
x 
 
x 
Pregnancy test j 
x 
x 
 
x 
Chemistry k  
x 
x 
 
x c 
Hematology/CBC with differential l 
x 
x 
 
x c 
Coagulation Panel m 
x 
 
 
x 
Thyroid function test (TSH, free T3 [or total], 
and free T4) n 
x 
C1, D1 and every 4 cycles 
thereafter 
 
 
ECHO or MUGA o 
x 
As clinically indicated  
C1, D15 and every 4 
cycles thereafter  
x o 
Atezolizumab administration p 
 
x 
 
 
Trastuzumab emtansine administration q 
 
x 
 
 
Response Assessments r, s 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) 
weeks 
 
Pre-treatment tumor tissue sample for central 
testing (if applicable) t 
 
Submit within 21 days  
of C1, D1 
 
 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2-Amplification or Mutation and TMB-High/MSI-High/dMMR 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
413/Protocol ML42439, Version 5 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment  
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 A 
(3) 
 (3) 
≤ 28 days after 
last study dose 
Whole blood samples u  
x 
 
see footnote u 
 
Adverse events v 
x  
Collected on an ongoing basis 
x v 
Concomitant Medications w 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; dMMRdeficient mismatch repair; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; 
eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection 
fraction; MSI-Hmicrosatellite-high; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; PETpositron 
emission tomography; RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 
1.1; SAEserious adverse event; TMB-Htumor mutational burden-high; TSH  thyroid-stimulating hormone. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if the 
hematology/CBC, chemistry panel, and thyroid function test are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 
1.  Scans to document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of 
treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment follow-
up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-trastuzumab emtansine 
discontinuation or 90 days post-atezolizumab discontinuation, whichever is longer.  If the patient’s worsening disease combined with travel 
distance makes this visit too difficult, follow-up with the patient may take place by telephone to include an assessment of AEs.  Alternatively, the 
patient's local physician may be contacted to collect AE data and any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive ERBB2 gene mutation or amplification plus TMB-H/MSI-H/dMMR status should occur prior to performing other trial-
related eligibility assessments.  TMB-H should be determined using a tissue-based NGS assay. 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2-Amplification or Mutation and TMB-High/MSI-High/dMMR 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
414/Protocol ML42439, Version 5 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline. 
i All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
j Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who 
have a positive pregnancy test must not receive study drug.  
k Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment. If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent 
chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
l Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  
m Coagulation includes INR and aPTT. 
n TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every four cycles 
thereafter (i.e., Cycles 5, 9, 13, etc.). 
o LVEF assessments will occur during the screening period, and on Day 15 of Cycle 1, and every fourth cycle thereafter (e.g. C5D15, C9D15, 
etc.).  ECHO or MUGA will be performed following study treatment discontinuation only if the most recent follow-up ECHO/MUGA was performed 
28 days before last study treatment administration and if no post-treatment evaluation was performed.  Evaluation of LVEF must be performed 
by the same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and operator perform 
ECHO/MUGA scan for each individual patient. 
p Atezolizumab will be administered first by IV infusion at a dose of 1200 mg on Cycle 1, and on Day 1 of each 21-day cycle thereafter.  For the 
first infusion of atezolizumab, vital signs should be determined within 60 minutes before, every 15 ( 5) minutes during, and 30 ( 10) minutes 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2-Amplification or Mutation and TMB-High/MSI-High/dMMR 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
415/Protocol ML42439, Version 5 
after the infusion, if clinically indicated.  For subsequent infusions, vital signs do not need to be obtained during the infusion if the prior infusion 
was tolerated without symptoms.   
q Trastuzumab emtansine will be administered second by IV infusion at a dose of 3.6 mg/kg on Day 1 of Cycle 1, and on Day 1 of each 21-day 
cycle thereafter.  Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of 
infusion-related adverse events, over approximately 30 minutes in subsequent doses.  Vital signs should be taken before and after the 
trastuzumab emtansine infusion.  Patients will be monitored for any untoward effects for at least 90 minutes after completion of the first 
trastuzumab emtansine infusion and, in the absence of infusion-related events, for a minimum of 30 minutes at subsequent infusions. 
r All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), 
a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  A CT or MRI 
scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or refute the 
diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
s At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors)(or loss of clinical benefit with 
Medical Monitor consultation, see Section 3.1.2), withdrawal of consent, termination of an individual study arm by the Sponsor, or death, 
whichever occurs first.   
t For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
u Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   
v After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of trastuzumab 
emtansine or 90 days after the final dose of atezolizumab, whichever is longer.  All patients will be followed until treatment-related toxicities 
resolve or for at least 28 days post-trastuzumab emtansine discontinuation or 90 days post-atezolizumab discontinuation, whichever is longer.  
After this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
w Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study treatment. 
   
 


Arm J:  Trastuzumab Emtansine plus Atezolizumab in Patients With ERBB2-Amplification or 
Mutation and TMB-High/MSI-High/dMMR Tumors 
 
MyTACTIC Study—Genentech, Inc. 
416/Protocol ML42439, Version 5 
J.7 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc 
Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 29 October 
2018; cited: 17 May 2019]. Available from: https://www.uptodate.com/contents/clinical-
features-and-diagnosis-of-hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk 
Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving PD-
1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. 
Blood 2015;125:290814. 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
417/Protocol ML42439, Version 5 
Appendix 20  
Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K 
(PIK3CA) Activating Mutation-Positive Tumors 
21. 
ARM K:  IPATASERTIB PLUS ATEZOLIZUMAB IN PATIENTS 
WITH PI3K (PIK3CA) ACTIVATING MUTATION-POSITIVE 
TUMORS 
TABLE OF CONTENTS 
K.4 
Materials and Methods .......................................................... 418 
K.4.1 
Patients .................................................................................. 418 
K.4.1.1 
Additional Inclusion Criteria ................................................... 418 
K.4.1.2 
Additional Exclusion Criteria .................................................. 419 
K.4.2 
Study Treatment .................................................................... 421 
K.4.2.1 
Formulation and Packaging ................................................... 422 
K.4.2.2 
Dosage, Administration, and Compliance for Ipatasertib ....... 422 
K.4.2.3 
Dosage, Administration, and Compliance for Atezolizumab .. 423 
K.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 425 
K.4.3.1 
Permitted Therapy ................................................................. 425 
K.4.3.2 
Cautionary Therapy ............................................................... 426 
K.4.3.2.1 
Corticosteroids and Tumor Necrosis Factor- Inhibitors ........ 426 
K.4.3.2.2 
Surgery or Radiation .............................................................. 427 
K.4.3.2.3 
Herbal Therapies ................................................................... 427 
K.4.3.2.4 
Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes .............................................. 427 
K.4.3.3 
Prohibited Therapy ................................................................ 428 
K.4.3.4 
Prohibited Food ..................................................................... 429 
K.4.4 
Arm-specific Assessments ..................................................... 429 
K.5 
Safety Plan ............................................................................ 430 
K.5.1 
Risks Associated with Ipatsertib and Atezolizumab ............... 430 
K.5.1.1 
Risks Associated with Ipatasertib .......................................... 430 
K.5.1.2 
Risks Associated with Atezolizumab ...................................... 430 
K.5.1.3 
Risks Associated with Combination Use of Ipatasertib and 
Atezolizumab ......................................................................... 430 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
418/Protocol ML42439, Version 5 
K.5.2 
Guidelines for Management of Adverse Events ..................... 430 
K.5.2.1 
Dose Modifications and Interruptions ..................................... 431 
K.5.2.2 
Guidelines for Management of Specific Adverse Events ....... 432 
K.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 447 
K.5.4 
Selected Adverse Events ....................................................... 447 
K.6 
Schedule of Activities ............................................................. 449 
K.7 
References ............................................................................ 454 
 
K.4 
MATERIALS AND METHODS 
K.4.1 
Patients 
To be enrolled in Arm K: ipatasertib in combination with atezolizumab treatment, patients 
must have met and continue to meet all general eligibility criteria (see Section 4.1), in 
addition to the arm-specific criteria below. 
K.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm K: 
ipatasertib plus atezolizumab treatment: 
 
PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
PIK3CA mutation positivity is defined by the presence of at least one nucleotide 
variant listed below: 
– 
H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V 
– 
Other activating mutations with Medical Monitor approval 
 
No available acceptable treatment for malignancy that is expected to provide clinical 
benefit 
 
ANC  1000/l within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c)  7.5% 
 
Ability to swallow ipatasertib intact, without chewing or crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
419/Protocol ML42439, Version 5 
28 days after the last dose of ipatasertib and 5 months after the last dose of 
atezolizumab; and agreement to refrain from donating eggs during this same period.  
See detailed contraception requirements in Appendix 2. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of  1% per year during the treatment period and for at least 28 days 
after the last dose of ipatasertib, and agreement to refrain from donating sperm 
during this same period.  See detailed contraception requirements in Appendix 2. 
 
K.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm K: ipatasertib plus atezolizumab treatment: 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Use of an indwelling catheter (e.g., PleurX®) is allowed. 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected serum calcium  ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid replacement hormone are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
420/Protocol ML42439, Version 5 
o Rash must cover  10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids 
within the previous 12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study   
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the final dose of atezolizumab 
 
Prior treatment with anti-PD-1 or anti PD-L1 therapeutics unless approved by 
Medical Monitor 
– 
 Up to approximately 12 such patients may be enrolled 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives 
(whichever is longer) prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
421/Protocol ML42439, Version 5 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
 
Prior treatment with ipatasertib or other Akt inhibitors 
 
History of malabsorption syndrome or other condition that would interfere with 
enteral absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class 
B or C, current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection 
fraction (LVEF)  50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia's 
formula (QTcF)  480 milliseconds  
 
History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion (including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of  10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants 
for a chronic disease.  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to 
initiation of study treatment are eligible for enrollment.  
Diabetic patients with fasting total serum glucose  8.3 mmol/L (150 mg/dL) 
and/or HbA1C  7.5 are not eligible for enrollment. 
 
History of or active inflammatory bowel disease (e.g., Crohn's disease and 
ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)  
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, 
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A 
inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to 
initiation of study treatment (see Appendix 7) 
 
K.4.2 
Study Treatment 
Study treatment in this arm will consist of ipatasertib in combination with atezolizumab. 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
422/Protocol ML42439, Version 5 
K.4.2.1 
Formulation and Packaging 
Ipatasertib will be supplied by the Sponsor as 100-mg and 200-mg tablets.  
For information on the formulation and handling of ipatasertib, see the pharmacy manual 
and the Ipatasertib Investigator's Brochure. 
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL 
glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
The study drug will be periodically tested and monitored for its acceptable shelf life.  Any 
study drug that fails to comply with the manufactured specifications will be promptly 
removed from the clinical trial site and replaced with new supplies by the Sponsor (or 
designee). 
Each bottle will be labeled with the required regulatory agency warning statement, the 
protocol number, the Sponsor’s name, and directions for patient use and storage.  The 
investigator should ensure that the study drug is stored in appropriate conditions in a 
secure location with controlled access. 
K.4.2.2 
Dosage, Administration, and Compliance for Ipatasertib  
Study treatment will be administered in 21 day cycles. 
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at 
the same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) 
once a day (QD) until disease progression or intolerable toxicity (or loss of clinical 
benefit with Medical Monitor consultation, see Section 3.1.2 for treatment beyond 
disease progression).   
The tablets will be swallowed whole (not chewed) with 3 ounces (90 mL) of fluid.  
Ipatasertib is recommended to be taken at least 2 hours after the last meal of the day, 
and patients should refrain from eating overnight.  Patients are required to receive 
prophylaxis  with loperamide throughout the first cycle (2 mg oral twice a day, or per 
local institutional guidelines) and at subsequent cycles as clinically indicated (see 
Table 3).  
For ipatasertib doses to be administered at home, a sufficient number of tablets should 
be dispensed to the patient to last until the next visit, or at the investigator’s discretion, 
through one cycle.  Patients will be asked to record in a medication diary the time and 
date for each dose taken. 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
423/Protocol ML42439, Version 5 
A missed dose can be taken within 8 hours of the scheduled time.  After that, patients 
should take the next dose the following day, without compensating for the missed dose 
(including vomited doses).  
Guidelines for ipatasertib dosage modification and treatment interruption or 
discontinuation are provided in Section K.5.2.1. 
See Section 4.3.2 for details on assessment of compliance for self-administered oral 
study drugs. 
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug. 
 
K.4.2.3 
Dosage, Administration, and Compliance for Atezolizumab 
Study treatment will be administered in 21 day cycles. 
Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 
mg for patients on Day 1 of each 21-day cycle until unacceptable toxicity or progressive 
disease (or loss of clinical benefit with Medical Monitor consultation, see Section 3.1.2 
for treatment beyond disease progression).   
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.   
Administration of atezolizumab will be performed in a monitored setting where there is 
access to trained personnel and adequate equipment/medicine to manage potentially 
serious reactions.  For anaphylaxis precautions, see Appendix 6.  Atezolizumab 
infusions will be administered per the instructions outlined in Table 1. 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
424/Protocol ML42439, Version 5 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 No premedication is permitted prior 
to the atezolizumab infusion, except 
as outlined in Section K.4.2.3. 
 Vital signs (pulse rate, respiratory 
rate, blood pressure, and 
temperature) should be measured 
within 60 minutes prior to the infusion 
a 
 Atezolizumab should be infused over 
60 (15) minutes. 
 If clinically indicated, vital signs 
should be measured every 
15 (5) minutes during the infusion 
and at 30 (10) minutes after the 
infusion. a 
 Patients should be informed about 
the possibility of delayed post-
infusion symptoms and instructed to 
contact their study physician if they 
develop such symptoms. 
 If the patient experienced an infusion-
related reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
 Vital signs should be measured within 
60 minutes prior to the infusion. a 
 Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
 If the patient experienced an infusion-
related reaction with the previous infusion or 
if clinically indicated, vital signs should be 
measured during the infusion and at 
30 (10) minutes after the infusion. a 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
 
No dose modification for atezolizumab is allowed. Guidelines for medical management 
of infusion-related reactions (IRRs) are provided in Section E.5.2.2.7 for atezolizumab. 
Owing to the risk of rash in Cycle 1, patients should receive the following prophylaxis 
during the first cycle when study treatments will be given (see Table 3 for AE 
management of dermatological toxicities, including rash):  
 
Unless contraindicated, daily PO antihistamine prophylaxis should be used for at 
least the first cycle. It is suggested that a non-sedating longer-acting oral 
antihistamine be used (such as 10 mg of cetirizine PO QD or comparable dose of 
other antihistamines, e.g., loratadine, fexofenadine).  
 
On day when patients will receive atezolizumab, patients should receive at least 10 
mg/day of prednisone (or equivalent dosing of other steroids e.g., 
methylprednisolone, prednisolone) as premedication prior to atezolizumab, followed 
by a fixed dose of 10 mg/day prednisone (or equivalent) for 24 consecutive days 
thereafter, unless contraindicated.  
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
425/Protocol ML42439, Version 5 
K.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug until 28 days after the last dose of study drug.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
K.4.3.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study:  
 
Oral contraceptives, as allowed per local guidelines 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:  
Palliative radiotherapy is permitted for a preexisting lesion, provided it does not 
interfere with the assessment of tumor target lesions (e.g., the lesion to be 
irradiated must not be a site of measurable disease).  Study treatment should be 
suspended during palliative radiotherapy.  Treatment with ipatasertib should be 
temporarily held for at least 7 days before and after the procedure (at least 14 
days after radiation is recommended).  For a single fraction of radiotherapy, this 
hold may be shorter, if discussed by the investigator with the Medical Monitor.  
The patient may continue ipatasertib treatment after treatment holding has been 
completed and the patient has sufficiently recovered.  
 
Prophylaxis use of loperamide is mandated in the first cycle and as clinically 
indicated in subsequent cycles to prevent diarrhea.  Patients who experience 
diarrhea should be on treatment doses of loperamide per the management 
guidelines provided in Table 3; please refer to that table for additional details.  
Patients should be educated/reminded to be cognizant of the onset, duration, 
severity, and frequency of symptoms and the medications administered.  
 
Prophylaxis use of antihistamines and prednisone (or equivalent dosing of other 
steroids) is mandated in the first cycle due to the risk of rash and is described in 
Section K.4.2.3.  
 
Granulocyte colony-stimulating factor treatment is permitted.  The primary 
prophylaxis should be administered per the American Society of Clinical Oncology 
(ASCO), European Organization for Research and Treatment of Cancer (EORTC), 
and European Society for Medical Oncology (ESMO) guidelines; namely, in patients 
who are  60 years of age and/or with comorbidities (Smith et al. 2006; Aapro et al. 
2011) 
 
Bisphosphonate therapy or RANKL inhibitor therapy (e.g., zolendronic acid and 
denosumab) used specifically to prevent skeletal events (e.g., bone metastasis, 
osteoporosis) is allowed.  Both types of agents have potential immunomodulatory 
properties, but may be used as clinically indicated.  


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
426/Protocol ML42439, Version 5 
 
Luteinizing hormone-releasing hormone or gonadotropin-releasing hormone 
agonists for ovarian function preservation are allowed.  
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)  
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section K.4.3.3) 
 
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Stable dose of calcium-channel blockers are permitted. 
 
Stable dose of β-blockers, if an alternative treatment cannot be used, are permitted 
with caution. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and per institutional practice.  For example, patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per institutional practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists; seeAppendix 6). 
K.4.3.2 
Cautionary Therapy  
K.4.3.2.1 
Corticosteroids and Tumor Necrosis Factor- Inhibitors 
Systemic corticosteroids and tumor necrosis factor alpha (TNF-) inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids or TNF- inhibitors would be 
routinely administered, alternatives, including antihistamines, should be considered.  If 
the alternatives are not feasible, systemic corticosteroids and TNF- inhibitors may be 
administered at the discretion of the investigator. Systemic corticosteroids are 
recommended, at the discretion of the investigator, for the treatment of specific adverse 
events when associated with atezolizumab therapy (refer to Section K.5.2.2.3 
[combination therapy] or Section E.5.2.2 [single agent]for guidelines for managing 
specific adverse events).  


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
427/Protocol ML42439, Version 5 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events associated with ipatasertib (refer to 
Section K.5.2.2.3 [combination therapy] or Section D.5.2.2.6, Section D.5.2.2.7 [single 
agent] for guidelines for managing specific adverse events).  If daily systemic 
corticosteroids are initiated for treatment of any toxicity or other condition, they must be 
tapered to 10 mg/day of oral prednisone or equivalent before ipatasertib or 
atezolizumab can be resumed. Steroids used as prophylaxis (i.e., as premedication prior 
to scans, or as protocol-directed rash prophylaxis) do not require holding of ipatasertib or 
atezolizumab.  Steroids used on a single day to manage infusion-related reactions 
(IRRs) or allergic reactions similarly do not require holding of ipatasertib.  
K.4.3.2.2 
Surgery or Radiation 
Patients who require radiation or surgery as part of medical treatment in the absence of 
radiographic disease progression must exercise caution, and all study treatment should 
be temporarily held for at least 7 days before and after the procedure (at least 14 days 
after radiation is recommended).  For minor surgeries or single-day radiotherapy, this 
hold may be shorter, if discussed by the investigator with the Medical Monitor.  After the 
temporary treatment hold is complete, study treatment may be re-initiated when the 
patient has sufficiently recovered.   
K.4.3.2.3 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug−drug interactions (DDIs) are 
generally unknown.  However, herbal therapies not intended for the treatment of cancer 
may be used during the study at the discretion of the investigator. 
K.4.3.2.4 
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
In vitro data suggest that ipatasertib is metabolized by CYP3A and may be a time-
dependent inhibitor of CYP3A4.  A clinical DDI study with midazolam (a sensitive CYP3A 
substrate) showed a 2.2-fold increase in midazolam exposures in presence of steady-
state ipatasertib dosed at 600 mg QD.  Therefore, sensitive CYP3A substrates with 
narrow therapeutic window should be avoided.  Given that ipatasertib is primarily 
metabolized by CYP3A, there is a high potential for drug−drug interactions of ipatasertib 
with any medication that strongly inhibits or induces CYP3A.  Data from a clinical study 
showed that ipatasertib exposures were reduced by ~50% when co-administered with 
enzalutamide, a strong CYP3A inducer.  Strong CYP3A inhibitors are expected to 
increase ipatasertib exposures significantly.  
Therefore, strong CYP3A4/5 inhibitors or inducers or CYP3A4/5 substrates with a 
narrow therapeutic index should be avoided or used with caution (see Appendix 7).  
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
428/Protocol ML42439, Version 5 
 (i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients are permitted to take moderate inhibitors of CYP3A4 with caution.  
Patients should be closely monitored.  Refer to the following information for further 
guidance on CYP450−drug interactions and a list of common substrates, inhibitors, and 
inducers:  
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and 
Inducers (U.S. Food and Drug Administration [FDA]): 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/ DrugInteractionsLabeling/ucm093664.htm  
The above lists of medications are not comprehensive.  The investigator should consult 
the prescribing information when determining whether a concomitant medication can be 
safely administered with study treatment.  In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications not listed above. 
K.4.3.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2, and during study treatment until disease progression is documented 
and the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and radiotherapy to the brain under circumstances outlined above 
in Section K.4.3.1.  
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 21 days prior to initiation of study treatment and during study treatment.  
 
Chronic use of a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A 
substrates with a narrow therapeutic window that are deemed not permissible by the 
Medical Monitor after enrollment (refer to the guidance in Section K.4.3.2.4 ) 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
429/Protocol ML42439, Version 5 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab. 
 
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment 
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients should be closely monitored.  Patients who require short-term use of 
moderate CYP3A4 inhibitors may continue study treatment with caution.  
Refer to the following information for further guidance on CYP450drug interactions and 
a list of common substrates, inhibitors, and inducers:  
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers (U.S. Food and Drug Administration [FDA]): 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ 
DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 
 
K.4.3.4 
Prohibited Food 
Use of the following foods is prohibited as described below:  
 
Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit, potent CYP3A4 enzyme 
inhibitors, is prohibited during the study treatment period and for 10 days after the 
last dose of study treatment. 
 
Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, is prohibited for 
up to 14 days prior to and during the study treatment period, and for 10 days after 
the last dose of study treatment. 
 
K.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in the Arm K: ipatasertib plus atezolizumab 
treatment.  Refer to the schedule of activities (see Section K.6) for arm-specific 
assessment timepoints. 
Local Laboratory Assessments 
 
Coagulation panel:  INR and aPTT 
 
HbA1c, blood glucose (fasting) 
 
Amylase, lipase (fasting) 
 
Lipid panel (fasting):  total cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (T4) 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
430/Protocol ML42439, Version 5 
 
Functional Assessments 
 
LVEF assessment:  echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
 
12-lead electrocardiogram 
 
K.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm K: ipatasertib plus 
atezolizumab treatment. 
K.5.1 
Risks Associated with Ipatsertib and Atezolizumab 
K.5.1.1 
Risks Associated with Ipatasertib 
Ipatasertib has been associated with risks such as the following: nausea, vomiting, 
diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, erythema 
multiforme, and rash.  Ipatasertib’s potential risks include hematologic or 
immunosuppressant effects, hyperlipidemia, hepatotoxicity, pneumonitis, colitis, and 
developmental toxicity.  Refer to the Ipatasertib Investigator’s Brochure for a detailed 
description of anticipated safety risks for ipatasertib. 
K.5.1.2 
Risks Associated with Atezolizumab  
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, 
myelitis, meningoencephalitis, myocarditis, peridardial disorders, nephritis, myositis, 
and severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 
involve any organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer 
to the Atezolizumab Investigator's Brochure for a detailed description of anticipated 
safety risks for atezolizumab.   
K.5.1.3 
Risks Associated with Combination Use of Ipatasertib and 
Atezolizumab 
On the basis of the frequency of adverse events associated with either ipatasertib or 
atezolizumab, the following adverse events are potential overlapping toxicities 
associated with combination use of ipatasertib and atezolizumab:  diarrhea, colitis, 
hepatotoxicity, rash, pneumonitis, and hyperglycemia.  
K.5.2 
Guidelines for Management of Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
431/Protocol ML42439, Version 5 
K.5.2.1 
Dose Modifications and Interruptions 
K.5.2.1.1 
Dose Modifications and Interruptions for Ipatasertib 
If the patient does not tolerate the QD dosing of ipatasertib, dosing with food may be 
used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or diarrhea.  
No more than two dose reductions of ipatasertib per patient (i.e., doses below 
200 mg/day of ipatasertib) will be allowed (see Table 2).  Dose re-escalation is not 
permitted for ipatasertib. 
If needed, dose reductions may occur in decrements of 100 mg and no more than two 
dose reductions will be allowed.  Accordingly, the possible daily doses of ipatasertib are 
shown in Table 2. If the patient continues to experience specified drug-related adverse 
events after the second reduction, the treatment should be discontinued. 
Any dose modification should be noted on the corresponding Study Drug Administration 
eCRF.  Cases of accidental overdose or medication error, along with any associated 
adverse events, should be reported as described in Section 5.3.5.12. 
Table 2 
Ipatasertib Dose Reductions 
Dose Level a 
Ipatasertib Dose 
Starting dose 
400 mg 
First dose reduction 
300 mg 
Second dose reduction 
200 mg 
Third dose reduction 
Not permitted 
Note:  After dose reduction, the dose of ipatasertib may not be re-escalated. 
 
Ipatasertib treatment may be temporarily interrupted in patients who experience toxicity 
considered to be related to study drug.  If ipatasertib has been withheld for 
28 consecutive days because of treatment-related toxicity, the patient should be 
discontinued from ipatasertib.  Ipatasertib may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor consultation.  If, in the judgment 
of the investigator, the patient is likely to derive clinical benefit from resuming study 
treatment after a hold of  28 consecutive days, study drug may be restarted.  The 
decision to re-challenge patients with ipatasertib should be based on the investigator’s 
benefitrisk assessment and documented by the investigator. The Medical Monitor is 
available to advise as needed. If corticosteroids are initiated for treatment of any toxicity, 
ipatasertib must be held and corticosteroids must be tapered over  1 month to 
 10 mg/day oral prednisone or equivalent before ipatasertib can be resumed. 
If either ipatasertib or atezolizumab is discontinued, the other drug can be continued if 
the patient is likely to derive clinical benefit.  The acceptable length of treatment 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
432/Protocol ML42439, Version 5 
interruption must be based on the investigator's benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
K.5.2.1.2 
Dose Modifications and Interruptions for Atezolizumab 
No dose reductions for atezolizumab are allowed.  Interruptions to atezolizumab 
treatment are described in Section E.5.2.1.1. 
If either atezolizumab or ipatasertib is discontinued, the other drug can be continued if 
the patient is likely to derive clinical benefit, as determined by the investigator and 
following discussion with the Medical Monitor. 
K.5.2.2 
Guidelines for Management of Specific Adverse Events 
K.5.2.2.1 
Guidelines for Management of Specific Adverse Events 
Associated with Ipatasertib 
Guidelines for management of specific adverse events for ipatasertib given as a single 
agent are provided in Section D.5.2.2. 
K.5.2.2.2 
Guidelines for Management of Specific Adverse Events 
Associated with Atezolizumab 
Guidelines for management of specific adverse events for atezolizumab given as a 
single agent are provided in Section E.5.2.2. 
K.5.2.2.3 
Guidelines for Management of Specific Adverse Events 
Associated with Ipatasertib plus Atezolizumab 
Guidelines for the management of patients who experience adverse events are provided 
in Section E.5.2.2, and Table 3, as outlined below: 
 
Section E.5.2.2 provides guidelines for the management of patients who experience 
atezolizumab-associated IRRs and immune-mediated endocrine, ocular, pancreatic, 
neurologic disorders (including facial paresis), myocarditis, myelitis, pericardial 
disorders, meningoencephalitis, renal, myositis, hemophagocytic 
lymphohistiocytosis, and macrophage activation syndrome events.  It is 
recommended that atezolizumab be withheld or discontinued per the guidelines in 
Section E.5.2.2 and that ipatasertib be withheld or discontinued per the guidelines in 
Table 3. 
 
Table 3 provides guidelines for the management of patients who experience the 
following potential overlapping toxicities:  gastrointestinal, dermatologic, hepatic, 
pulmonary, and hyperglycemia events.  It is recommended that study treatments be 
withheld or discontinued per the guidelines in Table 3.  For these potential 
overlapping toxicities guidelines in Table 3, should be followed instead of guidelines 
in Section E.5.2.2. 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
433/Protocol ML42439, Version 5 
 
Table 3 provides guidelines for the management of patients who experience 
adverse events associated with ipatasertib.  It is recommended that atezolizumab 
and/or ipatasertib be withheld or discontinued per the guidelines in Table 3. 
 
For cases in which management guidelines are not covered in Table 3 or 
Section E.5.2.2, patients should be managed and treatments should be withheld or 
discontinued as deemed appropriate by the investigator according to best medical 
judgment.


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
434/Protocol ML42439, Version 5 
 
Table 3 
Guidelines for Management of Patients Who Experience Adverse 
Events in Ipatasertib plus Atezolizumab 
Event 
Management 
IRRs and 
anaphylaxis 
 Guidelines for management of IRRs are provided in Section E.5.2.2  
 Withhold ipatasertib. 
 For anaphylaxis precautions, see Appendix 6. 
 For severe hypersensitivity reactions, permanently discontinue ipatasertib 
and atezolizumab. 
Hemophagocytic 
lymphohistiocytosis 
or macrophage 
activation syndrome 
 Follow guidelines for atezolizumab in Section E.5.2.2. 
 Withhold ipatasertib and contact the Medical Monitor for guidance. 
Gastrointestinal toxicity 
General guidance 
 All events of diarrhea or colitis should be thoroughly evaluated for more 
common etiologies other than drug-induced effects. 
 For diarrhea that persists for more than 5 days, despite treatment with 
anti-diarrheal agent(s) and/or with dose hold of ipatasertib, 
gastroenterologists should be consulted to rule out the risk of colitis and 
infection.  Patients should be educated on the symptoms and importance 
of early reporting of diarrhea to receive instructions of treatment and 
prevention of dehydration so that patients can be promptly and 
appropriately managed.  Educational materials will be provided to 
investigators and patients outlining these guidelines. 
 For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute phase reactants (e.g., increased CRP, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if 
appropriate) with colonic biopsy, with three to five specimens for standard 
paraffin block to check for inflammation and lymphocytic infiltrates to 
confirm colitis diagnosis. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
435/Protocol ML42439, Version 5 
Event 
Management 
Gastrointestinal toxicity (cont.) 
General guidance 
 Administer anti-diarrheal agents and other supportive care per 
institutional guidelines or per suggested supportive care outlined below: 
Medication 
– 
Treatment modifications for diarrhea (any grade), when it occurs, 
should be instituted as early as possible.  Guidelines for treatment of 
diarrhea, following the prophylactic dose of loperamide 4 mg initial 
daily dose (taken 2 mg twice a day or per local institutional standard), 
includes use of loperamide 2 mg after each loose watery stool, up to 
the maximum total dose of 16 mg/day or per institutional guidelines 
and standard of care, including, but not limited to, additional therapy 
with Lomotil (diphenoxylate and atropine), codeine, or octreotide. 
– 
Duration of diarrhea may be minimized by taking ipatasertib with food, 
avoiding lactose-containing foods, and hydrating with 810 glasses 
per day (~12 oz/glass) of electrolyte-containing clear liquid such as 
broth and Gatorade drinks. 
– 
Dose reductions of ipatasertib will be by one level at a time (i.e., 400 to 
300 mg; 300 to 200 mg) as outlined in If Grade  2 diarrhea persists 
following dose reductions of ipatasertib to 200 mg daily and with 
maximum treatment for diarrhea, ipatasertib should be discontinued.  
Oral Supplementation 
– 
Initiate potassium and/or magnesium if serum levels are less than the 
lower limit of normal. 
– 
Consider rehydration therapy with oral electrolyte solution for Grade  1 
diarrhea or vomiting. 
Dietary Modifications 
– 
Instruct patient to eat small meals and eliminate lactose-containing 
products from diet. 
– 
Suggest diet of bananas, rice, apples, and toast, while avoiding fiber 
from vegetables and other fruits. 
– 
Encourage adequate hydration with salt-containing liquids (e.g., broth, 
sports drinks such as Gatorade). 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
436/Protocol ML42439, Version 5 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Diarrhea, Grade 1 
or Grade 2 
 Continue ipatasertib and atezolizumab 
– Initiate supportive care and monitor patient closely. 
 Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis if appropriate. 
 For Grade 2 events, withhold  atezolizumab  and consider empiric steroids 
in case of strong suspicion for immune-mediated colitis while waiting for 
definitive diagnosis. Interrupt ipatasertib until diarrhea improves to 
Grade  1.  Ipatasertib can be resumed at the same dose or one dose lower 
per investigator evaluation upon improvement to Grade  1. 
Diarrhea, Grade 2 
(persisting  5 
days) or Grade 3 
 Withhold ipatasertib and atezolizumab 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs) while 
investigating etiology. 
 Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis, including biopsy if appropriate. 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
 If event resolves to Grade 1 or better within 28 days, resume ipatasertib with 
dose reduced by one level.  If not, permanently discontinue ipatasertib. 
 If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab 
at fixed dose.  If not, permanently discontinue ipatasertib and atezolizumab 
and contact the Medical Monitor. a, b, c 
 For recurrent Grade 3 diarrhea, reduce ipatasertib dose by one additional 
dose level or discontinue ipatasertib permanently per the Medical Monitor. 
Diarrhea, Grade 4   Permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. c 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs) while 
investigating etiology.  
 Rule out bowel perforation. 
 Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis, including a confirmatory biopsy if appropriate. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 
 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
437/Protocol ML42439, Version 5 
Event 
Management 
Gastrointestinal toxicity (cont.) 
Colitis, Grade 1 
 Continue ipatasertib and atezolizumab. 
 Initiate supportive care and monitor patient closely.  
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 For Grade 2 events, withhold  atezolizumab  and consider empiric steroids 
in case of strong suspicion for immune-mediated colitis while waiting for 
definitive diagnosis. 
 Refer patient to GI specialist for evaluation and confirmatory biopsy if 
symptoms persist for  5 days. 
Colitis, Grade 2 
 Withhold ipatasertib and atezolizumab. 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 For recurrent events or events that persist  5 days, initiate treatment with 
12 mg/kg/day oral prednisone or equivalent.  If the event does not improve 
within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab 
at fixed dose.  If not, permanently discontinue ipatasertib and atezolizumab 
and contact the Medical Monitor. a, b, c 
 If event resolves to Grade 1 or better within 28 days and corticosteroid dose 
10 mg oral prednisone or equivalent, resume ipatasertib with dose reduced 
by one level.  If not, permanently discontinue ipatasertib. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
438/Protocol ML42439, Version 5 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Colitis, Grade 3 
 Withhold ipatasertib and atezolizumab. 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.  If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue ipatasertib and 
atezolizumab and contact the Medical Monitor. a, b, c 
 If event resolves to Grade 1 or better within 28 days and corticosteroid dose 
10 mg oral prednisone or equivalent, resume ipatasertib with dose 
reduced by one level.  If not, permanently discontinue ipatasertib. 
Colitis, Grade 4 
 Permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. c 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.  
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
 
 
 
 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
439/Protocol ML42439, Version 5 
Event 
Management 
Endocrine disorders 
Grade 1 hypothyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 2 hypothyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 3 and 4 
hypothyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 1 hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 3-4 hyperthroidism. 
Grade 2 hyperthyroidism  Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 3 and 4 
hyperthyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
 For life-threatening immune-related hyperthyroidism, withhold 
ipatasertib.  If event becomes clinically manageable within 28 
days, resume ipatasertib with dose reduced by one level.  If not, 
permanently discontinue ipatasertib. 
Symptomatic adrenal 
insufficiency, Grade 2, 3, 
or 4 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
 Follow guidelines provided in Section E.5.2.2. 
 Withhold ipatasertib until Grade  2. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
440/Protocol ML42439, Version 5 
Event 
Management 
Endocrine disorders (cont.) 
Hyperglycemia, any 
grade 
 All events of hyperglycemia should be thoroughly evaluated for more 
common etiologies other than drug-induced effects. 
 Workup should include confirmation of fasting blood glucose, urinary 
glucose and ketones, arterial blood gas, serum bicarbonate, HbA1c, C-
peptide levels, anti-islet antibodies, anti-GADD45 antibody. 
 Hyperglycemia should be treated per institutional guidelines with fluid 
replacement, insulin, and correction of electrolyte abnormalities.  
Hyperglycemia, 
Fasting glucose value 
 ULN to 160 mg/dL 
(8.9 mmol/L) 
 Continue ipatasertib and atezolizumab. 
 The patient should receive education on a diabetic diet and consider 
home glucose monitoring. 
 Oral anti-diabetic medications (e.g., metformin) or insulin replacement 
may be started at the discretion of the investigator, guided by etiology 
of hyperglycemia.  
Hyperglycemia, 
Fasting glucose value 
 ULN to 250 mg/dL 
( 8.913.9 mmol/L) 
 Continue atezolizumab, consider interruption of ipatasertib. 
 The patient should adopt a diabetic diet and initiate home glucose 
monitoring. 
 Start oral anti-diabetic medications (e.g., metformin) or insulin 
replacement, guided by etiology of hyperglycemia. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have ful
recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by t
investigator.  The Medical Monitor is available to advise as needed. 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
441/Protocol ML42439, Version 5 
Event 
Management 
Endocrine disorders (cont.) 
Hyperglycemia, 
Glucose value 250 to 
500 mg/dL 
( 13.927.8 mmol/L) 
 Withhold ipatasertib and atezolizumab dosing until fasting 
hyperglycemia resolves to  160 mg/dL. 
 Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used.  Start (or increase dose of) oral anti-
diabetic medications (e.g., metformin). 
 Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
 The patient should adopt a diabetic diet and initiate home glucose 
monitoring. 
 If the fasting hyperglycemia resolves to  160 mg/dL within 3 days, 
ipatasertib may be resumed at the previous dose level. 
 If the fasting hyperglycemia does not resolve to  160 mg/dL within 3 
days or if  fasting hyperglycemia  250 mg/dL recurs within 14 days, 
the dose of ipatasertib should be reduced by one dose level (Table 2) 
when treatment is restarted.   
 Resume atezolizumab when symptoms resolve and glucose levels are 
stable. 
Hyperglycemia, 
Glucose value  500 
mg/dL  
( 27.8 mmol/L); life-
threatening 
consequences 
 Withhold ipatasertib and atezolizumab dosing until fasting 
hyperglycemia resolves to  160 mg/dL.  
 Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used.  Start (or increase dose of) oral anti-
diabetic medications (e.g., metformin). 
 Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
 The patient should adopt a diabetic diet and initiate home glucose 
monitoring. 
 Upon recovery of fasting glucose to  160 mg/dL, ipatasertib should be 
reduced by one dose level (Table 2) when treatment is restarted. 
 Resume atezolizumab when symptoms resolve and glucose levels are 
stable. 
 If hyperglycemia  500 mg/dL recurs, permanently discontinue 
ipatasertib and atezolizumab and contact the Medical Monitor.  
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
442/Protocol ML42439, Version 5 
Event 
Management 
Pulmonary events 
 
General guidance 
 All pulmonary events should be thoroughly evaluated for other 
commonly reported etiologies such as pneumonia/infection, 
lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary hypertension. 
Pulmonary event, 
Grade 1 
 Continue ipatasertib and atezolizumab. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
 For recurrent pneumonitis, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 2 
 Withhold ipatasertib and atezolizumab. 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy.  
 If bronchoscopy is consistent with immune-mediated etiology, initiate 
treatment with 1−2 mg/kg/day oral prednisone or equivalent.  
 If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue ipatasertib 
and atezolizumab and contact the Medical Monitor. a, b, c 
 If event resolves to Grade 1 or better within 28 days and corticosteroid 
dose  10 mg oral prednisone or equivalent, resume ipatasertib at 
current dose. c,d 
 For recurrent events or events with no improvement after 48–72 hours 
of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary event,  
Grade 3 or 4 
 Permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. c 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy.  
 If bronchoscopy is consistent with immune-mediated etiology, initiate 
treatment with 1−2 mg/kg/day IV methylprednisolone  
 If pulmonary event does not improve within 48 hours or worsens, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over   1 
month. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; LFT  liver 
function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation.  
 
 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
443/Protocol ML42439, Version 5 
Event 
Management 
Elevations in ALT, AST, and/or bilirubin 
AST/ALT  ULN to 
 3  ULN with total 
bilirubin  2  ULN 
 Continue ipatasertib and atezolizumab. 
AST/ALT  3  ULN 
to 5  ULN with total 
bilirubin  ULN to 
 2  ULN 
 Continue ipatasertib and atezolizumab. 
 Monitor LFTs at least weekly.   
 Consider patient referral to a hepatologist and liver biopsy. 
Suspected immune-mediated events of  5 days' duration: 
 Consider withholding atezolizumab. 
 Consider initiation of treatment with 12 mg/kg/day oral prednisone or 
equivalent. 
 If atezolizumab is withheld and event resolves to AST/ALT  3  ULN 
with total bilirubin  2  ULN within 12 weeks, resume atezolizumab at 
fixed dose.  If not, permanently discontinue ipatasertib and 
atezolizumab and contact the Medical Monitor. a, b, c 
AST/ALT  5  ULN to 
 10  ULN with total 
bilirubin  ULN to 
 2  ULN 
 Continue ipatasertib and atezolizumab. 
 Monitor LFTs at least weekly.   
 Consider patient referral to hepatologist and liver biopsy. 
Suspected immune-mediated events: 
 Withhold atezolizumab. 
 Consider initiation of treatment with 12 mg/kg/day oral prednisone or 
equivalent. 
 If corticosteroids are initiated and event does not improve within 48 
hours, consider adding an immunosuppressive agent. 
 If event resolves to AST/ALT  3  ULN with total bilirubin  2  ULN 
within 12 weeks, resume atezolizumab at fixed dose.  If not, 
permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. a, b, c 
AST/ALT  ULN to 
 3  ULN with total 
bilirubin  2  ULN 
 Investigate causes for elevated bilirubin and initiate treatment as 
indicated per institutional guidelines. 
 Use best medical judgment when determining whether to continue 
study treatment. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
444/Protocol ML42439, Version 5 
Event 
Management 
Elevations in ALT, AST, and/or bilirubin (cont.) 
AST/ALT  3  ULN 
with total bilirubin 
 2   ULN 
 Withhold ipatasertib and atezolizumab. 
 Monitor LFTs every 4872 hours until decreasing and then monitor 
weekly. 
 Refer patient to hepatologist and consider liver biopsy. 
 Consider initiation of treatment with 12 mg/kg/day oral prednisone or 
equivalent. 
 If corticosteroids are initiated and event does not improve within 48 
hours, consider adding an immunosuppressive agent. 
 If event resolves to AST/ALT  3  ULN with total bilirubin  2  ULN 
within 12 weeks, resume atezolizumab at fixed dose.  If not, 
permanently discontinue atezolizumab and contact the Medical 
Monitor. a, b, c 
 If event resolves to AST/ALT  3  ULN with total bilirubin  2  ULN 
within 28 days and corticosteroid dose  10 mg oral prednisone or 
equivalent, resume ipatasertib with dose reduced by one level.  If not, 
permanently discontinue ipatasertib. 
 Permanently discontinue ipatasertib and atezolizumab for 
life-threatening hepatic events and contact the Medical Monitor. 
AST/ALT  10  ULN 
 Permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. c 
 Monitor LFTs every 4872 hours until decreasing and then monitor 
weekly. 
 Refer patient to hepatologist and consider liver biopsy. 
 Consider administering 12 mg/kg/day oral prednisone or equivalent.   
 If corticosteroids are initiated and event does not improve within 48 
hours, consider adding an immunosuppressive agent or escalating the 
corticosteroid dose. 
 If event resolves to AST/ALT  3  ULN with total bilirubin  2  ULN, 
taper corticosteroids over  1 month. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
445/Protocol ML42439, Version 5 
Event 
Management 
Dermatologic toxicity  
General guidance 
 Consider having a dermatologist evaluate persistent and/or severe rash 
or pruritus. 
 Unless contraindicated, a daily oral antihistamine prophylaxis should be 
used for at least the first cycle. It is suggested that a non-sedating oral 
antihistamine (e.g. loratadine, cetirizine, fexofenadine) and longer-
acting formulated be used.  
 For the first 28-day cycle of ipatasertib plus atezolizumab: On days 
when patients will receive atezolizumab (Day 1), patients should 
received at least 10 mg prednisone (or equivalent) as premedication 
prior to atezolizumab, followed by 10 mg/day prednisone (or 
equivalent) for 2-4 consecutive days thereafter, unless contraindicated. 
 Ipatasertib should be permanently discontinued for rash-associated 
with Stevens-Johnson syndrome, toxic epidermal necrolysis, or other 
suspected severe hypersensitivity or allergic reaction. Dosage 
modification and symptom management guidelines for skin toxicity, 
including erythema multiforme, attributable to ipatasetib are shown 
below. 
 Although uncommon, cases of severe cutaneous adverse reactions 
such as Stevens-Johnson syndrome and toxic epidermal necrolysis 
have been reported with atezolizumab and atezolizumab should be 
permanently discontinued for confirmed cases. 
Dermatologic event,  
Grade 1 
 Consider referring patient to a dermatologist.  
 Continue ipatasertib and atezolizumab. 
 Initiate supportive care (e.g., topical corticosteroids and continue 
antihistamine administration).   
 Consider treatment with 10 mg/day oral prednisone or equivalent. 
Dermatologic event,  
Grade 2 
 Consider referring patient to dermatologist for evaluation and perform a 
biopsy, if appropriate. 
 Continue topical corticosteroids and antihistamine administration. 
 Consider treatment with 10 mg/day oral prednisone or equivalent; 
treatment with higher steroid dose may be necessary as clinically 
indicated. 
 Ipatasertib:  interrupt ipatasertib treatment until resolution to Grade  1 
or the toxicity is no longer clinically significant.  If steroid dose is  10 
mg/day, ipatasertib may be resumed if clinically appropriate. 
 Atezolizumab:  If steroid dose is  10 mg/day, atezolizumab should be 
continued. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; LFT  liver 
function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on the investigator's 
benefitrisk assessment and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
446/Protocol ML42439, Version 5 
Event 
Management 
Dermatologic toxicity (cont.) 
Dermatologic event,  
Grade 3 
 Withhold ipatasertib and atezolizumab. 
 Refer patient to dermatologist.  Perform a biopsy if appropriate. 
 If no prior steroid treatment has been initiated, consider treatment with 
10 mg/day oral prednisone or equivalent. 
 If prior oral steroid treatment or no improvement within 48 hours, 
consider increasing prednisone or equivalent dose to 12 mg/kg/day. 
 Atezolizumab:  if event resolves to Grade  1 within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
atezolizumab and contact the Medical Monitor.  Only restart 
atezolizumab if steroid dose is  10 mg/day. a, b, c 
 Ipatasertib:  if event resolves to Grade  1 or the toxicity is no longer 
clinically significant, resume ipatasertib at the same dose or dose 
reduced by one level after discussion with the Medical Monitor.  Only 
restart ipatasertib if steroid dose is  10 mg/day.  If not, permanently 
discontinue ipatasertib. 
Dermatologic event,  
Grade 4 
 Permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. c 
Ipatasertibrelated toxicities not described above 
Grade 3 
 Withhold ipatasertib.  Continue atezolizumab. 
 If event resolves to Grade 1 or baseline within 28 days and the Medical 
Monitor agrees that ipatasertib should be continued, resume 
ipatasertib.  If not, permanently discontinue ipatasertib. 
Grade 4 
 Withhold ipatasertib and atezolizumab. 
 If event resolves to Grade 1 or baseline within 28 days and the Medical 
Monitor agrees that ipatasertib should be continued, resume 
ipatasertib.  If not, permanently discontinue ipatasertib. 
 If event improves and the Medical Monitor agrees that atezolizumab 
should be continued, resume atezolizumab.  If not, permanently 
discontinue atezolizumab. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
447/Protocol ML42439, Version 5 
K.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients taking ipatasertib plus atezolizumab 
arm: 
Ipatasertib 
 
Grade  3 fasting hyperglycemia  
 
Grade  3 hepatotoxicity 
 
Grade  3 ALT/AST elevations 
 
Grade  2 colitis/enterocolitis 
 
Grade  3 diarrhea 
 
Grade  3 rash 
 
Grade  2 pneumonitis 
Atezolizumab 
 
Systemic lupus erythematosus 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade  2 cardiac disorders  
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  
 
K.5.4 
Selected Adverse Events 
Additional data may be analyzed for the following selected adverse events: 
 
Diarrhea 
 
Asthenia (fatigue) 
 
Nausea 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
448/Protocol ML42439, Version 5 
 
Neutropenia (neutrophil count decreased, febrile neutropenia) 
 
Rash (e.g., maculopapular, erythema, urticarial, dermatitis, rash popular, skin 
exfoliation, toxic skin eruption) 
 
Erythema multiforme 
 
Vomiting 
 
Oral mucositis (stomatitis, mucosal inflammation, mouth inflammation, mouth 
ulceration) 
 
Hyperlipidemia (hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, blood 
cholesterol increased, blood triglycerides increased) 
 
Hepatotoxicity (ALT, AST increased) 
 
Hyperglycemia (blood glucose increased) 
 
Pneumonitis (interstitial lung diseases) 
 
 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
449/Protocol ML42439, Version 5 
K.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as Specified 
 
 (Window) 
28 to 1 a 
(3) 
(3) 
 28 days after 
last study dose 
Informed consent d 
x 
 
 
 
Documentation of positive PIK3CA 
activating mutation status by local test 
e 
x 
 
 
 
Medical history and baseline 
conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
ECOG Performance Status h 
x 
x 
 
x 
Pregnancy test i 
x 
x 
 
x 
Chemistry j  
x 
x 
 
x c 
Hematology/CBC with differential k 
x 
x 
 
x c 
Coagulation panel l 
x 
 
 
x 
Fasting lipid panel, amylase, lipase m 
x 
x 
 
x 
Fasting HbA1C m 
x 
x 
 
x 
Fasting blood glucose n 
x 
x 
Weekly during C1 
x 
TSH, free T3 (or total T3), free T4 o 
x 
C1, D1 and every 3 cycles thereafter 
 
 
ECG p 
x 
As clinically indicated 
x 
ECHO or MUGA q 
x 
As clinically indicated 
Atezolizumab administration r, s 
 
x 
 
 
Ipatasertib dispensing 
 
x 
 
 
Ipatasertib compliance assessment t 
 
x 
 
x 
Prophylaxis anti-diarrheal u 
 
Every day of C1 and as clinically indicated 
 


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
450/Protocol ML42439, Version 5 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as Specified 
 
 (Window) 
28 to 1 a 
(3) 
(3) 
 28 days after 
last study dose 
Prophylaxis with 10 mg of prednisone 
(or equivalent) v 
 
D1 and 2-4 consecutive days after for C1only 
 
Daily antihistamine prophylaxis v 
 
Every day of C1 
 
Response assessments w, x 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) y 
 
Submit within 21 days of C1, D1 
 
 
Whole blood samples z 
x 
 
See footnote z 
 
Adverse events aa 
x 
Collected on an ongoing basis 
x aa 
Concomitant Medications bb 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic Case Report 
Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection fraction; MRImagnetic 
resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; RANOResponse Assessment in Neuro-Oncology; RECIST 
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious adverse event. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if 
the hematology/CBC, chemistry panel, and thyroid function test are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on 
Day 1, with the exception of glucose, which should be drawn within 3 days prior.  Scans to document measurable or evaluable disease 
(i.e., tumor measurement) should be performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment 
follow-up assessments. All patients will be followed until treatment-related toxicities resolve or for at least 28 days post ipatasertib 
discontinuation or 90 days post-atezolizumab discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit 
too difficult, follow-up with the patient may take place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician 
may be contacted to collect AE data and any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated.  


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
451/Protocol ML42439, Version 5 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive PIK3CA activating mutation status should occur prior to performing other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) 
used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who 
have a positive pregnancy test must not receive study drug.   
j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1 with the 
exception of glucose, which should be drawn within 3 days prior.  Subsequent chemistry evaluations should be completed prior to dosing on 
Day 1 of each indicated cycle (or up to 3 days before). 
k Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  
l Coagulation includes aPTT and INR. 
m Fasting lipid panel (cholesterol, triglyceride, HDL, and LDL), amylase, lipase, and HbA1c will be assessed after ≥8 hours of fasting. If results are 
obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.   
n Samples should be assessed weekly during the first Cycle and D1 at every other cycle. Mid-cycle fasting glucose levels may be obtained by 
glucometer (fingerstick).   If measurements are done at home, phone visits with site staff should be conducted to review results and assess any 
potential signs or symptoms of hyperglycemia.  


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
452/Protocol ML42439, Version 5 
o TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every third cycle 
thereafter (i.e., Cycles 4, 7, 10, etc.). 
p It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
q LVEF assessment by ECHO or MUGA to be performed at screening and as clinically indicated. Evaluation of LVEF must be performed by the 
same method (ECHO or MUGA) for each patient. It is strongly recommended that the same laboratory and operator perform ECHO/MUGA scan 
for each individual patient. 
r The initial infusion of atezolizumab will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the 
previous infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-
associated adverse event with the previous infusion.Refer to Section K.4.2.3 for details on atezolizumab infusions (including measurement of 
vital signs). 
s Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details). 
t Ipatasertib is administered 400 mg PO QD. On Day 1 of each cycle, review compliance from previous cycle and dispense ipatasertib for next 
cycle.  
u Loperamide 2 mg BID or equivalent or per local institutional guideline for the first cycle.  If loose watery stools occur, take additional 2 mg after 
each loose watery stool and up to 16 mg per day. 
v For the first cycle only: On day when patients will receive atezolizumab, patients should receive at least 10 mg/day prednisone (or equivalent) 
as premedication prior to atezolizumab, followed by 10 mg/day prednisone (or equivalent) for 24 consecutive days thereafter, unless 
contraindicated. Unless contraindicated, daily oral antihistamine prophylaxis should be used for at least the first cycle. It is suggested that a 
non-sedating oral antihistamine (such as loratadine, cetirizine, fexofenadine) and a longer-acting formulation be used.  
w All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  
A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
x At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
y For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
z Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.  


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
453/Protocol ML42439, Version 5 
aa After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation. All patients will be 
followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all deaths, regardless 
of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event 
that is believed to be related to prior study drug treatment (see Section 5.6). 
bb Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study drug. 
  


Arm K:  Ipatasertib plus Atezolizumab in Patients with PI3K (PIK3CA) Activating Mutation-
Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
454/Protocol ML42439, Version 5 
 
K.7 
REFERENCES 
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of 
granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced 
febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. 
Eur J Cancer 2011;47:832. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 
2006;24:3187205. 
 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
455/Protocol ML42439, Version 5 
Appendix 21  
Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN 
Loss/ Loss-of-Function or AKT Mutation-Positive Tumors 
22. 
ARM L:  IPATASERTIB PLUS ATEZOLIZUMAB IN PATIENTS 
WITH PTEN LOSS/ LOSS-OF-FUNCTION OR AKT ACTIVATING 
MUTATION-POSITIVE TUMORS 
TABLE OF CONTENTS 
L.4 
Materials and Methods .......................................................... 456 
L.4.1 
Patients .................................................................................. 456 
L.4.1.1 
Additional Inclusion Criteria ................................................... 456 
L.4.1.2 
Additional Exclusion Criteria .................................................. 457 
L.4.2 
Study Treatment .................................................................... 459 
L.4.2.1 
Formulation and Packaging ................................................... 459 
L.4.2.2 
Dosage, Administration, and Compliance for Ipatasertib ....... 460 
L.4.2.3 
Dosage, Administration, and Compliance for Atezolizumab .. 461 
L.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 463 
L.4.3.1 
Permitted Therapy ................................................................. 463 
L.4.3.2 
Cautionary Therapy ............................................................... 464 
L.4.3.3 
Prohibited Therapy ................................................................ 466 
L.4.3.4 
Prohibited Food ..................................................................... 467 
L.4.4 
Arm-specific Assessments ..................................................... 467 
L.5 
Safety Plan ............................................................................ 468 
L.5.1 
Risks Associated with Ipatasertib and Atezolizumab ............. 468 
L.5.1.1 
Risks Associated with Ipatasertib .......................................... 468 
L.5.1.2 
Risks Associated with Atezolizumab ...................................... 468 
L.5.1.3 
Risks Associated with Combination Use of Ipatasertib and 
Atezolizumab ......................................................................... 468 
L.5.2 
Guidelines for Management of Adverse Events ..................... 469 
L.5.2.1 
Dose Modifications and Interruptions ..................................... 469 
L.5.2.2 
Guidelines for Management of Specific Adverse Events ....... 470 
L.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 485 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
456/Protocol ML42439, Version 5 
L.5.4 
Selected Adverse Events ....................................................... 485 
L.6 
Schedule of Activities ............................................................. 487 
L.7 
References ............................................................................ 492 
 
L.4 
MATERIALS AND METHODS 
L.4.1 
Patients 
To be enrolled in Arm L: ipatasertib in combination with atezolizumab treatment, patients 
must have met and continue to meet all general eligibility criteria (see Section 4.1), in 
addition to the arm-specific criteria below. 
L.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm L: 
ipatasertib plus atezolizumab treatment: 
 
AKT1/2/3 mutant positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood) 
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as 
listed below: 
– 
AKT1:  E17K; L52R; Q79K 
– 
AKT2:  E17K 
– 
AKT3:  E17K; L51R; Q78K 
 
or PTEN protein loss of function or protein loss as determined by a CLIA or 
equivalently certified tissue-based NGS, in situ hybridization (ISH), or 
immunohistochemistry (IHC) assay (See Appendix 1 for details) 
 
No available acceptable treatment for malignancy that is expected to provide clinical 
benefit 
 
ANC  1000/l within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c)  7.5% 
 
Ability to swallow ipatasertib intact, without chewing or crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
28 days after the last dose of ipatasertib and 5 months after the last dose of 
atezolizumab; and agreement to refrain from donating eggs during this same period.  
See detailed contraception requirements in Appendix 2. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
457/Protocol ML42439, Version 5 
failure rate of  1% per year during the treatment period and for at least 28 days 
after the last dose of ipatasertib, and agreement to refrain from donating sperm 
during this same period.  See detailed contraception requirements in Appendix 2. 
 
L.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm L: ipatasertib plus atezolizumab treatment: 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Use of an indwelling catheter (e.g., PleurX®) is allowed. 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected serum calcium  ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid replacement hormone are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
o Rash must cover  10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
458/Protocol ML42439, Version 5 
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids 
within the previous 12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study   
 
Prior allogeneic stem cell or solid organ transplantation 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the final dose of atezolizumab 
 
Prior treatment with anti-PD-1 or anti PD-L1 therapeutics unless approved by 
Medical Monitor 
– 
 Up to approximately 12 such patients may be enrolled 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives 
(whichever is longer) prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
459/Protocol ML42439, Version 5 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation 
 
Prior treatment with ipatasertib or other Akt inhibitors 
 
History of malabsorption syndrome or other condition that would interfere with 
enteral absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class 
B or C, current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection 
fraction (LVEF)  50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia's 
formula (QTcF)  480 milliseconds  
 
History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion (including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of  10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants 
for a chronic disease.  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to 
initiation of study treatment are eligible for enrollment.  
Diabetic patients with fasting total serum glucose  8.3 mmol/L (150 mg/dL) 
and/or HbA1C  7.5 are not eligible for enrollment. 
 
Grade  2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia  
 
History of or active inflammatory bowel disease (e.g., Crohn's disease and 
ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)  
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, 
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A 
inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to 
initiation of study treatment (see Appendix 7) 
 
L.4.2 
Study Treatment 
Study treatment in this arm will consist of ipatasertib in combination with atezolizumab. 
L.4.2.1 
Formulation and Packaging 
Ipatasertib will be supplied by the Sponsor as 100-mg and 200-mg tablets.  


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
460/Protocol ML42439, Version 5 
For information on the formulation and handling of ipatasertib, see the pharmacy manual 
and the Ipatasertib Investigator's Brochure. 
Atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 20-mL 
glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
The study drug will be periodically tested and monitored for its acceptable shelf life.  Any 
study drug that fails to comply with the manufactured specifications will be promptly 
removed from the clinical trial site and replaced with new supplies by the Sponsor (or 
designee). 
Each bottle will be labeled with the required regulatory agency warning statement, the 
protocol number, the Sponsor’s name, and directions for patient use and storage.  The 
investigator should ensure that the study drug is stored in appropriate conditions in a 
secure location with controlled access. 
L.4.2.2 
Dosage, Administration, and Compliance for Ipatasertib  
Study treatment will be administered in 21-day cycles. 
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at 
the same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) 
once a day (QD) until disease progression or intolerable toxicity (or loss of clinical 
benefit with Medical Monitor consultation, see Section 3.1.2 for treatment beyond 
disease progression).   
The tablets will be swallowed whole (not chewed) with 3 ounces (90 mL) of fluid.  
Ipatasertib is recommended to be taken at least 2 hours after the last meal of the day, 
and patients should refrain from eating overnight.  Patients are required to receive 
prophylaxis  with loperamide throughout the first cycle (2 mg oral twice a day, or per 
local institutional guidelines) and at subsequent cycles as clinically indicated (see 
Table 3).  
For ipatasertib doses to be administered at home, a sufficient number of tablets should 
be dispensed to the patient to last until the next visit, or at the investigator’s discretion, 
through one cycle.  Patients will be asked to record in a medication diary the time and 
date for each dose taken. 
A missed dose can be taken within 8 hours of the scheduled time.  After that, patients 
should take the next dose the following day, without compensating for the missed dose 
(including vomited doses).  


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
461/Protocol ML42439, Version 5 
Guidelines for ipatasertib dosage modification and treatment interruption or 
discontinuation are provided in Section L.5.2.1.1. 
See Section 4.3.2 for details on assessment of compliance for self-administered oral 
study drugs. 
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug. 
L.4.2.3 
Dosage, Administration, and Compliance for Atezolizumab 
Study treatment will be administered in 21-day cycles. 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients 
on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss 
of clinical benefit with Medical Monitor consultation, see Section 3.1.2 for treatment 
beyond disease progression).   
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.   
Administration of atezolizumab will be performed in a monitored setting where there is 
access to trained personnel and adequate equipment/medicine to manage potentially 
serious reactions.  For anaphylaxis precautions, see Appendix 6.  Atezolizumab 
infusions will be administered per the instructions outlined in Table 1. 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
462/Protocol ML42439, Version 5 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 No premedication is permitted prior 
to the atezolizuamb infusion except 
as outlined in Section L.4.2.3 for the 
purpose of preventing rash. 
 Vital signs (pulse rate, respiratory 
rate, blood pressure, and 
temperature) should be measured 
within 60 minutes prior to the infusion 
a 
 Atezolizumab should be infused over 
60 (15) minutes. 
 If clinically indicated, vital signs 
should be measured every 
15 (5) minutes during the infusion 
and at 30 (10) minutes after the 
infusion. a 
 Patients should be informed about 
the possibility of delayed post-
infusion symptoms and instructed to 
contact their study physician if they 
develop such symptoms. 
 If the patient experienced an infusion-
related reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
 Vital signs should be measured within 
60 minutes prior to the infusion. a 
 Atezolizumab should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
 If the patient experienced an infusion-
related reaction with the previous infusion or 
if clinically indicated, vital signs should be 
measured during the infusion and at 
30 (10) minutes after the infusion. a 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
 
No dose modification for atezolizumab is allowed. Guidelines for medical management 
of infusion-related reactions (IRRs) are provided in Section E.5.2.2.7 for atezolizumab. 
Owing to the risk of rash in Cycle 1, patients should receive the following prophylaxis 
during the first cycle when study treatments will be given (see Table 3 for AE 
management of dermatological toxicities, including rash):  
 
Unless contraindicated, daily PO antihistamine prophylaxis should be used for at 
least the first cycle. It is suggested that a non-sedating longer-acting oral 
antihistamine be used (such as 10 mg of cetirizine PO QD or comparable dose of 
other antihistamines, e.g., loratadine, fexofenadine).  
 
On day when patients will receive atezolizumab, patients should receive at least 10 
mg/day of prednisone (or equivalent dosing of other steroids e.g., 
methylprednisolone, prednisolone) as premedication prior to atezolizumab, followed 
by a fixed dose of 10 mg/day prednisone (or equivalent) for 24 consecutive days 
thereafter, unless contraindicated.  
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
463/Protocol ML42439, Version 5 
L.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug until 28 days after the last dose of study drug.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
L.4.3.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study:  
 
Oral contraceptives, as allowed per local guidelines 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:  
Palliative radiotherapy is permitted for a preexisting lesion, provided it does not 
interfere with the assessment of tumor target lesions (e.g., the lesion to be 
irradiated must not be a site of measurable disease).  Study treatment should be 
suspended during palliative radiotherapy.  Treatment with ipatasertib should be 
temporarily held for at least 7 days before and after the procedure (at least 14 
days after radiation is recommended).  For a single fraction of radiotherapy, this 
hold may be shorter, if discussed by the investigator with the Medical Monitor.  
The patient may continue ipatasertib treatment after treatment holding has been 
completed and the patient has sufficiently recovered.  
 
Prophylaxis use of loperamide is mandated in the first cycle and as clinically 
indicated in subsequent cycles to prevent diarrhea.  Patients who experience 
diarrhea should be on treatment doses of loperamide per the management 
guidelines provided in Table 3; please refer to that section for additional details.  
Patients should be educated/reminded to be cognizant of the onset, duration, 
severity, and frequency of symptoms and the medications administered.  
 
Prophylaxis use of antihistamines and prednisone (or equivalent dosing of other 
steroids) is mandated in the first cycle due to the risk of rash and is described in 
Section L.4.2.3.  
 
Granulocyte colony-stimulating factor treatment is permitted.  The primary 
prophylaxis should be administered per the American Society of Clinical Oncology 
(ASCO), European Organization for Research and Treatment of Cancer (EORTC), 
and European Society for Medical Oncology (ESMO) guidelines; namely, in patients 
who are  60 years of age and/or with comorbidities (Smith et al. 2006; Aapro et al. 
2011) 
 
Bisphosphonate therapy or RANKL inhibitor therapy (e.g., zolendronic acid and 
denosumab) used specifically to prevent skeletal events (e.g., bone metastasis, 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
464/Protocol ML42439, Version 5 
osteoporosis) is allowed.  Both types of agents have potential immunomodulatory 
properties, but may be used as clinically indicated.  
 
Luteinizing hormone-releasing hormone or gonadotropin-releasing hormone 
agonists for ovarian function preservation are allowed.  
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)  
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section L.4.3.3) 
 
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Stable dose of calcium-channel blockers are permitted. 
 
Stable dose of β-blockers, if an alternative treatment cannot be used, are permitted 
with caution. 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and per institutional practice.  For example, patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per institutional practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists; see Appendix 6). 
L.4.3.2 
Cautionary Therapy  
L.4.3.2.1 
Corticosteroids and Tumor Necrosis Factor- Inhibitors 
Systemic corticosteroids and tumor necrosis factor alpha (TNF-) inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids or TNF- inhibitors would be 
routinely administered, alternatives, including antihistamines, should be considered.  If 
the alternatives are not feasible, systemic corticosteroids and TNF- inhibitors may be 
administered at the discretion of the investigator. Systemic corticosteroids are 
recommended, at the discretion of the investigator, for the treatment of specific adverse 
events when associated with atezolizumab therapy (refer to Section L.5.2.2.3 


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[combination therapy] and Section E.5.2.2 [single agent]for guidelines for managing 
specific adverse events).  
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events associated with ipatasertib (refer to 
Section L.5.2.2.3 [combination therapy] or Section D.5.2.2.6, Section D.5.2.2.7 [single 
agent] for guidelines for managing specific adverse events).  If daily systemic 
corticosteroids are initiated for treatment of any toxicity or other condition, they must be 
tapered to 10 mg/day of oral prednisone or equivalent before ipatasertib or 
atezolizumab can be resumed. Steroids used as prophylaxis (i.e., as premedication prior 
to scans, or as protocol-directed rash prophylaxis) do not require holding of ipatasertib or 
atezolizumab. Steroids used on a single day to manage infusion-related reactions (IRRs) 
or allergic reactions similarly do not require holding of ipatasertib. 
L.4.3.2.2 
Surgery or Radiation 
Patients who require radiation or surgery as part of medical treatment in the absence of 
radiographic disease progression must exercise caution, and all study treatment should 
be temporarily held for at least 7 days before and after the procedure (at least 14 days 
after radiation is recommended).  For minor surgeries or single-day radiotherapy, this 
hold may be shorter, if discussed by the investigator with the Medical Monitor.  After the 
temporary treatment hold is complete, study treatment may be re-initiated when the 
patient has sufficiently recovered.   
L.4.3.2.3 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug−drug interactions (DDIs) are 
generally unknown.  However, herbal therapies not intended for the treatment of cancer 
may be used during the study at the discretion of the investigator. 
L.4.3.2.4 
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes 
In vitro data suggest that ipatasertib is metabolized by CYP3A and may be a time-
dependent inhibitor of CYP3A4.  A clinical drug−drug interaction (DDI) study with 
midazolam (a sensitive CYP3A substrate) showed a 2.2-fold increase in midazolam 
exposures in presence of steady-state ipatasertib dosed at 600 mg QD.  Therefore, 
sensitive CYP3A substrates with narrow therapeutic window should be avoided.  Given 
that ipatasertib is primarily metabolized by CYP3A, there is a high potential for 
drug−drug interactions of ipatasertib with any medication that strongly inhibits or induces 
CYP3A.  Data from a clinical study showed that ipatasertib exposures were reduced by 
~50% when co-administered with enzalutamide, a strong CYP3A inducer.  Strong 
CYP3A inhibitors are expected to increase ipatasertib exposures significantly.  


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Therefore, strong CYP3A4/5 inhibitors or inducers or CYP3A4/5 substrates with a 
narrow therapeutic index should be avoided or used with caution (see Appendix 7).  
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment  
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients are permitted to take moderate inhibitors of CYP3A4 with caution.  
Patients should be closely monitored.  Refer to the following information for further 
guidance on CYP450−drug interactions and a list of common substrates, inhibitors, and 
inducers:  
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and 
Inducers (U.S. Food and Drug Administration [FDA]): 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/ DrugInteractionsLabeling/ucm093664.htm  
The above lists of medications are not comprehensive.  The investigator should consult 
the prescribing information when determining whether a concomitant medication can be 
safely administered with study treatment.  In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications not listed above. 
L.4.3.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2), and during study treatment until disease progression is documented 
and the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and radiotherapy to the brain under circumstances outlined above in 
Section L.4.3.1. 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 21 days prior to initiation of study treatment and during study treatment.  
 
Chronic use of a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A 
substrates with a narrow therapeutic window that are deemed not permissible by the 
Medical Monitor after enrollment (refer to the guidance in Section L.4.3.2.4) 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
467/Protocol ML42439, Version 5 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab. 
 
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment 
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients should be closely monitored.  Patients who require short-term use of 
moderate CYP3A4 inhibitors may continue study treatment with caution.  
Refer to the following information for further guidance on CYP450drug interactions and 
a list of common substrates, inhibitors, and inducers:  
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers (U.S. Food and Drug Administration [FDA]): 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ 
DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 
 
L.4.3.4 
Prohibited Food 
Use of the following foods is prohibited as described below:  
 
Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit, potent CYP3A4 enzyme 
inhibitors, is prohibited during the study treatment period and for 10 days after the 
last dose of study treatment. 
 
Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, is prohibited for 
up to 14 days prior to and during the study treatment period, and for 10 days after 
the last dose of study treatment. 
 
L.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in the Arm L: ipatsertib plus atezolizumab 
treatment.  Refer to the schedule of activities (Section L.6) for arm-specific assessment 
timepoints. 
Local Laboratory Assessments 
 
Coagulation panel:  INR and aPTT 
 
HbA1c, blood glucose (fasting) 
 
Amylase, lipase (fasting) 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
468/Protocol ML42439, Version 5 
 
Lipid panel (fasting):  total cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (T4) 
 
Functional Assessments 
 
LVEF assessment:  echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
 
12-lead electrocardiogram 
 
L.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm L: ipatatsertib plus 
atezolizumab treatment 
L.5.1 
Risks Associated with Ipatasertib and Atezolizumab 
L.5.1.1 
Risks Associated with Ipatasertib 
Ipatasertib has been associated with risks such as the following: nausea, vomiting, 
diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, erythema 
multiforme, and rash.  Ipatasertib’s potential risks include hematologic or 
immunosuppressant effects, hyperlipidemia, hepatotoxicity, pneumonitis, colitis, and 
developmental toxicity.  Refer to the Ipatasertib Investigator’s Brochure for a detailed 
description of anticipated safety risks for ipatasertib. 
L.5.1.2 
Risks Associated with Atezolizumab  
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, 
myelitis, meningoencephalitis, myocarditis, peridardial disorders, nephritis, myositis, 
and severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 
involve any organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer 
to the Atezolizumab Investigator's Brochure for a detailed description of anticipated 
safety risks for atezolizumab.    
L.5.1.3 
Risks Associated with Combination Use of Ipatasertib and 
Atezolizumab 
On the basis of the frequency of adverse events associated with either ipatasertib or 
atezolizumab, the following adverse events are potential overlapping toxicities 
associated with combination use of ipatasertib and atezolizumab:  diarrhea, colitis, 
hepatotoxicity, rash, pneumonitis, and hyperglycemia.  


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
469/Protocol ML42439, Version 5 
L.5.2 
Guidelines for Management of Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases. 
L.5.2.1 
Dose Modifications and Interruptions 
L.5.2.1.1 
Dose Modifications and Interruptions for Ipatasertib 
If the patient does not tolerate the QD dosing of ipatasertib, dosing with food may be 
used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or diarrhea.  
No more than two dose reductions of ipatasertib per patient (i.e., doses below 
200 mg/day of ipatasertib) will be allowed (see Table 2).  Dose re-escalation is not 
permitted for ipatasertib. 
If needed, dose reductions may occur in decrements of 100 mg and no more than two 
dose reductions will be allowed.  Accordingly, the possible daily doses of ipatasertib are 
shown in Table 2. If the patient continues to experience specified drug-related adverse 
events after the second reduction, the treatment should be discontinued. 
Any dose modification should be noted on the corresponding Study Drug Administration 
eCRF.  Cases of accidental overdose or medication error, along with any associated 
adverse events, should be reported as described in Section 5.3.5.12. 
Table 2 
Ipatasertib Dose Reductions 
Dose Level a 
Ipatasertib Dose 
Starting dose 
400 mg 
First dose reduction 
300 mg 
Second dose reduction 
200 mg 
Third dose reduction 
Not permitted 
Note:  After dose reduction, the dose of ipatasertib may not be re-escalated. 
 
Ipatasertib treatment may be temporarily interrupted in patients who experience toxicity 
considered to be related to study drug.  If ipatasertib has been withheld for 
28 consecutive days because of treatment-related toxicity, the patient should be 
discontinued from ipatasertib.  Ipatasertib may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor consultation.  If, in the judgment 
of the investigator, the patient is likely to derive clinical benefit from resuming study 
treatment after a hold of  28 consecutive days, study drug may be restarted.  The 
decision to re-challenge patients with ipatasertib should be based on the investigator’s 
benefitrisk assessment and documented by the investigator. The Medical Monitor is 
available to advise as needed. If corticosteroids are initiated for treatment of any toxicity, 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
470/Protocol ML42439, Version 5 
ipatasertib must be held and corticosteroids must be tapered over  1 month to 
 10 mg/day oral prednisone or equivalent before ipatasertib can be resumed. 
If either ipatasertib or atezolizumab is discontinued, the other drug can be continued if 
the patient is likely to derive clinical benefit.  The acceptable length of treatment 
interruption must be based on the investigator's benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
L.5.2.1.2 
Dose Modifications and Interruptions for Atezolizumab 
No dose reductions for atezolizumab are allowed.  No dose reductions for atezolizumab 
are allowed.  Interruptions to atezolizumab treatment are described in Section E.5.2.1.1. 
If either atezolizumab or ipatasertib is discontinued, the other drug can be continued if 
the patient is likely to derive clinical benefit, as determined by the investigator and 
following discussion with the Medical Monitor. 
L.5.2.2 
Guidelines for Management of Specific Adverse Events 
L.5.2.2.1 
Guidelines for Management of Specific Adverse Events 
Associated with Ipatasertib 
Guidelines for management of specific adverse events for ipatasertib given as a single 
agent are provided in Section D.5.2.2. 
L.5.2.2.2 
Guidelines for Management of Specific Adverse Events 
Associated with Atezolizumab 
Guidelines for management of specific adverse events for atezolizumab given as a 
single agent are provided in Section E.5.2.2. 
L.5.2.2.3 
Guidelines for Management of Specific Adverse Events 
Associated with Ipatasertib plus Atezolizumab 
Guidelines for the management of patients who experience adverse events are provided 
in Section E.5.2.2 and Table 3, as outlined below: 
 
Section E.5.2.2 provides guidelines for the management of patients who experience 
atezolizumab-associated IRRs and immune-mediated endocrine, ocular, pancreatic, 
neurologic disorders (including facial paresis), myocarditis, myelitis, pericardial 
disorders, meningoencephalitis, renal, myositis, hemophagocytic 
lymphohistiocytosis, and macrophage activation syndrome events.  It is 
recommended that atezolizumab be withheld or discontinued per the guidelines in 
Section E.5.2.2 and that ipatasertib be withheld or discontinued per the guidelines in 
Table 3. 
 
Table 3 provides guidelines for the management of patients who experience the 
following potential overlapping toxicities:  gastrointestinal, dermatologic, hepatic, 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
471/Protocol ML42439, Version 5 
pulmonary, and hyperglycemia events.  It is recommended that study treatments be 
withheld or discontinued per the guidelines in Table 3.  For these potential 
overlapping toxicities, guidelines in Table 3 should be followed instead of guidelines 
in Section E.5.2.2. 
 
Table 3 provides guidelines for the management of patients who experience 
adverse events associated with ipatasertib.  It is recommended that atezolizumab 
and/or ipatasertib be withheld or discontinued per the guidelines in Table 3. 
 
For cases in which management guidelines are not covered in Table 3 or 
Section E.5.2.2, patients should be managed and treatments should be withheld or 
discontinued as deemed appropriate by the investigator according to best medical 
judgment.


 
MyTACTIC Study—Genentech, Inc. 
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Table 3 
Guidelines for Management of Patients Who Experience Adverse 
Events in Ipatasertib plus Atezolizumab 
Event 
Management 
IRRs and 
anaphylaxis 
 Guidelines for management of IRRs are provided in Section E.5.2.2  
 Withhold ipatasertib. 
 For anaphylaxis precautions, see Appendix 6. 
 For severe hypersensitivity reactions, permanently discontinue 
ipatasertib and atezolizumab. 
Hemophagocytic 
lymphohistiocytosis 
or macrophage 
activation 
syndrome 
 Follow guidelines for atezolizumab in Section E.5.2.2. 
 Withhold ipatasertib and contact the Medical Monitor for guidance. 
Gastrointestinal toxicity 
General guidance 
 All events of diarrhea or colitis should be thoroughly evaluated for 
more common etiologies other than drug-induced effects. 
 For diarrhea that persists for more than 5 days, despite treatment with 
anti-diarrheal agent(s) and/or with dose hold of ipatasertib, 
gastroenterologists should be consulted to rule out the risk of colitis 
and infection.  Patients should be educated on the symptoms and 
importance of early reporting of diarrhea to receive instructions of 
treatment and prevention of dehydration so that patients can be 
promptly and appropriately managed.  Educational materials will be 
provided to investigators and patients outlining these guidelines. 
 For events of significant duration or magnitude or associated with 
signs of systemic inflammation or acute phase reactants 
(e.g., increased CRP, platelet count, or bandemia):  Perform 
sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, 
with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
473/Protocol ML42439, Version 6 
Event 
Management 
Gastrointestinal toxicity (cont.) 
General guidance 
 Administer anti-diarrheal agents and other supportive care per institutional 
guidelines or per suggested supportive care outlined below: 
Medication 
– 
Treatment modifications for diarrhea (any grade), when it occurs, 
should be instituted as early as possible.  Guidelines for treatment 
of diarrhea, following the prophylactic dose of loperamide 4 mg 
initial daily dose (taken 2 mg twice a day or per local institutional 
standard), includes use of loperamide 2 mg after each loose 
watery stool, up to the maximum total dose of 16 mg/day or per 
institutional guidelines and standard of care, including, but not 
limited to, additional therapy with Lomotil (diphenoxylate and 
atropine), codeine, or octreotide. 
– 
Duration of diarrhea may be minimized by taking ipatasertib with 
food, avoiding lactose-containing foods, and hydrating with 
810 glasses per day (~12 oz/glass) of electrolyte-containing clear 
liquid such as broth and Gatorade drinks. 
– 
Dose reductions of ipatasertib will be by one level at a time (i.e., 
400 to 300 mg; 300 to 200 mg) as outlined in If Grade  2 diarrhea 
persists following dose reductions of ipatasertib to 200 mg daily 
and with maximum treatment for diarrhea, ipatasertib should be 
discontinued.  
Oral Supplementation 
– 
Initiate potassium and/or magnesium if serum levels are less than 
the lower limit of normal. 
– 
Consider rehydration therapy with oral electrolyte solution for Grade 
 1 diarrhea or vomiting. 
Dietary Modifications 
– 
Instruct patient to eat small meals and eliminate lactose-containing 
products from diet. 
– 
Suggest diet of bananas, rice, apples, and toast, while avoiding 
fiber from vegetables and other fruits. 
– 
Encourage adequate hydration with salt-containing liquids (e.g., 
broth, sports drinks such as Gatorade). 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
474/Protocol ML42439, Version 6 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Diarrhea, Grade 1 
or Grade 2 
 Continue ipatasertib and atezolizumab 
– 
Initiate supportive care and monitor patient closely. 
 Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis if appropriate. 
 For Grade 2 events, withhold  atezolizumab  and consider empiric steroids in 
case of strong suspicion for immune-mediated colitis while waiting for 
definitive diagnosis. Interrupt ipatasertib until diarrhea improves to 
Grade  1.  Ipatasertib can be resumed at the same dose or one dose lower per 
investigator evaluation upon improvement to Grade  1. 
Diarrhea, Grade 2 
(persisting  5 
days) or Grade 3 
 Withhold ipatasertib and atezolizumab 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs) 
while investigating etiology. 
 Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis, including biopsy if appropriate. 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
 If event resolves to Grade 1 or better within 28 days, resume 
ipatasertib with dose reduced by one level.  If not, permanently 
discontinue ipatasertib. 
 If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at 
fixed dose.  If not, permanently discontinue ipatasertib and atezolizumab and 
contact Medical Monitor. a, b, c 
 For recurrent Grade 3 diarrhea, reduce ipatasertib dose by one additional dose 
level or discontinue ipatasertib permanently per the Medical Monitor. 
Diarrhea, Grade 4   Permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. c 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs) 
while investigating etiology.  
 Rule out bowel perforation. 
 Investigate etiology, referring patient to GI specialist for evaluation of 
possible colitis, including biopsy if appropriate. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator's benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
475/Protocol ML42439, Version 6 
Event 
Management 
Gastrointestinal toxicity (cont.) 
Colitis, Grade 1 
 Continue ipatasertib and atezolizumab. 
 Initiate supportive care and monitor patient closely.  
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 For Grade 2 events, withhold  atezolizumab  and consider empiric 
steroids in case of strong suspicion for immune-mediated colitis 
while waiting for definitive diagnosis. 
 Refer patient to GI specialist for evaluation and confirmatory biopsy if 
symptoms persist for  5 days. 
Colitis, Grade 2 
 Withhold ipatasertib and atezolizumab. 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 If strong clinical suspicion for immune-mediated colitis, start 
empiric IV steroids while waiting for definitive diagnosis. 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 For recurrent events or events that persist  5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent.  If the event does 
not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
ipatasertib and atezolizumab and contact the Medical Monitor. a, b, c 
 If event resolves to Grade 1 or better within 28 days and 
corticosteroid dose 10 mg oral prednisone or equivalent, resume 
ipatasertib with dose reduced by one level.  If not, permanently 
discontinue ipatasertib. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator's benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefitrisk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
476/Protocol ML42439, Version 6 
 
Event 
Action to Be Taken 
Gastrointestinal toxicity (cont.) 
Colitis, Grade 3 
 Withhold ipatasertib and atezolizumab. 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent 
upon improvement.  If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue ipatasertib 
and atezolizumab and contact the Medical Monitor. a, b, c 
 If event resolves to Grade 1 or better within 28 days and corticosteroid 
dose 10 mg oral prednisone or equivalent, resume ipatasertib with 
dose reduced by one level.  If not, permanently discontinue ipatasertib. 
Colitis, Grade 4 
 Permanently discontinue ipatasertib and atezolizumab and contact the 
Medical Monitor. c 
 Initiate supportive care and monitor patient closely. 
 Discontinue medications that may exacerbate colitis (e.g., NSAIDs). 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent 
upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.  
 If event resolves to Grade 1 or better, taper corticosteroids over  1 
month. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
477/Protocol ML42439, Version 6 
Event 
Management 
Endocrine disorders 
Grade 1 hypothyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 2 hypothyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 3 and 4 
hypothyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 1 hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 34 hyperthroidism. 
Grade 2 hyperthyroidism  Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Grade 3 and 4 
hyperthyroidism 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
 For life-threatening immune-related hyperthyroidism, withhold 
ipatasertib.  If event becomes clinically manageable within 28 
days, resume ipatasertib with dose reduced by one level.  If not, 
permanently discontinue ipatasertib. 
Symptomatic adrenal 
insufficiency, Grade 2, 3, 
or 4 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 
 Follow guidelines provided in Section E.5.2.2. 
 Continue ipatasertib. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
 Follow guidelines provided in Section E.5.2.2. 
 Withhold ipatasertib until Grade  2. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
478/Protocol ML42439, Version 6 
Event 
Management 
Endocrine disorders (cont.) 
Hyperglycemia, any 
grade 
 All events of hyperglycemia should be thoroughly evaluated for 
more common etiologies other than drug-induced effects. 
 Workup should include confirmation of fasting blood glucose, 
urinary glucose and ketones, arterial blood gas, serum 
bicarbonate, HbA1c, C-peptide levels, anti-islet antibodies, anti-
GADD45 antibody. 
 Hyperglycemia should be treated per institutional guidelines with 
fluid replacement, insulin, and correction of electrolyte 
abnormalities.  
Hyperglycemia, Fasting 
glucose value  ULN to 
160 mg/dL (8.9 mmol/L) 
 Continue ipatasertib and atezolizumab. 
 The patient should receive education on a diabetic diet and 
consider home glucose monitoring. 
 Oral anti-diabetic medications (e.g., metformin) or insulin 
replacement may be started at the discretion of the investigator, 
guided by etiology of hyperglycemia.  
Hyperglycemia, Fasting 
glucose value  ULN to 
250 mg/dL ( 8.913.9 
mmol/L) 
 Continue atezolizumab, consider interruption of ipatasertib. 
 The patient should adopt a diabetic diet and initiate home glucose 
monitoring. 
 Start oral anti-diabetic medications (e.g., metformin) or insulin 
replacement, guided by etiology of hyperglycemia. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented b
the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
479/Protocol ML42439, Version 6 
Event 
Management 
Endocrine disorders (cont.) 
Hyperglycemia, Glucose 
value 250 to 500 mg/dL 
( 13.927.8 mmol/L) 
 Withhold ipatasertib and atezolizumab dosing until fasting 
hyperglycemia resolves to  160 mg/dL. 
 Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used.  Start (or increase dose of) oral anti-
diabetic medications (e.g., metformin). 
 Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
 The patient should adopt a diabetic diet and initiate home glucose 
monitoring. 
 If the fasting hyperglycemia resolves to  160 mg/dL within 3 days, 
ipatasertib may be resumed at the previous dose level. 
 If the fasting hyperglycemia does not resolve to  160 mg/dL within 3 
days or if  fasting hyperglycemia  250 mg/dL recurs within 14 days, 
the dose of ipatasertib should be reduced by one dose level (Table 2) 
when treatment is restarted.   
 Resume atezolizumab when symptoms resolve and glucose levels are 
stable. 
Hyperglycemia, Glucose 
value  500 mg/dL  
( 27.8 mmol/L); life-
threatening 
consequences 
 Withhold ipatasertib and atezolizumab dosing until fasting 
hyperglycemia resolves to  160 mg/dL.  
 Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used.  Start (or increase dose of) oral anti-
diabetic medications (e.g., metformin). 
 Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
 The patient should adopt a diabetic diet and initiate home glucose 
monitoring. 
 Upon recovery of fasting glucose to  160 mg/dL, ipatasertib should be 
reduced by one dose level (Table 2) when treatment is restarted. 
 Resume atezolizumab when symptoms resolve and glucose levels are 
stable. 
 If hyperglycemia  500 mg/dL recurs, permanently discontinue 
ipatasertib and atezolizumab and contact the Medical Monitor.  
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
480/Protocol ML42439, Version 6 
Event 
Management 
Pulmonary events 
 
General guidance 
 All pulmonary events should be thoroughly evaluated for other 
commonly reported etiologies such as pneumonia/infection, 
lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary 
hypertension. 
Pulmonary event,  
Grade 1 
 Continue ipatasertib and atezolizumab. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
 For recurrent pneumonitis, treat as a Grade 3 or 4 event. 
Pulmonary event,  
Grade 2 
 Withhold ipatasertib and atezolizumab. 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial 
biopsy.  
 If bronchoscopy is consistent with immune-mediated etiology, 
initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent.  
 If event resolves to Grade 1 or better within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
ipatasertib and atezolizumab and contact the Medical Monitor. a, b, c 
 If event resolves to Grade 1 or better within 28 days and 
corticosteroid dose  10 mg oral prednisone or equivalent, resume 
ipatasertib at current dose. c,d 
 For recurrent events or events with no improvement after 48–
72 hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary event,  
Grade 3 or 4 
 Permanently discontinue ipatasertib and atezolizumab and contact 
the Medical Monitor. c 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial 
biopsy.  
 If bronchoscopy is consistent with immune-mediated etiology, 
initiate treatment with 1−2 mg/kg/day IV methylprednisolone  
 If pulmonary event does not improve within 48 hours or worsens, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over   1 
month. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
481/Protocol ML42439, Version 6 
Event 
Management 
Elevations in ALT, AST, and/or bilirubin 
AST/ALT  ULN to 
 3  ULN with total 
bilirubin  2  ULN 
 Continue ipatasertib and atezolizumab. 
AST/ALT  3  ULN 
to 5  ULN with total 
bilirubin  ULN to 
 2  ULN 
 Continue ipatasertib and atezolizumab. 
 Monitor LFTs at least weekly.   
 Consider patient referral to a hepatologist and liver biopsy. 
Suspected immune-mediated events of  5 days' duration: 
 Consider withholding atezolizumab. 
 Consider initiation of treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If atezolizumab is withheld and event resolves to AST/ALT 
 3  ULN with total bilirubin  2  ULN within 12 weeks, resume 
atezolizumab at fixed dose.  If not, permanently discontinue 
ipatasertib and atezolizumab and contact the Medical Monitor. a, b, 
c 
AST/ALT  5  ULN to 
 10  ULN with total 
bilirubin  ULN to 
 2  ULN 
 Continue ipatasertib and atezolizumab. 
 Monitor LFTs at least weekly.   
 Consider patient referral to hepatologist and liver biopsy. 
Suspected immune-mediated events: 
 Withhold atezolizumab. 
 Consider initiation of treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If corticosteroids are initiated and event does not improve within 
48 hours, consider adding an immunosuppressive agent. 
 If event resolves to AST/ALT  3  ULN with total bilirubin 
 2  ULN within 12 weeks, resume atezolizumab at fixed dose.  If 
not, permanently discontinue ipatasertib and atezolizumab and 
contact the Medical Monitor. a, b, c 
AST/ALT  ULN to 
 3  ULN with total 
bilirubin  2  ULN 
 Investigate causes for elevated bilirubin and initiate treatment as 
indicated per institutional guidelines. 
 Use best medical judgment when determining whether to continue 
study treatment. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
482/Protocol ML42439, Version 6 
 
Event 
Management 
Elevations in ALT, AST, and/or bilirubin (cont.) 
AST/ALT  3  ULN with 
total bilirubin  2   ULN 
 Withhold ipatasertib and atezolizumab. 
 Monitor LFTs every 4872 hours until decreasing and then 
monitor weekly. 
 Refer patient to hepatologist and consider liver biopsy. 
 Consider initiation of treatment with 12 mg/kg/day oral 
prednisone or equivalent. 
 If corticosteroids are initiated and event does not improve within 
48 hours, consider adding an immunosuppressive agent. 
 If event resolves to AST/ALT  3  ULN with total bilirubin 
 2  ULN within 12 weeks, resume atezolizumab at fixed dose.  If 
not, permanently discontinue atezolizumab and contact the 
Medical Monitor. a, b, c 
 If event resolves to AST/ALT  3  ULN with total bilirubin 
 2  ULN within 28 days and corticosteroid dose  10 mg oral 
prednisone or equivalent, resume ipatasertib with dose reduced 
by one level.  If not, permanently discontinue ipatasertib. 
 Permanently discontinue ipatasertib and atezolizumab for 
life-threatening hepatic events and contact the Medical Monitor. 
AST/ALT  10  ULN 
 Permanently discontinue ipatasertib and atezolizumab and 
contact the Medical Monitor. c 
 Monitor LFTs every 4872 hours until decreasing and then 
monitor weekly. 
 Refer patient to hepatologist and consider liver biopsy. 
 Consider administering 12 mg/kg/day oral prednisone or 
equivalent.   
 If corticosteroids are initiated and event does not improve within 
48 hours, consider adding an immunosuppressive agent or 
escalating the corticosteroid dose. 
 If event resolves to AST/ALT  3  ULN with total bilirubin 
 2  ULN, taper corticosteroids over  1 month. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
483/Protocol ML42439, Version 6 
Event 
Management 
Dermatologic toxicity 
 
General guidance 
 Consider having a dermatologist evaluate persistent and/or severe 
rash or pruritus. 
 Unless contraindicated, a daily oral antihistamine prophylaxis should 
be used for at least the first cycle. It is suggested that a non-sedating 
oral antihistamine (e.g. loratadine, cetirizine, fexofenadine) and 
longer-acting formulated be used.  
 For the first 28-day cycle of ipatasertib plus atezolizumab: On days 
when patients will receive atezolizumab (Day 1), patients should 
received at least 10 mg prednisone (or equivalent) as premedication 
prior to atezolizumab, followed by 10 mg/day prednisone (or 
equivalent) for 2-4 consecutive days thereafter, unless 
contraindicated. 
 Ipatasertib should be permanently discontinued for rash-associated 
with Stevens-Johnson syndrome, toxic epidermal necrolysis, or other 
suspected severe hypersensitivity or allergic reaction. Dosage 
modification and symptom management guidelines for skin toxicity, 
including erythema multiforme, attributable to ipatasetib are shown 
below. 
 Although uncommon, cases of severe cutaneous adverse reactions 
such as Stevens-Johnson syndrome and toxic epidermal necrolysis 
have been reported with atezolizumab and atezolizumab should be 
permanently discontinued for confirmed cases. 
Dermatologic event,  
Grade 1 
 Consider referring patient to a dermatologist.  
 Continue ipatasertib and atezolizumab. 
 Initiate supportive care (e.g., topical corticosteroids and continue 
antihistamine administration).   
 Consider treatment with 10 mg/day oral prednisone or equivalent. 
Dermatologic event,  
Grade 2 
 Consider referring patient to dermatologist for evaluation and perform 
a biopsy, if appropriate. 
 Continue topical corticosteroids and antihistamine administration. 
 Consider treatment with 10 mg/day oral prednisone or equivalent; 
treatment with higher steroid dose may be necessary as clinically 
indicated. 
 Ipatasertib:  interrupt ipatasertib treatment until resolution to Grade 
 1 or the toxicity is no longer clinically significant.  If steroid dose is 
 10 mg/day, ipatasertib may be resumed if clinically appropriate. 
 Atezolizumab:  If steroid dose is  10 mg/day, atezolizumab should 
be continued. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/Loss-of-Function or AKT 
MutationPositive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
484/Protocol ML42439, Version 6 
Event 
Management 
Dermatologic toxicity (cont.) 
Dermatologic event,  
Grade 3 
 Withhold ipatasertib and atezolizumab. 
 Refer patient to dermatologist.  Perform a biopsy if appropriate. 
 If no prior steroid treatment has been initiated, consider treatment 
with 10 mg/day oral prednisone or equivalent. 
 If prior oral steroid treatment or no improvement within 48 hours, 
consider increasing prednisone or equivalent dose to 
12 mg/kg/day. 
 Atezolizumab:  if event resolves to Grade  1 within 12 weeks, 
resume atezolizumab at fixed dose.  If not, permanently 
discontinue atezolizumab and contact the Medical Monitor.  Only 
restart atezolizumab if steroid dose is  10 mg/day. a, b, c 
 Ipatasertib:  if event resolves to Grade  1 or the toxicity is no 
longer clinically significant, resume ipatasertib at the same dose 
or dose reduced by one level after discussion with the Medical 
Monitor.  Only restart ipatasertib if steroid dose is  10 mg/day.  
If not, permanently discontinue ipatasertib. 
Dermatologic event,  
Grade 4 
 Permanently discontinue ipatasertib and atezolizumab and 
contact the Medical Monitor. c 
Ipatasertibrelated toxicities not described above 
Grade 3 
 Withhold ipatasertib.  Continue atezolizumab. 
 If event resolves to Grade 1 or baseline within 28 days and the 
Medical Monitor agrees that ipatasertib should be continued, 
resume ipatasertib.  If not, permanently discontinue ipatasertib. 
Grade 4 
 Withhold ipatasertib and atezolizumab. 
 If event resolves to Grade 1 or baseline within 28 days and the 
Medical Monitor agrees that ipatasertib should be continued, 
resume ipatasertib.  If not, permanently discontinue ipatasertib. 
 If event improves and the Medical Monitor agrees that 
atezolizumab should be continued, resume atezolizumab.  If not, 
permanently discontinue atezolizumab. 
BAL  bronchoscopic alveolar lavage; GI  gastrointestinal; IRR  infusion-related reaction; 
LFT  liver function test; NSAID  non-steroidal anti-inflammatory drug; ULN  upper limit of 
normal. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based the 
investigator's benefitrisk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available 
to advise as needed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
485/Protocol ML42439, Version 6 
L.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients taking ipatasertib plus atezolizumab 
arm: 
Ipatasertib 
 
Grade  3 fasting hyperglycemia  
 
Grade  3 hepatotoxicity 
 
Grade  3 ALT/AST elevations 
 
Grade  2 colitis/enterocolitis 
 
Grade  3 diarrhea 
 
Grade  3 rash 
 
Grade  2 pneumonitis 
Atezolizumab 
 
Systemic lupus erythematosus 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis  
 
L.5.4 
Selected Adverse Events 
Additional data may be analyzed for the following selected adverse events: 
 
Diarrhea 
 
Asthenia (fatigue) 
 
Nausea 
 
Neutropenia (neutrophil count decreased, febrile neutropenia) 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT 
Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
486/Protocol ML42439, Version 6 
 
Rash (e.g., maculopapular, erythema, urticarial, dermatitis, rash popular, skin 
exfoliation, toxic skin eruption) 
 
Erythema multiforme 
 
Vomiting 
 
Oral mucositis (stomatitis, mucosal inflammation, mouth inflammation, mouth 
ulceration) 
 
Hyperlipidemia (hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, blood 
cholesterol increased, blood triglycerides increased) 
 
Hepatotoxicity (ALT, AST increased) 
 
Hyperglycemia (blood glucose increased) 
 
Pneumonitis (interstitial lung diseases 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
487/Protocol ML42439, Version 6 
L.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit b 
Day and Study 
Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
 (Window) 
28 to 1 a 
(3) 
(3) 
 28 Days After 
Last Study 
Dose 
Informed consent d 
x 
 
 
 
Documentation of positive AKT 
activating mutation or PTEN 
loss/loss of function status by local 
test e 
x 
 
 
 
Medical history and baseline 
conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
ECOG Performance Status h 
x 
x 
 
x 
Pregnancy test i 
x 
x 
 
x 
Chemistry j  
x 
x 
 
x c 
Hematology/CBC with differential k 
x 
x 
 
x c 
Coagulation panel l 
x 
 
 
x 
Fasting lipid panel, amylase, lipase 
m 
x 
x 
 
x 
Fasting HbA1C n 
x 
x 
 
x 
Fasting blood glucose n 
x 
x 
Weekly during C1 
x 
TSH, free T3 (or total T3), free T4 o 
x 
C1, D1 and every 3 cycles thereafter 
 
 
ECG p 
x 
As clinically indicated 
x 
ECHO or MUGA q 
x 
As clinically indicated 
Atezolizumab administration r, s 
 
x 
 
 
Ipatasertib dispensing 
 
x 
 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
488/Protocol ML42439, Version 6 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit b 
Day and Study 
Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
 (Window) 
28 to 1 a 
(3) 
(3) 
 28 Days After 
Last Study 
Dose 
Ipatasertib compliance assessment 
t 
 
x 
 
x 
Prophylaxis anti-diarrheal u 
 
Every day of C1 and as clinically indicated 
 
Prophylaxis with 10 mg of 
prednisone (or equivalent) v 
 
D1 and 2-4 consecutive days after for C1 only 
 
Daily antihistamine prophylaxis v 
 
Every day of C1 
 
Response assessments w, x 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) 
weeks 
 
Pre-treatment tumor tissue sample 
for central testing (if applicable) y 
 
Submit within 21 days of C1, D1 
 
 
Whole blood samples z 
x 
 
See footnote z 
 
Adverse events aa 
x 
Collected on an ongoing basis 
x aa 
Concomitant Medications bb 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating 
tumor DNA; Dday; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic 
Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection fraction; 
MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; RANOResponse Assessment in 
Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious adverse event. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  
However, if the hematology/CBC, chemistry panel, and thyroid function test are obtained within 7 days of Cycle 1, Day 1 they do not 
have to be repeated on Day 1, with the exception of glucose, which should be drawn within 3 days prior.  Scans to document 
measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-
treatment follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
489/Protocol ML42439, Version 6 
ipatasertib discontinuation or 90 days post-atezolizumab discontinuation.  If the patient’s worsening disease combined with travel 
distance makes this visit too difficult, follow-up with the patient may take place by telephone to include an assessment of AEs.  
Alternatively, the patient's local physician may be contacted to collect AE data and any standard of care laboratory and CT data, if 
performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be 
repeated unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive AKT gene activating mutations or PTEN loss or loss of function status should occur prior to performing other 
trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), 
reproductive status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and 
nutritional supplements) used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, 
symptom-directed physical examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, 
that a patient’s performance status be assessed by the same person throughout the study. 
i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 
days before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the 
schedule of assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must 
be confirmed by a serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration 
of study drug.  Patients who have a positive pregnancy test must not receive study drug.   
j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, 
ALT, total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to 
administration of the first dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1, with the exception of glucose, which should be drawn within 3 days prior.  Subsequent chemistry 
evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
k Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). If results are obtained within 7 days of Cycle 1, Day 1 they 
do not have to be repeated on Cycle 1 Day 1.  
l Coagulation includes aPTT and INR. 
m Fasting lipid panel (cholesterol, triglyceride, HDL, and LDL), amylase, lipase, and HbA1c will be assessed after ≥8 hours of fasting.  If 
results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.   


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
490/Protocol ML42439, Version 6 
n Samples should be assessed weekly during the first Cycle and D1 at every other cycle. Mid-cycle fasting glucose levels may be 
obtained by glucometer (fingerstick).   If measurements are done at home, phone visits with site staff should be conducted to review 
results and assess any potential signs or symptoms of hyperglycemia.  
o TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every third 
cycle thereafter (i.e., Cycles 4, 7, 10, etc.). 
p It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
q LVEF assessment by ECHO or MUGA to be performed at screening and as clinically indicated. Evaluation of LVEF must be performed 
by the same method (ECHO or MUGA) for each patient. It is strongly recommended that the same laboratory and operator perform 
ECHO/MUGA scan for each individual patient. 
r The initial infusion of atezolizumab will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) 
minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced 
an infusion-associated adverse event with the previous infusion.  Refer to Section L.4.2.3 for details on atezolizumab infusions 
(including measurement of vital signs). 
s Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator (see Section 3.1.2 for 
details). 
t Ipatasertib is administered 400 mg PO QD. On Day 1 of each cycle, review compliance from previous cycle and dispense ipatasertib for 
next cycle.  
u Loperamide 2 mg BID or equivalent or per local institutional guideline for the first cycle.  If loose watery stools occur, take additional 2 
mg after each loose watery stool and up to 16 mg per day. 
v  For the first cycle only: On day when patients will receive atezolizumab, patients should receive at least 10 mg/day prednisone (or 
equivalent) as premedication prior to atezolizumab, followed by 10 mg/day prednisone (or equivalent) for 24 consecutive days 
thereafter, unless contraindicated. Unless contraindicated, daily oral antihistamine prophylaxis should be used for at least the first cycle. 
It is suggested that a non-sedating oral antihistamine (such as loratadine, cetirizine, fexofenadine) and a longer-acting formulation be 
used.  
w All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study 
treatment do not have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or 
impaired renal clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head 
should be performed.  A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the 
brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
x At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic 
procedures every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment 
discontinuation, until investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), 
withdrawal of consent, termination of an individual study arm by the Sponsor, or death, whichever occurs first.   


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
491/Protocol ML42439, Version 6 
y For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue 
samples (archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both 
archival and recent tissue is available, the recent tissue should be preferentially submitted.   
z Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at 
tumor progression (within 7 days after progression) for analyses including ctDNA.  
aa After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-
mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final 
dose of study drug.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation. All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  After this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified 
if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment 
(see Section 5.6). 
bb Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of 
study drug. 
 


Arm L:  Ipatasertib plus Atezolizumab in Patients with PTEN Loss/ Loss of Function or AKT Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
492/Protocol ML42439, Version 6 
 
L.7 
REFERENCES 
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of 
granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced 
febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. 
Eur J Cancer 2011;47:832. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 
2006;24:3187205


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
493/Protocol ML42439, Version 6 
Appendix 22  
Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations 
in PI3K (PIK3CA) Activating Mutations and PTEN Loss/ 
Loss-of-Function or AKT Activating Mutation-Positive Tumors 
23. 
ARM M:  IPATASERTIB PLUS PACLITAXEL IN PATIENTS WITH 
CO-MUTATIONS IN PI3K (PIK3CA) ACTIVATING MUTATIONS 
AND PTEN LOSS/ LOSS-OF-FUNCTION OR AKT ACTIVATING 
MUTATION-POSITIVE TUMORS  
TABLE OF CONTENTS 
M.4 
Materials and Methods .......................................................... 494 
M.4.1 
Patients .................................................................................. 494 
M.4.1.1 
Additional Inclusion Criteria ................................................... 494 
M.4.1.2 
Additional Exclusion Criteria .................................................. 495 
M.4.2 
Study Treatment .................................................................... 497 
M.4.2.1 
Formulation and Packaging ................................................... 497 
M.4.2.2 
Dosage, Administration, and Compliance for Ipatasertib ....... 497 
M.4.2.3 
Dosage, Administration, and Compliance for Paclitaxel ........ 498 
M.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 499 
M.4.3.1 
Permitted Therapy ................................................................. 499 
M.4.3.2 
Cautionary Therapy ............................................................... 500 
M.4.3.2.1 
Medications Given with Precaution due to Effects Related 
to Cytochrome P450 Enzymes .............................................. 501 
M.4.3.2.2 
Herbal Therapies ................................................................... 501 
M.4.3.3 
Prohibited Therapy ................................................................ 502 
M.4.3.4 
Prohibited Food ..................................................................... 502 
M.4.4 
Arm-specific Assessments ..................................................... 503 
M.5 
Safety Plan ............................................................................ 503 
M.5.1 
Risks Associated with Ipatasertib and Paclitaxel ................... 503 
M.5.1.1 
Risks Associated with Ipatasertib .......................................... 503 
M.5.1.2 
Risks Associated with Paclitaxel ............................................ 503 
M.5.1.3 
Risks Associated with Ipatasertib in Combination with 
Paclitaxel ............................................................................... 504 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
494/Protocol ML42439, Version 6 
M.5.2 
Guidelines for Management of Adverse Events ..................... 504 
M.5.2.1 
Dosage Modification and Interruptions .................................. 504 
M.5.2.2 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Ipatasertib ............................... 506 
M.5.2.3 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Paclitaxel ................................ 506 
M.5.2.4 
Adverse Event Management Guidelines for Ipatasertib plus 
Paclitaxel ............................................................................... 506 
M.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 518 
M.5.4 
Selected Adverse Events ....................................................... 519 
M.6 
Schedule of Activities ............................................................. 520 
M.7 
References ............................................................................ 525 
 
M.4 
MATERIALS AND METHODS 
M.4.1 
Patients 
To be enrolled in Arm M: ipatasertib in combination with paclitaxel treatment, patients 
must have met and continue to meet all general eligibility criteria (see Section 4.1), in 
addition to the arm-specific criteria below. 
M.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm M: 
ipatasertib plus paclitaxel treatment: 
 
A co-mutation of either PI3K activating mutation and AKT activating mutation or a 
PI3K activating and PTEN loss or loss of function based on the following 
biomarkers:  
– 
PIK3CA mutation positivity, as determined by a Clinical Laboratory 
Improvement Amendments (CLIA) or equivalently certified next-generation 
sequencing (NGS) assay (tissue or blood) 
PIK3CA mutation positivity is defined by the presence of at least one 
nucleotide variant listed below: 
o 
H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, 
Q546E/H/K/L/P/R, G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, 
C420R, R88Q, M1043I/T/V 
o 
Other activating mutations with Medical Monitor approval 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
495/Protocol ML42439, Version 6 
– 
AKT1/2/3 mutant positivity, as determined by a Clinical Laboratory 
Improvement Amendments (CLIA) or equivalently certified next-generation 
sequencing (NGS) assay (tissue or blood) 
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants 
as listed below: 
o 
AKT1:  E17K; L52R; Q79K 
o 
AKT2:  E17K 
o 
AKT3:  E17K; L51R; Q78K 
 
or PTEN protein loss of function or protein loss as determined by a CLIA or 
equivalently certified tissue-based NGS, in situ hybridization (ISH), or 
immunohistochemistry (IHC) assay (See Appendix 1 for details) 
 
ANC  1500/l within 14 days prior to initiation of study treatment 
 
Fasting glucose  150 mg/dL and hemoglobin A1c (HbA1c)  7.5% 
 
Ability to swallow ipatasertib intact, without chewing or crushing the tablets 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
28 days after the last dose of ipatasertib and 6 months after the last dose of 
paclitaxel, whichever occurs later, and agreement to refrain from donating eggs 
during this same period.  See detailed contraception requirements in Appendix 2. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of  1% per year during the treatment period and for at least 28 days 
after the last dose of ipatasertib, and 3 months after the last dose of paclitaxel, 
whichever occurs later and agreement to refrain from donating sperm during this 
same period.  See detailed contraception requirements in Appendix 2. 
 
M.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm M: ipatasertib plus paclitaxel treatment: 
 
History of malabsorption syndrome or other condition that would interfere with 
enteral absorption or results in the inability or unwillingness to swallow pills  
 
Known clinically significant history of liver disease consistent with Child-Pugh Class 
B or C, current drug or alcohol abuse, or cirrhosis 
 
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection 
fraction (LVEF)  50%; or active ventricular arrhythmia requiring medication 
 
Congenital long QT syndrome or screening QT interval corrected using Fridericia’s 
formula (QTcF)  480 milliseconds  


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
496/Protocol ML42439, Version 6 
 
History or presence of an abnormal ECG that is clinically significant in the 
investigator’s opinion (including complete left bundle branch block, second- or 
third-degree heart block, or evidence of prior myocardial infarction) 
 
Need for chronic corticosteroid therapy of  10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants 
for a chronic disease. 
 
Unresolved, clinically significant toxicity from prior therapy, except for alopecia and 
Grade 1 peripheral neuropathy  
 
Uncontrolled pleural effusion, pericardial effusion, or ascites 
Patients with indwelling catheters (e.g., PleurX) are allowed.  
 
Uncontrolled tumor-related pain 
– 
Patients requiring pain medication must be on a stable regimen at study entry 
– 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated  14 days 
prior to Cycle 1, Day 1.  The patient must have recovered from any resulting 
acute toxicity (to Grade  1) prior to study treatment initiation 
– 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment 
 
Uncontrolled hypercalcemia ( 1.5 mmol/L ionized calcium,  12 mg/dL calcium, or 
corrected serum calcium  ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy  
 
History of Type I or Type II diabetes mellitus requiring insulin.   
Patients who are on a stable dose of oral diabetes medication  2 weeks prior to 
initiation of study treatment are eligible for enrollment.  
 
Grade  2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia  
 
History of or active inflammatory bowel disease (e.g., Crohn’s disease and 
ulcerative colitis) or active bowel inflammation (e.g., diverticulitis)  
 
Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, 
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia) 
 
Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A 
inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to 
initiation of study treatment (see Appendix 7) 
 
Prior treatment with an Akt inhibitor 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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Note that prior PI3K or mTOR inhibitors are allowed. 
 
Known hypersensitivity or contraindication to any component of the study 
treatments, including the paclitaxel excipient macrogolglycerol ricinoleate  
 
Grade  2 peripheral neuropathy 
 
Prior treatment with paclitaxel treatment 
  
M.4.2 
Study Treatment 
Study treatment in this arm will consist of ipatasertib in combination with paclitaxel 
treatment.  
M.4.2.1 
Formulation and Packaging 
Ipatasertib will be supplied by the Sponsor as 100-mg and 200-mg tablets.   
The study drug will be periodically tested and monitored for its acceptable shelf life.  Any 
study drug that fails to comply with the manufactured specifications will be promptly 
removed from the clinical trial site and replaced with new supplies by the Sponsor (or 
designee). 
Each bottle will be labeled with the required regulatory agency warning statement, the 
protocol number, the Sponsor’s name, and directions for patient use and storage.  The 
investigator should ensure that the study drug is stored in appropriate conditions in a 
secure location with controlled access. 
For information on the packaging, handling and storage, see the Pharmacy Manual and 
Ipatasertib Investigator’s Brochure. 
For information on the formulation, packaging, and handling of paclitaxel, see the local 
prescribing information for paclitaxel. 
M.4.2.2 
Dosage, Administration, and Compliance for Ipatasertib 
Study treatment will be administered on days 1 through 21 of 28-day cycles.  
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at 
the same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) 
once a day (QD) on days 1 through 21 of 28-day cycles until disease progression, 
intolerable toxicity or consent withdrawal.  For more specific dosing instructions, refer to 
the pharmacy manual. 
The tablets will be swallowed whole (not chewed) with 3 ounces (90 mL) of fluid.  
Ipatasertib is recommended to be taken at least 2 hours after the last meal of the day, 
and patients should refrain from eating overnight.  Patients are required to receive 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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prophylaxis (see Section M.5.2.4.1) with loperamide throughout the first cycle and at 
subsequent cycles as clinically indicated.  
For ipatasertib doses to be administered at home, a sufficient number of tablets should 
be dispensed to the patient to last until the next visit, or at the investigator’s discretion, 
through one cycle.  Patients will be asked to record in a medication diary the time and 
date for each dose taken. 
A missed dose can be taken within 8 hours of the scheduled time.  After that, patients 
should take the next dose the following day, without compensating for the missed dose 
(including vomited doses).  
Guidelines for ipatasertib dosage modification and treatment interruption or 
discontinuation are provided in Section M.5.2.1.1. 
See Section 4.3.2 for details on assessment of compliance for self-administered oral 
study drugs. 
M.4.2.3 
Dosage, Administration, and Compliance for Paclitaxel 
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
and 15 of each 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can be given on 
Day 22.  Calculation of body surface area for the purposes of dosing of paclitaxel should 
be made according to the prescribing information.  If the patient’s weight changes by 
 10% during the study, the body surface area and drug doses should be recalculated.   
The paclitaxel infusion will be delivered over at least 60 minutes for each dose per 
institutional guidelines and administered after the oral dose of ipatasertib. 
Because of the known potential for allergic reactions to paclitaxel and/or the 
Cremophor vehicle, precautions must be taken to decrease the risk of anaphylaxis.  
Patients must be premedicated prior to paclitaxel with dexamethasone, 
diphenhydramine, and an H2-receptor blocker (i.e., ranitidine or famotidine) or per 
institutional practice.  H2-receptor antagonists, such as cimetidine, which are known to 
inhibit cytochrome P450, should be avoided.  
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug. 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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M.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug until 28 days after the last dose of study drug.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
M.4.3.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study:  
 
Oral contraceptives, as allowed per local guidelines 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:  
Palliative radiotherapy is permitted for a preexisting lesion, provided it does not 
interfere with the assessment of tumor target lesions (e.g., the lesion to be 
irradiated must not be a site of measurable disease).  Study treatment should be 
suspended during palliative radiotherapy.  Treatment with ipatasertib and 
paclitaxel should be temporarily held for at least 7 days before and after the 
procedure (at least 14 days after radiation is recommended).  For a single 
fraction of radiotherapy, this hold may be shorter, if discussed by the investigator 
with the Medical Monitor.  The patient may continue ipatasertib plus paclitaxel 
treatment after treatment holding has been completed and the patient has 
sufficiently recovered.  
 
Premedication with antihistamines, antipyretics, and/or analgesics for each 
paclitaxel administration as described in Section M.4.2.3 
 
Prophylaxis use of loperamide is mandated in the first cycle and as clinically 
indicated in subsequent cycles to prevent diarrhea.  Patients who experience 
diarrhea should be on treatment doses of loperamide per the management 
guidelines provided in Section M.5.2.4.1; please refer to that section for additional 
details.  Patients should be educated/reminded to be cognizant of the onset, 
duration, severity, and frequency of symptoms and the medications administered.  
 
Granulocyte colony-stimulating factor treatment is permitted.  The primary 
prophylaxis should be administered per the American Society of Clinical Oncology 
(ASCO), European Organization for Research and Treatment of Cancer (EORTC), 
and European Society for Medical Oncology (ESMO) guidelines; namely, in patients 
who are  60 years of age and/or with comorbidities (Smith et al. 2006; Aapro et al. 
2011) 
 
Bisphosphonate therapy or RANKL inhibitor therapy (e.g., zolendronic acid and 
denosumab) used specifically to prevent skeletal events (e.g., bone metastasis, 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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osteoporosis) is allowed.  Both types of agents have potential immunomodulatory 
properties, but may be used as clinically indicated.  
 
Luteinizing hormone-releasing hormone or gonadotropin-releasing hormone 
agonists for ovarian function preservation are allowed.  
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)  
 
Inactivated influenza vaccinations  
 
Megestrol acetate administered as an appetite stimulant after initiation of study 
treatment  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated and per institutional practice.  For example, patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per institutional practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and β2-adrenergic agonists; see Appendix 6). 
M.4.3.2 
Cautionary Therapy  
Patients who require radiation or surgery as part of medical treatment in the absence of 
radiographic disease progression must exercise caution, and all study treatment should 
be temporarily held for at least 7 days before and after the procedure (at least 14 days 
after radiation is recommended).  For minor surgeries or single-day radiotherapy, this 
hold may be shorter, if discussed by the investigator with the Medical Monitor.  After the 
temporary treatment hold is complete, study treatment may be re-initiated when the 
patient has sufficiently recovered.  Systemic corticosteroids are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events (refer to 
Section M.5.2.4.5 and Section M.5.2.4.6 for details).  All study treatment should be 
temporarily held during systemic corticosteroids treatment (except when corticosteroids 
are given as pre-medication to paclitaxel). 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
501/Protocol ML42439, Version 6 
M.4.3.2.1 
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes  
In vitro data suggest that ipatasertib is metabolized by CYP3A and may be a time-
dependent inhibitor of CYP3A4.  A clinical drug−drug interaction (DDI) study with 
midazolam (a sensitive CYP3A substrate) showed a 2.2-fold increase in midazolam 
exposures in presence of steady-state ipatasertib dosed at 600 mg QD.  Therefore, 
sensitive CYP3A substrates with narrow therapeutic window should be avoided.  Given 
that ipatasertib is primarily metabolized by CYP3A, there is a high potential for 
drug−drug interactions of ipatasertib with any medication that strongly inhibits or induces 
CYP3A.  Data from a clinical study showed that ipatasertib exposures were reduced by 
~50% when co-administered with enzalutamide, a strong CYP3A inducer.  Strong 
CYP3A inhibitors are expected to increase ipatasertib exposures significantly.  
Therefore, strong CYP3A4/5 inhibitors or inducers or CYP3A4/5 substrates with a 
narrow therapeutic index should be avoided or used with caution (see Appendix 7).  
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment 
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients are permitted to take moderate inhibitors of CYP3A4 with caution.  
 
Paclitaxel exposures may be increased due to CYP2C8 inhibition; therefore, strong 
and moderate CYP2C8 inhibitors, such as gemfibrozil, teriflunomide, clopidogrel, 
and deferasirox should be used with caution during treatment with paclitaxel.  
Similarly, CYP2C8 inducers should be avoided or used with caution.  
 
Patients should be closely monitored.  Refer to the following information for further 
guidance on CYP450−drug interactions and a list of common substrates, inhibitors, and 
inducers:  
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and 
Inducers (U.S. Food and Drug Administration [FDA]): 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/ DrugInteractionsLabeling/ucm093664.htm  
The above lists of medications are not comprehensive.  The investigator should consult 
the prescribing information when determining whether a concomitant medication can be 
safely administered with study treatment.  In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications not listed above. 
M.4.3.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug−drug interactions (DDIs) are 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
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generally unknown.  However, herbal therapies not intended for the treatment of cancer 
may be used during the study at the discretion of the investigator. 
M.4.3.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 21 days prior to initiation of study treatment and during study treatment.  
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy) is prohibited  
 
Chronic use of a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A 
substrates with a narrow therapeutic window that are deemed not permissible by the 
Medical Monitor after enrollment (refer to the guidance in Section M.4.3.2.1) 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment 
 
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of 
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment 
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 7 days after the last dose of these 
drugs.  Patients should be closely monitored.  Patients who require short-term use of 
moderate CYP3A4 inhibitors may continue study treatment with caution.  
Refer to the following information for further guidance on CYP450drug interactions and 
a list of common substrates, inhibitors, and inducers:  
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers (FDA): http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ 
DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 
 
M.4.3.4 
Prohibited Food 
Use of the following foods is prohibited as described below:  
 
Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit, potent CYP3A4 enzyme 
inhibitors, is prohibited during the study treatment period and for 10 days after the 
last dose of study treatment. 
 
Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, is prohibited for 
up to 14 days prior to and during the study treatment period, and for 10 days after 
the last dose of study treatment. 
 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
503/Protocol ML42439, Version 6 
M.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in the Arm M: ipatasertib plus paclitaxel treatment.  
Refer to the schedule of activities (Section M.6) for arm-specific assessment timepoints. 
Local Laboratory Assessments 
 
Coagulation panel:  INR and aPTT 
 
HbA1c, blood glucose (fasting) 
 
Amylase, lipase (fasting) 
 
Lipid panel (fasting):  total cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides 
 
Functional Assessments 
 
LVEF assessment:  echocardiogram (ECHO) or multiple-gated acquisition (MUGA) 
 
12 lead electrocardiogram (ECG) 
 
M.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm M: ipatasertib plus 
paclitaxel treatment. 
M.5.1 
Risks Associated with Ipatasertib and Paclitaxel 
M.5.1.1 
Risks Associated with Ipatasertib 
Ipatasertib has been associated with risks such as the following: nausea, vomiting, 
diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, erythema 
multiforme, and rash.  Ipatasertib’s potential risks include hematologic or 
immunosuppressant effects, hyperlipidemia, hepatotoxicity, pneumonitis, colitis, and 
developmental toxicity.  Refer to the Ipatasertib Investigator’s Brochure for a detailed 
description of anticipated safety risks for ipatasertib. 
M.5.1.2 
Risks Associated with Paclitaxel 
Paclitaxel has been associated with risks such as the following: Bone marrow 
suppression, neutropenia, alopecia, peripheral neuropathy, myalgia, arthralgia, nausea, 
and vomiting.  Additionally, reported adverse events which were less common are 
hypersensitivity reactions, infections, bleeding, diarrhea, mucositis, liver function test 
(LFT) elevations, injection-site reactions, and cardiovascular effects such as 
hypotension, bradycardia, hypertension, arrhythmias, other electrocardiogram (ECG) 
abnormalities, syncope, and venous thrombosis.  For more details regarding the safety 
profile of paclitaxel, see the Paclitaxel Prescribing Information or Summary of Product 
Characteristics. 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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M.5.1.3 
Risks Associated with Ipatasertib in Combination with 
Paclitaxel 
Ipatasertib in combination with paclitaxel has been administered to 61 cancer patients in 
Study GO29227 (LOTUS).  Adverse events related to ipatasertib/placebo whose 
incidences were higher by  10% in patients receiving ipatasertib  paclitaxel versus 
placebo  paclitaxel were diarrhea (93.4% vs. 21.0%) and nausea (52.5% vs. 33.9%).  
The most frequent Grade  3 adverse events (reported in  5% of patients in either 
treatment arm) in patients in the ipatasertib  paclitaxel arm vs placebo + paclitaxel arm 
were diarrhea (14 patients [23.0%], all Grade 3, vs. 0 patients), neutropenia (6 patients 
[9.8%] vs. 1 patient [1.6%]), decreased neutrophil count (5 patients [8.2%] vs. 4 patients 
[6.5%]), and fatigue (2 patients [3.3 %] vs. 4 patients [6.5%]), respectively. 
The incidence of overall neutropenia in the LOTUS Study was similar in both arms (34% 
in the ipatasertib  paclitaxel arm vs. 39% in the placebo  paclitaxel arm), but Grade 3 
neutropenia, analyzed by grouped terms of similar medical concept, was higher in the 
ipatasertib  paclitaxel arm (18% vs. 8%).  Thus, for recurrent Grade  3 neutropenia, 
ipatasertib should be reduced by one dose level when treatment is restarted (refer to the 
management guidelines in Section M.5.2.4).  
Ipatasertib in combination with paclitaxel (N=146) and placebo with paclitaxel (N=76) 
were observed in cohort B of study CO40016. Adverse events related to 
ipatasertib/placebo whose incidences were higher by  10% in patients receiving 
ipatasertib  paclitaxel versus placebo  paclitaxel were diarrhea (84.8% vs 37.3%), 
nausea (41.4% vs 20.0%), peripheral neuropathy (31.7% vs 16.0%), vomiting (29.0% vs 
6.7%) and rash (20.0% vs 12.0%). The most frequent Grade  3 adverse events 
(reported in  5% of patients in either treatment arm) in patients in the 
ipatasertib  paclitaxel arm vs placebo + paclitaxel arm were diarrhea (11.7% vs 1.3%), 
decreased neutrophil count (9.0% vs 6.7%) neutropenia (8.3% vs 9.3), peripheral 
sensory neuropathy (2.8% vs 5.3%) and hypertension (1.4% vs 5.3%), respectively.  
Refer to the Ipatasertib Investigator’s Brochure for further information regarding the 
nonclinical and clinical safety evaluation of ipatasertib as a single agent and in 
combination with paclitaxel. 
M.5.2 
Guidelines for Management of Adverse Events 
M.5.2.1 
Dosage Modification and Interruptions 
M.5.2.1.1 
Dosage Modification and Interruptions for Ipatasertib  
If the patient does not tolerate the QD dosing of the ipatasertib, dosing with food may be 
used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or diarrhea.  
No more than two dose reductions of ipatasertib per patient (i.e., doses below 
200 mg/day of ipatasertib) will be allowed (see Table 1).  Dose re-escalation is not 
permitted for ipatasertib. 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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Table 1 
Dose Reductions for Ipatasertib 
Dose Level a 
Ipatasertib 
Starting dose 
400 mg 
First dose reduction 
300 mg 
Second dose reduction 
200 mg 
Third dose reduction 
Not permitted   
a 
If the patient continues to experience specified drug-related adverse events after the 
second reduction, the treatment should be discontinued. 
 
Patients may hold the ipatasertib for up to 4 consecutive weeks (approximately 
28 consecutive days) in order to recover from toxicity or an adverse event related to the 
study drug.  If the ipatasertib is discontinued at any time during the study, patients may 
have the option of continuing on study with paclitaxel alone. 
Ipatasertib treatment may be temporarily interrupted in patients who experience toxicity 
considered to be related to study drug.  If ipatasertib has been withheld for  28 
consecutive days because of treatment-related toxicity, the patient should be 
discontinued from ipatasertib.  Ipatasertib and/or paclitaxel treatment may be suspended 
for reasons other than toxicity (e.g., surgical procedures) with Medical Monitor 
consultation.  If, in the judgment of the investigator, the patient is likely to derive clinical 
benefit from resuming study treatment after a hold of >28 consecutive days, study drug 
may be restarted after consultation with the Medical Monitor.  
M.5.2.1.2 
Dosage Modification and Interruptions for Paclitaxel 
To manage paclitaxel-related toxicity, no more than one dose reduction for paclitaxel is 
allowed (Table 2).  Paclitaxel doses other than specified in Table 2 will not be allowed. 
Table 2 
Dose Reductions for Paclitaxel 
Dose Level a 
Paclitaxel 
Starting dose 
80 mg/m2 
First dose reduction 
65 mg/m2 
Second dose reduction 
Not permitted  
Third dose reduction 
Not Applicable 
a If the patient continues to experience specified drug-related adverse events after the dose 
reduction, the treatment should be discontinued. 
 
If paclitaxel treatment is interrupted, consider delaying the ipatasertib and paclitaxel 
treatment concurrently for up to 7 days (i.e., shifting the 7 days-off week for ipatasertib 
so that 21 daily doses in every 28 days is maintained), at the discretion of the 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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investigator.  The interrupted dose of paclitaxel may be administered later in the same 
cycle, ideally on Day 22, taking into consideration the paclitaxel dosing starting on Day 1 
of the next cycle. 
M.5.2.2 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Ipatasertib 
Guidelines for management of specific adverse events for ipatasertib given as a single 
agent are provided in Section D.5.2.2. 
M.5.2.3 
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Paclitaxel 
Toxicities associated or possibly associated with paclitaxel treatment should be 
managed according to standard medical practice and in accordance with the respective 
packaging insert.  
M.5.2.4 
Adverse Event Management Guidelines for Ipatasertib plus 
Paclitaxel 
Guidelines for management of specific adverse events are provided in the subsections 
below. 
M.5.2.4.1 
Diarrhea Management Guidelines 
Specific guidelines for managing diarrhea to improve safety and tolerability are provided 
in Table 3.  In this study, all patients should receive loperamide (2 mg oral twice a day or 
4 mg once a day) as prophylaxis for diarrhea in the first cycle if allowed by local 
guidance.  Investigators are encouraged to continue this dosing for the remainder of the 
study, and the prophylaxis dose may be adjusted as necessary, using their discretion 
based on clinical judgment and per local guidance.  
Treatment modifications for diarrhea (any grade), when it occurs, should be instituted as 
early as possible.  Guidelines for treatment of diarrhea following the prophylactic dose of 
loperamide (where allowed) includes use of loperamide 2 mg every 4 hours or after each 
loose, watery stool, up to the maximum total dose of 16 mg/day or per institutional 
guidelines and standard of care, including, but not limited to, additional therapy with 
Lomotil (diphenoxylate and atropine), codeine, or octreotide.  Duration of diarrhea may 
be minimized by taking ipatasertib with food, avoiding lactose-containing foods, and 
hydrating with 810 glasses per day (~12 oz/glass) of electrolyte-containing clear liquid, 
such as broth or low-calorie drinks.   
For diarrhea that persists for more than 5 days, despite treatment with anti-diarrheal 
agent(s) and/or withholding dosing of ipatasertib, gastroenterologists should be 
consulted to rule out the risk of colitis and infection (e.g., obtaining CT images or a stool 
culture for infectious workup [Clostridium difficile, enteric bacteria, cytomegalovirus]).  
Patients should be educated on the symptoms and importance of early reporting of 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive 
Tumors 
 
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diarrhea to receive instructions of treatment and prevention of dehydration so that 
patients can be promptly and appropriately managed.  Educational materials will be 
provided to investigators and patients outlining these guidelines.  
Dose intensity of paclitaxel should be maintained as tolerated.  Dose reductions of 
ipatasertib will be by one level at a time (i.e., 400 to 300 mg; 300 to 200 mg) as outlined 
in Section M.5.2.1.1 and Table 1.  If Grade ≥ 2 diarrhea persists following dose 
reductions of ipatasertib to 200 mg daily and with maximum treatment for diarrhea, 
ipatasertib should be discontinued.  Paclitaxel dose reduction or discontinuation should 
be considered if diarrhea persists even after ipatasertib discontinuation. 
Table 3 
Diarrhea Management Guidelines 
Severity of Diarrhea a 
Management Guideline 
Prevention 
 
All patients are mandated to receive loperamide (2 mg 
BID or 4 mg QD) as prophylaxis for diarrhea in the 
first cycle, if allowed by local guidance.  If there are 
clinical concerns that preclude the use of loperamide 
prophylaxis in Cycle 1, discussion with the 
Medical Monitor is required.  Loperamide dose 
adjustment may be made per investigator discretion 
after discussion with the Medical Monitor. 
 
After the first cycle, investigators are encouraged to 
continue this dosing for the remainder of the study 
using their discretion as clinically indicated. 
Grade 1 
Increase of  4 stools per day over 
baseline; mild increase in ostomy 
output compared with baseline 
 
Continue study drugs at the current dose level. 
 
Manage with loperamide 4 mg initially and then 2 mg 
every 4 hours or after every unformed stool until after 
12-hour diarrhea free interval. 
 
Dietary modifications, such as avoiding any 
lactose-containing foods and eating small meals. 
 
Hydration with 810 glasses per day (~12 oz/glass) of 
clear liquid, such as broth or low-calorie drinks with 
electrolytes. 
 
Upon resolution, loperamide prophylaxis can be 
considered and continues as clinically indicated, if 
allowed by local guidance. 


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Table 3 
Diarrhea Management Guidelines (cont.) 
 
Severity of Diarrhea a 
Management Guideline 
Grade 2 
Increase of 46 stools per day 
over baseline; moderate increase 
in ostomy output compared with 
baseline 
 
Rule out infectious etiology. 
 
Manage with loperamide as early as possible 4 mg 
initially and then 2 mg every 4 hours or after every 
unformed stool until after 12-hour diarrhea free 
interval. 
 
Dietary modifications, such as avoiding any 
lactose-containing foods and eating small meals.  
 
Hydration with 8−10 glasses per day (~12 oz/glass) of 
clear liquid, such as broth or low-calorie drinks with 
electrolytes. 
 
For non-infectious diarrhea lasting more than 48 hours 
despite optimal loperamide treatment, manage with 
second-line anti-diarrheal agents, including, but not 
limited to Lomotil®, codeine, or octreotide, or as per 
institutional guidelines. 
 
Interrupt ipatasertib until diarrhea improves to Grade 1 
or better.  Ipatasertib can be resumed at the same 
dose or one dose lower per investigator’s evaluation 
upon improvement to Grade 1 or better. 
 
Reduce ipatasertib by o ne (or one additional) dose 
level (see Section M.5.2.1.1) for recurrent Grade 2 
diarrhea. 
 
When study treatment is resumed, loperamide 
prophylaxis should also be resumed and continues as 
clinically indicated, if allowed by local guidance. 
Grade 3 
Increase of  7 stools per day over 
baseline; incontinence; 
hospitalization indicated; severe 
increase in ostomy output 
compared to baseline; limiting 
self-care ADL 
 
Rule out infectious etiology. 
 
Treat per Grade 2 management guidelines and 
supportive care. 
 
Interrupt ipatasertib and paclitaxel until diarrhea 
improves to Grade 1 or better.  Ipatasertib should be 
reduced by one dose level (see Section M.5.2.1.1) 
when treatment is restarted.  Consider resuming 
paclitaxel at the same dose. 
 
For recurrent Grade 3 diarrhea, reduce ipatasertib dose 
by one additional dose level (see Section M.5.2.1.1).  
Consider reducing paclitaxel by one dose level when 
treatment is restarted (see Section M.5.2.1.2). 
 
When study treatment is resumed, loperamide 
prophylaxis should also be resumed and continues as 
clinically indicated, if allowed by local guidance. 


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Table 3 
Diarrhea Management Guidelines (cont.) 
 
Severity of Diarrhea a 
Management Guideline 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
 
Rule out infectious etiology. 
 
Treat per Grade 2 management guidelines and 
supportive care. 
 
Permanently discontinue ipatasertib. 
 
Interrupt paclitaxel until diarrhea improves to 
Grade 1 or better.  Consider resuming paclitaxel by 
one dose level lower or discontinuing paclitaxel per 
investigator’s discretion (see Section M.5.2.1.2). 
ADL  activities of daily living; BID  twice a day; NCI CTCAE v5.0  National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0; QD  once a day. 
a  Diarrhea, as defined by NCI CTCAE v5.0, a disorder characterized by frequent and watery 
bowel movements. 
 
M.5.2.4.2 
Fasting Hyperglycemia 
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours. 
Dose modification guidelines for fasting hyperglycemia attributable to study treatment 
are outlined below (see Table 4) and are intended to provide guidance for fasting 
glucose measurements assessed in the clinic.  Decisions regarding study treatment 
should be made on fasting levels drawn in the clinic whenever possible. 
Home glucose measurements may be used to trigger contact between patient and 
investigative site team and may lead to an unscheduled clinic visit to assess fasting 
glucose.  Guidance for when to call the investigator/site staff (or designated 
endocrinologist, if applicable) should be provided to patients for hypoglycemia 
(e.g., glucose value under 70 mg/dL) and hyperglycemia (e.g., glucose value over 
300 mg/dL).  For any patients performing home glucose monitoring, the blood glucose 
log should be reviewed at each clinic visit.   
In the event of ipatasertib interruption, anti-diabetic medications may need to be held or 
reduced (per investigator judgement) and glucose should be monitored closely to 
minimize the risk of hypoglycemia. 


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Table 4 
Fasting Hyperglycemia Management Guidelines 
Severity of Fasting 
Hyperglycemia 
Management Guideline 
Fasting glucose value 
 ULN to 160 mg/dL 
(8.9 mmol/L) a 
 
Monitor fasting glucose per protocol  
 
Consider initiating home glucose monitoring  
Fasting glucose value 
 160 to 250 mg/dL 
( 8.913.9 mmol/L) a 
 
Interruption of ipatasertib until fasting hyperglycemia resolves to 
 160 mg/dL. 
 
Initiate home glucose monitoring 
 
Start oral anti-diabetic medications (e.g., metformin).  
 
If patient is already on an oral anti-diabetic medication, the dose of 
ipatasertib should be reduced by one dose level (refer to Table 1). 
 
If the patient previously has not been receiving any oral anti-diabetic 
medication, ipatasertib may be resumed at the previous dose level 
with initiation of oral anti-diabetic medication. 
Fasting glucose value 
250 to 500 mg/dL 
( 13.927.8 mmol/L) a 
 
Interrupt ipatasertib dosing until fasting hyperglycemia resolves to 
 160 mg/dL.  
 
Initiate home glucose monitoring 
 
Treat hyperglycemia as medically appropriate.  Start (or increase dose 
of) oral anti-diabetic medications (e.g., metformin). 
 
If the patient is already on an oral anti-diabetic medication, ipatasertib 
should be reduced by one dose level when treatment is restarted. 
 
If previously, the patient has not been receiving any oral anti-diabetic 
medication, ipatasertib may be resumed at the previous dose level 
with initiation of oral anti-diabetic medication. 
 
If fasting hyperglycemia  250 mg/dL recurs, the dose of ipatasertib 
should be reduced by one dose level when treatment is restarted.   
Fasting glucose value 
 500 mg/dL 
( 27.8 mmol/L); 
life-threatening 
consequences a 
 
Interrupt ipatasertib dosing until resolution to  160 mg/dL. 
 
Treat hyperglycemia as medically appropriate.   
 
Initiate home glucose monitoring 
 
Start (or increase dose of) oral anti-diabetic medications (e.g., 
metformin). 
 
Assess for volume depletion and appropriate intravenous or oral 
hydration. 
 
Reduce ipatasertib by one dose level if and when treatment is 
restarted. 
 
If hyperglycemia  500 mg/dL recurs, permanently discontinue 
ipatasertib. 
ULNupper limit of normal. 
a For all grades, the patient should receive education on a diabetic diet. 
 
M.5.2.4.3 
Neutropenia and/or Thrombocytopenia 
Addition of hematopoietic growth factors is allowed.  If a dose delay is required as 
a result of neutropenia at any grade, patients should receive prophylactic granulocyte 


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colony-stimulating factor or granulocyte-macrophage colony-stimulating factor per 
institutional standards.  Patients should be counseled as to the risk of fever and infection 
and to the importance of contacting their treating physician immediately if these 
conditions occur so that they can be promptly and appropriately managed.  Dosage 
modification guidelines for neutropenia and/or thrombocytopenia attributable to 
ipatasertib and/or paclitaxel are outlined in Table 5. 


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Table 5 
Neutropenia and Thrombocytopenia Management Guidelines 
Severity of Neutropenia 
and/or 
Thrombocytopenia 
Management Guideline 
Grade 2 
 
Ipatasertib may be continued at the original dose.  Paclitaxel 
may be held and can then be administered at the previous 
dose, when ANC has recovered to  1500/L and when the 
platelet count has recovered to  100,000/L.  If clinically 
appropriate based on the investigator’s medical judgment, 
paclitaxel may be administered up to 14 days (2 doses), even 
with Grade 2 neutropenia, without a dose reduction, as long as 
G-CSF is used to manage the neutropenia.  If the hematologic 
criteria do not recover to Grade 1 or better within the 14-day 
window of treating for ongoing Grade 2 neutropenia, the 
subsequent paclitaxel dose(s) must be held until recovery of 
hematological criteria to Grade 1 or better. 
Grade 3 
 
Ipatasertib and paclitaxel should both be held until recovery to 
Grade 1 and if clinically appropriate based on the investigator’s 
medical judgment to Grade 2 as long as G-CSF is used to 
manage the neutropenia.  Please see guidelines in this table 
regarding treatment for ongoing Grade 2 hematological 
toxicities.   
– 
First episode:  If recovery is to Grade 1, resume the 
original dose.  If recovery to Grade 1 is achieved with the 
use of G-CSF, then continued use of G-CSF is 
recommended once dosing of the study drug is resumed.  
If recovery is to Grade 2, follow the guidance above.  
– 
Recurrent episode: Ipatasertib and paclitaxel should be 
reduced by one dose level when treatment is restarted.  If 
patient has had more than three Grade 3 neutropenia 
episodes on study, despite the above dose reduction to 
65 mg/m2, the paclitaxel dose should be permanently 
discontinued, but the patient may continue to receive 
ipatasertib following discussion with the Medical Monitor.  
 
Following a treatment hold of up to 4 weeks, if recovery to 
Grade 2 or better neutropenia does not occur, the patient will 
permanently discontinue paclitaxel but may continue 
ipatasertib following discussion with the Medical Monitor. 


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Table 5 Neutropenia and Thrombocytopenia Management Guidelines (Cont.) 
Severity of Neutropenia 
and/or Thrombocytopenia 
Management Guideline 
Febrile neutropenia and 
Grade 4 neutropenia 
 
Paclitaxel and ipatasertib should be held until recovery to 
Grade 1, and if clinically appropriate based on the 
investigator’s medical judgment to Grade 2, as long as G-CSF 
is used to manage the neutropenia.  Please see guidelines in 
this table regarding treatment for ongoing Grade 2 
hematological toxicities.   
First episode:  Ipatasertib and paclitaxel should be 
reduced by one dose level when treatment is restarted.   
Recurrent episode:  Ipatasertib and paclitaxel should be 
discontinued.  
 
Following a treatment hold of up to 4 weeks, if recovery to 
Grade 2 or better neutropenia does not occur, the patient will 
permanently discontinue paclitaxel and ipatasertib treatment. 
ANC  absolute neutrophil count; G-CSF Granulocyte-colony stimulating factor. 
 
M.5.2.4.4 
Nausea and/or Vomiting 
Dose reductions for nausea and/or vomiting should occur only if the symptoms persist 
despite a minimum of two treatments with adequate (combination) anti-emetic 
treatment(s), including ondansetron and other anti-emetics (i.e., prochlorperazine or 
metoclopramide per institutional guidelines; see Table 6).  For persistent nausea and/or 
vomiting attributable to ipatasertib, dosage modification guidelines are outlined in 
Section M.5.2.1.1, Table 1, and Table 6).  
Table 6 
Nausea and Vomiting Management Guidelines 
Severity of Nausea 
and /or Vomiting 
Management Guideline 
Grade 1 
 
Provide supportive care as needed. 
Grade 2 
 
Provide maximum supportive care as needed per local guidelines, 
with a minimum of two anti-emetics, including ondansetron. 
Grade  3 
 
Interrupt ipatasertib and paclitaxel until nausea or vomiting 
resolves to Grade 2 or better. 
 
Provide maximum supportive care per local guidelines, with 
a minimum of two anti-emetics, including ondansetron. 
 
If Grade  3 nausea or vomiting recurs, ipatasertib should be 
reduced by one dose level (see Section M.5.2.1.1) when 
treatment is restarted.  Paclitaxel dose may be reduced by one 
level if recurrent Grade 3 nausea or vomiting occurs after dose 
reduction of ipatasertib has occurred (see Section M.5.2.1.2). 
 


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M.5.2.4.5 
Rash 
Ipatasertib should be permanently discontinued for rash associated with Stevens-
Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, or other suspected 
severe hypersensitivity or allergic reaction.  Dosage modification and symptom 
management guidelines for skin toxicity attributable to study treatment are shown in 
Table 7 (see Section M.5.2.1.1 and Table 1 for dose modifications). 


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Tumors 
 
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Table 7 
Rash Management Guidelines 
Severity of Rash 
Management Guideline 
General 
guidance 
 
Consider having a dermatologist evaluate persistent and/or severe rash 
or pruritus. 
 
Unless contraindicated, a daily oral antihistamine prophylaxis should be 
used for at least the first cycle. It is suggested that a non-sedating oral 
antihistamine (e.g. loratadine, cetirizine, fexofenadine) and longer-
acting formulated be used.  
 
Ipatasertib should be permanently discontinued for rash-associated 
with Stevens-Johnson syndrome, toxic epidermal necrolysis, or other 
suspected severe hypersensitivity or allergic reaction. Dosage 
modification and symptom management guidelines for skin toxicity, 
including erythema multiforme, attributable to ipatasetib are shown 
below. 
Grade 1 
 
Consider referring patient to a dermatologist 
 
Continue ipatasertib plus paclitaxel.  
 
Initiate supportive care (e.g. topical corticosteroids and continue 
antihistamine administration) 
 
Consider treatment with 10 mg/day oral prednisone or equivalent  
Grade 2 
 
Consider referring patient to a dermatologist for evaluation and perform 
a biopsy, if appropriate 
 
Continue topical corticosteroids and antihistamine administration. 
Consider treatment with 10 mg/day oral prednisone or equivalent; 
treatment with higher steroid dose may be necessary as clinically 
indicated 
 
Ipatasertib: interrupt ipatasertib treatment until resolution to Grade 1 or 
the toxicity is no longer clinically significant. If steroid dose is 10 
mg/day, ipatasertib may be resumed if clinically appropriate. 
 
Grade 3 
 
Withhold ipatasertib and paclitaxel 
 
Refer patient to dermatologist. Perform a biopsy if appropriate. 
 
If no prior steroid treatment has been initiated, consider treatment with 
10 mg/day oral prednisone or equivalent 
 
If prior oral steroid treatment or no improvement within 48 hours, 
consider increasing prednisone or equivalent dose to 1-2 mg/kg/day 
 
Ipatasertib: if event resolves to Grade 1 or the toxicity is no longer 
clinically significant, resume ipatasertib at the same dose or dose 
reduced by one level after discussion with Medical Monitor. Only restart 
ipatasertib if steroid dose is 10 mg/day. If not, permanently 
discontinue ipatasertib. 
Grade 4 
 
Permanently discontinue ipatasertib and paclitaxel and contact Medical 
Monitor 
 


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M.5.2.4.6 
Pneumonitis 
Pneumonitis is not known to be causally related to any of the study drugs; however, it 
has been observed with other drugs treating pathways similar to ipatasertib.  Every effort 
should be made to determine the etiology of dyspnea and changes in pulmonary 
function (see Table 8). 
Table 8 
Pneumonitis Management Guidelines 
Severity of 
Pneumonitis 
Management Guideline 
Grade 1 
 
Continue study drugs. 
 
Perform CT scan and PFTs.  Repeat CT scan every 8 weeks until a return to 
baseline. 
Grade 2 
 
If infectious etiology is ruled out or if improvement is not evident with broad 
spectrum antibiotics, prescribe corticosteroids as clinically indicated. 
 
Interrupt ipatasertib and paclitaxel treatment until improvement to Grade 1 or 
better.  Consider resuming ipatasertib and paclitaxel at same dose level or 
one dose level below (see Section M.5.2.1.1 and Section M.5.2.1.2) per 
investigator’s assessment. 
 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return to 
baseline. 
 
For recurrent Grade 2 pneumonitis, ipatasertib must be resumed at one dose 
level below the previous dose (see Section M.5.2.1.1).  Consider resuming 
paclitaxel at same dose or one dose below (see Section M.5.2.1.2) per 
investigator’s assessment. 
 
Discontinue ipatasertib if recovery to Grade 1 or better is not evident within 28 
days.  Paclitaxel dose should be resumed at one dose level below previous 
dose (see Section M.5.2.1.2) or discontinued per investigator’s assessment. 
Grade 3 
 
If infectious etiology is ruled out or if improvement is not evident with broad 
spectrum antibiotics, prescribe corticosteroids as clinically indicated. 
 
Interrupt ipatasertib and paclitaxel treatment until improvement to Grade 1 or 
better.  Resume ipatasertib and paclitaxel at one dose level below previous 
dose (see Section M.5.2.1.1 and Section M.5.2.1.2) per investigator’s 
assessment.  If recovery to Grade 1 or better is not evident within 28 days, 
discontinue study treatments.   
 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return to 
baseline.  Bronchoscopy is recommended. 
 
For recurrent non-infectious Grade 3 pneumonitis events, ipatasertib and 
paclitaxel should be permanently discontinued. 
Grade 4 
 
If infectious etiology is ruled out or if improvement is not evident with broad 
spectrum antibiotics, prescribe corticosteroids as clinically indicated. 
 
Permanently discontinue ipatasertib and paclitaxel. 
 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return to 
baseline.  Bronchoscopy is recommended. 
CT  computed tomography; PFT  pulmonary function test. 
 


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M.5.2.4.7 
Mucositis 
Mouthwash such as magic mouth wash (if inaccessible, warm salt or bicarbonate water) 
should be used as supportive care per institution guidelines.  Brushing teeth after meals, 
keeping lips moisturized with non-Vaseline products, and avoiding alcohol, spicy food, 
and smoking have all been shown to reduce pain and infection related to mucositis.  
Ranitidine or omeprazole may be helpful if patients have epigastric pain.  Dosage 
modification guidelines for mucositis attributable to study treatment are outlined 
in Table 9. 
Table 9 
Mucositis Management Guidelines 
Severity of 
Mucositis 
Management Guidelines 
Grade 1 or 2 
 
Manage with maximum supportive care.   
 
If Grade  2 mucositis recurs in subsequent 4 week cycles, despite 
maximal supportive care, the dose of ipatasertib should be reduced by one 
dose level (see Section M.5.2.1.1).  The dose of paclitaxel may be 
maintained or reduced by one level for subsequent cycles per 
investigator’s discretion (see Section M.5.2.1.2). 
Grade  3 
 
Hold ipatasertib and paclitaxel until recovery to Grade 2 or better.  If the 
mucositis resolves to Grade 2 or better during the current cycle, the dose 
of ipatasertib should be reduced by one dose level (see 
Section M.5.2.1.1).  The dose of paclitaxel may be maintained or reduced 
by one dose level for subsequent cycles per investigator’s discretion (see 
Section M.5.2.1.2). 
 
If recovery of mucositis to Grade 2 or better does not occur within 
a maximum of 4 weeks, the patient will permanently discontinue paclitaxel 
and ipatasertib. 
 
M.5.2.4.8 
Peripheral Neuropathy 
If Grade  3 peripheral neuropathy attributable to paclitaxel develops in patients, 
paclitaxel should be held until the neuropathy recovers to Grade 2 or better, or resolution 
such that the peripheral neuropathy is no longer clinically significant.  During this time, 
patients may continue ipatasertib at the discretion of the investigator.  If the peripheral 
neuropathy recovers to Grade 2 or better within 4 weeks or resolution such that the 
peripheral neuropathy is no longer clinically significant, dosing of paclitaxel may resume 
reduced by one dose level (see Section M.5.2.1.2).  If recovery of the peripheral 
neuropathy to Grade 2 or better does not occur within a maximum of 4 weeks, the 
patient will permanently discontinue paclitaxel but may continue the ipatasertib.  
M.5.2.4.9 
Hypersensitivity  
If a hypersensitivity reaction due to infusion of paclitaxel develops in patients, treatment 
for the hypersensitivity reaction, including the possibility of rechallenging with the 


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attributable chemotherapy agent, in presence of premedication for paclitaxel should be 
administered as per institutional guidelines or at the discretion of the investigator.  The 
patient may continue the other study treatment components not associated with the 
toxicity (i.e., ipatasertib). 
M.5.2.4.10 
Other Non-Hematologic Toxicities 
If other Grade  3 non hematologic toxicities not described above develop in patients, 
treatment with ipatasertib and/or paclitaxel may be held, depending on the attribution of 
the toxicity, at the discretion of the investigator.  During this time, treatment may 
continue with the other non-attributable treatment agent (i.e., either ipatasertib or 
paclitaxel).  Grade  3 non-hematologic toxicity should be monitored at least weekly. 
If the toxicity resolves to Grade 1 or better within 2 weeks, treatment may resume with 
the attributable agent. 
If the toxicity resolves to Grade 1 or better in 24 weeks, the dose of the attributable 
drug should be reduced by one level per the suggested guidelines in Section M.5.2.1. 
Depending on the nature and the severity of the adverse event, if recovery to Grade 1 or 
better takes  4 weeks, treatment may resume with the attributable agent with dose 
reduction, or the attributable agent may be permanently discontinued, at the discretion of 
the investigator and after discussion with the Medical Monitor.   
For Grade  3 toxicities associated primarily with laboratory abnormalities only 
(e.g., elevation of ALT, AST, lipase, or amylase, or decreases in phosphorus without 
clinical or other evidence of pancreatitis or other hepatic dysfunction), study treatment 
may continue without interruption and/or dose reduction at the discretion of the 
investigator per institutional practice. 
M.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients taking ipatasertib plus paclitaxel: 
 
Grade  3 fasting hyperglycemia  
 
Grade  3 hepatotoxicity 
 
Grade  3 ALT/AST elevations 
 
Grade  2 colitis/enterocolitis 


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 
Grade  3 diarrhea 
 
Grade  3 rash 
 
Grade  2 pneumonitis 
 
M.5.4 
Selected Adverse Events 
Additional data may be analyzed for the following selected adverse events: 
 
Diarrhea 
 
Asthenia (fatigue) 
 
Nausea 
 
Neutropenia (neutrophil count decreased, febrile neutropenia) 
 
Rash (e.g., maculopapular, erythema, urticarial, dermatitis, rash popular, skin 
exfoliation, toxic skin eruption) 
 
Erythema multiforme 
 
Vomiting 
 
Oral mucositis (stomatitis, mucosal inflammation, mouth inflammation, mouth 
ulceration) 
 
Hyperlipidemia (hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, blood 
cholesterol increased, blood triglycerides increased) 
 
Hepatotoxicity (ALT, AST increased) 
 
Hyperglycemia (blood glucose increased) 
 
Pneumonitis (interstitial lung diseases) 
 
 


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M.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
 (Window) 
28 to 1 a 
(3) 
(3) 
 28 days after 
last study dose 
Informed consent d 
x 
 
 
 
Documentation of patients with co-
mutations in PIK3CA activating 
mutations and PTEN loss/ 
loss-of-function or AKT activating 
mutation-positive tumors by local test e 
x 
 
 
 
Medical history and baseline conditions 
f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
Weight h 
x 
x 
 
 
ECOG Performance Status i 
x 
x 
 
x 
Pregnancy test j 
x 
x 
 
x 
Chemistry k 
x 
x 
 
x c 
Hematology/CBC with differential l 
x 
x 
 
x c 
Coagulation panel m 
x 
 
 
x 
Fasting lipid panel, amylase, lipase n 
x 
x 
 
x 
Fasting HbA1C n 
x 
x 
 
x 
Fasting blood glucose o 
x 
x 
Weekly during C1 
x 
ECG p 
x 
As clinically indicated 
x 
ECHO or MUGA q 
x 
As clinically indicated 
Paclitaxel administration r 
 
x 
See footnote r 
 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating Mutations and PTEN Loss/ Loss of Function or AKT 
Activating Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
521/Protocol ML42439, Version 6 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
 (Window) 
28 to 1 a 
(3) 
(3) 
 28 days after 
last study dose 
Ipatasertib dispensing 
 
x 
 
 
Ipatasertib compliance assessment s 
 
x 
 
x 
Prophylaxis anti-diarrheal t 
 
Every day of Cycle 1 and as clinically indicated 
Response assessments u, v 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) w 
 
Submit within 21 days of C1, D1 
 
 
Whole blood samples x 
x 
 
See footnote x 
 
Adverse events y 
x 
Collected on an ongoing basis 
x y 
Concomitant Medications z 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic Case Report 
Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left ventricular ejection fraction; MRImagnetic 
resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; RANOResponse Assessment in Neuro-Oncology; RECIST 
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SAEserious adverse event. 
Note: Cycle28 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if the 
chemistry panel is obtained within 7 days of Cycle 1, Day 1 it does not have to be repeated on Day 1, with the exception of glucose, which 
should be drawn within 3 days prior.  Scans to document measurable or evaluable disease (i.e., tumor measurement) should be 
performed   4 weeks prior to initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment follow-
up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  If 
the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the patient may take place by telephone 
to include an assessment of AEs.  Alternatively, the patient’s local physician may be contacted to collect AE data and any standard-of-care 
laboratory and CT data, if performed.   


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating Mutations and PTEN Loss/ Loss of Function or AKT 
Activating Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
522/Protocol ML42439, Version 6 
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive co-mutation in PI3K activating mutation AND AKT gene activating mutations or PTEN loss or loss of function status 
should occur prior to performing other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline. 
i All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
j Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who 
have a positive pregnancy test must not receive study drug.   
k Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1, with the 
exception of glucose, which should be drawn within 3 days prior.  Subsequent chemistry evaluations should be completed prior to dosing on Day 
1 of each indicated cycle (or up to 3 days before). 
l Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). If results are obtained within 3 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  
m Coagulation includes aPTT and INR. 
n Fasting lipid panel (cholesterol, triglyceride, HDL, and LDL), amylase, lipase, and HbA1c will be assessed after ≥8 hours of fasting.  If results are 
obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.   


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating Mutations and PTEN Loss/ Loss of Function or AKT 
Activating Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
523/Protocol ML42439, Version 6 
o Samples should be assessed weekly during the first Cycle and D1 at every other cycle. Mid-cycle fasting glucose levels may be obtained by 
glucometer (fingerstick).  If measurements are done at home, phone visits with site staff should be conducted to review results and assess any 
potential signs or symptoms of hyperglycemia.  
p It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
q LVEF assessment by ECHO or MUGA to be performed at screening and as clinically indicated.  Evaluation of LVEF must be performed by the 
same method (ECHO or MUGA) for each patient.  It is strongly recommended that the same laboratory and operator perform ECHO/MUGA scan 
for each individual patient. 
r Paclitaxel is administered 80 mg/m2 by IV infusion on days 1, 8, 15 of each 28-day cycle including considerations for premedication, supportive 
medications, infusion times, infusion frequency, and total cycle count. If the patient's weight changes by 10% from baseline during the study, 
the body surface area and drug doses of paclitaxel should be recalculated. Patients must be premedicated prior to paclitaxel with 
dexamethasone, diphenhydramine and an H2-receptor blocker (i.e. ranitidine or famotidine) or per institutional practice. H2-receptor antagonist, 
such as cimetidine, which are known to inhibit cytochrome P450, should be avoided. 
s Ipatasertib is administered 400 mg PO QD on Days 1-21 of each 28-day cycle. On Day 1 of each cycle, review compliance from previous cycle 
and dispense ipatasertib for next cycle.  
t Loperamide 2 mg BID or equivalent or per local institutional guideline for the first cycle.  If loose watery stools occur, take additional 2 mg after 
each loose watery stool and up to 16 mg per day. 
u All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), 
a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  A CT or MRI 
scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or refute the 
diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
v At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), withdrawal of consent, 
termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
w For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both archival and recent 
tissue is available, the recent tissue should be preferentially submitted.   
x Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.  
y After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating Mutations and PTEN Loss/ Loss of Function or AKT 
Activating Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
524/Protocol ML42439, Version 6 
All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation. All patients will be 
followed until treatment-related toxicities resolve or for at least 28 days post-study drug discontinuation.  After this period, all deaths, regardless 
of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event 
that is believed to be related to prior study drug treatment (see Section 5.6). 
z Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of study drug. 
 
 
 


Arm M:  Ipatasertib plus Paclitaxel in Patients with Co-mutations in PI3K (PIK3CA) Activating 
Mutations and PTEN Loss/ Loss of Function or AKT Activating Mutation-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
525/Protocol ML42439, Version 6 
M.7 
REFERENCES 
Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use 
of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-
induced febrile neutropenia in adult patients with lymphoproliferative disorders and 
solid tumours. Eur J Cancer 2011;47:832. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice 
guideline. J Clin Oncol 2006;24:3187205


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
526/Protocol ML42439, Version 6 
Appendix 23  
Arm N:  Atezolizumab plus Tiragolumab in Patients with 
TMB-H/MSI-H/dMMR-Positive Tumors 
 
24. 
ARM N:  ATEZOLIZUMAB PLUS TIRAGOLUMAB IN PATIENTS 
WITH TMB-H/MSI-H/DMMR-POSITIVE TUMORS 
TABLE OF CONTENTS 
N.4 
Materials and Methods .......................................................... 527 
N.4.1 
Patients .................................................................................. 527 
N.4.1.1 
Additional Inclusion Criteria ................................................... 527 
N.4.1.2 
Additional Exclusion Criteria .................................................. 528 
N.4.2 
Study Treatment .................................................................... 530 
N.4.2.1 
Formulation and Packaging ................................................... 530 
N.4.2.2 
Dosage, Administration, and Compliance for Atezolizumab .. 531 
N.4.2.3 
Dosage, Administration, and Compliance for Tiragolumab .... 532 
N.4.2.4 
Guidelines for Administration of Atezolizumab in 
combination with Tiragolumab ............................................... 533 
N.4.3 
Concomitant Therapy ............................................................ 534 
N.4.3.1 
Permitted Therapy ................................................................. 534 
N.4.3.2 
Cautionary Therapy ............................................................... 535 
N.4.3.3 
Prohibited Therapies .............................................................. 535 
N.4.4 
Arm-specific Assessments ..................................................... 536 
N.5 
Safety Plan ............................................................................ 537 
N.5.1 
Risks Associated with Study Treatment ................................. 537 
N.5.1.1 
Risks Associated with Atezolizumab ...................................... 537 
N.5.1.2 
Risks Associated with Tiragolumab ....................................... 537 
N.5.1.3 
Risks Associated with Combination Use of Tiragolumab 
and Atezolizumab .................................................................. 537 
N.5.2 
Guidelines for Management of Adverse Events ..................... 538 
N.5.2.1 
Dose Modifications and Treatment Interruptions ................... 538 
N.5.2.2 
Management of Specific Adverse Events Associated with 
Atezolizumab and Tiragolumab ............................................. 538 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
527/Protocol ML42439, Version 6 
N.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 573 
N.6 
Schedule of Activities ............................................................. 575 
 
N.4 
MATERIALS AND METHODS 
N.4.1 
Patients 
To be enrolled in Arm N:  atezolizumab plus tiragolumab treatment, patients must have 
met and continue to meet all general eligibility criteria (see Section 4.1), in addition to the 
arm-specific criteria below. 
N.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm N: 
atezolizumab plus tiragolumab treatment: 
 
Documentation of one of the following biomarkers, as determined by a Clinical 
Laboratory Improvement Amendments (CLIA) or equivalently certified assay (tissue 
or blood): 
– 
Tumor mutational burden-high (TMB-H), defined as  10 mutations per 
megabase as determined by a tissue-based NGS assay  
– 
Microsatellite instability high (MSI-H) 
– 
Deficient mismatch repair (dMMR) 
 
ANC  1200/L within 14 days prior to initiation of study treatment 
 
Lymphocyte count  500/L 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 02 
 
For patients not receiving therapeutic anticoagulation:  INR and aPTT  1.5  ULN 
 
For females of childbearing potential:  Negative serum pregnancy test  7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined contraception methods that 
result in a failure rate of  1% per year during the treatment period and for at least 
90 days after the final dose of tiragolumab or 5 months after the last dose of 
atezolizumab, whichever is later; and agreement to refrain from donating eggs 
during this same period.  Please see Appendix 2 for complete details on 
contraception requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom during the treatment period and for 90 days after the last dose of 
tiragolumab and agreement to refrain from donating sperm during this same period.  
See detailed contraception requirements in Appendix 2. 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
528/Protocol ML42439, Version 6 
N.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm N: atezolizumab plus tiragolumab treatment: 
 
Primary CNS tumors with any of the following characteristics: 
– 
History of intracranial hemorrhage or spinal cord hemorrhage  
– 
Neurosurgical resection or brain biopsy to the primary brain tumor within 
28 days of Cycle 1, Day 1 
 
Metastases to the midbrain, pons, medulla, or spinal cord 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium  upper limit of normal [ULN]) 
 
Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded 
with the following exception (note that this is more stringent than the core criteria 
outlined in Section 4.1.2):  
– 
Patients who are HCV Ab positive but HCV RNA negative due to prior 
treatment or natural resolution are eligible  
 
Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) 
Patients with a history of HCV infection but who are negative for HCV RNA by 
PCR will be considered non-infected with HCV. 
 
Positive epstein-barr virus (EBV) viral capsid antigen IgM test at screening  
An EBV polymerase chain reaction (PCR) test should be performed as clinically 
indicated to screen for acute infection or suspected chronic active infection.  
Patients with a positive EBV PCR test are excluded. 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
529/Protocol ML42439, Version 6 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
– 
Patients with a history of autoimmune-related hypothyroidism who are on a 
stable dose of thyroid replacement hormone are eligible for the study 
– 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study 
– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
o Rash must cover  10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high potency or oral corticosteroids 
within the previous 12 months 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 
 
Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study   
 
Prior allogeneic stem cell or solid organ transplantation 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during study treatment, for 90 days after the final dose 
of tiragolumab, and for 5 months after the final dose of atezolizumab. 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti-TIGIT, anti-LAG3, antiPD-1, and antiPD-L1 therapeutic antibodies 
Patients who have had prior anti-CTLA-4 treatment may be enrolled, provided 
the following requirements are met: 
– 
Last dose of anti-CTLA-4 at least 6 weeks prior to enrollment 
– 
No history of severe immune-related adverse events from the anti-CTLA-4 
(National Cancer Institute Common Terminology Criteria for Research 
Adverse Events [NCI CTCAE] Grade 3 and 4)  


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
530/Protocol ML42439, Version 6 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives 
(whichever is longer) prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
– 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study  
– 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study 
 
Any prior Grade   3 immune-mediated adverse event or any unresolved Grade  1 
immune-mediated adverse event while receiving any previous immunotherapy agent 
other than immune checkpoint blockade agents  
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab or tiragolumab formulation  
 
N.4.2 
Study Treatment 
Study treatment in this arm will consist of atezolizumab in combination with tiragolumab, 
as determined by the investigator.  
N.4.2.1 
Formulation and Packaging 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation and handling of atezolizumab, see the pharmacy 
manual and the Atezolizumab Investigator's Brochure. 
Tiragolumab will be supplied by the Sponsor as a sterile liquid in a single-use, 15-mL 
glass vial.  The vial contains approximately 10 mL (600 mg) of tiragolumab solution.  
For further information on the formulation and handling of tiragolumab, please see the 
pharmacy manual and the Tiragolumab Investigator’s Brochure. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
531/Protocol ML42439, Version 6 
N.4.2.2 
Dosage, Administration, and Compliance for Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical 
benefit with Medical Monitor consultation, see Section 3.1.2 for treatment beyond 
disease progression). Atezolizumab should be administered prior to tiragolumab on days 
when both are administered. 
If a delay in administration of either agent is necessary, reasonable effort should be 
made to keep the administration synced if clinically feasible (e.g., briefly delay 
administration of the other agent).   
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.   
Administration of atezolizumab will be performed in a monitored setting where there is 
access to trained personnel and adequate equipment/medicine to manage potentially 
serious reactions.  For anaphylaxis precautions, see Appendix 6.  Atezolizumab 
infusions will be administered per the instructions outlined in Table 1. 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 No premedication is permitted prior to 
the atezolizumab infusion. 
 Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) 
should be measured within 60 minutes 
prior to the infusion a 
 Atezolizumab should be infused over 
60 (15) minutes. 
 If clinically indicated, vital signs should 
be measured every 15 (5) minutes 
during the infusion and at 
30 (10) minutes after the infusion. a 
 Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact 
their study physician if they develop 
such symptoms. 
 If the patient experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
 Vital signs should be measured within 
60 minutes prior to the infusion. a 
 Atezolizumab should be infused over 30 (10) 
minutes if the previous infusion was tolerated 
without an infusion-related reaction, or 60 
(15) minutes if the patient experienced an 
infusion-related reaction with the previous 
infusion. 
 If clinically indicated, vital signs should be 
measured during the infusion and at 
30 (10) minutes after the infusion. a 
a 
Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment.  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
Guidelines for medical management of infusion-related reactions (IRRs) are provided 
inSection N.5.2.2.7. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
532/Protocol ML42439, Version 6 
No dose reductions for atezolizumab are allowed.  See Section N.5.2.1  and 
Section N.5.2.2 for management guidelines. 
N.4.2.3 
Dosage, Administration, and Compliance for Tiragolumab 
Following the administration of atezolizumab and an observation period (see Table 1), 
patients will receive 600 mg tiragolumab at a fixed dose administered by IV infusion on 
Day 1 of each 21-day cycle.  The tiragolumab dose is fixed and is not dependent on 
body weight.   
Tiragolumab infusions will be administered per the instructions outlined in Table 2. 
No dose modification for tiragolumab is allowed.  Guidelines for treatment interruption or 
discontinuation are provided in Section N.5.2.1.  Guidance on study drug administration 
in the context of management of specific adverse events is provided in Section N.5.2.2.  
For further details on dose preparation, storage, and administration instructions for 
tiragolumab, refer to the pharmacy manual and/or the Tiragolumab Investigator’s 
Brochure.  


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
533/Protocol ML42439, Version 6 
Table 2 
Administration of First and Subsequent Infusions of Tiragolumab  
 
Day 1, Cycle 1 Infusion 
Day 1 Infusion of Subsequent Cycles 
Infusion of 
tiragolumab 
 No premedication is permitted 
prior to the tiragolumab 
infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood 
pressure, and temperature) 
should be recorded within 60 
minutes prior to the infusion.a 
 Tiragolumab should be 
infused over 60 ( 15) 
minutes. 
 Vital signs should be 
recorded every 15 ( 5) 
minutes during the infusion.a 
 If the patient experienced an IRR during 
any previous infusion of tiragolumab, 
premedication with an antihistamine 
and/or antipyretic may be administered 
for subsequent doses, at the discretion 
of the investigator. 
 Vital signs should be recorded within 60 
minutes prior to the tiragolumab 
infusion.a 
 Tiragolumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 ( 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
 Vital signs should be recorded during 
the infusion if clinically indicated.a 
Observation 
period after 
infusion of 
tiragolumab 
 After the infusion of 
tiragolumab, the patient 
begins a 60-minute 
observation period. 
 Vital signs should be 
recorded at 30 ( 10) minutes 
after the infusion of 
tiragolumab. 
 Patients will be informed 
about the possibility of 
delayed post-infusion 
symptoms and will be 
instructed to contact their 
study physician if they 
develop such symptoms. 
 If the patient tolerated the previous 
infusion of tiragolumab well without 
infusion-associated adverse events, the 
observation period may be reduced to 30 
minutes. 
 If the patient experienced an infusion-
associated adverse event in the previous 
infusion, the observation period should be 
60 minutes. 
 If clinically indicated, vital signs should be 
recorded at 30 ( 10) minutes after the 
infusion of tiragolumab.a 
 Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and will be instructed to 
contact their study physician if they 
develop such symptoms. 
IRR  infusion-related reaction. 
a Vital signs should be obtained and reviewed before and after each study treatment 
administration but are not required to be reported on the eCRF during study treatment. Record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF 
 
N.4.2.4 
Guidelines for Administration of Atezolizumab in combination 
with Tiragolumab  
The following rules apply as long as neither atezolizumab nor tiragolumab has been 
permanently discontinued:  
 
Treatment cycles will begin with dosing of atezolizumab followed by tiragolumab on 
Day 1 of each 21-day cycle.  If either study drug is delayed for a related toxicity, it is 
recommended that the other study drug is also delayed because the safety profiles 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
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for atezolizumab and tiragolumab are similar; however, a cycle may begin with the 
administration of atezolizumab as a single agent if considered appropriate at the 
discretion of the investigator, after consultation with the Medical Monitor.   
 
In case of delays in dosing of tiragolumab for study drugrelated toxicity while 
atezolizumab is given as planned, it is recommended that the study drug being 
delayed will be administered at the next scheduled infusion (i.e., at the next 
scheduled 21-day cycle).   
 
Guidelines for treatment interruption or discontinuation are provided in Section N.5.2.1 
and Section N.5.2.2. 
N.4.3 
Concomitant Therapy 
N.4.3.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives  
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section N.4.3.3) 
 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for chronic obstructive pulmonary disease (COPD) or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab may be 
continued during palliative radiotherapy. 
 
Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency 
ablation) as outlined below: 
Patients experiencing a mixed response requiring local therapy for control of 
three or fewer lesions may still be eligible to continue study treatment in 
consultation with the Medical Monitor.  Patients who receive local therapy 
directed at a target lesion will no longer be evaluable for radiographic response 
but will remain evaluable for progression. 


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 
Premedication with antihistamines, antipyretics, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, at the 
discretion of the investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Section N.4.3.2, Section N.4.3.3) as clinically indicated, per 
local standard practice.  Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-
receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion associated-events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 6). 
N.4.3.2 
Cautionary Therapy  
N.4.3.2.1 
Corticosteroids, Immunosuppressive Medications, and TNF- 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with tiragolumab and 
atezolizumab.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF- 
inhibitors may be administered at the discretion of the investigator. 
Patients with primary CNS tumors can be receiving concurrent treatment with 
corticosteroids in consultation with the Medical Monitor.  Patients must be receiving a 
stable or decreasing dose for  5 days prior to the baseline magnetic resonance imaging 
(MRI) scan and at the time of drug initiation. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with tiragolumab and atezolizumab therapy (refer to Section N.5.2.1 and 
Section N.5.2.2 for details). 
N.4.3.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions (DDIs) are 
generally unknown.  However, herbal therapies not intended for the treatment of cancer 
may be used during the study at the discretion of the investigator. 
N.4.3.3 
Prohibited Therapies 
Use of the following concomitant therapies is prohibited as described below: 


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 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited within 
3 weeks prior to starting study treatment and during study treatment, until disease 
progression is documented and the patient has discontinued study treatment, with 
the exception of palliative radiotherapy and local therapy under certain 
circumstances (see Section N.4.3.1 for details). 
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, for 90 days after the 
final dose of tiragolumab, and for 5 months after the final dose of study treatment. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with study treatment. 
 
N.4.4 
Arm-specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients receiving atezolizumab and tiragolumab.  Refer to 
the schedule of activities (Section N.6) for arm-specific assessment timepoints. 
Local Laboratory Assessments  
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (T4) 
 
HIV serology 
 
HBV serology, consisting of the following:   
– 
HBsAg, HBsAb, and total HBcAb for all patients  
– 
HBV DNA for patients with negative HBsAg and HBsAb tests and a positive 
total HBcAb test 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test must 
also be performed to determine if the patient has an HCV infection. 
 
EBV serology, including the following 
– 
EBV viral capsid antigen (VCA) immunoglobulin M (IgM)  
– 
EBV VCA immunoglobulin G (IgG) or Epstein-Barr nuclear antigen (EBNA) IgG 
– 
If clinically indicated:  EBV PCR 
 
Urinalysis:  pH, specific gravity, glucose, protein, ketones, and blood; dipstick 
permitted 


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 
Coagulation test:  INR and aPTT  
 
Functional Assessments 
 
12-lead electrocardiogram 
 
N.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm N: atezolizumab plus 
tiragolumab.  
N.5.1 
Risks Associated with Study Treatment  
N.5.1.1 
Risks Associated with Atezolizumab  
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, 
myelitis, meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, 
and severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 
involve any organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer 
to Section N.5.2.2 of the protocol and Section 6 of  the Atezolizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for atezolizumab.   
N.5.1.2 
Risks Associated with Tiragolumab 
IRR and immune-mediated hepatitis are an identified risk of tiragolumab. Additional 
immune-mediated adverse events, lymphopenia and embryofetal toxicity are potential 
risks with tiragolumab.  Although clinical evaluation of tiragolumab is limited and not all 
risks are known, as an antagonist of T-cell immunoreceptor with Ig and ITIM domains 
(TIGIT), tiragolumab is anticipated to enhance T-cell and NK-cell proliferation, survival, 
and function.  Therefore, tiragolumab may increase the risk of autoimmune inflammation 
(also described as immune-mediated adverse events).   
Refer to Section N.5.2.2 of the protocol and Section 6 of the Tiragolumab Investigator's 
Brochure for a detailed description of anticipated safety risks for tiragolumab.   
N.5.1.3 
Risks Associated with Combination Use of Tiragolumab 
and Atezolizumab 
Based on results from nonclinical and/or clinical studies with each molecule as a single 
agent, clinical data with tiragolumab plus atezolizumab, there are known and potential 
overlapping toxicities in patients treated with tiragolumab plus atezolizumab.  Because 
the expected pharmacologic activity of these two molecules is to increase adaptive 
tumor cell (TC) immune responses, there is the possibility of heightened immune 
responses.   


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Refer to Section 6 of the Tiragolumab Investigator's Brochure for a list of identified 
risks associated with tiragolumab in combination with atezolizumab.  Based on the 
mechanism of action of tiragolumab and atezolizumab, additional immune-mediated 
adverse events are potential overlapping toxicities associated with combination use of 
tiragolumab plus atezolizumab. 
Based on clinical experience to date, it is anticipated that immune-mediated adverse 
events following treatment with tiragolumab and atezolizumab will be amenable to 
monitoring and manageable in the setting of this combination study.  The extensive 
experience with immune checkpoint inhibitors (CPIs) to date has been incorporated into 
the design and safety management plan in order to reduce the potential risks to 
participating patients.  Patients with a history of autoimmune disease will be excluded 
from this study (see Section N.4.1.2).  Patients previously treated with approved or 
experimental cancer immunotherapy (CIT) will also be excluded from participation in this 
study.  Owing to the risks of active viral infection and viral reactivation (see Tiragolumab 
Investigator’s Brochure), patients with active HIV, HBV, HCV, or EBV infections, known 
and/or suspected chronic active EBV infection, or tuberculosis and/or patients with 
recent severe infections will be excluded from this study (see Sections 4.1.2 
and N.4.1.2). 
N.5.2 
Guidelines for Management of Adverse Events 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   
N.5.2.1 
Dose Modifications and Treatment Interruptions 
No dose reductions for atezolizumab or tiragolumab are allowed.  Interruptions to 
atezolizumab or tiragolumab treatment are described below (Section N.5.2.2). 
N.5.2.2 
Management of Specific Adverse Events Associated with 
Atezolizumab and Tiragolumab 
Toxicities associated or possibly associated with atezolizumab and/or tiragolumab 
treatment should be managed according to standard medical practice.  Additional tests, 
such as autoimmune serology or biopsies, should be used to evaluate for a possible 
immunogenic etiology when clinically indicated. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
and/or tiragolumab may not have an immediate therapeutic effect, and in severe cases, 
immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents.  


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The following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections.  
 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment.  There should be a high level of suspicion that new symptoms are 
treatment related. 
 
In general, atezolizumab and tiragolumab therapy should be continued with close 
monitoring for Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider holding atezolizumab and tiragolumab for most Grade 2 toxicities and 
resume when symptoms and/or laboratory values resolve to Grade 1 or better.  
Corticosteroids (initial dose of 0.51 mg/kg/day of prednisone or equivalent) may 
be administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold atezolizumab and tiragolumab for Grade 3 toxicities and initiate treatment 
with high-dose corticosteroids (12 mg/kg/day prednisone or equivalent).  
Corticosteroids should be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent, before atezolizumab can be resumed.  If symptoms do not improve 
within 48 to 72 hours of high-dose corticosteroid use, other immunosuppressants 
may be offered for some toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
and tiragolumab treatment, with the exception of endocrinopathies that are 
controlled by hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab and/or tiragolumab.  
Resumption of atezolizumab and/or tiragolumab may be considered in patients who are 
deriving benefit and has fully recovered from the immune-mediated event.  The decision 
to re-challenge patients with atezolizumab and/or tiragolumab should be based on 
investigator's assessment of benefitrisk and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
DOSE MODIFICATIONS  
There will be no dose modifications for atezolizumab and tiragolumab in this study. 
TREATMENT INTERRUPTION 
Atezolizumab and tiragolumab treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  If corticosteroids are 
initiated for treatment of the toxicity, they must be tapered over 1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab and tiragolumab can be 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
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resumed.  If atezolizumab and tiragolumab is withheld for  12 weeks after event onset, 
the patient will be discontinued from atezolizumab and tiragolumab.  However, 
atezolizumab and tiragolumab may be withheld for  12 weeks to allow for patients to 
taper off corticosteroids prior to resuming treatment.  Atezolizumab and tiragolumab 
can be resumed after being withheld for  12 weeks if the patient is likely to derive 
clinical benefit.  The decision to re-challenge patients with atezolizumab and 
tiragolumab should be based on the investigator’s benefitrisk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.  
Atezolizumab and tiragolumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption 
must be based on the investigator's benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
N.5.2.2.1 
Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in Table 3. 


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Table 3 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue tiragolumab and atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab and 
tiragolumab. 
Pulmonary 
event, Grade 2 
 Withhold tiragolumab and atezolizumab for up to 12 weeks after 
event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone. 
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding  
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact the Medical Monitor. c, d 
 For recurrent events or events with no improvement after 48–
72 hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue tiragolumab and atezolizumab and contact 
Medical Monitor. c, d 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
BAL  bronchoscopic alveolar lavage. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator's benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab and tiragolumab should based on the investigator’s 
benefitrisk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.   
d In case of pneumonitis, tiragolumab and atezolizumab should not be resumed after permanent 
discontinuation. 
 








Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
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Table 5 
Management Guidelines for Gastrointestinal Events  
(Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue tiragolumab and atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start 
empiric IV steroids while waiting for definitive diagnosis. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist  5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone.  If 
the event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab 
and atezolizumab and contact the Medical Monitor. c 
GI  gastrointestinal. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period 
of time must be based on the investigator’s benefitrisk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision 
to re-challenge patients with atezolizumab and tiragolumab should be based on the 
investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 


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Table 5 
Management Guidelines for Gastrointestinal Events  
(Diarrhea or Colitis) (cont.)  
Event 
Management 
Diarrhea or 
colitis, Grade 3 
 Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. If event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.  
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab 
and atezolizumab and contact the Medical Monitor. c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue tiragolumab and atezolizumab and contact the 
Medical Monitor. c 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
GI  gastrointestinal. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period 
of time must be based on the investigator’s benefitrisk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision 
to re-challenge patients with atezolizumab and tiragolumab should be based on the 
investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 
 
N.5.2.2.4 
Endocrine Events 
Management guidelines for endocrine events are provided in Table 6. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 


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thyroid, pituitary, or adrenal endocrinopathies.  Patients should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
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MyTACTIC Study—Genentech, Inc. 
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Table 6 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1  
hypothyroidism 
 Continue tiragolumab and atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 Consider withholding tiragolumab and atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider patient referral to endocrinologist. 
 Resume tiragolumab and atezolizumab when symptoms are 
controlled and thyroid function is improving. 
Grade 3 and 4 
hypothyroidism 
 Withhold tiragolumab and atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
 Resume tiragolumab and atezolizumab when symptoms are 
controlled and thyroid function is improving. 
 Permanently discontinue tiragolumab and atezolizumab 
and contact the Medical Monitor for life-threatening 
immune-mediated hypothyroidism. c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.  


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
549/Protocol ML42439, Version 6 
Table 6 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue tiragolumab and atezolizumab. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism 
 Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
 Consider withholding tiragolumab and atezolizumab. 
 Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume tiragolumab and atezolizumab when symptoms are 
controlled and thyroid function is improving. 
Grade 3 and 4 
hyperthyroidism 
 Withhold tiragolumab and atezolizumab. 
 Initiate treatment with anti-thyroid drugs such as 
methimazole or carbimazole as needed. 
 Refer to endocrinologist. 
 Resume tiragolumab and atezolizumab when symptoms are 
controlled and thyroid function is improving. 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor for life-threatening immune-
mediated hyperthyroidism. c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
550/Protocol ML42439, Version 6 
Table 6 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grades 24  
 Withhold tiragolumab and atezolizumab for up to 12 weeks 
after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding tiragolumab 
and atezolizumab, permanently discontinue tiragolumab and 
atezolizumab and contact the Medical Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
 Continue tiragolumab and atezolizumab. 
 Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 
diabetes, treat as per institutional guidelines. 
 Monitor for glucose control. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
551/Protocol ML42439, Version 6 
Table 6 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hyperglycemia, 
Grade 3 or 4 
 Withhold tiragolumab and atezolizumab. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
 Monitor for glucose control. 
 Resume tiragolumab and atezolizumab when symptoms 
resolve and glucose levels are stable. 
Hypophysitis 
(panhypopituitarism), 
Grade 2 or 3  
 Withhold tiragolumab and atezolizumab for up to 12 weeks 
after event onset. a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume tiragolumab 
and atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding tiragolumab and atezolizumab permanently 
discontinue tiragolumab and atezolizumab and contact the 
Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
552/Protocol ML42439, Version 6 
Table 6 
Management Guidelines for Endocrine Events (cont.)  
Event 
Management 
Hypophysitis 
(panhypopituitarism), 
Grade 4  
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 
N.5.2.2.5 
Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 7. 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
553/Protocol ML42439, Version 6 
Table 7 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue tiragolumab and atezolizumab. 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab 
and atezolizumab and contact the Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue tiragolumab and atezolizumab and contact 
Medical Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.   
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be 
resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based on 
the investigator’s benefitrisk assessment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 
N.5.2.2.6 
MANAGEMENT OF IMMUNE-MEDIATED CARDIAC 
EVENTS 
Management guidelines for cardiac events are provided in Table 8. 
Immune-Mediated Myocarditis 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-
type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 


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palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis or associated with pericarditis (see section on 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 8. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, 
and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 8.  Withhold treatment with tiragolumab and  
atezolizumab for Grade 1 pericarditis and conduct a detailed cardiac evaluation to 
determine the etiology and manage accordingly.


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
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Table 8 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2 
4 
 
Immune-mediated 
pericardial disorders, 
Grades 24 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD or 
pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to  
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
 
N.5.2.2.7 
Infusion-Related Reactions  
No premedication is indicated for the administration of the Day 1, Cycle 1 infusion of 
tiragolumab or atezolizumab.  However, patients who experience an infusion-related 
reaction (IRR) with the Day 1, Cycle 1 infusion of tiragolumab or atezolizumab may 
receive premedication with antihistamines, antipyretic medication, or analgesics (e.g., 
acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with tiragolumab and atezolizumab.  These reactions, which are thought 
to be due to release of cytokines and/or other chemical mediators, occur within 24 hours 
of tiragolumab or atezolizumab administration and are generally mild to moderate in 
severity.  Guidelines for medical management of IRRs during Cycle 1 are provided in 
Table 9.  For subsequent cycles, IRRs should be managed according to institutional 
guidelines. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
556/Protocol ML42439, Version 6 
Table 9 
Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grade 1  
 Reduce infusion rate to half the rate being given at the time of event 
onset. 
 After the event has resolved, the investigator should wait for 30 minutes 
while delivering the infusion at the reduced rate. 
 If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to the 
original rate. 
IRR, Grade 2 
 Interrupt infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
 After symptoms have resolved to baseline, resume infusion at half the 
rate being given at the time of event onset. 
 For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretic medications, and/or analgesics and 
monitor closely for IRRs. 
IRR, Grade 3 or 4  Stop infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
 Permanently discontinue tiragolumab or atezolizumab and contact the 
Medical Monitor. a 
IRR  infusion-related reaction. 
a Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  The decision to re-
challenge patients with tiragolumab and atezolizumab should be based on the investigator’s 
benefit-risk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
 
N.5.2.2.8 
Cytokine-Release Syndrome  
No premedication is indicated for the administration of Cycle 1 of tiragolumab or 
atezolizumab.  However, patients who experience cytokine-release syndrome (CRS) with 
tiragolumab or atezolizumab may receive premedication with antihistamines, 
antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 


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MyTACTIC Study—Genentech, Inc. 
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been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
Guidelines for medical management of CRS are provided in Table 10.
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and Martin 
2020).  If a patient develops suspected CRS during the study, a differential diagnosis 
should include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or 
radiologic evaluations per investigator’s judgment. If a diagnosis of SARS -CoV-2 
infection is confirmed, the disease should be managed as per local or institutional 
guidelines.


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
558/Protocol ML42439, Version 6 
Table 10 Management Guidelines for Cytokine-Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or without 
constitutional 
symptoms 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of IV 
fluids for hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in patients 
with significant symptoms and/or comorbidities, consider managing 
as per Grade 2. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics, and monitor closely for CRS. 
Grade 2 a 
Fever b with at least one 
of the following: 
 Hypotension not 
requiring 
vasopressors 
 Hypoxia requiring 
low-flow oxygen d by 
nasal cannula or 
blow-by 
 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup 
and assess for signs and symptoms of HLH or MAS as described in 
this appendix. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 Consider hospitalization until complete resolution of symptoms.  If 
no improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue tiragolumab and atezolizumab, and contact 
the Medical Monitor. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of tiragolumab and atezolizumab may be administered.  
For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics and monitor closely for CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact the Medical Monitor. 


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Tumors 
 
MyTACTIC Study—Genentech, Inc. 
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Table 10 Management Guidelines for Cytokine-Release Syndrome (cont.) 
Event 
Management 
Grade 3 a 
Fever b with at least 
one of the following: 
 Hypotension 
requiring a 
vasopressor (with or 
without vasopressin) 
 Hypoxia requiring 
high-flow oxygen d by 
nasal cannula, face 
mask, non-rebreather 
mask, or Venturi 
mask 
 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. e 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
 Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids as 
clinically indicated, and manage constitutional symptoms and 
organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in this appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  
 Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that 
is, admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of 
the investigator and in consultation with the Medical Monitor. 
Grade 4 a 
Fever b with at least 
one of the following: 
 Hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. e 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed.  Monitor other organ function closely.  Manage 
constitutional symptoms and organ toxicities as per 
institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS as 
described in this appendix. 
 Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.  For patients who are refractory 
to anti-cytokine therapy, experimental treatments f may be 
considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
 Hospitalize patient until complete resolution of symptoms. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
560/Protocol ML42439, Version 6 
Table 10 Management Guidelines for Cytokine-Release Syndrome (cont.) 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP   bi-level 
positive airway pressure; CAR  chimeric antigen receptor; CPAP   continuous positive 
airway pressure; CRS  cytokine-release syndrome; CTCAE  Common Terminology Criteria 
for Adverse Events; eCRF  electronic Case Report Form; HLH   hemophagocytic 
lymphohistiocytosis; ICU   intensive care unit; MAS  macrophage activation syndrome; 
NCCN  National Cancer Comprehensive Network; NCI   National Cancer Institute. 
The management guidelines have been adapted from the NCCN guidelines for the 
management of CAR T-cellrelated toxicities (Version 2.2019). 
a Grading system for management guidelines is based on the ASTCT CRS consensus 
grading scale.  NCI CTCAE v5.0 and the ASTCT CRS consensus grading scale should be 
used when reporting severity of CRS on the Adverse Event eCRF.  NCI CTCAE v5.0 
should be used when reporting severity of organ toxicities associated with CRS on the 
dedicated Cytokine-Release Syndrome eCRF.  Organ toxicities associated with CRS should 
not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause.  In patients 
who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, 
fever is no longer required when subsequently determining event severity (grade).  In this 
case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at  6 L/min. 
e Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision 
to re-challenge patients with tiragolumab and atezolizumab should be based on 
investigator's assessment of benefitrisk and documented by the investigator.  The 
Medical Monitor is available to advise as needed.  For subsequent infusions, administer 
oral premedication with antihistamines, antipyretic medications, and/or analgesics, and 
monitor closely for CRS.  Premedication with corticosteroids and extending the infusion 
time may also be considered after assessing the benefitrisk ratio. 
f Refer to Riegler et al. (2019). 
 
N.5.2.2.9 
Pancreatic Events 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 11. 
 
 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
561/Protocol ML42439, Version 6 
Table 11 Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue tiragolumab and atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold tiragolumab and atezolizumab for up to 12 weeks 
after event onset. a 
 Refer patient to gastrointestinal specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume tiragolumab 
and atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding tiragolumab and atezolizumab, permanently 
discontinue tiragolumab and atezolizumab and contact the 
Medical Monitor. c 
 For recurrent events, permanently discontinue tiragolumab 
and atezolizumab and contact the Medical Monitor. c 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab and tiragolumab should be based on the 
investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
562/Protocol ML42439, Version 6 
Table 11 Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 Withhold tiragolumab and atezolizumab for up to 12 weeks 
after event onset. a 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better, resume tiragolumab 
and atezolizumab. b 
 If event does not resolve to Grade 1 or better while 
withholding tiragolumab and atezolizumab, permanently 
discontinue tiragolumab and atezolizumab and contact the 
Medical Monitor. c 
 For recurrent events, permanently discontinue tiragolumab 
and atezolizumab and contact the Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. c 
 Refer patient to gastrointestinal specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
based the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab and tiragolumab should be based on the 
investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive 
Tumors 
 
MyTACTIC Study—Genentech, Inc. 
563/Protocol ML42439, Version 6 
N.5.2.2.10 
Dermatologic Events 
The majority of cases of rash reported with the use of atezolizumab and/or tiragolumab 
were mild in severity and self-limiting, with or without pruritus.  Although uncommon, 
cases of severe cutaneous adverse reactions such as Stevens-Johnson syndrome and 
toxic epidermal necrolysis have been reported with atezolizumab.  A dermatologist 
should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
considered unless contraindicated.  Management guidelines for dermatologic events are 
provided in Table 12. 
Table 12 Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue tiragolumab and atezolizumab. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue tiragolumab and atezolizumab. 
 Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
 If unresponsive to topical corticosteroids, consider oral 
prednisone 0.5 mg/kg/day. 
Dermatologic 
event, Grade 3  
 Withhold tiragolumab and atezolizumab for up to 12 weeks after 
event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact the Medical Monitor. c 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can 
be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who 
are deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be 
based on the investigator’s benefitrisk assessment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
 


 
MyTACTIC Study—Genentech, Inc. 
564/Protocol ML42439, Version 5 
Table 12 
Management Guidelines for Dermatologic Events (cont.) 
Event 
Management 
Dermatologic 
event, Grade 4 
 Permanently discontinue tiragolumab and atezolizumab and 
contact Medical Monitor. c 
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis, (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
 Withhold tiragolumab and atezolizumab for suspected 
Stevens-Johnson syndrome or toxic epidermal necrolysis. 
 Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist, or urologist as relevant) for 
evaluation and, if indicated, biopsy. 
 Follow the applicable treatment and management guidelines 
above. 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue tiragolumab and 
atezolizumab. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can 
be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who 
are deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be 
based on the investigator’s benefitrisk assessment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
 
N.5.2.2.11 
Neurologic Disorders 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 13 with specific guidelines for myelitis provided in Table 14. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
565/Protocol ML42439, Version 6 
Table 13 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy,  
Grade 1 
 Continue tiragolumab and atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, 
Grade 2  
 Withhold tiragolumab and atezolizumab for up to 12 weeks after 
event onset. a 
 Investigate etiology and refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume tiragolumab 
and atezolizumab. b 
– 
If event does not resolve to Grade 1 or better while 
withholding tiragolumab and atezolizumab, permanently 
discontinue tiragolumab and atezolizumab and contact the 
Medical Monitor. c 
 For facial paresis: 
– 
If event resolves fully, resume tiragolumab and 
atezolizumab b 
– 
If event does not resolve fully while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact the Medical 
Monitor. c 
Immune-mediated 
neuropathy, 
including facial 
paresis,  
Grade 3 or 4 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. c  
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of corticosteroids equivalent to  
12 mg/kg/day oral or IV prednisone. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can 
be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
566/Protocol ML42439, Version 6 
 
Table 14 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated 
myelitis, Grade 1 
 
Continue tiragolumab and atezolizumab unless symptoms 
worsen or do not improve. 
 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated 
myelitis, Grade 2 
 
Permanently discontinue tiragolumab and atezolizumab 
and contact the Medical Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated 
myelitis, Grade 3 or 4 
 
Permanently discontinue tiragolumab and atezolizumab 
and contact the Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
N.5.2.2.12 
Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis is a potential risk with tiragolumab.   
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 15. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
567/Protocol ML42439, Version 6 
Table 15 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor.  
 Refer patient to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 
 
N.5.2.2.13 
Renal Events 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as non-
steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 16. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
568/Protocol ML42439, Version 6 
Table 16 Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
 Continue tiragolumab and atezolizumab. 
 Monitor kidney function, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline 
values.  
Renal event, 
Grade 2 
 Withhold tiragolumab and atezolizumab for up to 12 weeks after 
event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact the Medical Monitor. 
c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor.  
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can 
be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who 
are deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be 
based on the investigator’s benefitrisk assessment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
569/Protocol ML42439, Version 6 
N.5.2.2.14 
Immune-Mediated Myositis 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy. 
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 17. 
Table 17 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, Grade 1 
 Continue tiragolumab and atezolizumab. 
 Refer patient to rheumatologist or neurologist.  
 Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, Grade 2 
 Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset a and contact the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 If corticosteroids are initiated and event does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab 
and atezolizumab and contact the Medical Monitor. c 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks 
after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The decision 
to re-challenge patients with atezolizumab and tiragolumab should be based on the 
investigator’s benefitrisk assessment and documented by the investigator.  The Medical 
Monitor is available to advise as needed. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
570/Protocol ML42439, Version 6 
Table 17 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-
mediated 
myositis, Grade 3 
 Withhold tiragolumab and atezolizumab for up to 12 weeks after 
event onset a and contact the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, 
or weakness that severely limits mobility); convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume tiragolumab and 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact the Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event.  Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can 
be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the.  The Medical 
Monitor is available to advise as needed. 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
571/Protocol ML42439, Version 6 
Table 17 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-
mediated 
myositis, Grade 4 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. c 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, 
or weakness that severely limits mobility); convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment by the 
investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can 
be resumed. 
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-mediated event.  The 
decision to re-challenge patients with atezolizumab and tiragolumab should be based 
on the investigator’s benefitrisk assessment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
 
N.5.2.2.15 
Hemophagocytic lymphohistiocytosis and 
Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).   
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
572/Protocol ML42439, Version 6 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [ 10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100  109/L ( 100,000/L) 
– 
ANC  1.0  109/L ( 1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (  500 ng/mL) 
 
Soluble IL-2 receptor (soluble CD25) elevated  2 standard deviations above age-
adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
– 
Platelet count  181  109/L ( 181,000/L) 
– 
AST  48 U/L 
– 
Triglycerides  1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L ( 360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 18. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
573/Protocol ML42439, Version 6 
Table 18 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue tiragolumab and atezolizumab and contact 
the Medical Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
N.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the investigator to the Sponsor immediately for all study treatments, and 
Section 5.4.2 provides reporting instructions.  In addition to the adverse events of special 
interest specified in Section 5.2.3, the following adverse events are required to be 
reported by the investigator immediately for patients receiving atezolizumab: 
 
Systemic lupus erythematosus 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Grade  2 cardiac disorders  
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
 
Hepatitis, including AST or ALT 10  ULN 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
  
MyTACTIC Study—Genentech, Inc. 
574/Protocol ML42439, Version 6 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Neurologic disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Myelitis 
 
Facial paresis  


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
575/Protocol ML42439, Version 6 
N.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 a 
(3) 
(3) 
28 days after last 
study dose 
Informed consent d 
x 
 
 
 
Documentation of TMB-H/ MSI-H/dMMR 
status by local test e 
x 
 
 
 
Medical history and baseline conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
ECOG Performance Status h 
x 
x 
 
x 
Pregnancy test i 
x 
x 
 
x 
Chemistry j 
x 
x 
 
x c 
Hematology/CBC with differential k 
x 
x 
 
x c 
Coagulation panel l 
x 
 
 
x 
HIV, HCV, HBV, EBV serology m 
x 
 
 
 
Urinalysis n 
x 
x 
 
x 
ECG o 
x 
As clinically indicated 
x 
Thyroid function test (TSH, free T3 [or 
total T3], free T4) p 
x 
C1, D1 and every 4 cycles thereafter 
 
x 
Atezolizumab administration q 
 
x 
 
 
Tiragolumab r 
 
x 
 
 
Response Assessment s, t 
x 
Every 8 (1) weeks for 3 evaluations, 
 then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample for 
central testing (if applicable) u 
 
Submit within 21 days of Cycle 1 Day 1 
 
 
Whole blood samples v 
x 
 
See footnote v 
 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
576/Protocol ML42439, Version 6 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of Treatment 
Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 a 
(3) 
(3) 
28 days after last 
study dose 
Adverse events w 
 
Collected on an ongoing basis 
x w 
Concomitant medications x 
x 
Collected on an ongoing basis 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating tumor 
DNA; Dday; dMMRdeficient mismatch repair; EBNAEpstein-Barr nuclear antigen; EBVEpstein-Barr virus; ECHO  echocardiogram; 
ECOG PSEastern Cooperative Oncology Group Performance Status; eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; 
HBVhepatitis B virus; HCV=hepatitis C virus; ICFinformed consent form; Igimmunoglobulin; IV  intravenous; LVEF  left ventricular ejection 
fraction; MSI-Hmicrosatellite-high; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PCR=polymerase chain 
reactionPDprogressive disease;; RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, 
Version 1.1; SAEserious adverse event; TMB-Htumor mutational burden-high; TSH  thyroid-stimulating hormone; VCAviral capsid antigen. 
Note: Cycle21 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  However, if the 
hematology/CBC, chemistry panel, and thyroid function test are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Day 
1.  Scans to document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to initiation of 
treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-treatment follow-
up assessments. All patients will be followed until treatment-related toxicities resolve or for at least 28 days post- chemotherapy discontinuation 
or 90 days post-atezolizumab discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, 
follow-up with the patient may take place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be 
contacted to collect AE data and any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be repeated 
unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of TMB-H/MSI-H/dMMR status should occur prior to performing other trial-related eligibility assessments. TMB-H should be 
determined using a tissue-based NGS assay. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
577/Protocol ML42439, Version 6 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used 
by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, symptom-directed physical 
examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
h All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
 i Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the schedule of 
assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must be confirmed by a 
serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration of study drug.  Patients who 
have a positive pregnancy test must not receive study drug.   
j Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, 
total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to administration of the first 
dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on Cycle 1 Day 1.  Subsequent 
chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before). 
k Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  
l Coagulation includes aPTT and INR. 
m All patients will be tested for HIV, HBV, HCV at screening.  Patients with HBV or HIV will be exluded based on the criteria detailed in 
Section 4.1.2. Patients with HCV will be excluded based on the criteria in Section N.4.1.2.  EBV serology samples will be collected at screening 
for the following: EBV VCA IgM, EBV VCA IgG or EBNA IgG. An EBV PCR test should be performed as clinically indicated to screen for active 
infection or suspected chronic active infection.  Patients with a positive EBV viral capsid antigen immunoglobulin M (IgM) test or positive EBV 
PCR test at screening are excluded. Additional EBV serology tests will be performed for patients who subsequently experience an acute 
inflammatory event, such as systemic inflammatory response syndrome, while receiving study treatment. 
n Urinalysis consists of specific gravity, pH, glucose, protein, ketones, and blood. 
o An ECG is required at screening, at the treatment discontinuation/completion visit, and when clinically indicated.  ECGs for each patient should 
be obtained from the same machine wherever possible.  Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes. 


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
578/Protocol ML42439, Version 6 
p  TSH, free T3 (or total T3 at sites where free T3 is not performed), and free T4 will be collected at screening, on Day 1 of Cycles 1 and 4, every 
fourth cycle thereafter (e.g., Cycles 1, 5, 9, and 13, etc.), and at the treatment discontinuation/completion visit.  
q Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Days 1 of each 21-day cycle. The initial infusion of atezolizumab 
will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion was tolerated 
without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse event with the 
previous infusion. 
r Tiragolumab will be administered by IV infusion at a fixed dose of 600 mg on Days 1 of each 21-day cycle. The initial dose will be delivered over 
60 ( 15) minutes.  If the first infusion is well tolerated, all subsequent infusions may be delivered over 30 ( 10) minutes.  Dosing of both study 
drugs will occur only if the clinical assessment and local laboratory test results are acceptable.  If a tumor assessment was performed, results 
must be reviewed by the investigator before dosing of study treatment. 
s All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not 
have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), 
a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head should be performed.  A CT or MRI 
scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the brain is required to confirm or refute the 
diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
t At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic procedures 
every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment discontinuation, until 
investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors) or loss of clinical benefit (with 
Medical Monitor consultation; see Section 3.1.2), withdrawal of consent, termination of an individual study arm by the Sponsor, or death, 
whichever occurs first.   
u For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue samples 
(archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing. If both archival and recent 
tissue are available, the recent tissue should be preferentially submitted.   
v Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at tumor 
progression (within 7 days after progression) for analyses including ctDNA.   
w After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of 
chemotherapy or 90 days after the final dose of atezolizumab, whichever is longer.  All patients will be followed until treatment-related toxicities 
resolve or for at least 28 days post-chemotherapy discontinuation or 90 days post-atezolizumab discontinuation, whichever is longer. After this 
period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6). 
x Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the last dose of study treatment.


Arm N:  Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
579/Protocol ML42439, Version 6 
N.7 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
580/Protocol ML42439, Version 6 
Appendix 24  
Arm O: Pralsetinib in Patients with RET Fusion-Positive 
Tumors 
 
25. 
ARM O: PRALSETINIB IN PATIENTS WITH RET FUSION-
POSITIVE TUMORS 
TABLE OF CONTENTS 
O.4 
Materials and Methods .......................................................... 581 
O.4.1 
PATIENTS ............................................................................. 581 
O.4.1.1 
Additional Inclusion Criteria ................................................... 581 
O.4.1.2 
Additional Exclusion Criteria .................................................. 581 
O.4.2 
STUDY TREATMENT ............................................................ 582 
O.4.2.1 
Formulation and Packaging ................................................... 582 
O.4.2.2 
Dosage, Administration, and Compliance .............................. 582 
O.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 583 
O.4.3.1 
Permitted Therapy ................................................................. 583 
O.4.3.2 
Concomitant Therapy to Be Used With Caution .................... 584 
O.4.3.3 
Prohibited Therapy ................................................................ 584 
O.4.3.4 
Prohibited Food ..................................................................... 585 
O.4.4 
Pralsetinib-Specific Assessments .......................................... 585 
O.5 
Safety Plan ............................................................................ 585 
O.5.1 
Risks Associated with Pralsetinib .......................................... 585 
O.5.2 
Management of Patients Who Experience Adverse Events 
with Pralsetinib ....................................................................... 585 
O.5.2.1 
Dose Modifications and Interruptions ..................................... 586 
O.5.2.2 
Guidelines for Management of Specific Adverse Events ....... 588 
O.5.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 589 
O.5.4 
Selected Adverse Events ....................................................... 589 
O.6 
Schedule of Activities ............................................................. 590 
O.7 
References ............................................................................ 594 


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
581/Protocol ML42439, Version 6 
O.4 
MATERIALS AND METHODS 
O.4.1 
PATIENTS 
To be enrolled in Arm O:  pralsetinib treatment, patients must have met and continue to 
meet all general eligibility criteria (see Section 4.1), in addition to the arm-specific criteria 
below.   
O.4.1.1 
Additional Inclusion Criteria 
Patients must meet the following additional inclusion criteria for entry into Arm O: 
pralsetinib treatment: 
 
RET fusion positivity, except patients with non-small cell lung cancer (NSCLC) or 
thyroid cancers, as determined by a Clinical Laboratory Improvement Amendments 
(CLIA) or equivalently certified next-generation sequencing (NGS) assay (tissue or 
blood) 
Gene fusion positivity is defined as a 3’ RET fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain.  
 
ANC  1000/L within 14 days prior to initiation of study treatment 
 
Ability to swallow pralsetinib intact, without chewing, crushing, or opening the 
capsules/tablets 
 
For females of childbearing potential:  Negative serum pregnancy test 7 days prior 
to initiating study treatment; agreement to remain abstinent (refrain from 
heterosexual intercourse) or use single or combined non-hormonal contraception 
methods that result in a failure rate of  1% per year during the treatment period and 
for at least 14 days after the last dose of pralsetinib; and agreement to refrain from 
donating eggs during this same period.  See Appendix 2 for details on contraception 
requirements. 
 
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) 
or use a condom plus an additional contraception method that together result in a 
failure rate of  1% per year during the treatment period and for at least 7 days after 
the last dose of pralsetinib, and agreement to refrain from donating sperm during 
this same period.  See Appendix 2 for details on contraception requirements. 
 
O.4.1.2 
Additional Exclusion Criteria 
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm O: pralsetinib treatment: 
 
RET fusion-positive NSCLC 
 
RET fusion-positive thyroid cancer 
 
Patient’s tumor has any additional known primary driver alterations other than RET, 
such as targetable mutations of EGFR, ALK, ROS1, MET, KRAS or BRAF. 
 
Known history of hypersensitivity to pralsetinib or any of its excipients 
 
Prior treatment with RET inhibitors (approved or investigational) 


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
582/Protocol ML42439, Version 6 
Note: Other prior anti-cancer therapy is allowed 
 
Screening QT interval corrected using Fridericia's formula (QTcF)  480 
milliseconds, history of prolonged QT syndrome or torsades de pointes, and/or 
familial history of prolonged QT syndrome 
 
History of pneumonitis during the prior 12 months 
 
Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or 
systemic steroids   10 mg/day of prednisone (or equivalent)  
 
Active, uncontrolled infection (viral, bacterial, or fungal) 
– 
Participants with controlled infections who are stable on treatment may be 
eligible if the benefitrisk assessment is justified  
 
Clinically symptomatic interstitial lung disease or interstitial pneumonitis, including 
radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic 
intervention) 
 
Neutrophil growth factor support within 14 days of the first dose of study drug 
 
Treatment with a prohibited medication or herbal remedy that cannot be 
discontinued at least 14 days before the start of study drug administration.   
 
O.4.2 
STUDY TREATMENT 
Study treatment in this arm will consist of pralsetinib. 
O.4.2.1 
Formulation and Packaging 
Pralsetinib will be supplied by the Sponsor as 100-mg capsules.  
The study drug will be periodically tested and monitored for its acceptable shelf life.  Any 
study drug that fails to comply with the manufactured specifications will be promptly 
removed from the clinical trial site and replaced with new supplies by the Sponsor (or 
designee). 
Each bottle will be labeled with the required regulatory agency warning statement, the 
protocol number, the Sponsor’s name, and directions for patient use and storage.  The 
investigator should ensure that the study drug is stored in appropriate conditions in a 
secure location with controlled access. For information on the packaging, handling, and 
storage, see the Pharmacy Manual and Pralsetinib Investigator's Brochure. 
 
O.4.2.2 
Dosage, Administration, and Compliance 
Study treatment will be administered in 28-day cycles. 
Pralsetinib will be self-administered by patients orally at home (except on clinic days 
Section O.6), at the same time each day, on a starting dose of 400 mg/day (four 100-mg 


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
583/Protocol ML42439, Version 6 
capsules per day) once a day (QD) until disease progression, intolerable toxicity, or 
consent withdrawal.  For more specific dosing instructions, refer to the pharmacy 
manual. 
Pralsetinib should be taken in the morning with a glass of water in a fasted state, with no 
food intake beginning 2 hours before until 1 hour after study drug administration.  The 
capsules should not be opened and the contents of the capsules should not be 
dissolved.   
A missed dose can be taken within 12 hours of the scheduled time. After that, patients 
should take the next dose the following day, without compensating for the missed dose 
(including vomited doses). 
Guidelines for pralsetinib dosage modification and treatment interruption or 
discontinuation are provided in Section O.5.2.1.  
See Section 4.3.2 for details on assessment of compliance for self-administered oral 
study drugs. 
Accidental overdose or medication errors should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Cases of accidental overdose or 
medication error, along with any associated adverse events, should also be reported as 
described in Section 5.3.5.12. 
At the end of the study, the Sponsor will provide instructions as to the disposition of any 
unused study drug. 
O.4.3 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions 
O.4.3.1 
Permitted Therapy 
Anti-emetic and anti-diarrheal treatments may be used at the investigator’s discretion (in 
accordance with the local guidelines) after documented nausea, vomiting, or diarrhea 
has occurred in patients who are not taking medications to manage these symptoms.  
Prophylaxis for nausea, vomiting, or diarrhea may be instituted beginning on Cycle 2 
Day 1 in patients who experience these toxicities during Cycle 1, and during Cycle 1 for 
patients who experience nausea, vomiting or diarrhea. 
In certain instances, palliative radiotherapy to specific sites is permitted if considered 
medically necessary by the investigator.  The Sponsor must be notified if palliative 
radiotherapy is started; however, the need for radiotherapy will generally be considered 
indicative of progressive disease. 


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If palliative radiation is indicated for bone lesions, palliative radiation may start within 
24 hours of the last dose of pralsetinib, unless, in the judgment of the investigator, 
patient safety will require a longer washout period prior to palliative therapy.  Dosing of 
pralsetinib may resume with the resolution of any radiation toxicity to Grade 1 or better. 
If radiation therapy or surgical excision of target lesion is determined to be in patient's 
best interest and cannot be avoided, the Medical Monitor should be consulted.  Note that 
radiation or surgical excision of target lesions may render patients unevaluable for 
further response assessments. 
O.4.3.2
Concomitant Therapy to Be Used With Caution 
The following medications are to be used with caution during the study. 

In vitro metabolism studies in human liver microsomes have demonstrated that
pralsetinib is a direct moderate inhibitor and inducer of multiple P450 enzymes
(CYP2C8, CYP3A4, and CYP2C9).  Pralsetinib is also a time-dependent inhibitor of
CYP3A4/5.

Pralsetinib is an inhibitor of P-glycoprotein (P-gp), BCRP, OATP1B1, OATP1B3,
OAT1, MATE1, and MATE2-K at clinically relevant concentrations.  In patients,
pralsetinib may alter or increase the plasma concentration of co-administered
sensitive CYP2C8, CYP3A4, CYP2C9, P-gp, BCRP, OATP1B1, OATP1B3, OAT1,
MATE1, and MATE2-K substrates.

Medications that are sensitive CYP2C8, CYP3A4, CYP2C9, P-gp, BCRP,
OATP1B1, OATP1B3, OAT1, MATE1, and MATE2-K substrates with known
drugdrug interaction potential should be used with caution.

Lists of relevant drugs to be used with caution are provided in Appendix 7.
O.4.3.3
Prohibited Therapy 

In vitro metabolism studies indicate that pralsetinib oxidation is primarily mediated
by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C9, and glucuronidation by
UGT1A4.  As a precaution, strong inhibitors as well as inducers of CYP3A4 are
prohibited.  Drug transporter studies in cells overexpressing P-gp indicate that
pralsetinib is likely also a P-gp substrate.  Medications that are strong dual inhibitors
of P-gp and CYP3A4 are prohibited.
–
Refer to Appendix 7 for a list of relevant prohibited medications.

Any investigational agent or device other than pralsetinib, including commercially
available agents that are investigational for the treatment of the patient’s underlying
malignancy.

Any anti-cancer treatment other than study drug.

Use of herbal medications (e.g., St. John’s Wort) should be avoided when possible.


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
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O.4.3.4 
Prohibited Food 
 
Consumption of grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit should be avoided for up to 14 
days prior to and during the treatment period. 
 
Consumption of St. John’s wort, a potent CYP3A4 enzyme inducer, is prohibited for 
up to 14 days prior to and during the study treatment period. 
 
O.4.4 
Pralsetinib-Specific Assessments 
In addition to the study assessments described in Section 4.5, the following 
assessments are required for patients in the pralsetinib treatment arm.  Refer to the 
schedule of activities (Section O.6) for arm-specific assessment timepoints. 
Local Laboratory Assessments  
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Coagulation:  INR and aPTT 
 
Urinalysis (dipstick):  (pH, specific gravity, glucose, protein, ketones, blood, nitrite, 
leukocyte esterase [or white blood cells]). Note that for sites that do not routinely 
perform leukocyte esterase in the urinalysis (dipstick) test, white blood cell result in 
the report of urinalysis with dry chemistry (dipstick) method is acceptable. 
Other Assessments 
 
Vital signs will include measurements of pulse rate, systolic and diastolic blood 
pressure while the patient is in a seated position, and temperature. 
 
Single 12-lead ECG  
 
O.5 
SAFETY PLAN 
Please refer to Section 5 for general instructions with regard to the assessment of safety 
in this study.  Following are further instructions specific to Arm O:  pralsetinib treatment. 
O.5.1 
Risks Associated with Pralsetinib 
Pralsetinib has been associated with risks such as the following:  pneumonitis, 
pneumonia/lung infections, tumor lysis syndrome, hypertension and hepatotoxicity.  
Refer to the Pralsetinib Investigator’s Brochure for a detailed description of anticipated 
safety risks for pralsetinib. 
O.5.2 
Management of Patients Who Experience Adverse Events with 
Pralsetinib 
Guidelines for management of specific adverse events and dose modification or 
interruption are outlined below.  These guidelines are intended to inform rather than 
supersede clinical judgment and the benefit-risk balance as assessed by the investigator 
in managing individual cases.   


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O.5.2.1 
Dose Modifications and Interruptions 
Adverse events associated with pralsetinib can often be managed with concomitant 
medications, supportive care (see Section O.4.3.1 and Section O.5.2.2), and/or dose 
modifications as per Table 1 and Table 2. 
The dose of pralsetinib can be reduced in decrements of 100 mg and no more than 3 
dose reductions will be allowed.  Pralsetinib dose reductions to below 100 mg QD are 
not permitted.  If a patient requires dose reduction below 100 mg QD, study treatment 
should be discontinued.   
The possible daily doses of pralsetinib are shown in Table 1. 
Table 1 
Pralsetinib Dose Reductions 
Dose Level 
Pralsetinib 
Starting dose 
400 mg QD 
First dose reduction 
300 mg QD 
Second dose reduction 
200 mg QD 
Third dose reduction 
100 mg QD 
Fourth dose reduction 
Not permitted 
QD  once a day. 
 
Pralsetinib treatment may be interrupted for a maximum of 56 days (8 weeks) to allow 
for sufficient recovery from any toxicity if a patient is still deriving clinical benefit in the 
judgment of the investigator.  In general, if a toxicity that is considered to be related to 
the study drug does not resolve to   Grade 1 or has not returned to baseline after dose 
interruption for more than 56 days, the patient should be discontinued from study 
treatment unless a specific exception is made following discussion with the Medical 
Monitor because resumption of treatment is considered to be in the best interest of the 
patient, and this is documented in writing.  Additionally, the Medical Monitor must be 
informed if an adverse event that is not considered to be related to the study treatment 
requires a dose interruption for more than 56 days.  
 
Pralsetinib may be suspended for reasons other than toxicity (eg, surgical procedures), 
however pralsetinib should be interrupted at least 5 days in advance of surgery and 
resumed 2 weeks after major surgery and until adequate wound healing. If there are 
questions regarding whether or not study drug should be interrupted, the investigator 
should consult with the Medical Monitor.   


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
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587/Protocol ML42439, Version 6 
Table 2 
Dose Modification and Interruptions for Pralsetinib Related 
Adverse Events 
Adverse Drug Reaction 
Severity a 
Dose Modification 
Non-Hematologic 
Toxicity b 
Grade 1 
 
No dose interruption or 
modification required 
Grade 2 
 
No dose interruption or 
modification required.  If dose 
interruption is necessary, on 
improvement resume dosing 
without dose reduction 
Grade 3 
 
Occurrence at 200400 mg dose:  
Hold until event is  Grade 2, or 
has returned to baseline, and then 
resume by reducing the dose by 
100 mg less than the current dose  
 
Occurrence at 100 mg dose:  
Discontinue pralsetinib 
Grade 4 
 
Discontinue pralsetinib unless 
resumption of dosing is approved 
by the medical monitor. 
Hematologic Toxicity:  
Anemia, Neutropenia, 
Thrombocytopenia  
Grade 1 or Grade 2 
 
No dose interruption or 
modification required 
Grade 3 or Grade 4 
 
Occurrence at 200400 mg dose:  
Hold until event is  Grade 2, or 
has returned to baseline, and then 
resume by reducing the dose by 
100 mg less than the current dose 
 
Occurrence at 100 mg:  
Discontinue pralsetinib 
Hematologic Toxicity:  
Lymphopenia 
Grade 1 or Grade 2 
 
No dose interruption or 
modification required 
Grade 3 
 
Occurrence at 200400 mg dose:  
Reduce the dose by 100 mg less 
than the current dose.  Interruption 
of dosing can be done based on 
clinical circumstances but is not 
required 
 
Occurrence at 100 mg:  
Discontinue pralsetinib 
Grade 4 
 
Occurrence at 200400 mg dose: 
Hold until event is  Grade 3, or 
has returned to baseline, and then 
resume by reducing the dose by 
100 mg less than the current dose 
 
Occurrence at 100 mg:  
Discontinue pralsetinib 
AE  adverse event; NCI CTCAE v5   National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5 
a 
According to NCI CTCAE v5.0 
b 
Except for selected AEs:  See specific advice for pneumonitis and hypertension. 


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O.5.2.2 
Guidelines for Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in the subsections 
below. 
O.5.2.2.1 
Pneumonia/Lung Infections  
The diagnosis of pneumonia and lung infections (including opportunistic infections), 
some of which have been fatal, have been reported with patients treated with pralsetinib.  
The determination of causal relationship to the drug is often confounded by 
immunosuppression related to the patient’s underlying disease, prior therapy (such as 
immunotherapy and steroids), and other risk factors for infection such as 
myelosuppression.  Pneumonias and other lung infections should be managed with 
systemic antibiotics and other supportive management.   
If the causality is at least possibly related to the study drug, dose interruption and 
potential dose reduction and/or discontinuation should follow the guidelines in Table 2 , 
dose modification for non-hematologic toxicity. 
O.5.2.2.2 
Tumor Lysis Syndrome  
Tumor lysis syndrome (TLS) has been observed following pralsetinib treatment.  
Investigators should monitor electrolyte status and renal function via laboratory testing.  
Patients with TLS may require supportive care with intravenous fluids and correction of 
electrolyte imbalances. 
Patients who are at risk for TLS at study entry, such as those with high tumor burden, 
should be well hydrated before initiation of pralsetinib and avoid dehydration during the 
first cycle.  If TLS is suspected, investigators should manage the adverse event(s) 
according to standard institutional practices or accepted oncology management 
guidelines (Coiffier et al. 2008; Klastersky et al. 2016).   
O.5.2.2.3 
Hypertension  
Treat with standard of care antihypertensive therapy.  Dose modification is not required if 
hypertension can be managed with supportive medications.  If dose modification is 
necessary, please use dose modification guidelines for non-hematologic toxicity 
(Table 2).   
O.5.2.2.4 
Hepatotoxicity 
Serious hepatic adverse reactions have been observed with pralsetinib.  Pralsetinib 
treatment must be discontinued permanently if either of the following occurs: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  upper limit of normal (ULN; of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 


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O.5.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Section 5.2.3 describes adverse events of special interest that are required to be 
reported by the Investigator to the Sponsor immediately for all study treatments, 
and Section 5.4.2 provides reporting instructions.  There are no additional adverse 
events of special interest for the RET fusion-positive cohort other than those specified in 
Section 5.2.3. 
O.5.4 
Selected Adverse Events 
Additional data may be analyzed for the following selected adverse events:  
 
Pneumonitis 
 
Pneumonia 
 
Hepatotoxicity 
 
Hypertension 
 
Hemorrhagic events 
 
Tumor lysis syndrome 
 
 


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
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O.6 
SCHEDULE OF ACTIVITIES 
Assessments 
Pre-treatment 
Screening 
Treatment Period  
End of 
Treatment Visit b 
Day and Study Cycle 
 
Day 1 of Each Cycle 
Other Days as 
Specified 
 
(Window) 
28 to 1 a 
(3) 
(3) 
≤ 28 days after 
last study dose 
Informed consent d 
x 
 
 
 
Documentation of positive RET 
fusion status by local test e 
x 
 
 
 
Medical history and baseline 
conditions f  
x 
 
 
 
Physical Examination g 
x 
As clinically indicated 
Vital signs 
x 
x 
x h 
 
ECOG Performance Status i 
x 
x 
 
x 
Pregnancy test j 
x 
x 
 
x 
Chemistry k  
x 
x 
x k 
x c 
Hematology/CBC with differential l 
x 
x 
 
x c 
Coagulation panel m 
x 
 
 
 
Urinalysis n 
x 
x 
 
x 
12-lead ECG o 
x 
D1 of each cycle and as clinically indicated 
x 
Response assessment p, q 
x 
Every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks 
 
Pre-treatment tumor tissue sample 
for central testing (if applicable) r 
 
Submit within 21 days of Cycle 1 Day 1 
 
 
Whole blood samples s  
x 
 
see footnote s  
 
Pralsetinib compliance assessment t 
 
x 
 
x 
Pralsetinib dispensing 
 
x 
 
 
Adverse events u  
 
Collected on an ongoing basis 
x u 
Concomitant medications v 
 
Collected on an ongoing basis 


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591/Protocol ML42439, Version 6 
AEadverse event; Ccycle; CBCcomplete blood count; CNScentral nervous system; CTcomputerized tomography; ctDNAcirculating 
tumor DNA; Dday; ECGelectrocardiogram; ECHO  echocardiogram; ECOG PSEastern Cooperative Oncology Group Performance 
Status; eCRFelectronic Case Report Form; FMIFoundation Medicine, Inc.; ICFinformed consent form; IV  intravenous; LVEF  left 
ventricular ejection fraction; MRImagnetic resonance imaging; MUGA  multiple-gated acquisition; PDprogressive disease; 
RANOResponse Assessment in Neuro-Oncology; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; 
SAEserious adverse event. 
Note: Cycle28 days. 
a The medical history, ECOG PS, hematology/CBC, and chemistry panel should be done   28 days prior to initiation of treatment.  
However, if the hematology/CBC and chemistry panel are obtained within 7 days of Cycle 1, Day 1 they do not have to be repeated on 
Day 1.  Scans to document measurable or evaluable disease (i.e., tumor measurement) should be performed   4 weeks prior to 
initiation of treatment.   
b After treatment is discontinued, patients will visit the study center within 28 days after the last dose of study treatment for end-of-
treatment follow-up assessments.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study 
drug discontinuation.  If the patient’s worsening disease combined with travel distance makes this visit too difficult, follow-up with the 
patient may take place by telephone to include an assessment of AEs.  Alternatively, the patient's local physician may be contacted to 
collect AE data and any standard of care laboratory and CT data, if performed.   
c If the hematology/CBC and chemistry panel are obtained within 7 days prior to treatment discontinuation, they do not have to be 
repeated unless clinically indicated. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Confirmation of positive RET fusion status should occur prior to performing other trial-related eligibility assessments. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), 
reproductive status, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, and 
nutritional supplements) used by the patient within 7 days prior to the Cycle 1, Day 1 visit. 
g A complete physical examination, performed at screening should include height, weight, an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  Limited, 
symptom-directed physical examinations should be performed as clinically indicated.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF. 
h Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
Vital signs should be assessed at screening and day 1 of each cycle. Additionally, blood pressure should be assessed at C1D8. 
i All performance status will be assessed according to ECOG PS definitions provided in Appendix 5.  It is recommended, where possible, 
that a patient’s performance status be assessed by the same person throughout the study. 
j Women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening, within 7 
days before the first dose of study drug.  Urine or serum pregnancy tests may be performed at subsequent visits, as indicated in the 
schedule of assessments.  Pregnancy tests must be done Day 1 prior to starting every cycle.  Any positive urine pregnancy test must 


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
MyTACTIC Study—Genentech, Inc. 
592/Protocol ML42439, Version 6 
be confirmed by a serum pregnancy test.  During the treatment period, pregnancy test results must be available prior to administration 
of study drug.   
k Will include measurements of glucose, BUN or urea, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, 
ALT, total bilirubin, direct bilirubin, total protein, and albumin.  Screening results must be reviewed and documented prior to 
administration of the first dose of study treatment.  If results are obtained within 7 days of Cycle 1, Day 1 they do not have to be 
repeated on Cycle 1 Day 1.  Subsequent chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle 
(or up to 3 days before). AST and ALT should also be assessed on D15 of cycles 1-3. 
l Hematology/CBC with differential includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). If results are obtained within 7 days of Cycle 1, Day 1 they 
do not have to be repeated on Cycle 1 Day 1.  
m Coagulation includes aPTT and INR. 
n Urinalysis (dipstick):  (pH, specific gravity, glucose, protein, ketones, blood, nitrite, leukocyte esterase [or white blood cells]). Note that 
for sites that do not routinely perform leukocyte esterase in the urinalysis (dipstick) test, white blood cell result in the report of urinalysis 
with dry chemistry (dipstick) method is acceptable. 
o A single 12-lead ECG should be performed during screening, on Day 1 of every treatment cycle, at the end of treatment, and as 
clinically indicated.  ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  Patients should be 
resting in a supine position for at least 10 minutes prior to ECG recording.  If at a particular post-dose timepoint (if applicable) the mean 
QTcF is  500 ms and/or  60 ms longer than the baseline value, another ECG must be recorded, ideally within the next 5 minutes, and 
ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  The Medical Monitor should be notified.  Standard 
of care treatment may be instituted per the discretion of the Investigator.  
p All known sites of disease must be assessed and documented at screening and reassessed at each subsequent tumor evaluation.  
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study 
treatment do not have to be repeated at screening.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast allergy or 
impaired renal clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the abdomen, pelvis, and head 
should be performed.  A CT or MRI scan of the head must be performed at screening to assess CNS metastasis.  An MRI scan of the 
brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.   
q At each subsequent tumor assessment, all measurable and evaluable lesions should be re-assessed using the same radiographic 
procedures every 8 (1) weeks for 3 evaluations, then every 12 (2) weeks thereafter regardless of dose delays or treatment 
discontinuation, until investigator-determined radiographic disease progression per RECIST v1.1 or RANO (for primary CNS tumors), 
withdrawal of consent, termination of an individual study arm by the Sponsor, or death, whichever occurs first.   
r For patients with a positive biomarker result from an assay other than a tissue-based assay conducted by FMI, pre-treatment tissue 
samples (archival or recent resection or biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If both 
archival and recent tissue is available, the recent tissue should be preferentially submitted.   
s Blood samples will be collected at screening, 8 weeks after first treatment (or within one week of the first tumor assessment), and at 
tumor progression (within 7 days after progression) for analyses including ctDNA.   


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
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593/Protocol ML42439, Version 6 
t Pralsetinib will be self-administered by patients orally at home (except on clinic days, Section O.4.2.2), at the same time each day, on a 
starting dose of 400 mg/day (four 100 mg capsules per day) once a day (QD) until disease progression, intolerable toxicity, or consent 
withdrawal. Compliance will be reviewed with the patient prior to starting each cycle. 
u After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-
mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final 
dose of study drug.  All patients will be followed until treatment-related toxicities resolve or for at least 28 days post-study drug 
discontinuation.  After this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified 
if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment 
(see Section 5.6). 
v Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study drug until 28 days after the final dose of 
study drug. 
 


Arm O:  Pralsetinib in Patients with RET Fusion-Positive Tumors 
 
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594/Protocol ML42439, Version 6 
O.7 
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595/Protocol ML42439, Version 6 
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[cited 31 December 2020]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf 
Subbiah V, Hu MI-N, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) 
in patients with RET fusion  solid tumors. J Clin Oncol 2020;38:109.  
Yang HS, Horten B. Gain of copy number and amplification of the RET gene in lung cancer. 
Exp Mol Pathol. 2014;97:4659. 
 
 


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SAP_001.pdf: 


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TABLE OF CONTENTS
1.
BACKGROUND.............................................................................................4
2.
STUDY DESIGN ...........................................................................................5
2.1
PROTOCOL SYNOPSIS .........................................................5
2.2
STUDY DESCRIPTION ...........................................................5
2.2.1
DOSING BEYOND DISEASE PROGRESSION.....................10
2.2.2
NUMBER OF PATIENTS.......................................................10
2.2.3
END OF STUDY AND LENGTH OF STUDY .........................11
2.3
Outcome Measures................................................................11
2.3.1
Primary Efficacy Objective .....................................................11
2.3.2
Secondary Efficacy Objective ................................................11
2.3.3
Exploratory Efficacy Objectives..............................................12
2.4
Safety Objective.....................................................................12
2.5
Biomarkers Objective.............................................................12
2.6
Analysis Timing......................................................................12
3.
STATISTICAL METHODS...........................................................................13
3.1
ANALYSIS POPULATION .....................................................13
3.2
ANALYSIS OF STUDY CONDUCT .......................................13
3.3
EFFICACY ANALYSIS...........................................................13
3.3.1
PRIMARY EFFICACY ENDPOINTS......................................13
3.3.2
Secondary Efficacy Endpoints ...............................................13
3.3.3
Exploratory Efficacy Analysis.................................................14
3.3.4
Biomarker Analyses...............................................................14
3.3.5
Sensitivity Analyses ...............................................................15
3.3.6
Subgroup Analyses................................................................15
3.4
SAFETY ANALYSIS ..............................................................15
3.4.1
Exposure to Study Medication ...............................................15
3.4.2
Adverse Events......................................................................16
3.4.3
Laboratory Data .....................................................................16


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3.4.4
Vital Signs..............................................................................16
3.5
Futility Analyses.....................................................................16
3.6
Optional Interim Analyses......................................................18
LIST OF TABLES
Table 1
Prevalences of Biomarkers for arms in MyTACTIC.......................9
Table 2
Arm Alteration and Study Treatment .............................................9
Table 3
cORR confidence intervals for N = 25 that exceed 10% .............17
Table 4
cORR confidence intervals for N = 25 that exceed 30% .............17
Table 5
Probabilities of equaling or exceeding the benchmark given 
results for 12 patients..................................................................18
LIST OF FIGURES
Figure 1
Study Schema...............................................................................8
LIST OF APPENDICES
Appendix 1
Protocol Synopsis........................................................................19


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1.
BACKGROUND
Oncology is rapidly evolving into a more personalized healthcare approach.  Improved 
understanding of the role of cancer biomarkers, further development of molecular-
targeted therapies, and the standardization of appropriate targeted treatment into 
treatment guidelines have shifted clinical practice to utilize genomic information as an 
integral component of clinical decision-making (Kris et al. 2014; Barlesi et al. 2016).  
Therapies that specifically target actionable oncogenic drivers have become the 
cornerstone of precision oncology. 
Currently, targeted agents are approved for use in specific cancer types (as defined by 
primary site), or a subset of that population harboring the specific molecular alteration.  
Usually, targeted agents have been approved in the cancer types that most frequently 
carry the specific molecular target.  However, it is now clear that molecular alterations 
can be found in cancers from other primary sites, although often at low incidence levels.  
The potential therapeutic importance of these abnormalities is not clear, although 
anecdotal reports have documented activity with the investigational use of appropriate 
targeted therapy (Cappuzzo et al. 2006; Masago et al. 2009; LoRusso et al. 2011; 
Masago et al. 2011; Kelly et al. 2012; Minor et al. 2012).  With the relative rarity of these 
alterations (usually <= 5%) in any specific cancer type, it is difficult to identify sufficient 
patients for clinical trials. 
With these recent advancements, numerous platforms have been developed to survey 
the cancer cell genome and detect critical molecular alterations.  With increased 
molecular profiling, gene alterations for which a targeted agent exists, or are associated 
with improved efficacy of cancer immunotherapies, are being identified more frequently 
in tumor types for which these agents are currently not approved.  These findings 
present a new opportunity to test the efficacy of available targeted agents and 
immunotherapies.
In addition, there have been recent drug approvals in pan-tumor indications paving the 
way for registration for molecular alterations in multiple tumor types.
For example, entrectinib (Rozlytrek®) was approved in the United States based on the 
results in 51 adult patients across three clinical trials.  A pooled analysis of 3 Phase I-II 
studies investigating patients with locally-advanced or metastatic ROS1 fusion-positive 
non-small-cell lung cancer demonstrated that treatment with entrectinib induced a 
durable and clinically meaningful response.  Among the efficacy-evaluable patients, 77% 
had an objective response, with a median duration of response of 24.6 months (95% CI 
11.4-34.8) (Drilon et al. 2020). The same analysis investigated patients with metastatic 
or locally advanced solid tumors harboring a fusion in the NTRK gene (NTRK1, NTRK2, 
or NTRK3), comprising of 10 different tumor types and 19 different histologies.  Similarly, 
treatment with entrectinib demonstrated a durable and clinically meaningful response, 
showing Entrectinib to be a viable treatment option for patients with NTRK fusion-


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positive solid tumors.  An objective response was observed in 57% of the evaluable 
patients (95%CI 43.2-70.8), with 4 complete responses and 27 partial responses.  The 
median duration of response was 10 months (95% CI 7.1 to NE), (Doebele et al. 2019). 
Tumor mutational burden has been associated with treatment outcomes with cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1)
inhibitors.  Pembrolizumab (Keytruda®) was granted accelerated approval by the FDA for 
the treatment of adult and pediatric patients with unresectable or metastatic tumor 
mutational burden-high (TMB-H) solid tumors, defined as >= 10 mutations/megabase 
(mut/Mb).  The Phase II basket study of pembrolizumab monotherapy in this patient 
population demonstrated that TMB-H was associated with higher response rates in a 
number of different unresectable or metastatic tumor types, suggesting that tumor 
mutational burden (TMB) may predict efficacy of pembrolizumab treatment.
In addition to testing targeted therapies in a pan-tumor setting, this study aims to expand 
study access to patients that are traditionally underrepresented in clinical trials.  
Classical registrational clinical trials often underrepresent patients of color, with data 
indicating that 88% of genetic sequencing/association studies have been done in 
individuals of European decent. In addition, industry study design standards may 
unintentionally prevent diverse patients from being enrolled, as most studies include 
certain inclusion/exclusion criteria that tend to exclude people of specific ethnicities.  
This study will focus on inclusion of underrepresented, understudied patients with 
broader entry criteria and with an emphasis on recruiting patients of color to ensure this 
study reflects the US population more accurately. 
Specific biomarkers of interest for this protocol and their respective targeted therapies 
are outlined in Table 1. Background and rationale for the biomarkers and the associated 
targeted therapies, are provided in the sections below.
2.
STUDY DESIGN
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  The Protocol Synopsis includes the study 
objectives, inclusion and exclusion criteria, outcome measures, and statistical methods 
as stated in the protocol.  
2.2
STUDY DESCRIPTION
MyTACTIC is a Phase II, multicenter, non-randomized, open-label, multi-arm study 
designed to evaluate the safety and efficacy of targeted therapies as single agents or in 
rational, specified combinations in patients with advanced unresectable or metastatic 
solid tumors determined to harbor specific biomarkers.  Patients will be enrolled based 
on local testing performed at a Clinical Laboratory Improvement Amendments (CLIA)-
certified or equivalently accredited diagnostic laboratory.  For all patients whose positive 
biomarker result is from an assay other than a tissue-based assay conducted by 


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Foundation Medicine, Inc. (FMI), central testing of pre-treatment tissue (preferably from 
the most recent block) and blood is required after enrollment.  Pre-treatment tissue will 
be submitted within 21 days after enrollment to a Sponsor-approved laboratory for 
central testing; this testing will not impact the study participation of enrolled patients.  
The multi-arm structure of the MyTACTIC study allows patients with solid tumors to be 
treated with a drug or drug regimen tailored to their biomarker identified at screening.  
Each study treatment arm may have separate endpoints, screening, and treatment 
requirements, defined in the respective appendix.  Futility analyses will be employed on 
all treatment arms to limit enrollment where evidence of very limited or lack of efficacy is 
observed.
During the study, the following biomarker samples will be collected:
Tumor tissue 

For patients with a positive biomarker result from an assay other than a tissue-
based assay conducted by FMI, pre-treatment tissue samples (archival or recent
resection or biopsy) must be submitted within 21 days of enrollment at baseline for
central testing.  If both archival and recent tissue is available, the recent tissue
should be preferentially submitted.
Blood samples

Mandatory blood samples will be collected at screening, 8 weeks after first
treatment, and at disease progression for analyses including ctDNA
These samples will be used to evaluate predictive and/or prognostic biomarkers, 
including but not limited to biomarkers related to driver oncogene signaling, response to 
study treatment, tumor pathogenesis, and mechanisms of resistance.
The requirements for tissue and blood samples for screening and standardized testing 
purposes are described in Section 4.5.7 of the protocol
Treatment will be assigned by the treating investigator on the basis of relevant specified 
biomarkers, and will continue until radiographic disease progression (per RECIST v1.1 
[Eisenhauer et al. 2009]; RANO Criteria for primary CNS tumors [Wen et al. 2017], or
loss of clinical benefit for specific treatment arms, with Medical Monitor approval, see 
Section 3.1.2 of the protocol for treatment beyond disease progression); unacceptable 
toxicity; patient or physician decision to discontinue; or death, whichever occurs first.  If a 
patient discontinues treatment prior to disease progression (because of adverse event or 
other reason), tumor assessments will continue as specified in the treatment-specific 
appendix until disease progression, death, withdrawal of consent, or arm/study closure 
by the Sponsor, whichever occurs first.  Patients that have disease progression while on 
study may qualify for re-screening and enrollment into a different treatment arm if they 
have more than one documented biomarker and if the associated treatment arm is open 
and enrolling patients.  Patients who qualify for more than one treatment arm and have 


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progressed on the first treatment must re-sign the informed consent form prior to re-
screening and undergo screening for the second treatment arm. 
Follow-up data, including survival and subsequent anti-cancer therapies, will be 
collected for each patient until death, loss to follow-up, withdrawal of consent, study/arm 
closure, or at least 1 year after end of treatment, whichever occurs first.  Information 
regarding the nature and duration of subsequent therapies will be collected.
Patients who do not meet the criteria for participation in this study (screen failure) or the 
timeline for the screening window may qualify for re-screening at the investigator's 
discretion.  Patients must re-sign the consent form prior to rescreening.  The investigator 
will record reasons for screen failure in the screening log.  




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Table 1
Prevalences of Biomarkers for arms in MyTACTIC
Target or Immune 
Marker
Biomarker Classification
Pan-tumor Prevalence
ROS1
Fusion-positive (excluding NSCLC)
0.11%
PI3K 
PIK3CA activating mutation(s)
11.2%
ALK
Fusion-positive (excluding NSCLC)
0.11%
AKT1/2/3
AKT-Activating mutation or
PTEN-Loss (deletion)/LOF
12.6%
ERBB2 (HER2)
Activating mutation or amplification 
(excluding breast cancer)
4.9%
PD-L1
TMB 10 mut/Mb or MSI-H/dMMR
13.2%
ERBB2 (HER2) & CD274 
(PD-L1)
ERBB2 Activating mutation or 
amplification & TMB 10 mut/Mb or 
MSI-H/dMMR 
0.5% 
AKT
Co-mutations in PIK3CA and PTEN 
Co-mutation in PIK3CA and AKT
1.4%
0.09%
PD-L1 & TIGIT
TMB 10 mut/Mb or MSI-H/dMMR
13.2%
RET
Fusion-positive (excluding NSCLC, 
thyroid cancer) 
0.48%
Table 2
Arm Alteration and Study Treatment
Biomarker alteration
Study Treatment
ROS1 gene fusion 
Arm A: Entrectinib
PIK3CA activating mutation
Arm B: Inavolisib (GDC-0077)
Arm K: Ipatasertib + atezolizumab
ALK gene fusion
Arm C: Alectinib
AKT activating mutations and/or 
PTEN loss/loss of function
Arm D: Ipatasertib
Arm L: Ipatasertib + atezolizumab
Co-mutation in PI3KCA 
activating mutation and AKT 
activating mutation or PI3KCA 
activating mutation and PTEN 
loss/loss of function
Arm M: Ipatasertib + paclitaxel 
TMB 10/MSI-H/dMMR
Arm E: Atezolizumab + chemotherapya 
Arm N: Atezolizumab + tiragolumab


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Biomarker alteration
Study Treatment
ERBB2 gene mutation or 
amplification
without known TMB ∃10/MSI-
H/dMMR
Arm F: Trastuzumab emtansine + atezolizumab
Arm G: PH FDC SC
Arm H: PH FDC SC + chemotherapy a
Arm I: Trastuzumab emtansine + tucatinib
ERBB2 gene amplification or 
mutation and
TMB ∃10/MSI-H/dMMR 
Arm J: Trastuzumab emtansine + atezolizumb  
RET gene fusion 
Arm O: Pralsetinib
chemo∀chemotherapy; dMMR∀deficient mismatch repair; HER2∀human epidermal growth factor 
receptor 2; PH FDC SC∀fixed dose combination of trastuzumab and pertuzumab administered 
subcutaneously; MSI-H∀microsatellite instability high; PI3K∀phosphatidylinositol 3-kinase; RET
RET∀Rearranged during Transfection; TMB∀tumor mutational burden. Investigator’s choice of 
docetaxel, paclitaxel, or capecitabine.
2.2.1
DOSING BEYOND DISEASE PROGRESSION
In the absence of unacceptable toxicity, dosing of study treatment beyond radiographic 
disease progression may be permitted for patients in specific treatment arms with 
approval of the Medical Monitor if evidence of persistent clinical benefit is determined by 
the investigator and documentation is provided to the Sponsor.
If the above criteria are met, dosing of study treatment will continue until unacceptable 
toxicity, loss of clinical benefit (as determined by the investigator), or withdrawal of 
patient consent.  Loss of clinical benefit is defined as the following:
!
Appearance of signs and symptoms (including worsening of laboratory values)
indicating disease progression
!
Decline in ECOG performance status due to disease progression
!
Presence of rapid progression of disease or of progressive tumor at critical
anatomical sites (e.g. cord compression) requiring alternative medical intervention
2.2.2
NUMBER OF PATIENTS
Approximately 260 patients are anticipated to be enrolled at approximately 60 sites.  
Each arm will be limited to approximately 25 patients or <= 10 patients as indicated in 
the study. Given the hypothesis-generating nature of the study and the potential for a 
variable population of patients to enroll, potentially including diverse tumor types and 
later line patients, a minimum acceptable ORR of 10% will be considered for each arm 
for the purposes of nonbinding futility. 


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2.2.3
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV), 
occurs or the date at which the last data point required for statistical analysis or safety 
follow-up is received from the last patient, whichever occurs later.  In order to obtain 1-
year follow up for all patients, LPLV is expected to occur approximately 1 year after the 
last patient is enrolled.
2.3
OUTCOME MEASURES
2.3.1
Primary Efficacy Objective
The primary objective for this study is to evaluate the efficacy of various treatments 
and/or combinations of treatments in eligible patients with advanced unresectable or 
metastatic solid tumors, on the basis of the following endpoint:

The primary endpoint for each arm of this study will be confirmed ORR (cORR) as
assessed by the investigator and according to response evaluation criteria in solid
tumors version 1.1 (RECIST v1.1), or Response Assessment in Neuro-Oncology
[RANO] Criteria for primary CNS tumors [Wen et al. 2017].  The cORR is defined as
the proportion of patients whose confirmed best response is a complete response
(CR) or partial response (PR) for those with measurable disease and CR for those
with non-measurable disease.  Confirmation is defined by two consecutive
evaluations at least 4 weeks apart for 3 week cycles and at least 6 weeks apart for 4
week cycles.  This considers the patient measured within 2 weeks of the planned
time between response evaluations.
2.3.2
Secondary Efficacy Objective 
The secondary efficacy objectives for this study are to evaluate the efficacy of each 
targeted treatment on the basis of the following endpoints:

PFS, defined as the time from start of treatment to the first occurrence of disease
progression or death from any cause (whichever occurs first), as determined by the
investigator according to RECIST v1.1.

DOR, defined as the time from the first occurrence of a documented objective
response to disease progression or death from any cause (whichever occurs first),
as determined by the investigator according to RECIST v1.1.

OS, defined as the time from start of treatment to death from any cause.

PFS rate at 3 months during treatment and every 3 months thereafter for at least up
to 1 year, defined as the proportion of patients who have not experienced disease
progression or death from any cause as determined by the investigator, according to
RECIST v1.1.

OS rate every 3 months during treatment and every 3 months thereafter for at least
up to 1 year, defined as the proportion of patients who have not experienced death
from any cause.

Disease control rate (DCR), defined as the proportion of patients whose best
response is confirmed CR, confirmed PR, or SD, where SD is confirmed by two
assessments a minimum of 6 weeks apart for 4 week cycles and 4 weeks apart for 3


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week cycles.  DCR will be summarized in the same fashion as the primary efficacy 
endpoint except, for DCR we will limit analysis to the subgroup in the analysis 
population consisting of those with measurable disease.

ORR as assessed by the investigator and according to response evaluation criteria
in solid tumors version 1.1 (RECIST v1.1), or Response Assessment in Neuro-
Oncology [RANO] Criteria for primary CNS tumors [Wen et al. 2017].  The ORR is
defined as the proportion of patients whose best response is a complete response
(CR) or partial response (PR) for those with measurable disease and CR for those
with non-measurable disease.
2.3.3
Exploratory Efficacy Objectives
Exploratory efficacy objectives are to evaluate efficacy based following the following:

Analysis of primary and secondary efficacy endpoints when sub grouped by basket,
tumor site of origin, and/or self-reported race and ethnicity.
2.4
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety and tolerability of the study 
medications for the tumor types studied based on the following endpoints: 

Incidence and severity of adverse events, with severity determined according to
National Cancer Institute Common Terminology Criteria for Adverse Events
version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted clinical laboratory test results
2.5
BIOMARKERS OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are early surrogates of efficacy or relapse, are associated with a more 
severe disease state (i.e., prognostic biomarkers), are associated with acquired 
resistance to study drug(s), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoint:

The association of baseline and changes in circulating tumor DNA (ctDNA) levels
with response and progression to therapy.

Determination of baseline and changes in expression or levels of biomarkers in the
tumor tissue or blood that may be associated with response or resistance to
therapy.
2.6
ANALYSIS TIMING
Analysis will be done on an arm by arm basis. Interim analysis will be performed 
approximately 6 months after treatment initiation for the 12th patient.  Primary analysis 
will be conducted approximately 12 months after LPI. Futility analysis will be performed 
approximately 2 months after the 12th patient has initiated treatment in order to allow 
time for at least one tumor assessment. 


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3.
STATISTICAL METHODS
3.1
ANALYSIS POPULATION
The analysis population is defined as patients enrolled who have received at least one 
dose of study treatment.  An efficacy-evaluable patient is defined as a patient in the 
analysis population.  
3.2
ANALYSIS OF STUDY CONDUCT
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and reasons for discontinuation from the study will be summarized for all 
patients.  Study treatment administration and reasons for discontinuation from study 
treatment will be summarized.
3.3
EFFICACY ANALYSIS 
3.3.1
PRIMARY EFFICACY ENDPOINTS
The primary endpoint for this study will be Confirmed Objective Response Rate (cORR) 
as assessed by the investigator and according to the corresponding assessment criteria 
(RECIST v1.1 or RANO).  The cORR is defined as the proportion of patients whose 
confirmed best response is a CR or PR for those with measurable disease and CR for 
those with non-measurable disease.  Confidence intervals at both 70% and 95% nominal 
levels will be reported using the Clopper-Pearson method.  The primary efficacy 
endpoint will be computed for all treatment arms.  If a patient receives at least one dose 
of study treatment and discontinues the study for any reason before confirmed response
can be assessed, the patient will be considered a non-responder (not PR and not CR) 
and will be added to the denominator of the computation of cORR.  
3.3.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints for each treatment arm will consist of DCR, PFS, 1-
year OS, and DOR, which are listed and defined below.  All secondary endpoints will be 
computed for all treatment arms.

PFS, defined as the time from start of treatment to the first occurrence of disease
progression or death from any cause (whichever occurs first), as determined by the
investigator according to the corresponding assessment criteria (RECIST v1.1 or
RANO).  The PFS will be estimated using the Kaplan-Meier method.  Median PFS
and 95% confidence interval will be computed using the Brookmeyer-Crowley
method.

DOR, defined as the time from the first occurrence of a documented objective
response to disease progression or death from any cause (whichever occurs first),
as determined by the investigator according to the corresponding assessment
criteria (RECIST v1.1 or RANO).  The DOR will be estimated using the Kaplan-
Meier method.  Median DOR and 95% confidence interval will be computed using
the Brookmeyer-Crowley method.


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
OS, defined as the time from start of treatment to death from any cause.  The OS 
will be estimated using the Kaplan-Meier method.  OS will be estimated using the 
Kaplan-Meier method and Median OS and 95% confidence interval will be 
computed using the Brookmeyer-Crowley method.  

PFS rate at 3 months and every 3 months thereafter for at least up to 1 year, 
defined as the proportion of patients who have not experienced disease progression 
or death from any cause as determined by the investigator, according to RECIST 
v1.1.  PFS rates will be computed using the Kaplan-Meier method with 95% 
confidence intervals for each rate given by Greenwood’s formula.

OS rate every 3 months during treatment and every 3 months thereafter for at least 
up to 1 year, defined as the proportion of patients who have not experienced death 
from any cause.  OS rates will be computed using the Kaplan-Meier method with 
95% confidence intervals for each rate given by Greenwood’s formula.

DCR is defined as the proportion of patients whose confirmed best response is CR, 
PR, or SD, where SD would require such assessment at least 98 days from 
treatment initiation for 4 week cycles and at least 70 days from treatment initiation 
for 3 week cycles and where PD has not been already designated.  DCR will be 
summarized in the same fashion as the primary efficacy endpoint except, for DCR 
we will limit analysis to the subgroup in the analysis population consisting of those 
with measurable disease.  95% confidence interval will be determined using 
clopper-pearson method.

ORR as assessed by the investigator and according to response evaluation criteria 
in solid tumors version 1.1 (RECIST v1.1), or Response Assessment in Neuro-
Oncology [RANO] Criteria for primary CNS tumors [Wen et al. 2017].  The ORR is 
defined as the proportion of patients whose best response is a complete response 
(CR) or partial response (PR) for those with measurable disease and CR for those 
with non-measurable disease.   95% confidence interval will be determined using 
clopper-pearson method.
3.3.3
Exploratory Efficacy Analysis
See Subgroup Analyses
3.3.4
Biomarker Analyses

For all treatment arms, descriptive statistics of biomarker data will include means 
medians, ranges, and standard deviations, as appropriate.  For categorical 
analyses, frequency distributions will be tabulated as appropriate. 

Biomarker data in blood and tumor tissue and biomarker data collected over time (if 
available) will be used for additional subgroup analyses where primary and 
secondary efficacy endpoints and safety will be evaluated.  
Although no formal statistical analysis of exploratory biomarkers will be performed, in an 
effort to understand the association of these markers with study treatment response, 
data may be analyzed in the context of this study and in aggregate with data from other 
studies.  Results will be presented in a separate report. 


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Analysis will include but is not limited to concordance of local TMB assays with central 
testing by FMI and concordance of ctDNA detected mutations and mutations detected in 
tissue.  
3.3.5
Sensitivity Analyses
Sensitivity analysis will be performed with arm-specific alterations confirmed by central 
re-testing.  
Analyses excluding patients who switched arms will be performed.   
3.3.6
Subgroup Analyses
The subgroups to be considered for efficacy analysis include but are not limited to the 
following:

Tumor Type

Age (≤65 years, >65 years) at enrollment

Race

Gender

ECOG performance status at randomization (0, 1)

Prior therapies (number and types)
3.4
SAFETY ANALYSIS
The safety analysis population will include all patients who received at least one dose of 
study drug.  Safety will be assessed through summaries of exposure to study treatment, 
adverse events, and changes in laboratory test results.  Study treatment exposure (such 
as treatment duration, total dose received, and number of cycles and dose 
modifications) will be summarized with descriptive statistics.  All verbatim adverse event 
terms will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) 
thesaurus terms, and adverse event severity will be graded according to the NCI CTCAE 
(v5.0).  All adverse events, serious adverse events, adverse events leading to death, 
adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur on or after the first dose of study treatment (i.e., treatment-
emergent adverse events) will be summarized by mapped term, appropriate thesaurus 
level, and severity grade.  For events of varying severity, the highest grade will be used 
in the summaries.  Deaths and cause of death will be summarized.  A shift table of 
selected laboratory tests will be used to summarize the baseline and maximum post 
baseline severity grade. 
3.4.1
Exposure to Study Medication
Study drug exposure, including treatment duration, number of cycles, and dose intensity, 
will be summarized with descriptive statistics.


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3.4.2
Adverse Events
Verbatim description of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms.  Adverse events will be graded by the 
investigator according to the NCI CTCAE v5.0.  Treatment-emergent adverse events will 
be summarized by mapped term, appropriate thesaurus level, NCI CTCAE grade and 
treatment arm.  Multiple occurrences of the same event will be counted once at the 
maximum grade.  All reported AEs, SAEs, Grade 5 AEs, treatment-related AEs (as 
assessed by the investigator), severe AEs (Grade ≥ 3), AESIs, AEs leading to study 
drug discontinuation, and AEs leading to interruption or reduction will be summarized.    
All listings of AEs will include all AEs with onset on or after the first study drug treatment 
up to the data cutoff date.  
All deaths and causes of death will be summarized, during the study treatment period 
and those reported during the follow-up period after treatment 
completion/discontinuation.   
3.4.3
Laboratory Data
Laboratory data will be graded according to NCI CTCAE and will be summarized 
descriptively, with shift tables from baseline to worst value post-baseline.  
Changes in laboratory data over time will be summarized.  Highest NCI CTCAE grade 
post-baseline will also be summarized. Values outside the normal ranges will be 
summarized.
3.4.4
Vital Signs
Changes from baseline in selected vital signs will be summarized.  
3.5
FUTILITY ANALYSES
For some arms, limited data are available regarding the efficacy and safety of the 
treatment across the eligible tumor population(s).  Therefore, data from the first 12 
patients in a given arm will be used to conduct non-binding tumor agnostic futility 
analyses.  Futility analyses for some arms maybe conducted with the integration of data 
from other ongoing studies, including TAPISTRY.  These analyses will be used to 
identify whether a treatment may be ineffective in a tumor agnostic population due to 
limited or lack of efficacy, and further accrual into such an arm may be stopped.  
Enrollment will not be stopped while awaiting results of the tumor agnostic futility 
analysis.  
The observed response rate (ORR), confirmation not necessary, will be the primary 
endpoint of the futility assessment.  ORR is strictly lower than cORR but is faster to 
assess and allows for sufficient assessment of benefit to patients.  


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To perform the futility analyses we will use Bayesian gating with arm-specific gating 
criteria and non-informative prior where futility will be declared if there is a posterior 
probability of greater than 60% that the true ORR is less than the minimum acceptable 
level of 10%.  In the case of our study,  0 out of 12 responses indicates futility.  If an arm 
has 0 out of 12 responses,the arm may continue enrollment if it is determined that 
treatment is still likely to be beneficial to patients beyond what is currently available 
under standard of care. We thus consider the futility analysis to be non-binding.  
POSTERIOR PROBABILITIES
Confidence intervals to exceed minimum acceptable levels of either 10% (arms 
B,E,F,G,H,I,J) or 30% (arms A,C,D) are given in Table 3 and Table 4.  
Table 3
cORR confidence intervals for N = 25 that exceed 10%
confidence
Benchmark Estimate
left bound
       right bound
70%
5/25
0.114
0.316
80%
5/25
0.101
0.34
90%
6/25
0.11
0.42
95%
7/25
0.121
0.494
Table 4
cORR confidence intervals for N = 25 that exceed 30%
confidence
Benchmark Estimate
left bound
right bound
70%
11/25
0.323
0.563
80%
11/25
0.301
0.587
90%
12/25
0.305
0.659
95%
13/25
0.313
0.722
For a projected sample size of 25, Table 5 provides probabilities of exceeding the 
benchmark estimates in Table 3 and Table 4, given the results after 12 patients  




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Appendix 1 Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
MYTACTIC:  AN OPEN-LABEL PHASE II STUDY 
EVALUATING TARGETED THERAPIES IN PATIENTS WHO 
HAVE ADVANCED SOLID TUMORS WITH GENOMIC 
ALTERATIONS OR PROTEIN EXPRESSION PATTERNS 
PREDICTIVE OF RESPONSE
PROTOCOL 
NUMBER:
ML42439
VERSION NUMBER:
4
Eudract Number:
Not Applicable
IND NUMBER:
152738
NCT NUMBER:
NCT04632992
TEST PRODUCT:
Entrectinib (RO7102122), Trastuzumab emtansine 
(RO5304020), Pertuzumab Trastuzumab Fixed Dose 
Combination Subcutaneous (PH FDC SC, RO7198574),
Inavolisib (GDC-0077; RO7113755), Alectinib (RO5424802), 
Ipatasertib (RO5532961), Atezolizumab (RO5541267),
Tucatinib, Pralsetinib (RO7499790), Tiragolumab (RO7092284)
PHASE:
Phase II
INDICATION:
Solid tumors
SPONSOR:
Genentech, Inc.


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Objectives and Endpoints
This study will evaluate the efficacy and safety of multiple therapies that are selected based on 
potential predictive biomarkers identified in patients with solid tumors. 
Efficacy
Primary Efficacy Objective 
The primary objective for this study is to evaluate the efficacy of various treatments and/or 
combinations of treatments in eligible patients with advanced unresectable or metastatic solid 
tumors, on the basis of the following endpoint:

The primary endpoint for each arm of this study will be confirmed ORR (cORR) as
assessed by the investigator and according to response evaluation criteria in solid tumors
version 1.1 (RECIST v1.1), or Response Assessment in Neuro-Oncology [RANO] Criteria
for primary CNS tumors.  The cORR is defined as the proportion of patients whose
confirmed best response is a complete response (CR) or partial response (PR) for those
with measurable disease and CR for those with non-measurable disease.
Secondary Efficacy Objective 
The secondary efficacy objectives for this study are to evaluate the efficacy of each targeted 
treatment on the basis of the following endpoints:

Progression-Free Survival (PFS) defined as the time from start of treatment to the first
occurrence of disease progression or death from any cause (whichever occurs first), as
determined by the investigator according to RECIST v1.1.

Duration of objective response (DOR), defined as the time from the first occurrence of a
documented objective response to disease progression or death from any cause
(whichever occurs first), as determined by the investigator according to RECIST v1.1.

Overall survival (OS), defined as the time from start of treatment to death from any cause.

PFS rate at 3 months during treatment and every 3 months thereafter for at least up to 1
year, defined as the proportion of patients who have not experienced disease progression
or death from any cause as determined by the investigator, according to RECIST v1.1.

OS rate every 3 months during treatment and every 3 months thereafter for at least up to 1
year, defined as the proportion of patients who have not experienced death from any
cause.

Disease control rate (DCR), defined as the proportion of patients whose best response is
confirmed CR, confirmed PR, or SD where SD is confirmed by two assessments a
minimum of 6 weeks apart.  DCR will be summarized in the same fashion as the primary
efficacy endpoint except, for DCR we will limit analysis to the subgroup in the efficacy
population consisting of those with measurable disease.
Exploratory Efficacy Objective 
Exploratory efficacy objectives are to evaluate efficacy based following the following:

Analysis of primary and secondary efficacy endpoints when subgrouped by basket, tumor
site of origin, and/or self-reported race and ethnicity.
Safety Objective
The safety objective for this study is to evaluate the safety and tolerability of the study 
medications for the tumor types studied based on the following endpoints: 

Incidence and severity of adverse events, with severity determined according to National
Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
(NCI CTCAE [v5.0])

Change from baseline in targeted clinical laboratory test results
Biomarkers Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are early surrogates of efficacy or relapse, are associated with a more severe disease state 


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(i.e., prognostic biomarkers), are associated wit h acquired resistance to study drug(s), or can 
increase the knowledge and understanding of disease biology and drug safety, on the basis of 
the following endpoint:

The association of baseline and changes in circulating tumor DNA (ctDNA) levels with 
response and progression to therapy.

Determination of baseline and changes in expression or levels of biomarkers in the tumor 
tissue or blood that may be associated with response or resistance to therapy.
Study Design
Description of Study
Overview of Study Design
MyTACTIC is a Phase II, multicenter, non-randomized, open-label, multi-arm study designed 
to evaluate the safety and efficacy of targeted therapies as single agents or in rational, 
specified combinations in patients with advanced unresectable or metastatic solid tumors 
determined to harbor specific biomarkers.  Patients will be enrolled based on local testing 
performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently 
accredited diagnostic laboratory.  For all patients whose positive biomarker result is from an 
assay other than a tissue-based assay conducted by Foundation Medicine, Inc. (FMI), central 
testing of pre-treatment tissue (preferably from the most recent block) and blood is required 
after enrollment.  Pre-treatment tissue will be submitted within 21 days after enrollment to a 
Sponsor-approved laboratory for central testing; this testing will not impact the study 
participation of enrolled patients.  
The multi-arm structure of the MyTACTIC study allows patients with solid tumors to be treated 
with a drug or drug regimen tailored to their biomarker identified at screening.  Each study 
treatment arm may have separate endpoints, screening, and treatment requirements, defined 
in the respective appendix.  Futility analyses will be employed on all treatment arms to limit 
enrollment where evidence of very limited or lack of efficacy is observed.
During the study, the following biomarker samples will be collected:
Tumor tissue 

For patients with a positive biomarker result from an assay other than a tissue-based 
assay conducted by FMI, pre-treatment tissue samples (archival or recent resection or 
biopsy) must be submitted within 21 days of enrollment at baseline for central testing.  If 
both archival and recent tissue is available, the recent tissue should be preferentially 
submitted. 
Blood samples

Mandatory blood samples will be collected at screening, 8 weeks after first treatment, and
at disease progression for analyses including ctDNA
These samples will be used to evaluate predictive and/or prognostic biomarkers, including but 
not limited to biomarkers related to driver oncogene signaling, response to study treatment, 
tumor pathogenesis, and mechanisms of resistance.
Treatment will be assigned by the treating investigator on the basis of relevant specified 
biomarkers, and will continue until radiographic disease progression (per RECIST v1.1; 
Response Assessment in Neuro-Oncology (RANO) Criteria for primary CNS tumors, or loss of 
clinical benefit for specific treatment arms, with Medical Monitor approval; unacceptable 
toxicity; patient or physician decision to discontinue; or death, whichever occurs first.  If a 
patient discontinues treatment prior to disease progression (because of adverse event or other 
reason), tumor assessments will continue as specified in the treatment-specific appendix until 
disease progression, death, withdrawal of consent, or arm/study closure by the Sponsor, 
whichever occurs first.  Patients that have disease progression while on study may qualify for 
re-screening and enrollment into a different treatment arm if they have more than one 
documented biomarker and if the associated treatment arm is open and enrolling patients.  
Patients who qualify for more than one treatment arm and have progressed on the first 
treatment must re-sign the informed consent form prior to re-screening and undergo screening 
for the second treatment arm. 


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Follow-up data, including survival and subsequent anti-cancer therapies, will be collected for 
each patient until death, loss to follow-up, withdrawal of consent, study/arm closure, or at least 
1 year after end of treatment, whichever occurs first.  Information regarding the nature and 
duration of subsequent therapies will be collected.
Patients who do not meet the criteria for participation in this study (screen failure) or the 
timeline for the screening window may qualify for re-screening at the investigator's discretion.  
Patients must re-sign the consent form prior to rescreening.  The investigator will record 
reasons for screen failure in the screening log.  
Number of Patients
Approximately 260 patients are anticipated to be enrolled at approximately 60 sites.  Each arm 
will be limited to approximately 25 patients, with the exception of Arms M and O, which will  be 
limited to approximately 10 patients.
Target Population
Inclusion Criteria
Patients must meet the following general inclusion criteria to be eligible to enroll in any 
treatment arm:  

Signed treatment-specific Informed Consent Form

Positive biomarker results from a CLIA-certified or equivalently accredited diagnostic
laboratory and availability of a full report of the testing results.  This may be from a tissue
or blood sample.

For patients with a positive biomarker result from an assay other than a tissue-based
assay conducted by FMI:  Sufficient archival tissue or a recent pretreatment tissue sample
must be available for central testing (i.e. at least 11 slides or equivalent block) unless
approved by Medical Monitor.  If both archival and recent tissues are available, the recent
tissue should be preferentially submitted.

Age 18 years at time of signing Informed Consent Form

Participation in a clinical trial is an appropriate treatment option, in the opinion of the
investigator

Ability to comply with the study protocol

Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic
solid malignancy

Evaluable or measurable disease (i.e., at least one target or non-target lesion per RECIST
V1.1 or one measurable or non-measurable lesion per RANO criteria for patients with
primary CNS tumors)

Eastern Cooperative Oncology Group (ECOG) Performance Status 02

Life expectancy 8 weeks

Adequate hematologic and end-organ function, defined by the following laboratory test
results, obtained within 14 days prior to initiation of study treatment:
-
ANC per arm-specific eligibility criteria
-
Platelet count 100 109/L (100,000/L) without transfusion
-
Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion.
-
AST, ALT, and alkaline phosphatase (ALP) 3 upper limit of normal (ULN), with the
following exceptions:
Patients with documented liver involvement:  AST and ALT 5 ULN
Patients with documented liver or bone involvement:  ALP 5 ULN
-
Total bilirubin 1.5 ULN with the following exception:


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Patients with known Gilbert disease:  total bilirubin 3 ULN
-
Serum creatinine 1.5 mg/dL or Glomerular filtration rate 50 mL/min/1.73 m2 as
calculated through use of the Chronic Kidney Disease Epidemiology Collaboration
equation
Glomerular filtration rate (GFR) estimation:  GFR141 min(Scr/κ, 
1)α max(Scr/κ, 1)-1.209 0.993Age 1.018 [if female] 1.159 [if black] where:
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr/κ or 1, and
max indicates the maximum of Scr/κ or 1
-
Albumin 25 g/L (2.5 g/dL)

Agrees to take measures to prevent pregnancy in the patient or partner

In addition to the general inclusion criteria above, in order to be enrolled in a treatment arm
of the study, patients must meet all of the treatment-specific inclusion criteria for the
respective arm as detailed in the treatment-specific appendix.
Note:  The requirements for enrollment into a specific arm may be more stringent.
Exclusion Criteria
Patients who meet any of the following criteria will be ineligible and excluded from study entry 
in any arm:

Current participation or enrollment in another therapeutic clinical trial
-
Re-screening for a different arm of this study is permitted after disease progression if
another applicable mutation/biomarker is present

Eligible for an approved indication included in the local prescribing information for the
applicable study treatment

Symptomatic or actively progressing CNS metastases
Asymptomatic patients with treated or untreated CNS metastases are eligible, provided
that all of the following criteria are met:
--No ongoing requirement for corticosteroids as therapy for CNS metastases, unless 
noted otherwise in the arm-specific appendix
--No evidence of interim progression between the completion of CNS-directed therapy 
and screening radiographic study
--No history of intracranial hemorrhage or spinal cord hemorrhage
--Evaluable disease must be present outside the CNS

History of leptomeningeal disease, unless noted otherwise in the arm-specific appendix

Wide field radiotherapy within 14 days prior to start of study treatment

Stereotactic radiosurgery within 7 days prior to start of study treatment

Severe infection within 4 weeks prior to initiation of study treatment, including, but not
limited to, hospitalization for complications of infections, or any active infection that, in the
opinion of the investigator, could impact patient safety
--
In the setting of a pandemic or epidemic, screening for active infections should be
considered according to local or institutional guidelines or those of applicable 
professional societies (e.g., American Society of Clinical Oncology [ASCO] or 
European Society for Medical Oncology [ESMO]).

Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to Cycle
1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1;
recovery of treatment-related toxicity consistent with other eligibility criteria
--
Androgen blockage may be continued for male patients with prostate cancer


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
Patients known to be positive for HIV are excluded if they meet any of the following
criteria:
--
CD4+ T-cell count of 350 cells/L
--
Detectable HIV viral load
--
History of an opportunistic infection within the past 12 months
--
On stable antiretroviral therapy for 4 weeks

Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded with
the following exceptions:
--
Patients who are HCV Ab positive but HCV RNA negative due to prior treatment or 
natural resolution are eligible 
--
Patients with untreated HCV may be enrolled if the HCV is stable, the patient is not at 
risk for hepatic decompensation, and the intended treatment is not expected to 
exacerbate the HCV infection 
--
Patients on concurrent HCV treatment may be enrolled if they have HCV below the 
limit of quantification 

Patients known to have active hepatitis B (chronic or acute; defined as having a positive
hepatitis B surface antigen [HBsAg] test)
--
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined
as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible only if they are negative for HBV DNA

History of or concurrent serious medical condition or abnormality in clinical laboratory tests
that, precludes the patient's safe participation in and completion of the study or confounds
the ability to interpret data from the study (e.g., clinically significant cardiovascular,
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures)
--
Patients with well-controlled comorbid disease on a stable treatment regimen for
4 weeks prior to screening are eligible for the study.

History of malignancy other than disease under study within 3 years prior to screening,
with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-
year OS rate 90%), such as adequately treated carcinoma in situ of the cervix,
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or
Stage I uterine cancer

Incomplete recovery from any surgery prior to the start of study treatment that would
interfere with the determination of safety or efficacy of study treatment

Major surgical procedure, other than for diagnosis, or significant traumatic injury within
4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical
procedure during the study

Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months
prior to enrollment, unstable arrhythmias, or unstable angina

Pregnant or breastfeeding, or intending to become pregnant during the study

In addition to the general exclusion criteria above, in order to be enrolled in a treatment
arm of the study, patients must meet all of the treatment-specific exclusion criteria for the
respective arm as detailed in the treatment-specific appendix.
Note:  The requirements for enrollment into a specific arm may be more stringent
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV), occurs or 
the date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  In order to obtain 1-year follow up for all 
patients, LPLV is expected to occur approximately 1 year after the last patient is enrolled.


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Length of Study
In order to obtain 1-year follow up for all patients, LPLV is expected to occur approximately 1 
year after the last patient is enrolled.
Investigational Medicinal Products
Test Products (Investigational Drugs)
Biomarker alteration
Study Treatment
ROS1 gene fusion 
Arm A: Entrectinib
PIK3CA activating mutation
Arm B: Inavolisib (GDC-0077)
Arm K: Ipatasertib + atezolizumab
ALK gene fusion
Arm C: Alectinib
AKT activating mutations and/or PTEN
loss/loss of function
Arm D: Ipatasertib
Arm L: Ipatasertib + atezolizumab
Co-mutation in PI3KCA activating mutation
and AKT activating mutation or PI3KCA 
activating mutation and PTEN loss/loss of 
function
Arm M: Ipatasertib + paclitaxel 
TMB 10/MSI-H/dMMR
Arm E: Atezolizumab + chemotherapya 
Arm N: Atezolizumab + tiragolumab
ERBB2 gene mutation or amplification
without known TMB 10/MSI-H/dMMR
Arm F: Trastuzumab emtansine + 
atezolizumab
Arm G: PH FDC SC
Arm H: PH FDC SC + chemotherapy a
Arm I: Trastuzumab emtansine + tucatinib
ERBB2 gene amplification or mutation and
TMB 10/MSI-H/dMMR 
Arm J: Trastuzumab emtansine + 
atezolizumb  
RET gene fusion 
Arm O: Pralsetinib


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chemochemotherapy; dMMRdeficient mismatch repair; HER2human epidermal growth 
factor receptor 2; IVintravenous; PH FDC SCfixed dose combination of trastuzumab and 
pertuzumab administered subcutaneously; MSI-Hmicrosatellite instability high; 
PI3Kphosphatidylinositol 3-kinase; SCsubcutaneous; TMBtumor mutational burden.
a
Investigator’s choice of docetaxel, paclitaxel, or capecitabine.
Statistical Methods
Primary Analysis
The primary endpoint for this study will be cORR as assessed by the investigator and 
according to the corresponding assessment criteria (RECIST v1.1 or RANO).  The cORR is 
defined as the proportion of patients whose confirmed best response is a CR or PR for those 
with measurable disease and CR for those with non-measurable disease.  Confidence 
intervals at both 70% and 95% nominal levels will be reported using the Clopper-Pearson 
method.  The primary efficacy endpoint will be computed for all treatment arms.  If a patient 
receives at least one dose of study treatment and discontinues the study for any reason before 
confirmed response can be assessed, the patient will be considered a non-responder (not PR 
and not CR) and will be added to the denominator of the computation of cORR.  
Determination of Sample Size  
The focus for this study will be estimation since the study is composed of many single arms 
specific to a targeted therapy.  Estimation of the primary endpoint will be 95% confidence 
intervals using the Clopper-Pearson method.  As such, the maximum margin of error for 
sample sizes 25, 50, and 75 are 20.7%, 14.5%, and 11.8%, respectively.  On a per arm basis, 
if the lower bound of the confidence interval is larger than a benchmark specific to that arm, 
then we will consider the given treatment as a significant improvement over the benchmark.  
Interim Analyses
Non-binding Futility Analyses 
For some arms, limited data are available regarding the efficacy and safety of the treatment 
across the eligible tumor population(s).  Therefore, data from the first 12 efficacy-evaluable 
patients in a given arm will be used to conduct non-binding interim tumor agnostic futility 
analyses.  Futility analyses for some arms may be conducted with the integration of data from 
other ongoing studies (see the Statistical Analysis Plan [SAP] for details).  These analyses 
may be used to identify whether a treatment may be ineffective in a tumor agnostic population 
due to limited or lack of efficacy, and further accrual into such an arm may be stopped.  
Enrollment will not be stopped while awaiting results of the tumor agnostic futility analysis.  To 
perform the analysis we will use Bayesian gating with arm-specific gating criteria and non-
informative prior where futility will be declared if there is a posterior probability of greater than 
60% that the true cORR is less than an arm-specific unacceptable level.
Optional Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct 
additional interim efficacy analyses.  The decision to conduct an optional interim analysis and 
the timing of the analysis will be documented in the Sponsor's trial master file prior to the 
conduct of the interim analysis.  The interim analysis will be performed and interpreted by 
Sponsor study team personnel.
ARM A:  ENTRECTINIB IN PATIENTS WITH ROS1 FUSION-POSITIVE TUMORS
Target Population
To be enrolled in Arm A:  entrectinib treatment, patients must have met and continue to meet 
all general eligibility criteria, in addition to the arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm A: entrectinib 
treatment:


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
ROS1 gene fusion positivity, except patients with non-small cell lung cancer (NSCLC), as 
determined by a Clinical Laboratory Improvement Amendments (CLIA) or equivalently 
certified next-generation sequencing (NGS) assay (tissue or blood)
Gene fusion positivity is defined as a 3’ ROS1 fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain. 

ANC 1000/L within 14 days prior to initiation of study treatment

Ability to swallow entrectinib intact, without chewing, crushing, or opening the 
capsules/tablets

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
1% per year during the treatment period and for at least 5 weeks after the last dose of 
entrectinib; and agreement to refrain from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 
1% per year during the treatment period and for at least 3 months after the last dose of 
entrectinib, and agreement to refrain from donating sperm during this same period.
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm 
A: entrectinib treatment:

ROS1 fusion-positive NSCLC

Prior treatment with crizotinib

Whole-brain radiotherapy and/or stereotactic radiosurgery for CNS disease within 14 days 
prior to the start of entrectinib treatment.

Symptomatic or uncontrolled CNS involvement
--
Patients with CNS involvement, including leptomeningeal carcinomatosis or prior brain 
metastases, which are either asymptomatic or previously treated and controlled, are 
allowed.  
--
Patients requiring corticosteroids must be at stable or decreasing doses for at least 
2 weeks prior to the start of entrectinib treatment.

Requirement for enzyme inducing anti-epileptic drugs (EIAEDs) or use within 14 days or 
5 half lives (whichever is longer) prior to the start of entrectinib treatment
--
The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme 
inducing anti-epileptic drugs (non-EIAEDs). 
--
If patients require an anti-epileptic medication, a cytochrome (CYP) 3A4 non-EIAED 
can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or 
lacosamide.  Moderate inducers of CYP450, such as dexamethasone or other 
glucocorticoids, may be used at the discretion of the investigator.  

History of non-pharmacologically induced prolonged corrected QT (QTc) interval 
(e.g., repeated demonstration of a QTc interval 450 ms from ECGs performed at least 
24 hours apart)

History of recent (within the past 3 months) symptomatic congestive heart failure or ejection 
fraction 50% observed during screening for the study

History of additional risk factors for torsade de pointes (e.g., family history of long QT 
syndrome)

Grade 2 peripheral neuropathy 

Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut 
syndrome) or other malabsorption syndromes that would reasonably affect drug absorption


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
Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase
inhibitorinduced pneumonitis
Note:  Radiation-induced lung disorders are not included in this exclusion criterion.
Test Product (Investigational Drug)
Entrectinib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose of 600 mg/day (three 200-mg capsules per day) once a 
day (QD) until disease progression, intolerable toxicity or consent withdrawal.  Modification may 
be needed in cases of coadministration with moderate or strong CYP3A4 inducers.  For more 
specific dosing instructions, refer to the pharmacy manual.
ARM B:  Inavolisib (GDC-0077) IN PATIENTS WITH PIK3CA ACTIVATING MUTATION-
POSITIVE TUMORS
Target Population
To be enrolled in Arm B:  inavolisib (GDC-0077) treatment, patients must have met and 
continue to meet all general eligibility criteria, in addition to arm-specific criteria below. 
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm B:  inavolisib 
(GDC-0077) treatment:

PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay
(tissue or blood)
PIK3CA mutation positivity is defined by the presence of at least one nucleotide variant 
listed below:
-- H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V
-- Other activating mutations with Medical Monitor approval

ANC 1000/L within 14 days prior to initiation of study treatment

Fasting glucose 126 mg/dL and glycosylated hemoglobin (HbA1c) 5.7%

Willingness and ability to swallow GDC-0077 intact, without chewing, or crushing the tablets

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to
initiating study treatment; agreement to remain abstinent (refrain from heterosexual
intercourse) or use single or combined contraception methods that result in a failure rate of
1% per year during the treatment period and for at least 60 days after the last dose of
inavolisib (GDC-0077); and agreement to refrain from donating eggs during this same
period.  For all other women, documentation must be present in medical history confirming
that patient is not of childbearing potential.

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a
condom plus an additional contraception method that together result in a failure rate of 1%
per year during the treatment period and for at least 98 days after the last dose of inavolisib
(GDC-0077), and agreement to refrain from donating sperm during this same period.
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm B:  
inavolisib (GDC-0077) treatment:

Primary CNS tumors

Type 2 diabetes requiring antihyperglycemic medication or any history of type 1 diabetes
Patients with elevated fasting glucose at baseline (fasting glucose 126 mg/dL 
[7.0 mmol/L]) or HbA1c 5.7% will be excluded from the study


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
Malabsorption syndrome or other condition that would interfere with enteral absorption

Uncontrolled pleural effusion or ascites requiring recurrent drainage procedures twice 
monthly or more frequently 
Indwelling pleural or abdominal catheters may be allowed provided the patient has 
adequately recovered from the procedure, is hemodynamically stable and 
symptomatically improved, and with prior approval from the Medical Monitor 

Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in 
the opinion of the investigator and/or study ophthalmologist, would require medical or 
surgical intervention during the study period to prevent or treat vision loss that might result 
from that condition

Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, 
scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-
associated uveitis in either eye

Patients requiring any daily supplemental oxygen

History of or active inflammatory disease (e.g., Crohn’s disease or ulcerative colitis) or any 
active bowel inflammation (including diverticulitis) 
Patients currently receiving immunosuppressants (e.g., sulfasalazines) are considered
to have active disease and are, therefore, ineligible.

Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab
therapy
Bisphosphonate and denosumab therapy for bone metastases or 
osteopenia/osteoporosis is allowed.

Clinically significant and active history of liver disease, including severe liver impairment 
(ChildPugh score B/C), current alcohol abuse, or cirrhosis 

Congenital long QT syndrome or QT interval corrected using Fridericia’s formula (QTcF) 
470 ms demonstrated by at least two ECGs 30 minutes apart, or family history of 
sudden unexplained death or long QT syndrome

Current treatment with medications that are well known to prolong the QT interval 

Allergy or hypersensitivity to components of the inavolisib (GDC-0077) formulation

Any symptomatic active lung disease, including pneumonitis
Test Product (Investigational Drug)
Inavolisib (GDC-0077) will be self-administered by patients orally at home (except on clinic 
days) at the same time each day, on a starting dose of 9 mg/day (one 9-mg tablet per day) once 
a day (QD) until disease progression, intolerable toxicity or consent withdrawal.  For more 
specific dosing instructions, refer to the pharmacy manual.
ARM C:  ALECTINIB IN PATIENTS WITH ALK REARRANGEMENT-POSITIVE TUMORS
Target Population
To be enrolled in Arm C:  alectinib treatment, patients must have met and continue to meet all 
general eligibility criteria, in addition to the arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm C: alectinib 
treatment:

ALK gene fusion positivity, in indications other than non-small cell lung cancer (NSCLC), as 
determined by a Clinical Laboratory Improvement Amendments (CLIA) or equivalently 
certified next generation sequencing (NGS) assay (tissue or blood)


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Gene fusion positivity is defined as a 3’ ALK fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain. 

ANC 1000/L within 14 days prior to initiation of study treatment

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to
initiating study treatment; agreement to remain abstinent (refrain from heterosexual
intercourse) or use single or combined contraception methods that result in a failure rate of
1% per year during the treatment period and for at least 90 days after the last dose of
alectinib; and agreement to refrain from donating eggs during this same period.

For males with female partners of childbearing potential:  Agreement to remain abstinent
(refrain from heterosexual intercourse) or use a condom plus an additional contraception
method that together result in a failure rate of 1% per year during the treatment period
and for at least 90 days after the last dose of alectinib, and agreement to refrain from
donating sperm during this same period.
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm C: 
alectinib treatment:

ALK-positive NSCLC

Inability to swallow pills

Any gastrointestinal disorder that may affect absorption of oral medications, such as
refractory vomiting, malabsorption syndrome, external biliary shunt, or significant bowel
resection that would preclude absorption of alectinib

Detection of the following ALK point mutations:  I1171N/S, G1202R

Symptomatic or uncontrolled CNS involvement
--
Patients with CNS involvement, including leptomeningeal carcinomatosis or prior brain 
metastases, which are either asymptomatic or previously treated and controlled, are 
allowed.  
--
Patients requiring corticosteroids must be at stable or decreasing doses for at least 
2 weeks prior to the start of alectinib treatment.

Liver disease, characterized by any of the following:
--
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other 
conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices
--
Active autoimmune, alcoholic, or other types of acute hepatitis

History of organ transplant

Symptomatic bradycardia

History of hypersensitivity to any of the additives in the alectinib drug formulation
This includes, but is not limited to, patients with galactose intolerance, a congenital
lactase deficiency, or glucose-galactose malabsorption.
Test Product (Investigational Drug)
Alectinib will be self-administered by patients orally at home (except on clinic days), at the same 
times each day, on a starting dose of 600 mg (four 150-mg capsules) twice a day (BID) until 
disease progression, intolerable toxicity or consent withdrawal.  For more specific dosing 
instructions, refer to the pharmacy manual.


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ARM D:  IPATASERTIB IN PATIENTS WITH PTEN LOSS-OF-FUNCTION OR AKT1/2/3
MUTANT-POSITIVE SOLID TUMORS
Target Population
To be enrolled in Arm D:  ipatisertib treatment, patients must have met and continue to meet all 
general eligibility criteria, in addition to the arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm D:  ipatasertib 
treatment:

AKT1/2/3 mutant positivity or PTEN loss of function, as determined by a Clinical Laboratory 
Improvement Amendments (CLIA) or equivalently certified next-generation sequencing 
(NGS) assay (tissue or blood)
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as listed 
below:
-- AKT1:  E17K; L52R; Q79K
-- AKT2:  E17K
-- AKT3:  E17K; L51R; Q78K
PTEN loss of function is defined as PTEN dominant negative missense mutations or 
deleterious in-frame and missense mutations affecting protein function
Other applicable mutations are eligible with Medical Monitor approval
or PTEN protein loss as determined by a CLIA or equivalently certified 
immunohistochemistry assay 

ANC 1000/L within 14 days prior to initiation of study treatment

Fasting glucose 150 mg/dL and hemoglobin A1c (HbA1c) 7.5%

Ability to swallow ipatasertib intact, without chewing, crushing, or opening the capsules

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib; and agreement to refrain from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 1% 
per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib, and agreement to refrain from donating sperm during this same period.  
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm D: 
ipatasertib treatment:

Triple negative adenocarcinoma of the breast (TNBC)
TNBC tumors are defined as HER2 negative, estrogen receptor (ER) negative, and 
progesterone receptor (PgR) negative:
-- ER or PgR negativity is defined as 1% of tumor cell nuclei immunoreactive to the 
respective hormonal receptor
-- HER2 negativity is assessed by IHC and/or in situ hybridization according to 2018 
American Society of Clinical Oncology/College of American Pathologists 
(ASCO/CAP) guidelines 

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills 

Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
current drug or alcohol abuse, or cirrhosis


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
New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction 
(LVEF) 50%; or active ventricular arrhythmia requiring medication

Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF) 480 milliseconds

History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion (including complete left bundle branch block, second- or third-degree heart block, or 
evidence of prior myocardial infarction)

Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease. 

History of Type I or Type II diabetes mellitus requiring insulin.  
Patients who are on a stable dose of oral diabetes medication 2 weeks prior to 
initiation of study treatment are eligible for enrollment. 

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia 

History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis) 

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A inducers 
within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study 
treatment

Uncontrolled pleural effusion, pericardial effusion, or ascites
Test Product (Investigational Drug)
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) until disease progression, intolerable toxicity or consent withdrawal.  For more specific 
dosing instructions, refer to the pharmacy manual.
ARM E:  ATEZOLIZUMAB PLUS CHEMOTHERAPY IN PATIENTS WITH TMB-H/
MSI-H/DMMR-POSITIVE TUMORS
Target Population
To be enrolled in Arm E:  atezolizumab plus chemotherapy treatment, patients must have met 
and continue to meet all general eligibility criteria, in addition to the arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm E:  atezolizumab 
plus chemotherapy treatment:

Documentation of one of the following biomarkers, as determined by a Clinical Laboratory 
Improvement Amendments (CLIA) or equivalently certified assay (tissue or blood):
--
Tumor mutational burden-high (TMB-H), defined as 10 mutations per megabase
--
Microsatellite instability high (MSI-H)
--
Deficient mismatch repair (dMMR)

ANC 1500/L within 14 days prior to initiation of study treatment

Lymphocyte count 500/L


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
For females of childbearing potential:  Negative serum pregnancy test 7 days prior to
initiating study treatment; agreement to remain abstinent (refrain from heterosexual
intercourse) or use single or combined contraception methods that result in a failure rate of
1% per year during the treatment period and for at least 5 months after the last dose of
atezolizumab or 6 months after the last dose of chemotherapy, whichever is later; and
agreement to refrain from donating eggs during this same period.

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a
condom plus an additional contraception method that together result in a failure rate of 1%
per year during the treatment period and for 3 months after the last dose of chemotherapy
and agreement to refrain from donating sperm during this same period.
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm E:  
atezolizumab plus chemotherapy treatment:

Primary CNS tumors with any of the following characteristics:
--
History of intracranial hemorrhage or spinal cord hemorrhage
--
Neurosurgical resection or brain biopsy to the primary brain tumor within 28 days of
Cycle 1, Day 1

Metastases to the midbrain, pons, medulla, or spinal cord

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium
12 mg/dL, or corrected calcium upper linit of normal  [ULN])

Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV)
Patients with a history of HCV infection but who are negative for HCV RNA by PCR 
will be considered non-infected with HCV.

Active or history of autoimmune disease or immune deficiency, including, but not limited to,
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome,
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple
sclerosis, with the following exceptions:
--
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose
of thyroid replacement hormone are eligible for the study
--
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen
are eligible for the study
--
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
o
Rash must cover 10% of body surface area


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o
Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
o
No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
calcineurin inhibitors, or high potency or oral corticosteroids within the previous
12 months

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Active tuberculosis

Treatment with therapeutic oral or intraveneous (IV) antibiotics within 2 weeks prior to
initiation of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study  

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or
within 5 months after the final dose of atezolizumab

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
antiPD-1, and antiPD-L1 therapeutic antibodies
Patients who have had prior anti-cytotoxic Tlymphocyte-associated protein 4 
(CTLA-4) treatment may be enrolled, provided the following requirements are met:
-- Last dose of anti-CTLA-4 at least 6 weeks prior to enrollment
-- No history of severe immune-related adverse events from the anti-CTLA-4 (National 
Cancer Institute Common Terminology Criteria for Research Adverse Events 
version 5.0 [NCI CTCAE v5.0] Grade 3 and 4) 

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon
and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer)
prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study treatment,
with the following exceptions:
--
Patients who received acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor 
approval has been obtained
--
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or
fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the
atezolizumab formulation
Test Products (Investigational Drugs)
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients on 
Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical 
benefit with approval of Medical Monitor). 


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Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.
Docetaxel, paclitaxel, or capecitabine will be administered per package insert and institutional 
guidelines, including considerations for premedication, supportive medications, infusion times, 
infusion frequency, and total cycle count.
ARM F:  TRASTUZUMAB EMTANSINE PLUS ATEZOLIZUMAB IN PATIENTS WITH ERBB2
AMPLIFICATION OR MUTATION-POSITIVE TUMORS
Target Population
To be enrolled in Arm F:  trastuzumab emtansine plus atezolizumab treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm F:  trastuzumab 
emtansine plus atezolizumab treatment:

ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood)
ERBB2 mutation positivity is defined by selected single nucleotide variants listed
below:
-- Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; 
C311R/S; E321G; C334S
-- Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C
-- Transmembrane domain:  S653C; V659E; G660D; R678Q
-- GFR domain IV:  P551L; R552S
-- Receptor L:  S418T; A440T
Other applicable mutations are eligible with Medical Monitor approval
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of 6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio 2.0 and average HER2 
copy number/cell 4.0 signals/cell

ANC 1200/L within 14 days prior to initiation of study treatment

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
1% per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or 5 months after the last dose of atezolizuamb, whichever is 
longer; and agreement to refrain from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine and agreement to refrain from donating sperm during this same 
period.  
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm F: 
trastuzumab emtansine plus atezolizumab treatment:


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
Breast cancer 

Known tumor mutational burden (TMB) 10, microsatellite instability high (MSI-H), deficient 
mismatch repair (dMMR) status

Metastases to the midbrain, pons, medulla, or spinal cord

History of exposure to the following cumulative doses of anthracyclines as specified below:
--
Doxorubicin 500 mg/m2
--
Liposomal doxorubicin 500 mg/m2
--
Epirubicin 720 mg/m2
--
Mitoxantrone 120 mg/m2
--
Idarubicin 90 mg/m2
If another anthracycline or more than one anthracycline has been used, the cumulative 
dose must not exceed the equivalent of 500 mg/m2 doxorubicin.

Patients who received prior trastuzumab, DS-8201, or other human epidermal growth factor 
receptor 2 (HER2)-targeting agents are eligible

History of severe hypersensitivity to components of the trastuzumab emtansine formulation

Cardiopulmonary dysfunction as defined by any of the following:
--
Uncontrolled hypertension (systolic 150 mmHg and/or diastolic 100 mmHg)
--
Inadequate left ventricular ejection fraction at baseline, 50% by echocardiogram
(ECHO) or multiple-gated acquisition (MUGA)
--
History of symptomatic congestive heart failure Grade 3 per National Cancer Institute
Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) 
--
History of decrease in left ventricular ejection function to 40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment
--
Myocardial infarction or unstable angina within 6 months of enrollment
--
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy 
--
Evidence of transmural infarction on ECG
--
Significant symptoms (Grade 2) relating to left ventricular ejection fraction (LVEF), 
cardiac arrhythmia, or cardiac ischemia 
--
Serious cardiac arrhythmia not controlled by adequate medication

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, or sclerosis cholangitis 

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, 
calcium 12 mg/dL, or corrected calcium upper limite of normal [ULN])

Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV)
--
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV

Grade 3 peripheral neuropathy, as defined by National Cancer Institute Common 
Terminology Criteria for Research Adverse Events version 5.0 [NCI CTCAE v5.0]

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:
--
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid replacement hormone are eligible for the study


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--
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen 
are eligible for the study
--
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
o
Rash must cover 10% of body surface area
o
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
o
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 
12 months

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study 
entry
Symptomatic lesions (e.g., bone metastases or metastases causing 
nerve impingement) amenable to palliative radiotherapy should be 
treated 14 days prior to Cycle 1, Day 1.  The patient must have 
recovered from any resulting acute toxicity (to Grade 1) prior to study 
treatment initiation
Asymptomatic metastatic lesions that would likely cause functional 
deficits or intractable pain with further growth (e.g., epidural metastasis 
that is not currently associated with spinal cord compression) should be 
considered for loco-regional therapy if appropriate prior to enrollment

Symptomatic pleural effusion, pericardial effusion, or ascites.  History of idiopathic 
pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan.  Patients with a 
history of radiation pneumonitis in the radiation field (fibrosis) are eligible. 

Active tuberculosis

Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab

Current treatment with anti-viral therapy for hepatitis B virus (HBV)

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer)
prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor-alpha (TNF-α) agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study treatment, 
with the following exceptions:
--
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor 
confirmation has been obtained


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--
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids
for orthostatic hypotension or adrenal insufficiency are eligible for the study

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation
Test Products (Investigational Drugs)
Atezolizumab will be administered first followed by trastuzumab emtansine.  Atezolizumab will 
be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle until 
unacceptable toxicity or progressive disease (or loss of clinical benefit with Medical Monitor 
approval).  Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.  The size 
of the infusion bag for each dose is listed below and will accommodate fluid restrictions needed 
for smaller patients.
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 21 days 
(unless dose reduction and/or dose delays are required) until disease progression or 
unacceptable toxicity.  The dose of trastuzumab emtansine will be administered on the basis of 
the patient’s baseline weight.  Weight will be measured at each visit and dose must be 
re-adjusted for weight changes 10% compared to the previous visit or baseline.  The 
investigator may choose to recalculate the dose at every cycle using actual weight at that time, 
according to their local practice.  
ARM G:  PH FDC SC IN PATIENTS WITH ERBB2 AMPLIFICATION OR MUTATION-
POSITIVE TUMORS
Target Population
To be enrolled in Arm G:  fixed dose combination of trastuzumab and pertuzumab administered 
subcutaneously (PH FDC SC) treatment, patients must have met and continue to meet all
general eligibility criteria, in addition to the arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm G:  PH FDC SC 
treatment:

ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood)
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below:
-- Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y;
C311R/S; E321G; C334S
-- Kinase domain: T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD);
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C
-- Transmembrane domain:  S653C; V659E; G660D; R678Q
-- GFR domain IV:  P551L; R552S
-- Receptor L:  S418T; A440T
Other applicable mutations are eligible with Medical Monitor approval
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of 6 for NGS 


MyTACTIC Study—Genentech, Inc.
39/ Protocol ML42439, Version 4
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio 2.0 and average HER2 
copy number/cell 4.0 signals/cell

Intact skin at planned site of subcutaneous (SC) injections (thigh)

ANC 1000/L within 14 days prior to initiation of study treatment

Baseline and most recent (within 3 months) left ventricular ejection fraction (LVEF) 50%
measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to
initiating study treatment; agreement to remain abstinent (refrain from heterosexual
intercourse) or use single or combined contraception methods that result in a failure rate of
1% per year during the treatment period and for at least 7 months after the last dose of
PH FDC SC; and agreement to refrain from donating eggs during this same period.

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a
condom plus an additional contraception method that together result in a failure rate of
1% per year during the treatment period and for at least 7 months after the last dose of
PH FDC SC, and agreement to refrain from donating sperm during this same period.
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm G: 
PH FDC SC treatment: 

Breast cancer

Known tumor mutational burden (TMB) 10, microsatellite instability high (MSI-H), deficient
mismatch repair (dMMR) status

History of National Cancer Institute Common Terminology Criteria for Adverse Events
version 5.0 (NCI CTCAE v5.0) Grade 3 symptomatic congestive heart failure (CHF)

In addition to the core exclusion criterion for significant cardiovascular disease, patients
will be excluded if they have any of the following:
--
High-risk arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at rest, significant
ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block, 
such as second-degree AV-block Type 2 [Mobitz type II] or third-degree AV-block) not 
controlled by adequate medication
--
Evidence of transmural infarction on ECG
--
Evidence of myocardial infarction within 12 months prior to enrollment, cerebrovascular 
accident within 3 months prior to enrollment
--
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg)
--
Angina pectoris requiring anti-angina medication
--
Clinically significant valvular heart disease

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as
structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g.,
hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained
death or long QT syndrome

Known active liver disease, for example, autoimmune hepatic disorders, or sclerosing
cholangitis

Current treatment with anti-viral therapy for hepatitis B virus (HBV)

Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins

Previously experienced severe injection related reactions with pertuzumab plus
trastuzumab IV and/or PH FDC SC


MyTACTIC Study—Genentech, Inc.
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
Current chronic daily treatment with corticosteroids (dose 10 mg methylprednisolone or 
equivalent excluding inhaled steroids)
Test Product (Investigational Drug)
PH FDC SC is given as a fixed dose (i.e. non-weight based) by SC injection.  Two doses of 
PH FDC SC may be administered in the study:  a 15 mL loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab and a 10 mL maintenance dose consisting of 600 mg 
pertuzumab and 600 mg trastuzumab.  Patients who have had 6 weeks since a prior dose of 
Perjeta and Herceptin intravenous (IV) or PH FDC subcutaneous (SC) at study entry, or have 
had 6 weeks since their last study treatment during the study treatment periods, must receive 
a loading dose before continuing with maintenance doses for subsequent administrations. 
ARM H:  PH FDC SC PLUS CHEMOTHERAPY IN PATIENTS WITH ERBB2 AMPLIFICATION 
OR MUTATION-POSITIVE TUMORS-POSITIVE TUMORS
Target Population
To be enrolled in Arm H:  fixed dose combination of trastuzumab and pertuzumab administered 
subcutaneously (PH FDC SC) plus chemotherapy treatment, patients must have met and 
continue to meet all general eligibility criteria, in addition to the arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm H:  PH FDC SC 
plus chemotherapy treatment:

ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood)
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below:
-- Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y;
C311R/S; E321G; C334S
-- Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD);
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C
-- Transmembrane domain:  S653C; V659E; G660D; R678Q
-- GFR domain IV:  P551L; R552S
-- Receptor L:  S418T; A440T
Other applicable mutations are eligible with Medical Monitor approval
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of 6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio 2.0 and average HER2 
copy number/cell 4.0 signals/cell

Intact skin at planned site of subcutaneous (SC) injections (thigh)

ANC 1500/L within 14 days prior to initiation of study treatment

Baseline and most recent (witin 3 months) left ventricular ejection fraction (LVEF) 50% 
measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) 

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
1% per year during the treatment period and for at least 7 months after the last dose of PH 
FDC SC or 6 months after the last dose of chemotherapy, whichever is later; and 
agreement to refrain from donating eggs during this same period.  


MyTACTIC Study—Genentech, Inc.
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
For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 1% 
per year during the treatment period and for at least 7 months after the last dose of PH FDC 
SC or for 3 months after the last dose of chemotherapy, whichever is longer, and 
agreement to refrain from donating sperm during this same period.  
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm H: 
PH FDC SC plus chemotherapy treatment: 

Breast cancer 

Known tumor mutational burden (TMB) 10, microsatellite instability high (MSI-H), deficient 
mismatch repair (dMMR) status

History of National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 5.0 (NCI CTCAE v5.0) Grade 3 symptomatic congestive heart failure (CHF) 

In addition to the core exclusion criterion for significant cardiovascular disease, patients 
will be excluded if they have any of the following: 
--
High-risk arrhythmias (i.e., atrial tachycardia with a heart rate 100/min at rest, significant 
ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block, 
such as second-degree AV-block Type 2 [Mobitz type II] or third-degree AV-block) not 
controlled by adequate medication
--
Evidence of transmural infarction on ECG
--
Evidence of myocardial infarction within 12 months prior to enrollment, cerebrovascular 
accident within 3 months prior to enrollment
--
Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg)
--
Angina pectoris requiring anti-angina medication
--
Clinically significant valvular heart disease

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left 
ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., 
hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained 
death or long QT syndrome

Known active liver disease, for example, autoimmune hepatic disorders, or sclerosing 
cholangitis

Current treatment with anti-viral therapy for hepatitis B virus (HBV)

Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins

Previously experienced severe injection related reactions with pertuzumab plus 
trastuzumab IV and/or PH FDC SC

Current chronic daily treatment with corticosteroids (dose 10 mg methylprednisolone or 
equivalent excluding inhaled steroids)
Test Products (Investigational Drugs)
PH FDC SC is given as a fixed dose (i.e. non-weight based) by SC injection.  Two doses of 
PH FDC SC may be administered in the study:  a 15 mL loading dose consisting of 1200 mg 
pertuzumab and 600 mg trastuzumab and a 10 mL maintenance dose consisting of 600 mg 
pertuzumab and 600 mg trastuzumab.  Patients who have had 6 weeks since a prior dose of 
Perjeta and Herceptin intravenous (IV) or PH FDC SC at study entry, or have had 6 weeks 
since their last study treatment during the study treatment periods, must receive a loading dose 
before continuing with maintenance doses for subsequent administrations. 
Docetaxel, paclitaxel, or capecitabine will be administered per package insert and institutional 
guidelines, including considerations for premedication, supportive medications, infusion times, 
infusion frequency, and total cycle count.


MyTACTIC Study—Genentech, Inc.
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ARM I:  TRASTUZUMAB EMTANSINE PLUS TUCATINIB IN PATIENTS WITH ERBB2
AMPLIFICATION OR MUTATION-POSITIVE TUMORS
Target Population
To be enrolled in Arm I: trastuzumab emtansine plus tucatinib treatment, patients must have 
met and continue to meet all general eligibility criteria, in addition to the arm-specific criteria 
below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm I:  trastuzumab 
emtansine plus tucatinib treatment:

ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood)
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below:
-- Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y;
C311R/S; E321G; C334S
-- Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C
-- Transmembrane domain:  S653C; V659E; G660D; R678Q
-- GFR domain IV:  P551L; R552S
-- Receptor L:  S418T; A440T
Other applicable mutations are eligible with Medical Monitor approval
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of 6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio 2.0 and average HER2 
copy number/cell 4.0 signals/cell

ANC 1200/L within 14 days prior to initiation of study treatment

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
1% per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or at least 1 week after last administration of tucatinib, whichever is 
longer; and agreement to refrain from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or at least 1 week after last dose of tucatinib, whichever is longer 
and agreement to refrain from donating sperm during this same period.  
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm I:  
trastuzumab emtansine plus tucatinib treatment:

Breast cancer 

History of exposure to the following cumulative doses of anthracyclines as specified below:
--
Doxorubicin 500 mg/m2
--
Liposomal doxorubicin 500 mg/m2


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--
Epirubicin 720 mg/m2
--
Mitoxantrone 120 mg/m2
--
Idarubicin 90 mg/m2
If another anthracycline or more than one anthracycline has been used, the cumulative 
dose must not exceed the equivalent of 500 mg/m2 doxorubicin.

Patients who received prior trastuzumab, DS-8201, or other human epidermal growth factor
receptor 2 (HER2)-targeting agents are eligible

History of severe hypersensitivity to components of the trastuzumab emtansine or tucatinib
formulations

Cardiopulmonary dysfunction as defined by any of the following:
--
Uncontrolled hypertension (systolic 150 mmHg and/or diastolic 100 mmHg)
--
Inadequate left ventricular ejection fraction at baseline, 50% by echocardiogram
(ECHO) or multiple-gated acquisition (MUGA)
--
History of symptomatic congestive heart failure Grade 3 per National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) 
--
History of decrease in left ventricular ejection function to 40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment
--
Myocardial infarction or unstable angina within 6 months of enrollment
--
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy 
--
Evidence of transmural infarction on ECG
--
Significant symptoms (Grade 2) relating to left ventricular ejection fraction (LVEF), 
cardiac arrhythmia, or cardiac ischemia 
--
Serious cardiac arrhythmia not controlled by adequate medication

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse,
autoimmune hepatic disorders, sclerosis cholangitis

Have used a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor,
or have used a strong CYP3A4 or CYP2C8 inducer within 5 day prior to start of treatment

Grade 3 peripheral neuropathy, as defined by NCI CTCAE v5.0

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
Test Product (Investigational Drug)
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 21 days 
(unless dose reduction and/or dose delays are required) until disease progression or 
unacceptable toxicity.  The dose of trastuzumab emtansine will be administered on the basis of 
the patient’s baseline weight.  Weight will be measured at each visit and dose must be 
re-adjusted for weight changes 10% compared to the previous visit or baseline.  The 
investigator may choose to recalculate the dose at every cycle using actual weight at that time, 
according to their local practice.  
Tucatinib drug product may be supplied as both a coated yellow oval-shaped tablet in a 150 mg 
dosage strength and a coated yellow round convex tablet in a 50 mg dosage strength.  The 
tablets are manufactured from a drug product intermediate amorphous dispersion of tucatinib in 
polyvinylpyrrolidone-vinyl acetate copolymer, which is then combined with the pharmaceutical 
excipients (microcrystalline cellulose, sodium chloride, potassium chloride, sodium bicarbonate, 
silicon dioxide, crospovidone, and magnesium stearate), and compressed into tablets.


MyTACTIC Study—Genentech, Inc.
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ARM J:  TRASTUZUMAB EMTANSINE PLUS ATEZOLIZUMAB IN PATIENTS WITH ERBB2-
AMLIFICATION or MUTATAION AND TMB-H/MSI-H/DMMR TUMORS
Target Population
To be enrolled in Arm J: trastuzumab emtansine plus atezolizumab treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm J:  trastuzumab 
emtansine plus atezolizumab treatment:

ERBB2 mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood)
ERBB2 mutation positivity is defined by selected single nucleotide variants listed 
below:
-- Furin-like domain:  G222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; 
C311R/S; E321G; C334S
-- Kinase domain:  T733I; L755P/S; L755_T759del; I767M; L768S; D769H/N/Y; 
Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C
-- Transmembrane domain:  S653C; V659E; G660D; R678Q
-- GFR domain IV:  P551L; R552S
-- Receptor L:  S418T; A440T
Other applicable mutations are eligible with Medical Monitor approval
or evidence of ERBB2 gene amplification determined by CLIA or equivalently certified in-
situ hybridization or NGS assay. Amplification is defined as a copy number of 6 for NGS 
assays or, for in-situ hybridization assays, as a HER2:CEP17 ratio 2.0 and average HER2 
copy number/cell 4.0 signals/cell

Documentation of one of the following biomarkers, as determined by a CLIA or equivalently 
certified assay (tissue or blood):
--
Tumor mutational burden high (TMB-H) high, defined as 10 mutations per megabase
--
Microsatellite instability high (MSI-H)
--
Deficient mismatch repair (dMMR) 

ANC 1200/L within 14 days prior to initiation of study treatment

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate of 
1% per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine or 5 months after the last dose of atezolizuamb, whichever is 
longer; and agreement to refrain from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom plus an additional contraception method that together result in a failure rate of 1% 
per year during the treatment period and for at least 7 months after the last dose of 
trastuzumab emtansine and agreement to refrain from donating sperm during this same 
period.  
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into Arm J:
trastuzumab emtansine plus atezolizumab treatment:

Breast cancer 


MyTACTIC Study—Genentech, Inc.
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
Metastases to the midbrain, pons, medulla, or spinal cord

History of exposure to the following cumulative doses of anthracyclines as specified below:
--
Doxorubicin 500 mg/m2
--
Liposomal doxorubicin 500 mg/m2
--
Epirubicin 720 mg/m2
--
Mitoxantrone 120 mg/m2
--
Idarubicin 90 mg/m2
If another anthracycline or more than one anthracycline has been used, the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.

Patients who received prior trastuzumab, DS-8201, or other human epidermal growth factor 
receptor 2 (HER2)-targeting agents are eligible

History of severe hypersensitivity to components of the trastuzumab emtansine formulation

Cardiopulmonary dysfunction as defined by any of the following:
--
Uncontrolled hypertension (systolic 150 mmHg and/or diastolic 100 mmHg)
--
Inadequate left ventricular ejection fraction (LVEF) at baseline, 50% by 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA)
--
History of symptomatic congestive heart failure Grade 3 per National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) or 
Class II New York Heart Association
--
History of decrease in left ventricular ejection function to 40% or symptomatic 
congestive heart failure (CHF) with prior trastuzumab treatment
--
Myocardial infarction or unstable angina within 6 months of enrollment
--
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy 
--
Evidence of transmural infarction on ECG
--
Significant symptoms (Grade 2) relating to LVEF, cardiac arrhythmia, or cardiac 
ischemia 
--
Serious cardiac arrhythmia not controlled by adequate medication

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, sclerosis cholangitis 

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, 
calcium 12 mg/dL, or corrected calcium upper limite of normal [ULN])

Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV)
--
Patients with a history of HCV infection but who are negative for HCV RNA by PCR will 
be considered non-infected with HCV

Grade 3 peripheral neuropathy, as defined by NCI CTCAE v5.0

Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:
--
Patients with a history of autoimmune-related hypothyroidism who are on a stable dose 
of thyroid replacement hormone are eligible for the study
--
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen 
are eligible for the study


MyTACTIC Study—Genentech, Inc.
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--
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
o
Rash must cover 10% of body surface area
o
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
o
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 
12 months

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study 
entry.
Symptomatic lesions (e.g., bone metastases or metastases causing 
nerve impingement) amenable to palliative radiotherapy should be 
treated 14 days prior to Cycle 1, Day 1.  The patient must have 
recovered from any resulting acute toxicity (to Grade 1) prior to study 
treatment initiation.
Asymptomatic metastatic lesions that would likely cause functional 
deficits or intractable pain with further growth (e.g., epidural metastasis 
that is not currently associated with spinal cord compression) should be 
considered for loco-regional therapy if appropriate prior to enrollment.

Symptomatic pleural effusion, pericardial effusion, or ascites.  History of idiopathic 
pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan.  Patients with a 
history of radiation pneumonitis in the radiation field (fibrosis) are eligible. 

Active tuberculosis

Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are 
eligible for the study

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab

Current treatment with anti-viral therapy for hepatitis B virus (HBV)

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of 
need for systemic immunosuppressive medication during study treatment, with the following 
exceptions:
--
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor 
confirmation has been obtained


MyTACTIC Study—Genentech, Inc.
47/ Protocol ML42439, Version 4
--
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation
Test Product (Investigational Drug)
Atezolizumab will be administered first followed by trastuzumab emtansine.  Atezolizumab will 
be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle until 
unacceptable toxicity or progressive disease (or loss of clinical benefit with Medical Monitor 
approval).  Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.  The size 
of the infusion bag for each dose is listed below and will accommodate fluid restrictions needed 
for smaller patients.
Trastuzumab emtansine is administered intravenously at 3.6 mg/kg by IV infusion every 21 days 
(unless dose reduction and/or dose delays are required) until disease progression or 
unacceptable toxicity.  The dose of trastuzumab emtansine will be administered on the basis of 
the patient’s baseline weight.  Weight will be measured at each visit and dose must be 
re-adjusted for weight changes 10% compared to the previous visit or baseline.  The 
investigator may choose to recalculate the dose at every cycle using actual weight at that time, 
according to their local practice.
ARM K:  IPATASERTIB PLUS ATEZOLIZUMAB IN PATIENTS WITH PIK3CA 
ACTIVATING MUTATION POSITIVE TUMORS
Target Population
To be enrolled in Arm K: ipatasertib in combination with atezolizumab treatment, patients 
must have met and continue to meet all general eligibility criteria, in addition to the 
arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm K: 
ipatasertib in combination with atezolizumab treatment:

PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay 
(tissue or blood)
PIK3CA mutation positivity is defined by the presence of at least one nucleotide 
variant listed below:
-- H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V
-- Kinase domain:  T733I; L755P/S; I767M; L768S; D769H/N/Y; Y772_A775dup; 
A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); L755P/S/_T759del; 
G776delins(VC/VV/LC); V777L;  G778_P780dup; V779A/L; T798M; L841V; V842I; 
N857S; T862A; L869R; H878Y; R896C
Other activating mutations with Medical Monitor approval

No available acceptable treatment for malignancy that is expected to provide clinical 
benefit

ANC 1000/l within 14 days prior to initiation of study treatment

Fasting glucose 150 mg/dL and hemoglobin A1c (HbA1c) 7.5%

Ability to swallow ipatasertib intact, without chewing, crushing, or opening the capsules


MyTACTIC Study—Genentech, Inc.
48/ Protocol ML42439, Version 4

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate 
of 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib and 5 months after the last dose of atezolizumab; and agreement to refrain 
from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom plus an additional contraception method that together result in a failure rate of 
1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib, and agreement to refrain from donating sperm during this same period.  
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm K: ipatasertib plus atezolizumab treatment:

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Use of an indwelling catheter (e.g., PleurX®) is allowed.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at 
study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated 
prior to enrollment.  Patients should be recovered from the effects of 
radiation.  There is no required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional 
deficits or intractable pain with further growth (e.g., epidural 
metastasis that is not presently associated with spinal cord 
compression) should be considered for loco-regional therapy if 
appropriate prior to enrollment.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12 
mg/dL, or corrected serum calcium ULN)

Active or history of autoimmune disease or immune deficiency, including, but not limited 
to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are 
on thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on a stable 
insulin regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo 
with dermatologic manifestations only (e.g., patients with psoriatic 
arthritis are excluded) are eligible for the study provided all of 
following conditions are met:
-- Rash must cover 10% of body surface area
-- Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
-- No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan


MyTACTIC Study—Genentech, Inc.
49/ Protocol ML42439, Version 4
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Active tuberculosis

Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to
initiation of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study  

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or
within 5 months after the final dose of atezolizumab

Prior treatment with anti-PD-1 or anti PD-L1 therapeutics unless approved by Medical
Monitor
-- Up to approximately 12 such patients may be enrolled

Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives
(whichever is longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
antitumor necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of
study treatment, or anticipation of need for systemic immunosuppressive medication
during study treatment, with the following exceptions:
--
Patients who received acute, low-dose systemic immunosuppressant medication or a one-time
pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a 
contrast allergy) are eligible for the study after Medical Monitor approval has been obtained
--
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic 
obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic 
hypotension or adrenal insufficiency are eligible for the study

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or
fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation

Prior treatment with ipatasertib or other Akt inhibitors

History of malabsorption syndrome or other condition that would interfere with enteral
absorption or results in the inability or unwillingness to swallow pills

Known clinically significant history of liver disease consistent with Child-Pugh Class B
or C, current drug or alcohol abuse, or cirrhosis

New York Heart Association Class II, III, or IV heart failure; left ventricular ejection
fraction (LVEF) 50%; or active ventricular arrhythmia requiring medication

Congenital long QT syndrome or screening QT interval corrected using Fridericia's
formula (QTcF) 480 milliseconds

History or presence of an abnormal ECG that is clinically significant in the investigator's
opinion (including complete left bundle branch block, second- or third-degree heart block,
or evidence of prior myocardial infarction)

Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an equivalent
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic
disease.

History of Type I or Type II diabetes mellitus requiring insulin.
Patients who are on a stable dose of oral diabetes medication 2 weeks 
prior to initiation of study treatment are eligible for enrollment. 


MyTACTIC Study—Genentech, Inc.
50/ Protocol ML42439, Version 4
Diabetic patients with fasting total serum glucose 8.3 mmol/L 
(150 mg/dL) and/or HbA1C 7.5 are not eligible for enrollment.

History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative
colitis) or active bowel inflammation (e.g., diverticulitis)

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A
inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to
initiation of study treatment

Uncontrolled pleural effusion, pericardial effusion, or ascites
Test Product (Investigational Drug)
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) until disease progression, intolerable toxicity or consent withdrawal.  For more specific 
dosing instructions, refer to the pharmacy manual.  
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients on 
Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of 
clinical benefit with Medical Monitor approval).
ARM L: IPATASERTIB PLUS ATEZOLIZUMAB IN PATIENTS WITH PTEN LOSS/ 
LOSS OF FUNCTION OR AKT ACTIVATING MUTATIONPOSITIVE TUMORS
Target Population
To be enrolled in Arm L: ipatasertib in combination with atezolizumab treatment, patients 
must have met and continue to meet all general eligibility criteria, in addition to the 
arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm L: 
ipatasertib in combination with atezolizumab treatment:

AKT1/2/3 mutant positivity, as determined by a Clinical Laboratory Improvement
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) assay
(tissue or blood)
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as listed 
below:
-- AKT1:  E17K; L52R; Q79K
-- AKT2:  E17K
-- AKT3:  E17K; L51R; Q78K
or PTEN protein loss of function or protein loss as determined by a CLIA or equivalently 
certified tissue-based NGS, in situ hybridization (ISH), or immunohistochemistry (IHC) 
assay 

No available acceptable treatment for malignancy that is expected to provide clinical benefit

ANC 1000/l within 14 days prior to initiation of study treatment

Fasting glucose 150 mg/dL and hemoglobin A1c (HbA1c) 7.5%

Ability to swallow ipatasertib intact, without chewing, crushing, or opening the capsules


MyTACTIC Study—Genentech, Inc.
51/ Protocol ML42439, Version 4

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate 
of 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib and 5 months after the last dose of atezolizumab; and agreement to refrain 
from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom plus an additional contraception method that together result in a failure rate of 
1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib, and agreement to refrain from donating sperm during this same period.  
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm L: ipatasertib plus atezolizumab treatment:

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Use of an indwelling catheter (e.g., PleurX®) is allowed.

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment.  Patients 
should be recovered from the effects of radiation.  There is no required minimum 
recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not presently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12 
mg/dL, or corrected serum calcium ULN)

Active or history of autoimmune disease or immune deficiency, including, but not limited 
to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are 
on thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on a stable 
insulin regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo 
with dermatologic manifestations only (e.g., patients with psoriatic 
arthritis are excluded) are eligible for the study provided all of 
following conditions are met:
-- Rash must cover 10% of body surface area
-- Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
-- No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan


MyTACTIC Study—Genentech, Inc.
52/ Protocol ML42439, Version 4
History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted.

Active tuberculosis

Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary 
tract infection or chronic obstructive pulmonary disease exacerbation) 
are eligible for the study  

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab

Prior treatment with anti-PD-1 or anti PD-L1 therapeutics unless approved by Medical 
Monitor
--
Up to approximately 12 such patients may be enrolled

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives 
(whichever is longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions:
--
Patients who received acute, low-dose systemic immunosuppressant medication or a one-time 
pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a 
contrast allergy) are eligible for the study after Medical Monitor approval has been obtained
--
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic 
obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic 
hypotension or adrenal insufficiency are eligible for the study

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of 
the atezolizumab formulation

Prior treatment with ipatasertib or other Akt inhibitors

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills 

Known clinically significant history of liver disease consistent with Child-Pugh Class B 
or C, current drug or alcohol abuse, or cirrhosis

New York Heart Association Class II, III, or IV heart failure; left ventricular ejection 
fraction (LVEF) 50%; or active ventricular arrhythmia requiring medication

Congenital long QT syndrome or screening QT interval corrected using Fridericia's 
formula (QTcF) 480 milliseconds 

History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion (including complete left bundle branch block, second- or third-degree heart block, 
or evidence of prior myocardial infarction)

Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease. 

History of Type I or Type II diabetes mellitus requiring insulin.  


MyTACTIC Study—Genentech, Inc.
53/ Protocol ML42439, Version 4
Patients who are on a stable dose of oral diabetes medication 2 weeks prior to 
initiation of study treatment are eligible for enrollment. 
Diabetic patients with fasting total serum glucose 8.3 mmol/L (150 mg/dL) and/or 
HbA1C 7.5 are not eligible for enrollment.

History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative 
colitis) or active bowel inflammation (e.g., diverticulitis) 

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A 
inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to 
initiation of study treatment 

Uncontrolled pleural effusion, pericardial effusion, or ascites
Test Product (Investigational Drug)
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) until disease progression, intolerable toxicity or consent withdrawal.  For more specific 
dosing instructions, refer to the pharmacy manual.  
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg for patients on 
Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of 
clinical benefit with Medical Monitor approval).
ARM M: Ipatasertib Plus Paclitaxel In Patients With Co-Mutations In PIK3CA
Activating Mutations And PTEN Loss/ Loss-of-Function or AKT Activating 
Mutation-Positive Tumors
Target Population
To be enrolled in Arm M: ipatasertib in combination with paclitaxel treatment, patients must 
have met and continue to meet all general eligibility criteria, in addition to the arm-specific 
criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm M: 
ipatasertib in combination with paclitaxel treatment:

A co-mutation of either PIK3CA activating mutation and AKT activating mutation or a 
PIK3CA activating mutation and PTEN loss or loss of function based on the following 
biomarkers:
--
PIK3CA mutation positivity, as determined by a Clinical Laboratory Improvement 
Amendments (CLIA) or equivalently certified next-generation sequencing (NGS) 
assay (tissue or blood)
PIK3CA mutation positivity is defined by the presence of at least one nucleotide 
variant listed below:
o
H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, 
E453A/D/G/K/Q/V, E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, 
G106A/D/R/S/V, N345D/H/I/K/S/T/Y, G118D, C420R, R88Q, M1043I/T/V
o
Other activating mutations with Medical Monitor approval
--
AKT1/2/3 mutant positivity, as determined by a Clinical Laboratory 
Improvement Amendments (CLIA) or equivalently certified next-generation 
sequencing (NGS) assay (tissue or blood)
AKT1/2/3 mutant positivity is defined by selected single nucleotide variants as 
listed below:
o
AKT1:  E17K; L52R; Q79K


MyTACTIC Study—Genentech, Inc.
54/ Protocol ML42439, Version 4
o
AKT2:  E17K
o
AKT3:  E17K; L51R; Q78K
or PTEN protein loss of function or protein loss as determined by a CLIA or 
equivalently certified tissue-based NGS, in situ hybridization (ISH), or 
immunohistochemistry (IHC) assay 

ANC 1500/l within 14 days prior to initiation of study treatment

Fasting glucose 150 mg/dL and hemoglobin A1c (HbA1c) 7.5%

Ability to swallow ipatasertib intact, without chewing, crushing, or opening the capsules

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to
initiating study treatment; agreement to remain abstinent (refrain from heterosexual
intercourse) or use single or combined contraception methods that result in a failure rate
of 1% per year during the treatment period and for at least 28 days after the last dose of
ipatasertib and 6 months after the last dose of paclitaxel, whichever occurs later, and
agreement to refrain from donating eggs during this same period.

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use
a condom plus an additional contraception method that together result in a failure rate of
1% per year during the treatment period and for at least 28 days after the last dose of
ipatasertib, and 6 months after the last dose of paclitaxel, whichever occurs later and
agreement to refrain from donating sperm during this same period.
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm M: ipatasertib in combination with paclitaxel treatment:

History of malabsorption syndrome or other condition that would interfere with enteral
absorption or results in the inability or unwillingness to swallow pills

Known clinically significant history of liver disease consistent with Child-Pugh Class B
or C, current drug or alcohol abuse, or cirrhosis

New York Heart Association Class II, III, or IV heart failure; left ventricular ejection
fraction (LVEF) 50%; or active ventricular arrhythmia requiring medication

Congenital long QT syndrome or screening QT interval corrected using Fridericia's
formula (QTcF) 480 milliseconds

History or presence of an abnormal ECG that is clinically significant in the investigator's
opinion (including complete left bundle branch block, second- or third degree heart block,
or evidence of prior myocardial infarction)

Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an equivalent
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic
disease

Unresolved, clinically significant toxicity from prior therapy, except for alopecia and
Grade 1 peripheral neuropathy

Uncontrolled pleural effusion, pericardial effusion, or ascites
Patients with indwelling catheters (e.g., PleurX) are allowed. 

Uncontrolled tumor-related pain
--
Patients requiring pain medication must be on a stable regimen at study entry
--
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement)
amenable to palliative radiotherapy should be treated 14 days prior to Cycle 1, Day 
1. The patient must have recovered from any resulting acute toxicity (to Grade 1)
prior to study treatment initiation
--
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 


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associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium, 12 mg/dL calcium, or 
corrected serum calcium ULN) or symptomatic hypercalcemia requiring continued use 
of bisphosphonate therapy 

History of Type I or Type II diabetes mellitus requiring insulin.  
Patients who are on a stable dose of oral diabetes medication 2 weeks prior to initiation 
of study treatment are eligible for enrollment. 

Grade 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia 

History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative 
colitis) or active bowel inflammation (e.g., diverticulitis) 

Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia)

Treatment with strong cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A 
inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to 
initiation of study treatment 

Prior treatment with an Akt inhibitor

Note that prior PI3K or mTOR inhibitors are allowed.

Known hypersensitivity or contraindication to any component of the study treatments, 
including the paclitaxel excipient macrogolglycerol ricinoleate 

Grade 2 peripheral neuropathy

Prior treatment with paclitaxel treatment 
Test Product (Investigational Drug)
Ipatasertib will be self-administered by patients orally at home (except on clinic days), at the 
same time each day, on a starting dose 400 mg/day (two 200-mg tablets per day) once a day 
(QD) until disease progression, intolerable toxicity or consent withdrawal.  For more specific 
dosing instructions, refer to the pharmacy manual.  
The dose of paclitaxel in this study is 80 mg/m2 administered by IV infusion on Days 1, 8, 
and 15 of each 28-day cycle. The paclitaxel infusion will be delivered over at least 60 minutes 
for each dose per institutional guidelines and administered after the oral dose of ipatasertib.
ARM N: Atezolizumab plus Tiragolumab in Patients with TMB-H/MSI-H/dMMR-
Positive Tumors
Target Population
To be enrolled in Arm N: atezolizumab plus tiragolumab treatment, patients must have met 
and continue to meet all general eligibility criteria, in addition to the arm-specific criteria 
below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm N: 
atezolizumab plus tiragolumab treatment:

Documentation of one of the following biomarkers, as determined by a CLIA or 
equivalently certified assay (tissue or blood):
--
Tumor mutational burden high (TMB-H) high, defined as 10 mutations per 
megabase
--
Microsatellite instability high (MSI-H) 
--
Deficient mismatch repair (dMMR) 

ANC 1200/L within 14 days prior to initiation of study treatment


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
Lymphocyte count 500/L

Eastern Cooperative Oncology Group (ECOG) Performance Status 02

For patients not receiving therapeutic anticoagulation:  INR and aPTT 1.5 ULN

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate 
of 1% per year during the treatment period and for at least 90 days after the final dose 
of tiragolumab or 5 months after the last dose of atezolizumab, whichever is later; and 
agreement to refrain from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom during the treatment period and for 90 days after the last dose of tiragolumab
and agreement to refrain from donating sperm during this same period.   
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm N: atezolizumab plus tiragolumab treatment:

Primary CNS tumors with any of the following characteristics:
--
History of intracranial hemorrhage or spinal cord hemorrhage 
--
Neurosurgical resection or brain biopsy to the primary brain tumor within 28 days of 
Cycle 1, Day 1

Metastases to the midbrain, pons, medulla, or spinal cord

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12 
mg/dL, or corrected calcium upper limit of normal [ULN])

Patients known to be positive for hepatitis C virus (HCV) antibody (Ab) are excluded 
with the following exception (note that this is more stringent than the core criterion): 
Patients who are HCV Ab positive but HCV RNA negative due to prior treatment or 
natural resolution are eligible 

Co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV)
Patients with a history of HCV infection but who are negative for HCV RNA by 
PCR will be considered non-infected with HCV.

Positive EBV viral capsid antigen IgM test at screening 
An EBV polymerase chain reaction (PCR) test should be performed as clinically 
indicated to screen for acute infection or suspected chronic active infection.  Patients 
with a positive EBV PCR test are excluded.

Active or history of autoimmune disease or immune deficiency, including, but not limited 
to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:


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Patients with a history of autoimmune-related hypothyroidism who are on thyroid  
replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met:
-- Rash must cover 10% of body surface area
-- Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
-- No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high potency or oral corticosteroids within the 
previous 12 months

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Active tuberculosis

Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
initiation of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection 
or chronic obstructive pulmonary disease exacerbation) are eligible for the study  

Prior allogeneic stem cell or solid organ transplantation

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during study treatment, for 90 days after the final dose of 
tiragolumab, and for 5 months after the final dose of atezolizumab.

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti-TIGIT, anti-LAG3, antiPD-1, and antiPD-L1 therapeutic antibodies
Patients who have had prior anti-CTLA-4 treatment may be enrolled, provided the 
following requirements are met:
-- Last dose of anti-CTLA-4 at least 6 weeks prior to enrollment
-- No history of severe immune-related adverse events from the anti-CTLA-4 
(National Cancer Institute Common Terminology Criteria for Research Adverse 
Events [NCI CTCAE] Grade 3 and 4) 

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives 
(whichever is longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor-alpha [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions:
--
Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor 
approval has been obtained
--
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids 
for orthostatic hypotension or adrenal insufficiency are eligible for the study


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--
Any prior Grade 3 immune-mediated adverse event or any unresolved Grade 1 
immune-mediated adverse event while receiving any previous immunotherapy agent 
other than immune checkpoint blockade agents 

History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of 
the atezolizumab or tiragolumab formulation
Test Product (Investigational Drug)
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 
21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit with 
Medical Monitor approval). Atezolizumab should be administered prior to tiragolumab on 
days when both are administered. 
Following the administration of atezolizumab and an observation period, patients will receive 
600 mg tiragolumab at a fixed dose administered by IV infusion on Day 1 of each 21-day 
cycle.  The tiragolumab dose is fixed and is not dependent on body weight.
ARM O: Pralsetinib in Patients with RET Fusion-Positive Tumors
Target Population
To be enrolled in Arm O: pralsetinib treatment, patients must have met and continue to meet 
all general eligibility criteria, in addition to the arm-specific criteria below.
Additional Inclusion Criteria
Patients must meet the following additional inclusion criteria for entry into Arm O: 
pralsetinib treatment:

RET fusion positivity, except patients with non-small cell lung cancer (NSCLC) or 
thyroid cancers, as determined by a Clinical Laboratory Improvement Amendments 
(CLIA) or equivalently certified next-generation sequencing (NGS) assay (tissue or blood)
Gene fusion positivity is defined as a 3’ RET fusion with a protein coding 5’ gene 
fusion partner, which are predicted to be in frame with an intact kinase domain.

ANC 1000/L within 14 days prior to initiation of study treatment

Ability to swallow pralsetinib intact, without chewing, crushing, or opening the 
capsules/tablets

For females of childbearing potential:  Negative serum pregnancy test 7 days prior to 
initiating study treatment; agreement to remain abstinent (refrain from heterosexual 
intercourse) or use single or combined contraception methods that result in a failure rate 
of 1% per year during the treatment period and for at least 14 days after the last dose of 
pralsetinib; and agreement to refrain from donating eggs during this same period.  

For males:  Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom plus an additional contraception method that together result in a failure rate of 
1% per year during the treatment period and for at least 7 days after the last dose of 
pralsetinib, and agreement to refrain from donating sperm during this same period.   
Additional Exclusion Criteria
Patients who meet any of the following additional criteria will be excluded from entry into 
Arm O: pralsetinib treatment:

RET fusion-positive NSCLC

RET fusion-positive thyroid cancer

Patient’s tumor has any additional known primary driver alterations other than RET, 
such as targetable mutations of EGFR, ALK, ROS1, MET, KRAS or BRAF.

Known history of hypersensitivity to pralsetinib or any of its excipients


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
Prior treatment with RET inhibitors (approved or investigational)

Note: Other prior anti-cancer therapy is allowed

Screening QT interval corrected using Fridericia's formula (QTcF) 480 milliseconds,
history of prolonged QT syndrome or torsades de pointes, and/or familial history of
prolonged QT syndrome

History of pneumonitis during the prior 12 months

Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic
steroids 10 mg/day of prednisone (or equivalent)

Active, uncontrolled infection (viral, bacterial, or fungal)
--
Participants with controlled infections who are stable on treatment may be eligible if
the benefitrisk assessment is justified and permission is granted from the Sponsor.

Clinically symptomatic interstitial lung disease or interstitial pneumonitis, including
radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic
intervention)

Neutrophil growth factor support within 14 days of the first dose of study drug

Treatment with a prohibited medication or herbal remedy that cannot be discontinued at
least 14 days before the start of study drug administration.  Pralsetinib may be started
within 14 days or 5 half-lives (whichever is longer) of prior therapy if this is considered
by the investigator to be safe and in the best interest of the patient, with prior Sponsor
approval.
Test Product (Investigational Drug)
Pralsetinib will be self-administered by patients orally at home, at the same time each day, on 
a starting dose of 400 mg/day (four 100 mg capsules per day) once a day (QD) until disease 
progression, intolerable toxicity, or consent withdrawal.  For more specific dosing 
instructions, refer to the pharmacy manual.