Clinical trial NCT03498521
Conditions: Cancer of Unknown Primary Site
Sponsor: Hoffmann-La Roche
Start date: 2018-07-10; Completion date: 2024-11-07
Enrollment: 528 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will compare the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in participants with poor-prognosis cancer of unknown primary site (CUP; non-specific subset) who have achieved disease control after 3 cycles of first-line platinum based induction chemotherapy.

Detailed description:

Arms: arm 1: Participants will be assigned to molecularly-guided therapy based on genomic profile. arm 2: Participants will receive platinum-based chemotherapy (Carboplatin or Cisplatin in combination with Gemcitabine or Paclitaxel).
Interventions: intervention 1: Alectinib intervention 2: Vismodegib intervention 3: Ipatasertib intervention 4: Olaparib intervention 5: Erlotinib intervention 6: Bevacizumab intervention 7: Vemurafenib intervention 8: Cobimetinib intervention 9: Trastuzumab Subcutaneous (SC) intervention 10: Pertuzumab intervention 11: Atezolizumab intervention 12: Carboplatin intervention 13: Paclitaxel intervention 14: Cisplatin intervention 15: Gemcitabine intervention 16: Entrectinib intervention 17: Ivosidenib intervention 18: Pemigatinib
Intervention descriptions: intervention 1: Alectinib will be administered orally at the label-recommended dose (600 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months). intervention 2: Vismodegib will be administered orally at the label-recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months). intervention 3: Ipatasertib will be administered orally at the label-recommended dose (400 mg) once daily on Days 1-21 of each 28-day Cycle in combination with paclitaxel, and as monotherapy after the final administration of paclitaxel, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months). intervention 4: Olaparib will be administered orally at the label-recommended dose (400 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months). intervention 5: Erlotinib will be administered orally in combination with Bevacizumab at the label recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months) intervention 6: Bevacizumab will be administered intravenously at 15mg/kg every 3 weeks in combination with Erlotinib until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months) intervention 7: Vemurafenib will be administered orally, 960 mg twice daily, in combination with Cobimetinib, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months) intervention 8: Cobimetinib will be administered orally, 60mg once daily, in combination with Vemurafenib, on Days 1-21 of each 28-day Cycle, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months) intervention 9: Trastuzumab will be administered subcutaneously, 600 mg every 3 weeks, in combination with Pertuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months) intervention 10: Pertuzumab will be initially be administered intravenously, 840 mg, followed by 420 mg every 3 weeks, in combination with Trastuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months) intervention 11: Atezolizumab will be administered intravenously at the label-recommended dose (1200 mg), alone or in combination with chemotherapy, every 3 weeks until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months). intervention 12: Carboplatin will be administered intravenously at the area under the curve (AUC) dose once every 3 weeks for up to 9 Cycles (Cycle = 21 days) in some combination with the following: Paclitaxel, Gemcitabine, Atezolizumab, Pertuzumab, and Trastuzumab SC. intervention 13: Paclitaxel will be administered intravenously, 175 mg/m\^2, once every 3 weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Carboplatin, Ipatasertib, Atezolizumab, Pertuzumab, and Trastuzumab SC intervention 14: Cisplatin will be administered intravenously, 60-75 mg/m\^2, once every three weeks, for up to 9 cycles (Cycle = 21 days) in some combination with the following: Gemcitabine, Paclitaxel, Atezolizumab, Pertuzumab, and Trastuzumab SC. intervention 15: Gemcitabine will be administered intravenously, 1000 mg/m\^2, twice every three weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Cisplatin, Carboplatin, Atezolizumab, Pertuzumab, and Trastuzumab SC. intervention 16: Entrectinib will be administered orally at the label-recommended dose (600 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months). intervention 17: Ivosidenib will be administered orally at the label-recommended dose (500mg) once daily across a 28-day treatment cycle until loss of clinical benefit or unacceptable toxicity. intervention 18: Pemigatinib will be administered orally at the label-recommended dose (13.5mg) once daily across a 21-day treatment cycle until loss of clinical benefit or unacceptable toxicity.

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (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 Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
Protocol MX39795, Version 11 
PROTOCOL 
TITLE: 
A PHASE II, RANDOMIZED, ACTIVE-CONTROLLED, 
MULTICENTER STUDY COMPARING THE EFFICACY AND 
SAFETY OF TARGETED THERAPY OR CANCER 
IMMUNOTHERAPY GUIDED BY GENOMIC PROFILING VERSUS 
PLATINUM-BASED CHEMOTHERAPY IN PATIENTS WITH 
CANCER OF UNKNOWN PRIMARY SITE WHO HAVE RECEIVED 
THREE CYCLES OF PLATINUM DOUBLET CHEMOTHERAPY 
PROTOCOL NUMBER: MX39795 
VERSION NUMBER: 
11 
EUDRACT NUMBER: 
2017-003040-20 
IND NUMBER: 
Not applicable. 
NCT NUMBER: 
NCT03498521 
Performance Study 
Identification Number 
(PS ID) 
PLAN-00024 (FoundationOne® FMI F1CDx (tissue) test) and 
PLAN-00025 (FoundationOne® F1LCDx (Liquid) test) 
TEST PRODUCTS: 
Alectinib (RO5424802) 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
Cobimetinib (RO5514041) 
Entrectinib (RO7102122) 
Erlotinib (RO508231) 
Ipatasertib (RO5532961) 
Ivosidenib (RO7499824) 
Olaparib (RO5508245) 
Pemigatinib (RO7496200) 
Pertuzumab (RO4368451) 
Trastuzumab (RO0452317) 
Vemurafenib (RO5185426) 
Vismodegib (RO5450815) 
Carboplatin (RO4843791) 
Cisplatin (RO0232538) 
Gemcitabine (RO0249587) 
Paclitaxel (RO0247506) 
And combinations thereof 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd. 
APPROVAL: 
See electronic signature and date stamp on the final page of this 
document. 


 
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2/Protocol MX39795, Version 11 
PROTOCOL HISTORY 
Protocol 
Associated Country Specific Protocol 
Version 
Date final 
Country 
Version 
Date Final 
V11.0 
See date stamp 
on the final page 
of this document. 
Germany 
11.0 
See date stamp 
on the final page 
of this document 
Japan 
11.0 
See date stamp 
on the final page 
of this document 
V10 
24 January 2022 
Germany 
10.0 
1 February 2022 
Japan 
10.0 
4 February 2022 
V9.0 
16 August 2021 
Germany 
9.1 
16 August 2021 
Japan 
9.2 
31 August 2021 
France 
9.3 
01 December 2021 
V8.0 
19 February 2021 
Germany 
8.1 
19 February 2021 
Japan 
8.2 
8 March 2021 
V7.0 
11 February 2020 
Germany 
7.2 
6 July 2020 
Germany 
7.1 
11 February 2020 
6.0 
29 July 2019 
Germany 
6.1 
29 July 2019 
5.0 
5 November 2018 
Germany 
5.1 
5 November 2018 
4.0 
13 July 2018 
Germany 
4.1 
13 July 2018 
3.0 
6 May 2018 
- 
- 
- 
2.1 
18 April 2018 
- 
- 
- 
2.0 
5 April 2018 
- 
- 
- 
1.1 
13 January 2018 
- 
- 
- 
1.0 
22 December 2017 
- 
- 
- 


 
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PROTOCOL AMENDMENT, VERSION 11:  
RATIONALE 
Protocol MX39795 has been amended based on current experience with the trial, as well 
as on new advancements in the field.  General descriptions of the changes in this 
version of the protocol and rationales for these changes are summarized below: 
 
MAIN MEDICAL/SAFETY CHANGES 
Simplification of the Schedule of Activities after the primary analysis cut-off date 
(CCOD) 
Some endpoints will only be analyzed in the primary analysis, and will not be repeated in 
the final analysis. To decrease the burden on patients, a new Schedule of Activity 
(Appendix 1-1) has been created to keep only the safety and efficacy exams relevant for 
the final analysis. 
PROs for all patients and scans have been removed for patients continuing treatment 
beyond disease progression (Sections 3.3.9, 4.5.6.2, 4.5.9, 6.4.4 and Appendix 1). 
Change of Reference Safety Information document for Bevacizumab and Erlotinib 
As Bevacizumab and Erlotinib are established products, the respective Investigator’s 
Brochures v31 and V26 are being retired, and will not be updated anymore. 
Consequently, the Reference Safety Information documents are changed for these two 
IMPs from the Investigator’s Brochures to the current European Medicines Agency 
(EMA) Summary of Product Characteristics (EU SmPC). 
Safety management guidelines for atezolizumab 
The list of identified risks for atezolizumab has been revised to include myelitis and facial 
paresis (Appendix 10-2) 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an 
identified risk associated with atezolizumab and language has been revised accordingly 
(Appendix 10-2) 
The list of adverse events of special interest has been revised to include myelitis and 
facial paresis (Appendix 10-2). 
Appendix 4 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. 
Appendix 4 has been revised to include autoimmune myelitis  


 
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The adverse event management guidelines have been updated to align with the 
Addendum 1 and 2 to the Atezolizumab Investigator's Brochure, Version 19. 
ADMINISTRATIVE CHANGES AND CLARIFICATIONS 
Recruitment end length of study adapted 
The recruitment has been finalized end of October 2022. Recruitment period and study 
durations have been updated accordingly to reflect the exact timelines (Section 3.2). 
Appendix 11 has been added to match the latest Roche protocol template and to have 
this information available in the protocol (Appendix 11). 
In alignment with the In Vitro Diagnostic Medical Devices Regulation, the Clinical 
Performance Study Identification Number (PS ID) has been added to the title page of the 
protocol.  Text has also been added to indicate that the FoundationOne® FMI F1CDx 
(tissue) and FoundationOne® F1LCDx (Liquid) tests are investigational and to cross-
reference the associated clinical performance study protocol (Section 4.5.7). 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.10.6) 
The medical term “Wegener granulomatosis” has been replaced by the 
term “granulomatosis with polyangiitis” to align with the updated preferred term in 
MedDRA (Section 4.1.3.9). 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section 8.4 
Confidentiality). 
Language has been clarified in Section 9.6 to indicate that any substantial amendments 
to the protocol will require IRB/EC and health authority approval (as locally required) 
before implementation of changes, with the exception of administrative changes or 
changes necessary to eliminate an immediate hazard to study participants. 
Additional minor changes have been made to repair typographical errors and to improve 
clarity and consistency.  Substantive new information appears in italics in the amended 
protocol.  This amendment represents cumulative changes to the original protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL HISTORY ........................................................................................ 2 
PROTOCOL AMENDMENT, VERSION 11:  RATIONALE ................................... 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
1. 
BACKGROUND ............................................................................ 50 
1.1 
Background on Cancer of Unknown Primary ........................... 50 
1.1.1 
Current Treatments for Cancer of Unknown Primary Origin .... 51 
1.1.1.1 
Assessment of the Tissue of Origin ......................................... 52 
1.1.1.2 
Treatment of CUP .................................................................... 53 
1.2 
Background on Test Products.................................................. 56 
1.3 
Study Rationale and Benefit-Risk Assessment ........................ 57 
1.3.1 
Study Rationale ....................................................................... 57 
1.3.2 
Benefit-Risk Assessment ......................................................... 61 
1.3.2.1 
Molecularly-Guided Therapy .................................................... 61 
1.3.2.2 
The COVID-19 Pandemic ........................................................ 62 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 64 
3. 
STUDY DESIGN ........................................................................... 66 
3.1 
Description of the Study ........................................................... 66 
3.1.1 
Screening Period ..................................................................... 67 
3.1.1.1 
During Screening ..................................................................... 70 
3.1.1.2 
Re-Screening and Extension of the Screening Period ............. 72 
3.1.2 
Induction Period ....................................................................... 72 
3.1.3 
End of Induction Visit ............................................................... 73 
3.1.4 
MTB and Randomization ......................................................... 74 
3.1.5 
Treatment Period ..................................................................... 75 
3.1.5.1 
Pre-Treatment Work-Up .......................................................... 75 
3.1.5.2 
Category 1 Patients: Treatment Assignment and 
Treatment ................................................................................ 76 
3.1.5.3 
Category 2 Patients: Treatment Assignment and 
Treatment ................................................................................ 80 
3.1.6 
Follow-Up Period ..................................................................... 80 
3.1.7 
Study Committees ................................................................... 80 


 
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3.2 
End of Study and Length of Study ........................................... 81 
3.3 
Rationale for Study Design ...................................................... 81 
3.3.1 
Rationale for Population Selection ........................................... 81 
3.3.2 
Rationale for the Control Group ............................................... 82 
3.3.3 
Rationale for Three Cycles of Induction Chemotherapy .......... 82 
3.3.4 
Rationale for Sub-Dividing the Study Population Into Two 
Categories of Patients ............................................................. 82 
3.3.5 
Rationale for 3:1 Randomization in Category 1 Patients ......... 83 
3.3.6 
Rationale for Progression-Free Survival as the Primary 
Efficacy Endpoint and Frequency of Tumor Assessments ....... 83 
3.3.7 
Rationale for Combining Data from Different Experimental 
Treatment Cohorts for the Primary Endpoint Analysis ............. 83 
3.3.8 
Rationale for Investigational Medicinal Products Doses and 
Schedules ................................................................................ 84 
3.3.9 
Rationale for Patient-Reported Outcomes ............................... 87 
3.3.10 
Rationale for Exploratory Biomarker Assessments .................. 88 
4. 
MATERIALS AND METHODS ...................................................... 89 
4.1 
Patients .................................................................................... 89 
4.1.1 
General Inclusion Criteria ........................................................ 89 
4.1.1.1 
At Study Entry .......................................................................... 89 
4.1.1.2 
Prior to Start of Therapy in the Treatment Period .................... 93 
4.1.2 
Main Exclusion Criteria ............................................................ 95 
4.1.3 
Exclusion Criteria Specific to Molecularly-Guided 
Therapies ................................................................................. 98 
4.1.3.1 
All Molecularly-Guided Therapies ............................................ 98 
4.1.3.2 
All Oral Therapies .................................................................... 98 
4.1.3.3 
Alectinib ................................................................................... 98 
4.1.3.4 
Vismodegib .............................................................................. 98 
4.1.3.5 
Ipatasertib in Combination with Paclitaxel (or Ipatasertib 
Monotherapy in Patients who are not Receiving the 
Combination) ........................................................................... 98 
4.1.3.6 
Ivosidenib................................................................................. 99 
4.1.3.7 
Olaparib ................................................................................. 100 
4.1.3.8 
Pemigatinib ............................................................................ 100 


 
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4.1.3.9 
Atezolizumab Monotherapy or in Combination with 
Platinum-Based Chemotherapy ............................................. 100 
4.1.3.10 
Erlotinib in Combination With Bevacizumab .......................... 101 
4.1.3.11 
Vemurafenib in Combination With Cobimetinib...................... 102 
4.1.3.12 
Trastuzumab SC Plus Pertuzumab Plus Platinum-Based 
Chemotherapy ....................................................................... 103 
4.1.3.13 
Entrectinib .............................................................................. 103 
4.2 
Method of Treatment Assignment .......................................... 104 
4.3 
Study Treatment .................................................................... 105 
4.3.1 
Induction Period ..................................................................... 105 
4.3.2 
Treatment Period ................................................................... 105 
4.3.3 
Study Treatment Formulation and Packaging ........................ 106 
4.3.4 
Study Treatment Dosage, Administration, and Compliance .. 106 
4.3.4.1 
Alectinib, Atezolizumab, Entrectinib, Ivosidenib, Olaparib, 
Pemigatinib and Vismodegib Monotherapy ........................... 107 
4.3.4.2 
Erlotinib/Bevacizumab Combination Therapy ........................ 108 
4.3.4.3 
Ipatasertib/Paclitaxel Combination Therapy .......................... 108 
4.3.4.4 
Vemurafenib/Cobimetinib Combination Therapy ................... 109 
4.3.4.5 
Trastuzumab/Pertuzumab/Platinum-Based Chemotherapy 
Combination ........................................................................... 110 
4.3.4.6 
Atezolizumab/Platinum-Based Chemotherapy Combination . 110 
4.3.4.7 
Platinum-Based Chemotherapy ............................................. 111 
4.3.4.8 
Alternative Therapy ................................................................ 113 
4.3.5 
Investigational Medicinal Product Handling and 
Accountability ......................................................................... 113 
4.3.6 
Continued Access to Investigational Medicinal Products ....... 114 
4.4 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions ............................................................................ 115 
4.4.1 
Permitted Therapy ................................................................. 115 
4.4.2 
Cautionary Therapy ............................................................... 116 
4.4.2.1 
Medications Given with Precaution due to Effects Related 
to CYP Enzymes .................................................................... 116 
4.4.2.2 
Herbal Therapies ................................................................... 116 
4.4.2.3 
Medications Given with Precaution Due to Potential 
Additive Nephrotoxicity and Ototoxicity with Platinum-
Based Chemotherapy ............................................................ 117 


 
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4.4.2.4 
Medications Given with Precaution with Atezolizumab .......... 117 
4.4.2.5 
Medications Given with Precaution with Ipatasertib ............... 117 
4.4.2.6 
Medications Given with Precaution with Entrectinib ............... 117 
4.4.2.7 
Medications Given with Precaution with Pemigatinib ............. 118 
4.4.2.8 
Medications Given with Precaution with Ivosidenib ............... 118 
4.4.3 
Prohibited Therapy ................................................................ 119 
4.4.4 
Prohibited Food ..................................................................... 120 
4.4.5 
Additional Restrictions ........................................................... 121 
4.5 
Study Assessments ............................................................... 121 
4.5.1 
Informed Consent Forms and Screening Log ........................ 121 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ....................................... 122 
4.5.3 
Physical Examinations ........................................................... 122 
4.5.4 
Vital Signs .............................................................................. 123 
4.5.5 
Performance Status ............................................................... 124 
4.5.6 
Tumor and Response Evaluations ......................................... 124 
4.5.6.1 
Screening and Induction Periods ........................................... 124 
4.5.6.2 
Treatment Period ................................................................... 124 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples .......... 126 
4.5.8 
Electrocardiograms and Cardiac Function Assessment ........ 130 
4.5.9 
Clinical Outcome Assessments ............................................. 130 
4.5.10 
Optional Samples for Research Biosample Repository ......... 132 
4.5.10.1 
Overview of the Research Biosample Repository .................. 132 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................. 132 
4.5.10.3 
Sample Collection .................................................................. 132 
4.5.10.4 
Confidentiality ........................................................................ 133 
4.5.10.5 
Consent to Participate in the Research Biosample 
Repository.............................................................................. 133 
4.5.10.6 
Withdrawal from the Research Biosample Repository ........... 134 
4.5.10.7 
Monitoring and Oversight ....................................................... 134 
4.6 
Treatment, Patient, Study, and Site Discontinuation .............. 134 
4.6.1 
Study Treatment Discontinuation ........................................... 134 
4.6.2 
Study Discontinuation ............................................................ 137 


 
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4.6.3 
Site Discontinuation ............................................................... 137 
5. 
ASSESSMENT OF SAFETY ....................................................... 137 
5.1 
Safety Plan ............................................................................ 137 
5.1.1 
Risks Associated with Test Agents ........................................ 138 
5.1.1.1 
Alectinib, Atezolizumab, Entrectinib, Ivosidenib, Olaparib, 
Pemigatinib and Vismodegib Monotherapy ........................... 138 
5.1.1.2 
Ipatasertib/Paclitaxel Combination Therapy .......................... 138 
5.1.1.3 
Erlotinib/Bevacizumab Combination Therapy ........................ 139 
5.1.1.4 
Vemurafenib/Cobimetinib Combination Therapy ................... 139 
5.1.1.5 
Trastuzumab/Pertuzumab/Platinum-Based Chemotherapy 
Combination ........................................................................... 139 
5.1.1.6 
Atezolizumab/Platinum-Based Chemotherapy Combination . 140 
5.1.1.7 
Platinum-Based Chemotherapy ............................................. 140 
5.1.2 
Management of Patients Who Experience Adverse Events ... 140 
5.1.2.1 
Dose Modifications ................................................................ 140 
5.1.2.2 
Treatment Interruption ........................................................... 140 
5.1.2.3 
Management Guidelines ........................................................ 141 
5.2 
Safety Parameters and Definitions ........................................ 141 
5.2.1 
Adverse Events ...................................................................... 141 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 142 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 142 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 143 
5.3.1 
Adverse Event Reporting Period ............................................ 143 
5.3.2 
Eliciting Adverse Event Information ....................................... 144 
5.3.3 
Assessment of Severity of Adverse Events ........................... 144 
5.3.4 
Assessment of Causality of Adverse Events.......................... 144 
5.3.5 
Procedures for Recording Adverse Events ............................ 145 
5.3.5.1 
Infusion-Related Reactions/Administration-Related 
Reactions and Cytokine-Release Syndrome ......................... 145 
5.3.5.2 
Diagnosis Versus Signs and Symptoms ................................ 146 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 146 


 
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5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 147 
5.3.5.5 
Abnormal Laboratory Values ................................................. 147 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 148 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 148 
5.3.5.8 
Deaths ................................................................................... 149 
5.3.5.9 
Pre-existing Medical Conditions ............................................. 149 
5.3.5.10 
Lack of Efficacy or Worsening of Cancer of Unknown 
Primary Site ........................................................................... 150 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 150 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 151 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 153 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 153 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............. 154 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 154 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation ................... 154 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 154 
5.4.3 
Reporting Requirements for Pregnancies .............................. 155 
5.4.3.1 
Pregnancies in Female Patients ............................................ 155 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 155 
5.4.3.3 
Abortions................................................................................ 156 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 156 
5.5 
Follow Up of Patients after Adverse Events ........................... 156 
5.5.1 
Investigator Follow Up ........................................................... 156 
5.5.2 
Sponsor Follow Up ................................................................ 157 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 157 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 157 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 158 
6.1 
Determination of Sample Size ............................................... 159 
6.2 
Summaries of Conduct of Study ............................................ 159 


 
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6.3 
Summaries of Treatment Group Comparability ...................... 159 
6.4 
Efficacy Analyses ................................................................... 159 
6.4.1 
Primary Efficacy Endpoint ...................................................... 160 
6.4.2 
Secondary Efficacy Endpoints ............................................... 161 
6.4.2.1 
Overall Survival ...................................................................... 161 
6.4.2.2 
Objective Response Rate ...................................................... 161 
6.4.2.3 
Duration of Response ............................................................ 161 
6.4.2.4 
Disease Control Rate ............................................................. 162 
6.4.3 
Exploratory Endpoints ............................................................ 162 
6.4.4 
Exploratory PRO Endpoints ................................................... 163 
6.5 
Safety Analyses ..................................................................... 163 
6.6 
Interim Analyses .................................................................... 164 
6.6.1 
Planned Interim Analysis ....................................................... 164 
6.6.2 
Optional Interim Analysis ....................................................... 164 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 164 
7.1 
Data Quality Assurance ......................................................... 164 
7.2 
Electronic Case Report Forms ............................................... 165 
7.3 
Source Data Documentation .................................................. 165 
7.4 
Use of Computerized Systems .............................................. 166 
7.5 
Retention of Records ............................................................. 166 
8. 
ETHICAL CONSIDERATIONS .................................................... 167 
8.1 
Compliance with Laws and Regulations ................................ 167 
8.2 
Informed Consent .................................................................. 167 
8.3 
Institutional Review Board or Ethics Committee .................... 168 
8.4 
Confidentiality ........................................................................ 168 
8.5 
Financial Disclosure ............................................................... 169 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 169 
9.1 
Study Documentation ............................................................ 169 
9.2 
Protocol Deviations ................................................................ 170 
9.3 
Management of Study Quality ................................................ 170 
9.4 
Site Inspections ..................................................................... 170 


 
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9.5 
Administrative Structure ......................................................... 170 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 171 
9.7 
Protocol Amendments ........................................................... 172 
10. 
REFERENCES............................................................................ 173 
 
 
LIST OF TABLES 
Table 1 
Examples of Immunohistochemical Work-Up to Identify 
Tissue of Origin ........................................................................... 53 
Table 2 
Therapy for Patients With Favorable Prognosis Cancer of 
Unknown Primary ........................................................................ 54 
Table 3 
Commonly Used Low-Toxicity Chemotherapy Regimens for 
Patients With Cancer of Unknown Primary in the Non-
Specific Subset ........................................................................... 55 
Table 4 
Objectives and Corresponding Endpoints ................................... 65 
Table 5 
Identified Genomic Alterations and Corresponding 
Molecularly-Guided Therapies .................................................... 78 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 144 
Table 7 
Causal Attribution Guidance ..................................................... 145 
 
 
LIST OF FIGURES 
Figure 1 
Clinical Management of Patients With CUP ................................ 52 
Figure 2 
Study Design ............................................................................... 67 
Figure 3 
Summary of Events on and Between the End of Induction 
Visit and the Start of Treatment in the Treatment Period ............ 75 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 183 
Appendix 2 
Timeline of Key Study Events ................................................... 206 
Appendix 3 
Schedule of Study Sample Collection ....................................... 211 
Appendix 4 
Pre-existing Autoimmune Diseases and Immune 
Deficiencies Contraindicating Atezolizumab Use ...................... 216 
Appendix 5 
Response Evaluation Criteria in Solid Tumors, Version 1.1: 
Excerpt from Original Publication .............................................. 218 
Appendix 6 
Eastern Cooperative Oncology Group (ECOG)  Performance 
Status Scale Study .................................................................... 229 


 
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Appendix 7 
Functional Assessment of Cancer Therapy – General 
(FACT-G) .................................................................................. 230 
Appendix 8 
Hospital Anxiety and Depression Scale (HADS) ....................... 231 
Appendix 9 
EQ-5D-5L Scale ........................................................................ 232 
Appendix 10 IMP-Specific Safety and Administration Information ................. 233 
Appendix 11 Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European 
Economic Area and United Kingdom) ...................................... 387 
 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
14/Protocol MX39795, Version 11 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
 
TITLE: 
A PHASE II, RANDOMIZED, ACTIVE-CONTROLLED, 
MULTICENTER STUDY COMPARING THE EFFICACY AND 
SAFETY OF TARGETED THERAPY OR CANCER 
IMMUNOTHERAPY GUIDED BY GENOMIC PROFILING 
VERSUS PLATINUM-BASED CHEMOTHERAPY IN PATIENTS 
WITH CANCER OF UNKNOWN PRIMARY SITE WHO HAVE 
RECEIVED THREE CYCLES OF PLATINUM DOUBLET 
CHEMOTHERAPY 
PROTOCOL NUMBER: 
MX39795 
VERSION NUMBER: 
11 
EUDRACT NUMBER: 
2017-003040-20 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT03498521 
Performance Study 
Identification Number 
(PS ID) 
PLAN-00024 (FoundationOne® FMI F1CDx (tissue) test) and 
PLAN-00025 (FoundationOne® F1LCDx (Liquid) test) 
TEST PRODUCTS: 
Alectinib (RO5424802) 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
Cobimetinib (RO5514041)  
Entrectinib (RO7102122) 
Erlotinib (RO508231) 
Ipatasertib (RO5532961) 
Ivosidenib (RO7499824) 
Olaparib (RO5508245) 
Pemigatinib (RO7496200) 
Pertuzumab (RO4368451) 
Trastuzumab (RO0452317) 
Vemurafenib (RO5185426) 
Vismodegib (RO5450815) 
Carboplatin (RO4843791) 
Cisplatin (RO0232538) 
Gemcitabine (RO0249587) 
Paclitaxel (RO0247506) 
And combinations thereof 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 


 
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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 as instructed by your local study monitor. 
 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, RANDOMIZED, ACTIVE-CONTROLLED, 
MULTICENTER STUDY COMPARING THE EFFICACY AND 
SAFETY OF TARGETED THERAPY OR CANCER 
IMMUNOTHERAPY GUIDED BY GENOMIC PROFILING VERSUS 
PLATINUM-BASED CHEMOTHERAPY IN PATIENTS WITH 
CANCER OF UNKNOWN PRIMARY SITE WHO HAVE RECEIVED 
THREE CYCLES OF PLATINUM DOUBLET CHEMOTHERAPY 
PROTOCOL NUMBER: 
MX39795 
VERSION NUMBER: 
11 
EUDRACT NUMBER: 
2017-003040-20 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT03498521 
Performance Study 
Identification 
Number (PS ID) 
PLAN-00024 (FoundationOne® FMI F1CDx (tissue) test) and 
PLAN-00025 (FoundationOne® F1LCDx (Liquid) test) 
TEST PRODUCTS: 
Alectinib (RO5424802) 
Atezolizumab (RO5541267) 
Bevacizumab (RO4876646) 
Cobimetinib (RO5514041)  
Entrectinib (RO7102122) 
Erlotinib (RO508231) 
Ipatasertib (RO5532961) 
Ivosidenib (RO7499824) 
Olaparib (RO5508245) 
Pemigatinib (RO7496200) 
Pertuzumab (RO4368451) 
Trastuzumab (RO0452317) 
Vemurafenib (RO5185426) 
Vismodegib (RO5450815) 
Carboplatin (RO4843791) 
Cisplatin (RO0232538) 
Gemcitabine (RO0249587) 
Paclitaxel (RO0247506) 
And combinations thereof 
PHASE: 
Phase II 
INDICATION: 
Cancer of unknown primary 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 


 
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OBJECTIVES AND ENDPOINTS 
Study MX39795 will compare the efficacy and safety of molecularly-guided therapy versus 
standard platinum-containing chemotherapy in patients with poor prognosis cancer of unknown 
primary site (CUP; non-specific subset) who have achieved disease control (CR, PR or SD) 
after 3 cycles of first-line platinum-based induction chemotherapy.  Molecularly-guided therapies 
will include 10 targeted cancer therapy regimens and 2 cancer immunotherapy regimens and 
will be chosen based on each patient’s comprehensive genomic profile (see below for further 
details). 
Specific objectives and corresponding endpoints for the study are outlined in Synopsis Table 1, 
where “molecularly-guided therapy” refers to a pooled treatment group comprising patients who 
received a targeted agent or cancer immunotherapy. 
 
SYNOPSIS TABLE 1. OBJECTIVES AND CORRESPONDING ENDPOINTS 
PRIMARY EFFICACY OBJECTIVE 
CORRESPONDING ENDPOINTS 
 
To evaluate the efficacy of 
molecularly-guided therapy versus 
platinum chemotherapy in term of 
progression-free survival in patients 
with CUP whose best response to 
3 cycles of platinum induction 
chemotherapy was assessed CR, PR 
or SD 
 
Progression-free survival (PFS1), defined in 
Category 1 patients as the time from randomization to 
the first occurrence of disease progression, as 
assessed by the investigator according to Response 
Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), or death from any cause, whichever 
occurs first 
SECONDARY EFFICACY OBJECTIVES 
CORRESPONDING ENDPOINTS 
 
To evaluate the efficacy of 
molecularly-guided therapy versus 
platinum chemotherapy in terms of 
overall survival, objective response 
rate, duration of response and disease 
control rate in patients with CUP 
whose best response to 3 cycles of 
platinum induction chemotherapy was 
assessed CR, PR or SD 
 
Overall survival (OS), defined as the time from 
randomization to death from any cause 
 
Objective response rate (ORR1), defined in Category 
1 patients as the proportion of randomized patients 
who exhibit a CR or PR on two consecutive occasions 
≥ 4 weeks apart 
 
Duration of response (DOR1), defined in Category 1 
patients with an objective response as the time from 
when response (CR or PR) is first documented to 
disease progression or death due to any cause, 
whichever occurs first 
 
Disease Control Rate (DCR1), defined as the 
proportion of Category 1 patients with confirmed CR, 
PR, SD or NA, per RECIST v1.1 
 
Responses will be determined by the investigator 
according to RECIST v1.1 
SAFETY OBJECTIVE 
CORRESPONDING ENDPOINTS 
 
To evaluate the safety of molecularly-
guided therapy in all patients with CUP 
who receive targeted therapy or 
cancer immunotherapy 
 
Incidence and severity of adverse events (AEs), with 
severity determined according to NCI CTCAE v5.0 
 
Incidence and reasons for any dose reductions, 
interruptions, or premature discontinuation of any 
component of study treatment 
 
Change from baseline in targeted vital signs 
 
Incidence in clinical laboratory abnormalities 


 
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EXPLORATORY OBJECTIVES 
CORRESPONDING ENDPOINTS 
 
To evaluate the efficacy of 
molecularly-guided therapy in 
patients with CUP who progressed 
(PD) during 3 cycles of platinum 
induction chemotherapy 
 
PFS2, OS2, ORR2, DOR2 and DCR2, assessed by 
the investigator in Category 2 patients according to 
RECIST v1.1 as described above 
 
To evaluate the mutagenic effects of 
3 cycles of platinum induction 
chemotherapy in all patients with 
CUP 
 
Genomic profiles pre and post platinum induction 
chemotherapy, as assessed using FoundationOne® 
F1LCDx (Liquid) test 
 
To evaluate clonal evolution of CUP 
during targeted or cancer 
immunotherapy treatment 
 
Genomic profiles pre-treatment and at disease 
progression in patients receiving targeted therapy or 
cancer immunotherapy 
 
To characterize CUP tumors and 
their microenvironment on a 
molecular level 
 
Molecular profiling by, e.g., gene expression and 
immunohistochemistry analyses, and tumor immune 
signatures 
 
To evaluate the HRQol effects of 
molecularly-guided therapy in 
patients with CUP whose best 
response to 3 cycles of platinum 
induction chemotherapy was 
assessed CR, PR or SD  
 
Absolute change from Treatment Period Cycle 1 
Day 1 in FACT-G score in Category 1 patients 
 
Absolute change from Treatment Period Cycle 1 
Day 1 in HADS score in Category 1 patients 
 
To evaluate health status utility of 
molecularly-guided therapy in 
patients with CUP whose best 
response to 3 cycles of platinum 
induction chemotherapy was 
assessed CR, PR or SD 
 
Absolute change from Treatment Period Cycle 1 
Day 1 in EQ-5D-5L index-based score in Category 1 
patients 
CR, complete response; CUP, cancer of unknown primary; EQ-5D-5L, EuroQol 5-Dimensional 5-Level 
questionnaire; FACT-G, Functional Assessment of Cancer Therapy: General; HADS, Hospital Anxiety and 
Depression Scale; HRQol, health-related quality of life; ORR, objective response rate; OS, overall survival; 
PFS, progression-free survival; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid 
Tumors, version 1.1; SD, stable disease. 
NOTE:  Category 1 patients are those who achieved disease control (CR, PR or SD) after 3 cycles of first-
line platinum-based induction chemotherapy; Category 2 patients are those who experienced PD during 
3 cycles of platinum induction chemotherapy (see Study Design [below] for more details). 
 
 
 


 
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STUDY DESIGN 
DESCRIPTION OF STUDY 
Study MX39795 is a phase II, randomized, open-label, active-controlled, multicenter trial.  The 
study will consist of a Screening Period, an Induction Period including an End of Induction Visit, 
a Treatment Period, a Safety Follow-Up Visit occurring 30 (± 7) days from last treatment or at 
initiation of other systemic anticancer therapy (whichever occurs first), and a Follow-Up Period.  
The first day of treatment during the Induction Period will be Day 1 (baseline) of the study.  
The overall study design is presented in Synopsis Figure 1.  A Schedule of Activities is provided 
in Appendix 1.  A timeline of key study events is summarized in Appendix 2 and further detailed 
below. 
 
Synopsis Figure 1 
Study Design 
 
CUP, cancer of unknown primary site; CR, complete response; ECOG PS, Eastern Cooperative 
Oncology Group performance status; EoT, End of Treatment; MTB, Molecular Tumor Board; PD, 
progressive disease; PR, partial response; R, randomization; SD, stable disease. 
a. Confirmation according to the 2015 ESMO Clinical Practice Guidelines for CUP (Fizazi et al. 
2015). 
b. A tumor tissue sample that is suitable for: 1) the initial diagnosis of CUP at the study site’s 
local laboratory, and 2) confirmation of diagnosis compatible with CUP and generation of a 
comprehensive genomic profile using a FoundationOne® FMI F1CDx (tissue) test at a 
central reference pathology laboratory.  If, after local diagnosis of CUP, insufficient tumor 
tissue (in quantity or quality) remains for the central pathology laboratory to confirm the CUP 
diagnosis and generate profile using a FoundationOne® FMI F1CDx (tissue) test, then a 
fresh biopsy sample must be collected during the Screening Period that meets the study’s 
requirements (refer to the Laboratory Manual for suitability details and specimen collection 
instructions).  In exceptional cases where a repeat biopsy is not possible, or where a repeat 
biopsy would lead to significant delay in treatment start, the reason will be documented by the 
investigator and the patient will proceed through the eligibility review process without such new 
biopsy; in these cases, a blood sample will be used to generate a profile using the 
FoundationOne® F1LCDx (Liquid) test. 
 
Screening Period 
The population to be included in this study corresponds to patients with CUP of epithelial origin 
with poor-prognosis, for whom a likely tissue of origin cannot be posited. 


 
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To be eligible, patients must have a histological diagnosis compatible with CUP (non-specific 
subset per 2015 ESMO guidelines), with available pathology report, as determined by the study 
site’s local laboratory on a contemporaneous tissue sample. 
Only patients with the histological subtypes and the poor-prognosis subsets of CUP allowed in 
the study should enter the Screening Period.  
The diagnosis of poor prognosis CUP must be ascertained prior to entering the Screening 
Period of the study, following the 2015 ESMO Clinical Practice Guidelines for CUP (Fizazi et al. 
2015) and any additional protocol-specific eligibility requirements for the diagnosis of CUP.  
Where ESMO CUP guidelines are outdated or fail to provide guidance, an appropriate work-up 
using state-of the art diagnostic methods (per guidelines for the suspected tumor) should be 
used to exclude a potential primary origin for the cancer.  All tests/examinations (e.g., 
pathology, clinical and imaging work-up) performed to ascertain the diagnosis of CUP and 
exclude a tumor of known origin must be available when entering the Screening Period.  
The pre-screening tests/examinations performed to diagnose CUP will be re-assessed by an 
Eligibility Review Team (ERT), in consultation with a referent oncologist in complex cases (if 
necessary).  Potential participants will be excluded from the study if their clinical presentations 
and pathology work-ups (including IHC) indicate primary origins for their tumors (for further 
information, see below [“During Screening”]). 
The diagnosis of CUP according to the 2015 ESMO guidelines should have included:  
Minimal basic work-up:  
 
Thorough physical examination (including, e.g., head and neck, rectal, pelvic and breast 
examination) 
 
Basic blood and biochemical analyses 
 
Computed tomography (CT) scans of thorax, abdomen and pelvis  
 
Further work-up (including, but not limited to): 
 
Mammography in women  
 
Breast MRI in women with axillary disease 
 
Endoscopies guided by sign-, symptom- or laboratory abnormalities  
 
Serum assessment of α-fetoprotein, human chorionic gonadotropin, plasma chromogranin 
A and PSA suggested in male patients to exclude potentially curable extragonadal germ-
cell tumors, neuroendocrine tumors and prostate cancers amenable to hormonal treatment 
 
Whole-body FDG–PET/CT suggested for patients with cervical adenopathies from CUP and 
those with a single CUP metastasis 
 
In situations where clinical and histopathological pictures are suggestive of a specific primary 
origin for the cancer, an appropriate work-up to exclude this specific cancer should have been 
performed.  These situations include (but are not limited to) the following:  
 
Breast MRI in women with lymph nodes in the breast drainage areas in the context of IHC 
results suggestive of breast cancer 
 
High-definition CT scan of the thorax in patients with TTF-1 negative IHC in the context of 
poorly characterized lung masses or in the context of hilar lesions (with or without lung 
masses) 
 
MRI in patients with one or few liver lesions presenting with no extra-hepatic disease or with 
extra-hepatic disease limited to lung metastases and/or lesions in the upper abdomen, in 
the context of IHC suggestive of cholangiocarcinoma or pancreatobiliary or upper 
gastrointestinal disease 
 
Adequate abdominal and pelvic imaging in the presence of high-grade serous carcinoma 
 
Bosniak classification of any kidney lesion in the context of IHC suggestive of renal cell 
carcinoma or other kidney malignancy 


 
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 
ENT (Ear-Nose-Throat) examination and MRI and/or PET imaging in patients with IHC 
and/or a clinical picture suggestive of salivary gland carcinoma (this includes poorly defined 
masses in the neck or predominance of neck lymph nodes in the clinical presentation) 
 
Acceptable histology will include:  
 
Adenocarcinoma  
 
Poorly differentiated adenocarcinoma  
 
Poorly differentiated carcinoma  
 
The following patients will not be eligible: 
 
Patients with squamous cell CUP 
 
Patients with histology and immunohistology profiles (per ESMO guidelines) that are not 
adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma), such as but not 
limited to non-epithelial cancer, extragonadal germ-cell tumor, neuroendocrine tumors, 
sarcoma, melanoma, mesothelioma, hematologic malignancies 
 
Patients who can be assigned to a specific subset of CUP for which a specific treatment is 
recommended by the 2015 ESMO Clinical Practice Guidelines for CUP (Fizazi et al. 2015) 
or with a clinical and IHC profile indicative of a specific primary tumor (favorable prognosis 
CUP subsets). These are: 
- 
Poorly differentiated carcinoma with midline distribution 
- 
Women with papillary adenocarcinoma of the peritoneal cavity 
- 
Women with adenocarcinoma involving only the axillary lymph nodes 
- 
Squamous cell carcinoma of the cervical lymph nodes 
- 
Poorly differentiated neuroendocrine tumors 
- 
Men with blastic bone metastases and elevated PSA 
- 
Patients with a single, small, potentially resectable tumor 
- 
Colon cancer-type CUP with a CK7 negative, CK20 positive, CDX-2 positive 
immunohistochemistry profile 
- 
CK7 positive, CK20 negative and TTF-1 positive tumors in a context suggestive of lung 
adenocarcinoma or thyroid cancer (i.e., with lesions in the lung or thyroid or the lymph 
nodes in their drainage areas) 
- 
IHC profile definitely indicative of breast cancer OR an IHC profile indicative of breast 
cancer and either a history of breast cancer or lymph nodes in the drainage areas of the 
breast 
- 
High-grade serous carcinoma histology and elevated CA125 tumor marker and/or a 
mass in the gynecological tract or any tumor mass or lymph node in the abdominal 
cavity (i.e., below the diaphragm) 
- 
IHC profile suggestive of renal cell carcinoma and renal lesions, with a Bosniak 
classification higher than IIF 
- 
IHC profile compatible with cholangiocarcinoma or pancreatobiliary (or upper 
gastrointestinal carcinoma) AND 1 or 2 liver lesions without extrahepatic disease or with 
only pulmonary metastases and/or lymph nodes in the drainage areas of the liver 
 
Patients with a history of malignancy within 5 years prior to initiation of study treatment, with 
the exception of the cancer under investigation in this study and malignancies with a 
negligible risk of metastasis or death (e.g., 5-year OS rate > 90%). 
 
General inclusion and exclusion criteria must also be satisfied for a patient to be considered for 
screening (Refer to specific section below). 
 
During Screening 
As this study aims to direct treatment according to genomic profiles, it is further mandated that 
participants are willing and able to provide: 


 
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 
A tumor tissue sample for generation of a comprehensive genomic profile using the 
FoundationOne® FMI F1CDx (tissue) test at a central reference pathology laboratory 
(refer to the Laboratory Manual for suitability details and specimen collection instructions) 
 
Archival tumor FFPE block ≤ 4 months prior to screening will be acceptable for these central 
analyses.  However, if an acceptable archival tumor FFPE block is not available or is not 
suitable (in quantity and quality) at screening, an FFPE block from a freshly obtained biopsy 
sample must be provided that meets the study’s requirements 
- 
In cases, where the first tissue sample sent to the central laboratory is considered 
unsuitable for generation of a comprehensive genomic profile using the 
FoundationOne® FMI F1CDx (tissue) test but allows for the confirmation of CUP (or 
the confirmation of CUP can be ascertained on a prior sample deemed suitable by the 
referent pathologist), and all other eligibility criteria are met for the study, the patient 
may start platinum-based induction chemotherapy prior to a fresh biopsy sample being 
received by the central laboratory, providing that the fresh sample has been collected 
(e.g., when shipment could delay an urgent start of treatment) 
In exceptional cases where a repeat biopsy is not possible, or where a repeat 
biopsy would lead to significant delay in treatment start, the reason will be 
documented by the investigator and the patient will proceed through the eligibility 
review process without such new biopsy 
Tumor FFPE blocks are preferred.  In exceptional cases, 25 slides (4 µm slide 
thickness each) may be accepted 
 
 
The local pathology reports confirming compatibility with CUP diagnosis and the associated 
slides used for the diagnosis (refer to the Laboratory Manual for further details) 
- 
Expectations are that the histology and routine immunohistochemistry performed locally 
are compatible with CUP following the algorithm suggested in the 2015 ESMO 
guidelines for CUP, which recommends CK7 and CK20 as first step markers 
- 
If the slides used for the local test confirming local CUP diagnosis are not available, the 
FFPE block submitted for genomic profiling must be sufficient to allow central 
confirmation of CUP diagnosis (i.e., performing relevant IHC and ISH if required) 
 
A central pathology laboratory will interpret the local histopathology results (including 
immunohistochemistry) and perform additional tests if required to confirm that the pathology and 
immunohistochemistry profiles are compatible with the diagnosis of poor prognosis CUP.  The 
assessment performed by the central pathology laboratory will be oriented by pathological and 
clinical features and the choice of immunohistochemistry markers (and in-situ hybridization if 
required) to be reviewed and additional tests to be performed will be in line with 2015 ESMO 
Clinical Practice Guidelines for CUP and with the Study Laboratory Manual. 
NOTE: The Eligibility Review Team (ERT) will review pathology and immunohistology 
reports from central and local laboratories, and details of the CUP work-up (as reported 
in the eCRF) to determine patient eligibility.  Identification of acceptable poor-prognosis 
CUP will be carried out according to ESMO guidelines and, in cases where these 
guidelines may be insufficient or outdated, by adequately excluding potential primary 
tumors via newer genetic, immunologic, etc., methodologies.  The ERT may not be able 
to confirm the diagnosis of poor prognosis CUP without a complete and proper pre-
screening CUP work-up, i.e., one that was carried out to completion per ESMO guidelines 
(see beginning of this section).  Therefore, failure by the investigator to provide this 
necessary pre-screening CUP work-up information may lead to screen failure. 
In order to enter the Induction Period (see below), patients must have completed Part 1 and the 
RBR section of the Informed Consent Form (ICF).  Since the molecularly-guided therapy 
eventually assigned to a patient is unknown during the Screening Period, Part 1 of the ICF will 
cover all aspects of the trial except for information related to any specific molecularly-guided 
therapies.  Information related to the specific molecularly-guided therapy eventually assigned to 
an individual patient (e.g., identified targetable alteration, background on selected agent, and 
tolerability profile) will be provided in Part 2 of the ICF, which must be completed prior to the first 
dose of molecularly-guided therapy (see below for more detail).  Patients who are randomly 


 
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assigned to receive additional cycles of platinum chemotherapy will not be required to complete 
Part 2 of the ICF (see below). 
 
Re-Screening and Extension of the Screening Period 
The Screening Period will be 28 days (from signature of the ICF until the first dose of study 
treatment).  Potential participants who are unable to fulfill all eligibility criteria within the 
Screening Period can be re-screened, provided that the reason for screen failure is one that can 
change over time and that all eligibility criteria will likely be fulfilled at or by the end of the time of 
re-screening. 
The 28-day Screening Period may be extended under the following circumstances: 
 
Up to 42 days (extension by 2 weeks) in case the first tissue submitted was not suitable or 
insufficient per central pathology assessment and a fresh biopsy has to be taken (see 
above)  
 
Up to 35 days (extension by 1 week): 
- 
If there has been a delay in the shipment of the tissue sample 
- 
If escalation of the eligibility review to the referent oncologist and further information are 
requested, or further tests are needed to determine eligibility 
 
In cases where the Screening Period has been extended (see Section 3.1.1.2), screening 
assessments conducted during the initial Screening Period (e.g., CT scans) that met protocol 
requirements will remain valid during the Screening Period extension, with the following 
exceptions: 
 
- Pregnancy tests and tests that should be repeated at baseline 
 
- Imaging tests performed up to 49 days prior to first dose of study treatment are acceptable 
 
Induction Period 
All patients fulfilling eligibility criteria will enter the Induction Period. 
A blood sample suitable for analysis of circulating tumor DNA using the FoundationOne® 
F1LCDx (Liquid) test (refer to the Laboratory Manual for specimen collection instructions) will 
be collected before initiation of chemotherapy. 
Patients will receive 3 cycles of standard first-line platinum-based chemotherapy per 
investigator choice (carboplatin/paclitaxel, cisplatin/gemcitabine or carboplatin/gemcitabine) 
until the end of the Induction Period or documented early disease progression (Synopsis 
Figure 1). 
Patients who cannot tolerate their initial platinum-based induction therapy will be managed until 
the end of the Induction Period or documented early disease progression as follows: 
 
Patients should undergo dose reductions or interruptions of one or both components of the 
chosen chemotherapy regimen per institutional standards 
 
If dose reductions and interruptions are not sufficient or if intolerant to the initial platinum-
based therapy, patients may be switched to another protocol-mandated induction 
chemotherapy regimen, if judged clinically relevant by the investigator 
 
If intolerant of the second induction chemotherapy regimen, or if switching to another 
platinum induction therapy is not the optimal option, the treatment may be continued with 
only one component of the induction chemotherapy regimen.  If treatment is reduced to one 
component and tolerance improves, then switching to another accepted platinum regimen 
will be possible if judged clinically relevant by the investigator 
 
If all options to manage intolerance to the induction chemotherapy are exhausted prior to 
Cycle 3 Day 1, the patient will discontinue from study treatment.  The patient will move 
directly to the Safety Follow-Up Visit, receive further treatment per institutional standards, 
and enter the Follow-up Period (see below) 
 
Also during the Induction Period, the patient’s tumor and blood samples will be analyzed to 
generate comprehensive genomic profiles based on FoundationOne® FMI F1CDx (tissue) 


 
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test and FoundationOne® F1LCDx (Liquid) test respectively.  Results from these analyses will 
be used to inform treatment decisions during the subsequent Treatment Period (see below). 
 
End of Induction Visit 
For patients, who reach Cycle 3, the End of Induction Visit will occur between Cycle 3 Day 14 
and Day 21 (+ 3 days).  
For patients who progress (PD) before Cycle 3, the End of Induction Visit will take place within 
10 days of disease progression assessment.  
Patients who permanently discontinue at or before the end of induction will not attend an End of 
Induction Visit, but instead will move directly to the Safety Follow-Up Visit. 
During the End of Induction Visit: 
 
Response to platinum induction chemotherapy will be evaluated by the investigator 
according to RECIST v1.1 (Appendix 5) based on disease assessment performed between 
Cycle 3 Day 7 and the End of Induction Visit (except for patients with documented PD prior 
to Cycle 3).  Based on these results, participants will be grouped into two categories 
(Synopsis Figure 1):  
- 
Category 1: Patients with a CR, PR or SD after 3 cycles of platinum induction 
chemotherapy 
- 
Category 2: Patients with a documented PD during 3 cycles of platinum induction 
chemotherapy or at any time during the Induction Period 
 
In exceptional cases, where response according to RECIST v1.1 would be Not Evaluable, 
the case will be referred to the referent radiologist for adjudication.  Patients without a 
RECIST v1.1 assessment at the End of Induction Visit will discontinue from the study 
 
 
Selected inclusion and exclusion criteria will be re-evaluated in all patients at the End of 
Induction Visit.  This re-evaluation will include: 
- 
IMP-specific exclusions: to determine whether any IMP-specific restrictions have 
developed since Day 1, e.g., development of diabetes since start of chemotherapy, etc.  
Since data from this re-assessment will be used at the Molecular Tumor Board (MTB) to 
assign treatment (see below), each patient will be re-evaluated for all IMP-specific 
exclusions at the End of Induction Work-up 
- 
Re-assessment of general safety criteria: the purpose of this re-assessment is not to 
limit choice of targeted therapy, but rather to delay start of treatment or elicit a treatment 
discontinuation if safety criteria are not met 
 
MTB and Randomization 
The MTB must be scheduled to take place no later than 10 calendar days after the End of 
Induction Visit for all patients. The MTB will be cancelled for Category 1 patients randomized to 
continue chemotherapy. 
Randomization (for Category 1 patients only) should occur between the End of Induction Visit 
and no less than 48 hours before the planned MTB meeting date. 
The MTB (for all patients) and randomization (for Category 1 patients) must be delayed after the 
End of Induction Visit if general safety criteria for entrance into the Treatment Period are not 
met, however the Sponsor’s study team must be informed of the delay (see below and in 
Sections 4.1.1.2 and 4.2). If the MTB is delayed, starting treatment in the Treatment Period of 
the study will be subject to verifying that the general safety criteria for entry into the study are 
met:  
 
If the MTB is delayed up to Cycle 3 Day 42 (or until 42 days after Day 1 of the last induction 
treatment cycle for Category 2 patients who receive less than 3 cycles), only the general 
safety criteria previously not met will need verifying. 


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
If the MTB is delayed beyond Cycle 3 Day 42 (or until 42 days after Day 1 of the last
induction treatment cycle for Category 2 patients who receive less than 3 cycles), all
general safety eligibility criteria must be checked, and if they are still not met, the patient will
not be eligible to receive further treatment in the study.  Instead, the patient will move
directly to the Safety Follow-Up Visit and, then, proceed into the Follow-up Period, where he
or she will receive non-IMP treatment outside of the study (see below).
Synopsis Figure 2. Summary of Events on and Between the End of Induction Visit and 
the Start of Treatment in the Treatment Period 
* If the patient experiences progressive disease before Cycle 3, the End of Induction Visit should
occur within 10 days of the disease progression assessment.
** The MTB and randomization should be postponed if any re-assessed general safety eligibility 
criteria are not met at the End of Induction Visit. 
***If start of treatment in the Treatment Period is delayed > 42 days post Cycle 3 Day 1 (or 42 
days post Day 1 of last induction cycle for Category 2 patients who receive less than 3 cycles), 
all general safety criteria must be checked and verified prior to starting treatment in the 
Treatment period. 
If the MTB is delayed to Day 15 or more after the End of Induction Visit, Investigator’s judgment 
will be exercised to determine which tests need repeating prior to the MTB. 
Treatment Period 
Pre-Treatment Work-Up 
As the efficacy and safety assessments for the main study endpoints are evaluated from 
randomization in Category 1 patients (including patients randomized to chemotherapy) and from 
start of molecularly-guided therapy for Category 2 patients, Treatment Period baseline 
assessments for efficacy and safety data will be as follows: 
•
Tumor assessments: the End of Induction Visit will be used for the Treatment Period 
baseline tumor assessment.  In exceptional cases where the interval between end of 
Induction Period assessments and Day 1 of treatment in the Treatment Period are > 42 
days, tumor assessments would need repeating to ensure reliable baseline tumor 
assessments. Investigators will review the CT scans and any other tests used for tumor 
assessment according to RECIST v1.1 to establish new baseline assessments.  The target 
and non-target lesions chosen for baseline in the Treatment Period may differ from those 
chosen at baseline for the Induction Period.  It is accepted that in patients with complete 
response and in some patients with partial response at the end of the Induction Period, 
there will/may not be any measurable lesion 


 
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 
Physical examination, performance status, vital signs, weight and laboratory results at 
Day 1 of the first cycle of treatment in the Treatment Period will be used as baseline for the 
Treatment Period 
 
Any ongoing AEs from the induction chemotherapy and all concomitant medications will be 
reported at the End of Induction Visit and re-assessed on Day 1 of the Treatment Period 
 
The pre-treatment work-up does not require a dedicated visit, as it combines examinations 
performed as part of the End of Induction Visit and the Cycle 1 Day 1 visit in the Treatment 
Period.  
 
Category 1 Patients: Treatment Assignment and Treatment 
The primary and secondary efficacy endpoints will be analyzed exclusively in Category 1 
patients.  Thus, patients with a CR, PR or SD during the Induction Period will be randomized in 
a 3:1 ratio to receive either molecularly-guided therapy or to continuation of the same 
chemotherapy regimen used during induction, respectively (Synopsis Figure 1).  An assessment 
cycle will be considered to be 21 days for all treatment arms (including for cohorts with oral 
therapies), except for cobimetinib and vemurafenib, ipatasertib and paclitaxel, and ivosidenib, 
where the administration cycle will be 28 days.  Administration of therapy will be according to 
the treatment schedules specified in Section 4.3.  
To ensure balanced treatment groups, randomization will be stratified by the following factors: 
 
Gender 
 
Response to platinum induction chemotherapy (CR + PR vs. SD) 
 
For patients randomized to the control arm, the chemotherapy will be administered per Section 
4.3.4.7 of the protocol.  
For patients randomized to the investigational arm, molecularly-guided therapy will be decided 
based on results from the FoundationOne® FMI F1CDx (tissue) test and/or FoundationOne® 
F1LCDx (Liquid) test reports (dependent on availability of one or both) during a virtual 
Molecular Tumor Board (MTB), consisting of the treating investigator (or their designee), 
referent pathologist, referent oncologist and FoundationOne® expert (if needed). 
A detailed description of the process for assigning molecularly-guided therapy is provided in the 
Molecular Tumor Board Charter.  In brief: 
 
Specific therapies for potentially actionable alterations in each patient’s FoundationOne® 
FMI F1CDx (tissue) test and/or FoundationOne® F1LCDx (Liquid) test reports 
(dependent on availability of one or both) will be categorized for their relevance to treatment 
decisions in consultation with an experienced FoundationOne® pathologist (if required)  
 
At the same time, the FoundationOne® FMI F1CDx (tissue) test and/or FoundationOne® 
F1LCDx (Liquid) test reports will be shared with the MTB standing members and, if 
required, will be discussed during preparatory MTB meetings in the absence of the 
investigator  
 
At a virtual MTB, the FoundationOne® FMI F1CDx (tissue) test and/or FoundationOne® 
F1LCDx (Liquid) test results and relevant patient information (including exclusions criteria 
for specific targeted therapies) will be reviewed by all members of the MTB, and a patient-
specific treatment regimen will be decided upon by the treating investigator in consultation 
with other board members  
 
It is expected that choice of molecularly-guided therapies may be ambiguous in some 
cases.  Guidance and rationales for choosing therapy under such circumstances are 
presented in the Molecular Tumor Board Charter 
 
After the MTB, the investigator will have 24 hours to finalize the treatment choice, and if 
different from the MTB recommendations, a new MTB discussion will need to be organized 
to validate the choice 
 
During the above process, all treatment choices will be made according to the guidance 
provided in Synopsis Table 2 and based on exclusions criteria for specific targeted therapies. 
 


 
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Those Category 1 patients who are randomized to the investigational arm will complete Part 2 
of the ICF and will then receive one of the molecularly-guided therapies in Synopsis Table 2 
until loss of clinical benefit, unacceptable toxicity, patient or investigator decision to discontinue, 
or death (whichever occurs first). 
 
For Category 1 patients randomized to the investigational arm and receiving treatment given in 
combination with chemotherapy, the chemotherapy will be administered per Section 4.3.4.7 of 
the protocol. 
 
Synopsis Table 2 
Identified Genomic Alterations and Corresponding  
Molecularly-Guided Therapies 
 
Molecularly-Guided Therapies 
Actionable Genomic Alterations 
Targeted Therapies 
 
 
Alectinib 
● 
ALK, RET fusions or rearrangements 
 
Entrectinib 
● 
NTRK gene fusions, ROS1 rearrangements 
 
Ivosidenib 
● 
IDH1 alterations 
 
Olaparib 
● 
BRCA1, BRCA2  
● 
PALB2 and RAD51B/C/D 
● 
gLOH (FMI score 20 or above) 
 
Pemigatinib 
● 
FGFR1, FGFR2 and FGFR3 alterations 
 
Vismodegib 
● 
Inactivating PTCH1, SMO alterations 
 
Erlotinib + bevacizumab 
● 
EGFR alterations 
 
Ipatasertib + paclitaxel 
● 
AKT1, PIK3CA, PTEN  
 
Vemurafenib + cobimetinib  
● 
BRAF V600 alterations, BRAF K601E 
 
Trastuzumab SC + pertuzumab + 
chemotherapy a 
● 
ERBB2/ERBB3 alterations  
Immunotherapy 
 
 
Atezolizumab 
● 
TMB–High (≥ 16 mutations/Mb) or MSI-High 
 
Atezolizumab + chemotherapy a 
● 
TMB–Low or Unknown (< 16 mutations/Mb) 
Other Treatment Options 
Potential Rationales  
for Other Options 
 
Alternative therapies  
 
(Only if the investigator in consultation 
with the MTB has strong evidence to 
support a therapy not represented in the 
investigational treatment arms above) 
● 
Strong suspicion of a primary tumor revealed by 
comprehensive genomic profiling 
● 
Strong rationale for alternative, commercially-
available, targeted therapy 
● 
Negative predictor of response to anti-PD-1/PD-L1 
agents 
● 
Patients who do not have a genetic alteration 
allowing for assignment to a protocol-mandated 
targeted therapy and who are contraindicated for 
atezolizumab 
TMB, tumor mutational burden; MSI, microsatellite instability. 
a. Platinum-based chemotherapy allowed per protocol (see other Sections for details). 
 
Alternative Therapy arm: 
If the investigator and MTB have strong evidence to support a therapy not represented in any of 
the investigational treatment arms, the investigator can choose to discontinue study treatment 
and allow the patient to receive an “alternative treatment option.”  Examples of cases suitable 
for an alternative treatment option include: 


 
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 
Patients with a defined treatment path revealed by comprehensive genomic profiling (CGP) 
(e.g., prostate cancer revealed by CGP) 
 
Patients who have a strong rationale for an alternative targeted therapy and have access to 
that alternative (e.g., crizotinib for cancers with MET-amplification) 
 
Patients not eligible for atezolizumab plus chemotherapy (due to a safety contraindication to 
atezolizumab), for whom chemotherapy may remain the best treatment option 
 
Patients with a safety contraindication to the preferred molecularly-guided therapy and/or 
atezolizumab (at time of randomization) for whom chemotherapy may remain the best 
treatment option 
 
Patients for whom an alternative therapy is selected by the MTB will go off study treatment.  
They will be managed per standard of care at their institution and will receive the alternative 
therapy outside of this study.  They will proceed to the Safety Follow-Up Visit and post-
treatment follow-up (refer to Section 3.1.6).  
 
Specific Scenarios: 
 
Reasons for a report not being generated include, but are not limited to, poor tumor tissue 
quantity or quality or other technical issues.  Patients for whom neither a FoundationOne® 
FMI F1CDx (tissue) test report nor a FoundationOne® F1LCDx (Liquid) test report could 
be generated will be discontinued from study treatment at the end of Induction Period. 
These patients will not be randomized. 
 
Category 1 patients with a valid result from the FoundationOne® FMI F1CDx (tissue) test 
and/or FoundationOne® F1LCDx (Liquid) test reports, but turn out to be ineligible for any 
molecularly-guided therapy will have the opportunity to receive the control therapy, i.e., the 
same platinum-based chemotherapy in place at the end of the Induction Period, for a 
minimum of 3 additional cycles. 
 
Patients who show evidence of clinical benefit after meeting RECIST v1.1 criteria for 
progressive disease will be permitted to continue treatment with molecularly-guided therapy 
until loss of clinical benefit, unacceptable toxicity, patient or physician decision to discontinue, or 
death (whichever occurs first), if they meet all of the following criteria: 
 
Evidence of clinical benefit (i.e., in the absence of symptomatic deterioration attributed to 
disease progression, as determined by the investigator after an integrated assessment of 
radiographic data, biopsy results [if available], clinical status, and worsening of laboratory 
values)  
 
Absence of unacceptable toxicity 
 
No decline in ECOG performance status that can be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions (refer to Section 4.4.1) 
 
Timelines for randomization, selection of treatment and start of treatment are described in 
Sections 4.2 and 4.3 and in Appendix 2. 
 
Category 2 Patients: Treatment Assignment and Treatment  
Category 2 patients (i.e., PD after or during 3 cycles of platinum induction chemotherapy) will be 
assigned molecularly-guided therapy by the investigator in consultation with the MTB, and will 
receive treatment as described for Category 1 patients, except for continuing induction 
chemotherapy in case of ineligibility for all molecularly-guided therapies. 
For Category 2 patients receiving treatment given in combination with chemotherapy, the 
chemotherapy will be administered per Section 4.3.4.7 of the protocol.  
 
Follow-Up Period 
Following completion or discontinuation of all study treatments (whether the patient discontinues 
after the Induction Period or After the Treatment Period), all patients will return to the clinic 30 


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(± 7) days from last treatment or at initiation of other systemic anticancer therapy (whichever 
occurs first) for a Safety Follow-Up Visit.   
After the Safety Follow-Up Visit, Patients in the control chemotherapy arm and patients who 
discontinue treatment for reason other than disease progression (including patient receiving 
alternative therapy) but who do not withdraw consent to follow-up will be assessed for 
progression as described during the Treatment Period (including scans) until disease 
progression per RECIST v1.1 (refer to Section 4.5.6). 
Thereafter, all patients will be contacted by the physician by phone for survival status every 3 
(± 1) months until death, loss to follow-up, withdrawal of consent or end of the study.  Data on 
nature of and response to further anticancer therapies will also be collected during the survival 
follow-up (refer to Appendix 1 for additional details).   
Study Committees 

A Steering Committee (SC), guided by a Steering Committee Charter, will be responsible for
overseeing the general conduct of the study.

An Eligibility Review Team (ERT), guided by Eligibility Review guidelines, will be
responsible for ensuring that patients who enroll in the trial have the correct diagnosis of
CUP (following ESMO guidelines).  The ERT will be able to take advice from a referent
oncologist, a referent radiologist and a referent pathologist, as appropriate.  In case the ERT
cannot confirm a diagnosis of CUP due to an incomplete pre-screening work-up, the ERT
will inform the investigator and provide the reason prior to declaring the patient ineligible.

A Molecular Tumor Board (MTB) will provide guidance to the investigator regarding the
choice of molecularly-guided therapy.  The MTB will be independent of the Sponsor, i.e., the
Sponsor will not participate in the MTB meetings nor in the decision-making process.
However, if there is a disagreement among MTB members regarding choice of molecularly-
guided therapies or safety concerns associated with choice of such agents, the Sponsor
should be consulted for advice.  MTB members cannot grant any waiver from the protocol in
regard to eligibility criteria or mandated study procedures.  Further information on the MTB
and the MTB process are described in the Molecular Tumor Board Charter.

An independent data monitoring committee (iDMC), guided by an iDMC Charter, will be
responsible for evaluating the safety and ongoing efficacy data of trial patients at regular
intervals throughout the study.  This includes an ongoing evaluation of the benefit-risk
balance, based on accumulating safety and, as warranted, efficacy data.  The iDMC will
make recommendations as to whether cohort recruitment should continue based on ongoing
assessments.

If applicable, an Independent Review Committee (IRC) may perform a centralized,
independent review of images, and other clinical data as needed, prior to the efficacy
analyses. IRC membership and procedures would be detailed in an IRC charter.
NUMBER OF PATIENTS 
The target sample for this study is 472 randomized patients with CUP who exhibited disease 
control (CR, PR or SD) after 3 cycles of platinum induction chemotherapy (Category 1 patients).  
Assuming a 60% disease control rate at the end of induction and a 15% dropout rate, it is 
estimated that approximately 790 patients with CUP will need to be enrolled in this study. 
If the actual number of patients who achieve a CR, PR, or SD during induction deviates from 
these estimates, the study will enroll patients until 472 patients have been randomized.  
In addition, if both the actual disease control and dropout rates differ from the protocol 
assumptions, the 330 PFS events may be reached before 790 patients are enrolled. In this 
case, screening will be stopped, when 330 PFS events have been observed. 
GENERAL INCLUSION CRITERIA 
At Study Entry 
Prior to eligibility review, as assessed during the Screening Period enrollment and initiation of 
platinum doublet chemotherapy, patients must meet the following main inclusion criteria for 
study entry: 


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•
Signed Informed Consent Form
•
Able and willing to comply with the study protocol
•
Age  ≥ 18 years at time of signing Informed Consent Form
•
Histologically-confirmed unresectable CUP diagnosed according to the criteria defined in the 
2015 ESMO Clinical Practice Guidelines for CUP (Fizazi et al. 2015).  Acceptable disease 
includes:
-
Adenocarcinoma
-
Poorly differentiated adenocarcinoma
-
Poorly differentiated carcinoma
•
Disease should not be amenable to resection and/or irradiation with curative intent during 
the course of the study
•
At least one lesion that is measurable according to RECIST v1.1 (Appendix 5)
-
If a fresh biopsy is needed during Screening, the biopsy procedure must not affect 
measurability of disease
•
Availability of a tumor FFPE block  ≤ 4 months old at the start of screening that is expected to 
be sufficient and suitable (in quantity and quality) for generation of a comprehensive 
genomic profile using FoundationOne® FMI F1CDx (tissue) test at a central reference 
pathology laboratory (refer to the Laboratory Manual for suitability details and specimen 
collection instructions)
•
Availability of local pathology reports confirming compatibility with CUP diagnosis and the 
associated slides used for the diagnosis (histology and routine immunohistochemistry 
compatible with CUP; refer to the Laboratory Manual for details).  If the slides used for the 
local test confirming CUP diagnosis are not available, an FFPE block must be submitted that 
is sufficient to allow for central confirmation of CUP diagnosis (i.e., performing relevant IHC 
and ISH if required).
-
If the available tumor sample is insufficient or not suitable (in quantity and quality) to 
enable the above assessments, a fresh biopsy sample must be collected during the 
Screening Period that meets the study’s requirements (refer to the Laboratory Manual 
for suitability details and specimen collection instructions and to Section 3.1.1 for special 
circumstances).  There is no restriction in the number of repeat biopsies performed 
locally to obtain a suitable sample for a submission to the central laboratory
•
No prior systemic therapy for the treatment of CUP
-
Prior local intratumoral therapy may be accepted.  If prior local intratumoral therapy, at 
least one of the measurable lesion(s) must have not benefited from local intratumoral 
therapy
-
Patients who have received prior surgery and/or radiotherapy (including 
radioembolization of tumor) are eligible.  If the patient had prior radiotherapy, the 
measurable lesion(s) must not have been irradiated
-
The last dose of radiotherapy must have been administered at least one week prior to 
the first dose of study treatment and the patient must have recovered to Grade 1 or less 
from any toxicity of radiotherapy 
In cases where radiotherapy has been administered for post brain surgery 
adjuvant treatment or as definitive intervention (e.g., stereotactic radiosurgery) for 
brain metastases, there must be at least 4 weeks between the end of the 
radiotherapy and start of study treatment 

ECOG performance status of 0 or 1

Life expectancy   12 weeks


 
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 
Eligible for platinum-based chemotherapy (according to the reference information for the 
intended chemotherapy) 
 
Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to initiation of study treatment: 
- 
Absolute neutrophil count (ANC)   1  109 cells/L (1000/L) (without granulocyte 
colony-stimulating factor [G-CSF] support within 2 weeks prior to the first study 
treatment) 
- 
Platelet count   100  109 cells/L (100,000/L) (without transfusion within 2 weeks prior 
to the first study treatment) 
- 
Hemoglobin   90 g/L (9.0 g/dL)  
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT)   2.5 times the upper 
limit of normal (ULN), with the following exceptions: 
Patients with documented liver metastases:  AST and/or ALT   5  ULN 
- 
Serum bilirubin   1.5  ULN  
Patients with known Gilbert disease who have serum bilirubin   3  ULN may be 
enrolled 
- 
Creatinine clearance   30 mL/min (calculated through use of the Cockcroft-Gault 
formula) 
In patients who receive cisplatin, creatinine clearance must be   60 mL/min 
- 
For patients not receiving therapeutic anticoagulation: International normalized ratio 
(INR) or activated partial thromboplastin time (aPTT)   1.5  ULN 
Patients receiving heparin treatment should have an aPTT between 1.5 to 
2.5  ULN (or patient value before starting heparin treatment).  Patients receiving 
coumarin derivatives should have an INR between 2.0 and 3.0 assessed in two 
consecutive measurements 1 to 4 days apart 
 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception with a failure rate of   1% per year during 
the Induction and Treatment Periods and after the final dose of study treatment for at least: 
- 
2 weeks for erlotinib 
- 
1 month for ipatasertib and olaparib 
- 
5 weeks for entrectinib and pemigatinib 
- 
3 months for alectinib and ivosidenib 
- 
5 months for atezolizumab 
- 
6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, cisplatin, paclitaxel 
and gemcitabine 
- 
7 months for trastuzumab and pertuzumab 
- 
24 months for vismodegib 
 
Women must refrain from donating eggs during this same period 
- 
A woman is considered to be of childbearing potential if she is postmenarcheal, 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 
- 
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.  Hormonal 
contraceptive methods must be supplemented by a barrier method 


 
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- 
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 
not adequate methods of contraception 
- 
If required per local guidelines or regulations, locally recognized adequate periods and 
methods of contraception and information about the reliability of abstinence will be 
described in the local Informed Consent Form 
- 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to first dose.  If the serum pregnancy test is uninterpretable (e.g., 
beta-HCG is elevated in the absence of other signs of pregnancy), the reason for non-
interpretability should be adequately documented, and intra- or extra-uterine pregnancy 
should be ruled out by ultrasound within 7 days prior to the first administration of study 
treatment (Goldstein et al. 2016) 
 
For male patients: acceptance that most of the study treatments require specific reliable 
and effective contraception measures, as well as measures related to sperm donation.  This 
includes agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraception, and agreement to refrain from donating sperm, as defined below: 
- 
With a female partner of childbearing potential who is not pregnant, men 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 Induction and Treatment Periods and after 
the final dose of study treatment for at least: 
2 weeks for erlotinib 
1 month for ipatasertib 
2 months for vismodegib 
3 months for alectinib, olaparib, entrectinib, ivosidenib and pemigatinib 
6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, cisplatin, 
paclitaxel and gemcitabine 
7 months for trastuzumab and pertuzumab 
 
Men must refrain from donating sperm during this same period 
 
- 
With pregnant female partners, men must remain abstinent or use a condom to avoid 
exposing the embryo during the Induction and Treatment Periods and for at least: 
2 weeks for erlotinib 
1 month for ipatasertib 
2 months for vismodegib 
3 months for alectinib, olaparib, entrectinib, ivosidenib and pemigatinib 
6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, cisplatin, 
paclitaxel and gemcitabine 
7 months for trastuzumab and pertuzumab 
 
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 not adequate methods of contraception  
If required per local guidelines or regulations, locally recognized adequate periods and 
methods of contraception and information about the reliability of abstinence will be 
described in the local Informed Consent Form 
 
Prior to Start of Therapy in the Treatment Period 
If any of the below criteria are NOT met, randomization and/or the MTB will be delayed or study 
treatment will be discontinued (see Section 3.1.3): 
 
Head CT or MRI scans must meet the following criteria: 


 
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- 
Category 1 patients:  
No change from baseline 
- 
Category 2 patients: 
No change from baseline, OR; 
Asymptomatic brain metastases (if necessary, concomitant treatment to control 
CNS involvement and/or provide symptom prophylaxis is allowed) 
Patients who have had a resection of brain metastases by, for example, 
conventional surgery or stereotactic radiosurgery may continue into the Treatment 
Period, provided they have recovered from the surgery (see below) and any 
ongoing symptomatic therapy or prophylaxis is compatible with the treatment-
specific exclusion criteria described in Section 4.1.3 
 
Recovery to Grade   1 of significant toxicities attributable to induction chemotherapy, with 
the following exceptions: 
- 
Alopecia of any grade is allowed 
- 
Neurosensory toxicity must have recovered to   Grade 2 
- 
Laboratory values must be as per inclusion criteria described below 
 
With the exception of resection of brain metastases by conventional surgery or stereotactic 
radiosurgery (see prior inclusion criterion), the patient must not have had a major surgical 
procedure within 2 weeks prior to initiation of the Treatment Period and/or there must be no 
anticipation of a need for a major surgical procedure during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that occurred 
 2 weeks before initiation of the Treatment Period, including sufficient wound healing, 
with the following exceptions: 
Patients assigned to erlotinib in combination with bevacizumab, to ipatasertib (in 
combination with paclitaxel or as monotherapy), or to ivosidenib must have 
recovered from any major surgical procedure that occurred  4 weeks before 
initiation of the Treatment Period, including sufficient wound healing 
 
No history or known presence of leptomeningeal disease 
 
ECOG performance status of 0 or 1 for Category 1 patients 
 
ECOG performance status of 0, 1 or 2 for Category 2 patients 
 
Adequate hematologic function, defined by the following laboratory results (criteria must be 
verified and fulfilled prior to first dose in the Treatment Period, but will not delay 
randomization): 
- 
ANC   1.0  109 cells/L (1000/L) (without granulocyte colony-stimulating factor [G-CSF] 
support within 2 weeks prior to planned study treatment date) 
- 
Platelet count   100  109 cells/L (100,000/L) (without transfusion within 2 weeks prior 
to the planned treatment date) 
- 
Hemoglobin   90 g/L (9.0 g/dL)  
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion 
 
Adequate end-organ function, defined by the following laboratory results: 
- 
AST and ALT   2.5  ULN, with the following exceptions: 
Patients with documented liver metastases: AST and/or ALT   5  ULN 
- 
Serum bilirubin   1.5  ULN  
Patients with known Gilbert disease who have serum bilirubin ≤ 3 × ULN may be 
randomized (Category 1 patients) or considered for molecularly-guided therapy 
(Category 2 patients) 
- 
Creatinine clearance   30 mL/min (calculated through use of the Cockcroft-Gault 
formula) 
In patients who receive cisplatin, creatinine clearance must be   60 mL/min 


 
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- 
For patients not receiving therapeutic anticoagulation: International normalized ratio 
(INR) or activated partial thromboplastin time (aPTT)   1.5  ULN 
Patients receiving heparin treatment should have an aPTT between 1.5 to 
2.5  ULN (or patient value before starting heparin treatment) 
Patients receiving coumarin derivatives should have an INR between 2.0 and 3.0 
assessed in two consecutive measurements 1 to 4 days apart 
 
At least 2 weeks between the last dose of radiotherapy administered during the Induction 
Period and the first dose of study treatment administered during the Treatment Period 
- 
Patients must have recovered from all radiation-related toxicities, must not require 
corticosteroids and must not have had radiation pneumonitis 
 
Recovery from active infections requiring intravenous antibiotics, with antibiotic therapy 
ceased for ≥ 7 days prior to planned start of therapy 
 
Women of childbearing potential must have a negative serum pregnancy test result within 
7 days prior to the first dose.  If the serum pregnancy test is uninterpretable (e.g., beta-HCG 
is elevated in the absence of other signs of pregnancy), the reason for non-interpretability 
should be adequately documented, and intra- or extra-uterine pregnancy should be ruled 
out by ultrasound within 7 days prior to the first administration of study treatment 
 
MAIN EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Squamous cell CUP 
 
Patients with histology and immunohistology profiles (per 2015 ESMO guidelines) that are 
not adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma), i.e., non-epithelial 
cancer, extragonadal germ-cell tumor, neuroendocrine tumors, sarcoma, melanoma, 
mesothelioma, hematologic malignancies (this list is not limitative) 
 
Patients who can be assigned to a specific subset of CUP for which a specific treatment is 
recommended by the 2015 ESMO Clinical Practice Guidelines for CUP (Fizazi et al. 2015) 
or with a clinical and IHC profile indicative of a specific primary tumor (favorable prognosis 
CUP subsets).  These are: 
- 
Poorly differentiated carcinoma with midline distribution 
- 
Women with papillary adenocarcinoma of the peritoneal cavity 
- 
Women with adenocarcinoma involving only the axillary lymph nodes 
- 
Squamous cell carcinoma of the cervical lymph nodes 
- 
Poorly differentiated neuroendocrine tumors 
- 
Men with blastic bone metastases and elevated PSA 
- 
Patients with a single, small, potentially resectable tumor 
- 
Colon cancer-type CUP with a CK7 negative, CK20 positive, CDX-2 positive 
immunohistochemistry profile 
- 
CK7 positive, CK20 negative and TTF-1 positive tumors in a context suggestive of lung 
adenocarcinoma or thyroid cancer (i.e., with lesions in the lung or thyroid or the lymph 
nodes in their drainage areas) 
- 
IHC profile definitely indicative of breast cancer OR an IHC profile indicative of breast 
cancer and either a history of breast cancer or lymph nodes in the drainage areas of the 
breast 
- 
High-grade serous carcinoma histology and elevated CA125 tumor marker and/or a 
mass in the gynecological tract or any tumor mass or lymph node in the abdominal 
cavity (i.e., below the diaphragm) 
- 
IHC profile suggestive of renal cell carcinoma and renal lesions, with a Bosniak 
classification higher than IIF 
- 
IHC profile compatible with cholangiocarcinoma or pancreatobiliary (or upper 
gastrointestinal carcinoma) AND 1 or 2 liver lesions without extrahepatic disease or with 
only pulmonary metastases and/or lymph nodes in the drainage areas of the liver 


 
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Note:  For the aforementioned patients, but not limited to them, an escalation to a referent 
oncologist or radiologist may be required by the study team for adjudication 
 
● Known presence of brain or spinal cord metastasis (including metastases that have been 
irradiated only), as determined by CT or magnetic resonance imaging (MRI) evaluation 
during screening 
- 
Patients who had a complete resection of brain metastases by surgery with or without a 
combination of stereotactic radiosurgery, whole-brain irradiation or intensity-modulated 
radiation therapy may be accepted, provided that there were 3 (at maximum) or less 
metastases resected or treated and that an MRI or high resolution CT scan of the brain 
not older than 3 months post intervention shows the absence of residual disease at 
least, no other ongoing brain metastases and no leptomeningeal carcinomatosis.  
Benign lesions such as meningiomas may be accepted if it can be demonstrated that 
they may not affect the interpretation of the study results or render the patient at high-
risk from treatment complications 
 
History or known presence of leptomeningeal disease 
 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis, current alcohol abuse, or cirrhosis  
 
Human immunodeficiency virus (HIV) infection 
 
Positive for hepatitis C virus (HCV) antibody at screening 
- 
If a patient has a positive HCV antibody test at screening, an HCV RNA test must also 
be performed.  A patient will be excluded from the study only if the HCV antibody and 
the HCV RNA test are positive.  If the HCV antibody test is positive, but the HCV RNA 
test is negative, the patient may enroll in the study 
 
Positive for hepatitis B surface antigen (HBsAg) at screening 
- 
If the HBsAg test is negative but the total hepatitis B core antibody (HBcAb) test is 
positive, assessment of HBV DNA must be performed.  If the resulting HBV DNA test is 
positive, the patient will be excluded from the study 
 
Active tuberculosis at screening 
 
Active infections requiring intravenous antibiotics.  If prior infection required IV antibiotic 
therapy, antibiotic therapy must have ceased   2 days prior to planned start of study 
treatment 
 
Significant cardiovascular disease (such as New York Heart Association Class II or greater 
cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to 
initiation of study treatment, unstable arrhythmia (including active ventricular arrhythmia 
requiring medication), or unstable angina  
 
History of malignancy within 5 years prior to initiation of study treatment, with the exception 
of the cancer under investigation in this study and 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 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high-risk from treatment 
complications 
 
Treatment with investigational therapy within 28 days or the equivalent of 5 half-lives 
(whichever is the longest) prior to initiation of study treatment 
 
Known allergy or hypersensitivity to any component of the platinum-based chemotherapy 
 
Pregnant or breastfeeding, or intending to become pregnant during study treatment or for 
up to 24 months after the final dose of treatment 
 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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EXCLUSION CRITERIA SPECIFIC TO MOLECULARLY-GUIDED THERAPIES 
Details of exclusion criteria described below will be collected prior to study entry and re-
assessed at the End of Induction Visit to capture any exclusion criteria that may have developed 
during the Induction Period.  Meeting any of these exclusion criteria will not prevent patients 
from entering the study, a Category 1 patient from being randomized, or a Category 2 patient 
from proceeding to study treatment.  Rather, if a patient does meet an exclusion criterion for a 
particular molecularly-guided therapy, then only that specific therapy will be excluded as a 
choice for this patient.  This will be clearly notified to the investigator and the MTB and no 
patient will be allowed to start treatment with a therapy he/she is not eligible to receive within 
the study. 
 
All Molecularly-Guided Therapies 
 
Known allergy or hypersensitivity to any component of the molecularly-guided agents 
- 
This includes history of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins and to Chinese hamster ovary cell products or other 
recombinant human or humanized antibodies for atezolizumab, bevacizumab, 
pertuzumab and trastuzumab 
 
All Oral Therapies 
 
History of malabsorption syndrome, lack of physical integrity of the upper gastrointestinal 
tract, or other condition that would interfere with enteral absorption or results in the inability 
or unwillingness to swallow pills 
 
Alectinib 
 
Hereditary galactose intolerance, a congenital lactase deficiency or glucose-galactose 
malabsorption 
 
Symptomatic bradycardia 
 
Vismodegib 
 
Males unwilling to use condoms (with spermicide, where available), even after a vasectomy, 
during heterosexual intercourse while being treated with vismodegib, and for 2 months after 
the final dose. (Men must refrain from donating sperm during this same period) 
 
Ipatasertib in Combination with Paclitaxel (or Ipatasertib Monotherapy in Patients who are not 
Receiving the Combination) 
 
Fasting total serum glucose   150 mg/dL 
 
Glycated hemoglobin (HbA1C)   7.5% 
 
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 
 
Creatinine clearance   50 mL/min (calculated through the use of the Cockcroft-Gault 
formula) 
 
Ongoing corticosteroid therapy (use of topical steroids or inhaled steroids is acceptable) or 
immunosuppressants for a chronic disease 
 
Active small or large intestine inflammation (such as Crohn’s disease or ulcerative colitis) 
 
With the exception of resection of brain metastases by conventional surgery or stereotactic 
radiosurgery, the patient must not have had a major surgical procedure within 4 weeks prior 
to initiation of the Treatment Period and/or there must be no anticipation of a need for a 
major surgical procedure during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that occurred 
≥ 4 weeks before initiation of the Treatment Period, including sufficient wound healing 


 
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 
Patients who have received palliative radiation treatment to peripheral sites (e.g., bone 
metastases) for pain control and whose last treatment was completed 14 days prior to 
Day 1 of Cycle 1 may be enrolled in the study if they have recovered from all acute, 
reversible effects (e.g., resolved to Grade   1 by enrolment) 
- 
More guidance on permitted therapies, including palliative radiotherapy, can be found in 
Section 4.4 
 
Ivosidenib 
 
ANC   1.5  109 cells/L (1500/L) 
 
Creatinine clearance   50 mL/min (calculated through the use of the Cockcroft-Gault 
formula) 
 
Known medical history of progressive multifocal leukoencephalopathy (PML) 
 
Ongoing treatment with drugs known to be strong cytochrome P450 (CYP) 3A4 inducers or 
sensitive CYP3A4 substrate medications with a narrow therapeutic window, unless they can 
be switched to other medications within   5 half-lives prior to dosing 
 
Ongoing treatment with P-glycoprotein (P-gp) transporter-sensitive substrate medications 
with a narrow therapeutic window, unless they can be transferred to other medications 
within   5 half-lives prior to administration of study treatment 
 
LVEF   40% by ECHO scan (or by other methods according to institutional practice) 
obtained within 28 days prior to the start of study treatment 
 
Heart rate corrected QT interval (using Fridericia’s formula) (QTcF)   450 msec or other 
factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, 
hypokalemia, family history of long QT interval syndrome).  Bundle branch block are 
permitted 
 
Concomitant medications that are known to prolong the QT interval, unless they can be 
transferred to other medications within   5 half-lives prior to dosing or unless the 
medications can be properly monitored during the study.  (If equivalent medication is not 
available, QTcF should be closely monitored.) 
 
With the exception of resection of brain metastases by conventional surgery or stereotactic 
radiosurgery, the patient must not have had a major surgical procedure within 4 weeks prior 
to initiation of the Treatment Period and/or there must be no anticipation of a need for a 
major surgical procedure during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that 
occurred   4 weeks before initiation of the Treatment Period, including sufficient wound 
healing 
 
Olaparib 
 
None 
 
Pemigatinib 
 
Current evidence of clinically significant corneal (including, but not limited to, bullous/band 
keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivitis) or retinal 
disorder (including, but not limited to, macular/retinal degeneration, diabetic retinopathy, 
retinal detachment) as confirmed by ophthalmologic examination 
 
Serum phosphate   ULN 
 
Serum calcium outside of normal range, or serum-albumin-corrected calcium outside of the 
normal range when serum albumin is outside of the normal range 
 
History of calcium and phosphate homeostasis disorder or systemic mineral imbalance with 
ectopic calcification of soft tissues (exception: commonly observed calcifications in soft 
tissues such as the skin, kidney tendon, or vessels due to injury, disease, or aging in the 
absence of systemic mineral imbalance)  
 
Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 
14 days or five half-lives (whichever is longer) before the first dose of pemigatinib 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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- 
Note:  Moderate CYP3A4 inhibitors are not prohibited 
 
Atezolizumab Monotherapy or in Combination with Platinum-Based Chemotherapy 
 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, myocarditis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid 
antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix 4 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 thyroid-
replacement hormone are eligible for the study. 
- 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for treatment with atezolizumab. 
- 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
treatment with atezolizumab provided all of following conditions are met: 
Rash must cover   10% of body surface area 
Disease is well controlled on Day 1 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 
 
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti− 
tumor necrosis factor–TNF- agents) within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of immunosuppressive medication during treatment 
with atezolizumab, 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 or anti-emetic prophylaxis for chemotherapy) are 
eligible 
- 
Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose 
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-
dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for 
the study 
● In patients who receive concomitant chemotherapy, all criteria for administration of 
chemotherapy must be verified 
 
Alkaline phosphatase (ALP)   2.5  ULN, with the following exception: 
- 
Patients with documented liver or bone metastases must have ALP   5  ULN 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium 
 12 mg/dL, or corrected serum calcium   2.9 mmol/L) 
 
Erlotinib + Bevacizumab 
 
Poorly controlled hypertension (e.g., systolic   140 mmHg or diastolic   90 mmHg) 
 
History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding 
 
History of thrombotic disorders within the last 6 months prior first dose of bevacizumab 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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 
Patients discovered to have   2  proteinuria on dipstick urinalysis at end of induction work-
up or at Cycle 1 Day1 assessment should undergo a 24-hour urine collection and must 
demonstrate   1 g of protein in 24 hours prior to first administration of bevacizumab 
 
Non-healing wound, active peptic ulcer or bone fracture at Cycle 3 of induction 
chemotherapy 
 
History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 
6 months of planned study treatment 
 
Recent pulmonary hemorrhage/hemoptysis ( 1/2 teaspoon red blood) 
 
Unwillingness to stop smoking and vaping 
 
With the exception of resection of brain metastases by conventional surgery or stereotactic 
radiosurgery, the patient must not have had a major surgical procedure within 4 weeks prior 
to initiation of the Treatment Period and/or there must be no anticipation of a need for a 
major surgical procedure during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that occurred 
 4 weeks before initiation of the Treatment Period, including sufficient wound healing 
 
Vemurafenib + Cobimetinib 
 
LVEF below institutional LLN or below 50%, whichever is lower  
 
QTc   500 msec at Cycle 3 of induction chemotherapy 
 
Long QT syndrome 
 
Uncorrectable electrolyte abnormalities 
 
Known risk factors for ocular toxicity, consisting of any of the following: 
- 
History of serous retinopathy 
- 
History of retinal vein occlusion (RVO) 
- 
Evidence of ongoing serous retinopathy or RVO at screening 
 
Any Grade   3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1 
 
Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme 
inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment 
- 
These include St. John’s wort or hyperforin (strong CYP3A4 enzyme inducer) and 
grapefruit juice (strong cytochrome P450 CYP3A4 enzyme inhibitor) 
 
Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline 
hypertension consistently above systolic   140 mmHg or diastolic   90 mmHg despite 
optimal medical management 
 
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 
 
Hereditary galactose intolerance, a congenital lactase deficiency or glucose-galactose 
malabsorption 
 
Trastuzumab SC Plus Pertuzumab Plus Platinum-Based Chemotherapy 
 
Serious cardiac illness or medical conditions including but not confined to: 
- 
History of documented congestive heart failure or systolic dysfunction (baseline LVEF 
 55% at Cycle 3 of induction chemotherapy, measured by echocardiography or 
multiple-gated radionuclide angiography (MUGA) scan prior to first dose of 
trastuzumab) 
- 
High-risk uncontrolled arrhythmias i.e., atrial tachycardia with a heart rate   100/min at 
rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade 
AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block) 
- 
Angina pectoris requiring anti-anginal medication 
- 
Clinically significant valvular heart disease 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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- 
Evidence of transmural infarction on ECG 
- 
Poorly controlled hypertension (e.g., systolic   140 mmHg or diastolic   90 mmHg) 
 
Dyspnea at rest or other diseases that require continuous oxygen therapy 
 
Current chronic daily treatment with corticosteroids (dose   10 mg methylprednisolone or 
equivalent [excluding inhaled steroids]) 
 
Current severe, uncontrolled systemic disease that may interfere with planned treatment 
(e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing 
disorders) 
 
Type 1 or Type 2 diabetes mellitus requiring insulin 
- 
Patients who are on a stable dose of oral diabetes medication ≥ 4 weeks prior to 
initiation of trastuzumab plus pertuzumab may be eligible for treatment.  Fasting total 
serum glucose must be   150 mg/dL and glycated hemoglobin (HbA1c) must be   7.5% 
at Cycle 3 of induction chemotherapy 
 
History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), active 
bowel inflammation (e.g., diverticulitis) 
 
In patients who receive concomitant chemotherapy, all criteria for administration of 
chemotherapy must be verified 
 
Entrectinib 
 
History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval 
 450 milliseconds from ECGs performed at least 24 hours apart) 
 
History of additional risk factors for torsade de pointes (e.g., family history of long QT 
syndrome) 
 
History of recent (within 3 months from MTB) symptomatic congestive heart failure or 
ejection fraction   50%  
 
Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-
induced pneumonitis 
 
Peripheral sensory neuropathy Grade   2 
 
END OF STUDY 
The end of study will occur when all enrolled patients have either died, withdrawn consent, are 
lost to follow-up, or have been followed for 18 months after the last study patient is enrolled, 
whichever occurs first. 
If the sufficient number of events for the OS follow-up analysis is not reached (refer to 
Section 6.4.2.1 of the protocol) by time of the planned end of the study as defined above, the 
study will be prolonged until this number is reached. 
 
LENGTH OF STUDY 
Recruitment is expected to occur over approximately 52 months.  It is therefore estimated that 
the study will last for a total of approximately 70 months. 
 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Alectinib, Atezolizumab, Entrectinib, Ivosidenib, Olaparib, Pemigatinib, and Vismodegib 
Monotherapy 
These treatments will be administered, per results from comprehensive genomic profiling (see 
Section 3.1 and the Molecular Tumor Board Charter), as recommended in their respective 
investigator’s brochures and/or reference safety information for currently approved (non-CUP) 
indications.  With the exception of entrectinib, none of these agents are approved for the 
treatment of CUP, although all have been approved for other cancer indications: 
 
Alectinib will be administered as recommended for ALK-positive NSCLC, i.e., at an oral 
dosage of 600 mg BID until loss of clinical benefit or unacceptable toxicity 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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 
Atezolizumab will be administered as recommended for urinary carcinoma or NSCLC, i.e., 
as a 1200 mg intravenous infusion over 60 minutes every 3 weeks until loss of clinical 
benefit or unacceptable toxicity 
 
Entrectinib will be administered as recommended in its US label for patients with NTRK 
gene fusions or ROS1 gene rearrangements at an oral dosage of 600 mg QD (three 
200-mg capsules per day) until loss of clinical benefit or unacceptable toxicity 
 
Ivosidenib will be administered as recommended in its US label for patients with newly-
diagnosed or relapsed/refractory acute myeloid leukemia with a susceptible IDH1 mutation, 
i.e., at an oral dose of 500 mg QD (with or without food) across a 28-day treatment cycle 
until loss of clinical benefit or unacceptable toxicity 
 
Olaparib will be administered until loss of clinical benefit or unacceptable toxicity, as 
recommended for patients with germline BRCA-mutated advanced ovarian cancer, i.e., at 
an oral dosage of:  
- 
400 mg BID if administered as capsules 
- 
or 300 mg BID if administered as film-coated tablets 
– 
Note: After the film-coated tablets are available for use in the study,   
▪ 
patients newly randomized should start olaparib treatment with 300 mg BID using 
film-coated tablets.  
▪ 
patients who already started treatment with 400 mg BID using capsules should 
only switch to 300 mg BID using film-coated tablets, after capsules are not any 
more available (when the last batch of capsules expires). 
 
Pemigatinib will be administered as recommended for advanced or metastatic 
cholangiocarcinoma with FGFR2 fusions or other rearrangements, i.e., at an oral dosage of 
13.5 mg QD (given in the morning with water, with or without food) across a 21-day 
treatment cycle until loss of clinical benefit or unacceptable toxicity.  (As described in 
Appendix 10-11, pemigatinib may be up-titrated to 18 mg QD after one cycle of therapy if 
the patient does not reach the target serum phosphate level of   5.5 mg/dL at any time 
during Cycle 1, is compliant with taking study drug, and does not experience an ongoing 
Grade 2 or higher treatment-related AE) 
 
Vismodegib will be administered as recommended for metastatic basal cell carcinoma, i.e., 
at an oral dosage of 150 mg QD until loss of clinical benefit or unacceptable toxicity 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
alectinib, atezolizumab, entrectinib, ivosidenib, olaparib, pemigatinib and vismodegib are 
provided in their respective investigator’s brochures and/or reference safety information.  
Summaries are provided in Appendices 10-1, 10-2, 10-5, 10-9, 10-10, 10-11, and 10-14, 
respectively. 
 
Erlotinib/Bevacizumab Combination Therapy 
Erlotinib plus bevacizumab will be administered in patients with EGFR alterations (see 
Section 3.1).  While neither of these agents are approved for the treatment of CUP, the 
combination has been approved by the EMA in patients with advanced EGFR-positive NSCLC.   
Erlotinib and bevacizumab will be administered as recommended in their respective European 
Medicines Agency (EMA) Summary of Product Characteristics (EU SmPC) for advanced 
NSCLC: 
 
Erlotinib will be administered at an oral dosage of 150 mg QD (on an empty stomach) until 
loss of clinical benefit or unacceptable toxicity 
 
Bevacizumab will be administered as a 15 mg/kg Q3W intravenous infusion until loss of 
clinical benefit or unacceptable toxicity 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
erlotinib and bevacizumab are provided in their respective reference safety information.  
Summaries are provided in Appendices 10-6 and 10-3, respectively. 


 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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In exceptional cases of patients with a contraindication to bevacizumab but not to erlotinib, 
erlotinib may be administered as a monotherapy.  
 
Ipatasertib  Paclitaxel 
The investigational therapy ipatasertib plus paclitaxel will be administered in patients with AKT1, 
PTEN, or PIK3CA alterations (see Section 3.1). 
Ipatasertib will be administered as recommended in the current Ipatasertib Investigator’s 
Brochure for patients with AKT1-, PIK3CA- or PTEN-altered tumors, i.e., at a once-daily dosage 
of 400 mg.  In combination with paclitaxel, the dosages and schedule of administration will be: 
 
Ipatasertib will be administered orally at a dose of 400 mg QD on Days 1 to 21 of a 28-day 
cycle until loss of clinical benefit or unacceptable toxicity.  Ipatasertib will continue to be 
dosed as a monotherapy with the same schedule after the final administration of paclitaxel 
(see next bullet) until loss of clinical benefit or unacceptable toxicity 
 
Paclitaxel will be administered at a dose of 80 mg/m2 IV over 1 hour on Days 1, 8, and 15 of 
a 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can be given on Day 22.  
Paclitaxel will be given for 3 cycles.  If tolerated, it may be continued beyond 3 cycles (refer 
to Section 4.3.4.7) 
 
For Category 2 patients previously treated with paclitaxel or those patients with a 
contraindication to paclitaxel, administering ipatasertib without paclitaxel may be considered. 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
ipatasertib are provided in the Ipatasertib Investigator’s Brochure.  A summary of dose 
reductions, interruptions and discontinuation for ipatasertib and paclitaxel in combination is 
provided in Appendix 10-8. 
Any patient who started ipatasertib monotherapy under Versions 2–5 of the protocol can be 
switched to ipatasertib combined with paclitaxel if judged clinically appropriate by the 
investigator and accepted by the patient.  
Patients (both Category 1 or 2) who have contraindications for paclitaxel, or Category 2 patients 
who were previously treated with paclitaxel, may receive ipatasertib monotherapy without 
paclitaxel at the discretion of the investigator.  Likewise, patients who initiated ipatasertib 
without paclitaxel, as recommended in earlier versions of this protocol, may continue to receive 
ipatasertib monotherapy at the investigator’s discretion.  In all of these cases, single-agent 
ipatasertib will be administered as recommended in the current Ipatasertib Investigator’s 
Brochure for patients with AKT-, PTEN- or PIK3CA-altered tumors, i.e., at a once-daily dosage 
of 400 mg across a 21-day treatment cycle. 
 
Vemurafenib/Cobimetinib Combination Therapy 
Vemurafenib plus cobimetinib will be administered in patients with BRAF mutations (see 
Section 3.1).  While neither of these agents are approved for the treatment of CUP, the 
combination has been approved by the FDA in patients with advanced BRAF-positive 
melanoma. 
Vemurafenib and cobimetinib will be administered as recommended in their respective 
investigator’s brochures for advanced melanoma: 
 
Vemurafenib will be administered at an oral dosage of 960 mg BID until loss of clinical 
benefit or unacceptable toxicity 
 
Cobimetinib will be administered at an oral dosage of 60 mg QD for the first 21 days of a 
28-day treatment cycle until loss of clinical benefit or unacceptable toxicity 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
vemurafenib and cobimetinib are provided in their respective investigator’s brochures.  
Summaries are provided in Appendix 10-13 and 10-4, respectively. 
In exceptional cases of patients with a contraindication to cobimetinib but not to vemurafenib, 
vemurafenib may be administered as monotherapy. 
 
Trastuzumab/Pertuzumab/Platinum-based Chemotherapy Combination 


 
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Trastuzumab SC plus pertuzumab plus platinum-based chemotherapy will be administered in 
patients with HER2 alterations. 
While neither trastuzumab SC nor pertuzumab are approved for the treatment of CUP, the 
combination has been approved by the EMA in metastatic breast cancer patients with HER2 
alterations, while the combination of trastuzumab, pertuzumab and chemotherapy has been 
approved by the EMA for the neoadjuvant treatment of adult patients with HER2-positive, locally 
advanced, inflammatory, or early stage breast cancer at high-risk of recurrence. 
Trastuzumab SC and pertuzumab will be administered as recommended in their respective 
investigator’s brochures and/or reference safety information for advanced breast cancer with 
HER2 alterations: 
 
Pertuzumab:  Initial loading dose of 840 mg administered as a 60 (± 10) minute IV infusion, 
followed every 3 weeks thereafter by a maintenance dose of 420 mg administered over a 
period of 30 to 60 (± 10) minutes.  An observation period of 30–60 minutes is recommended 
after completion of each pertuzumab infusion.  If a dose is delayed (i.e., the time between 
two sequential infusions is less than 6 weeks), the 420 mg dose of pertuzumab should be 
administered.  If a dose is missed (i.e., the time between two sequential infusions is 
6 weeks or more), a re-loading dose of pertuzumab (840 mg) should be given as described 
for a loading dose 
 
Trastuzumab:  600 mg fixed dose SC injection every 3 weeks 
 
Chemotherapy will be administered for a minimum of 3 additional cycles.  If relevant and 
tolerated, the chemotherapy may be continued beyond 3 cycles with one or both drugs. 
Refer to Section 4.3.4.7 for details. 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
pertuzumab and trastuzumab are provided in their respective investigator’s brochures.  A 
summary is provided in Appendix 10-12.  
 
Atezolizumab/Platinum-Based Chemotherapy Combination 
Atezolizumab plus platinum-based chemotherapy will be administered in patients with no 
actionable alterations and who are not TMB-high or MSI-high. 
The combination of atezolizumab and a platinum-based chemotherapy is currently undergoing 
investigation in several clinical trials, including a Phase III study (NCT02807636) assessing the 
combination of atezolizumab with gemcitabine and cisplatin or carboplatin, and a Phase III 
study (NCT02367794) assessing the combination of atezolizumab with carboplatin and 
paclitaxel.  
Atezolizumab will be administered as recommended in its investigator’s brochure and/or 
reference safety information for urinary carcinoma or NSCLC: 
 
Atezolizumab:  1200 mg IV infusion over 60 minutes every 3 weeks 
 
Chemotherapy will be administered for a minimum of 3 additional cycles.  If relevant and 
tolerated, the chemotherapy may be continued beyond 3 cycles, with one or both drugs.  
Refer to Section 4.3.4.7 for details 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
atezolizumab are provided in its investigator’s brochure.  A summary is provided in 
Appendix 10-2.  
 
Platinum-based Chemotherapy 
All patients in this study will initially receive 3 cycles of platinum-based induction chemotherapy. 
Three platinum-based chemotherapy regimens will be permitted in this study: 
 
Carboplatin/paclitaxel:  paclitaxel 175 mg/m2  carboplatin AUC 56 on Day 1 of a 3-week 
cycle, monitoring for neurotoxicity (Fizazi et al. 2015).  Carboplatin AUC dose will be 
calculated by the Calvert formula (http://reference.medscape.com/calculator/carboplatin-
auc-dose-calvert) (Calvert et al. 1989) 


 
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 
Cisplatin/gemcitabine:  cisplatin 60–75 mg/m2 on Day 1 with gemcitabine 1000 mg/m2 on 
Day 1 and Day 8 of a 3-week cycle, ensuring adequate hydration (Fizazi et al. 2015) 
 
Carboplatin/gemcitabine:  gemcitabine 1000 mg/m2 on Day 1 and Day 8 with carboplatin 
AUC 5–6 on Day 1 of a 3-week cycle (Pittman et al. 2006).  Carboplatin AUC dose will be 
calculated by the Calvert formula (http://reference.medscape.com/calculator/carboplatin-
auc-dose-calvert) (Calvert et al. 1989) 
 
The carboplatin/paclitaxel or cisplatin/gemcitabine regimens may be administered using weekly 
schedules as follows: 
 
Paclitaxel 60 mg/m2 with carboplatin AUC 2 mg/mL every week for 9 weeks (equivalent to 
3 cycles of 21 days) (Pignata et al. 2014) 
 
Carboplatin AUC dose will be calculated by the Calvert formula  
 
Cisplatin 25 mg/m² on Day 1 and Day 8 with gemcitabine 1000 mg/m² on Day 1 and Day 8 
of a 3-week cycle, ensuring adequate hydration (Valle et al. 2010) 
 
The following alternative regimen may be administered as follows (Albers et al. 2011): 
 
Paclitaxel:  175 mg/m2 on Day 1 only 
 
Gemcitabine:  1000 mg/m2 on Days 1 and 8  
This regimen is only possible after the Induction Period, in exceptional circumstances, if the 
patient has contraindication to platinum-based regimens, and in association with either 
trastuzumab  pertuzumab or atezolizumab (not allowed for patients in the chemotherapy arm). 
 
If an investigating site typically uses slightly different dosages or schedule of administration for a 
chemotherapy regimen authorized in the study (carboplatin/paclitaxel, cisplatin/gemcitabine, 
carboplatin/gemcitabine or paclitaxel/gemcitabine), the local regimen may be used if sufficiently 
close to the regimen described in the protocol (similar dose intensity and similar efficacy and 
safety profiles).  The regimen will be used for all patients at a given site, except for management 
of intolerance as described in Section 3.1.2. 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
cisplatin, carboplatin, gemcitabine and paclitaxel are indicated in their respective safety 
reference information.  This includes any dose or schedule adjustments at baseline that are 
suggested for elderly patients or any special population. 
 
For Category 1 patients (randomized to the control arm, or randomized to the 
investigational arm and receiving treatment given in combination with chemotherapy), the 
same chemotherapy regimen in place at the end of the Induction Period will be continued for a 
minimum of 3 additional cycles: 
 
In exceptional circumstances, the chemotherapy may be changed, but only upon the 
recommendation of the MTB.  Such changes in chemotherapy will be limited to the 
chemotherapy regimens allowed per protocol, or to any of their individual components used 
as single agents   
 
Any intolerance to the chemotherapy will be managed similarly to intolerance during the 
Induction Period 
 
After completion of 3 additional cycles, if relevant and tolerated, one of the components of 
the platinum-doublet therapy may be removed, and the single remaining agent may be 
continued beyond 3 cycles 
 
In selected cases, where the local practice is to give more than 6 cycles of chemotherapy for 
the treatment of CUP, 3 or more additional cycles of chemotherapy (same regimen as used 
for prior cycles, unless change is required for management of intolerance; see Section 3.1.2) 
may be administered, if tolerated and there is no disease progression per RECIST v1.1 
 


 
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For Category 2 patients receiving treatment given in combination with chemotherapy, the 
chemotherapy regimen in place at the end of the Induction Period may be switched to another 
chemotherapy regimen or continued for a minimum of 3 additional cycles. Such changes in 
chemotherapy regimen must be limited to the chemotherapy regimens allowed per protocol, or 
to any of their individual components used as single agents. 
 
Any intolerance to the chemotherapy will be managed similarly to intolerance during the 
Induction Period 
 
After completion of 3 additional cycles, if relevant and tolerated, one of the components of 
the platinum-doublet therapy may be removed, and the single remaining agent may be 
continued beyond 3 cycles 
 
In selected cases, where the local practice is to give more than 6 cycles of chemotherapy for 
the treatment of CUP, 3 or more additional cycles of chemotherapy (same regimen as used 
for prior cycles, unless change is required for management of intolerance; see Section 3.1.2) 
may be administered, if tolerated and there is no disease progression per RECIST v1.1 
 
Alternative Therapy 
Patients for whom an alternative therapy is selected by the MTB will go off study treatment.  
They will be managed per standard of care at their institution and will receive the alternative 
therapy outside of this study.  They will proceed to the Safety Follow-Up Visit and post 
treatment Follow-up Period (refer to Section 3.1.6). 
 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy endpoint for this study, PFS, is defined as the time from randomization to 
the first occurrence of disease progression, as determined by the investigator according to 
RECIST v1.1, or death from any cause, whichever occurs first. 
The primary analysis of PFS will be based on the ITT population to evaluate the efficacy of 
patients randomized to molecularly-guided therapy versus patients randomized to platinum 
chemotherapy in patients with CUP whose response to 3 cycles of platinum induction 
chemotherapy was CR, PR or SD.  Stratified analysis of the primary endpoint will be completed 
according to the pre-defined randomization stratification factors (gender and response to 
platinum induction chemotherapy).  Results from an unstratified analysis will also be provided 
as a sensitivity analysis. 
Data for patients without disease progression or death will be censored at the last tumor 
assessment date.  If no tumor assessment was performed after randomization, data will be 
censored at the date of randomization +1 day. 
Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, 
together with the 95% confidence interval, and Kaplan-Meier curves will be produced.  PFS will 
be compared between treatment arms by the stratified log-rank test.  Estimates and the 
corresponding 95% confidence intervals will also be reported by treatment arm for the 6- and 
12-month survival rates.  The hazard ratio (HR) for PFS will be estimated using a Cox 
proportional hazards model, and the 95% confidence interval for the HR will be provided. 
Additionally, first-line PFS will be described by Kaplan-Meier methodology for each molecularly-
guided therapy (targeted therapy or cancer immunotherapy) and/or for each genomic alteration, 
where relevant, based on the patients in the cohort-specific safety population. 
The clinical cut-off date for the primary endpoint analysis will occur when 330 PFS events have 
been observed in the ITT population. In case the recruitment is still ongoing when 330 PFS 
events have been observed, all patients still in screening will proceed to enrollment, if eligible, 
and will be included in the primary endpoint analysis. In that scenario, the clinical cut-off date 
for the primary endpoint analysis will be the date of randomization (or assignment in to Category 
2) of the last patient enrolled. 


 
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DETERMINATION OF SAMPLE SIZE 
The sample size has been estimated based on assumptions derived from Hainsworth et al. 
(Hainsworth et al. 2015), giving an estimated median PFS of 5 months for CUP patients.  
Kaplan-Meier plots in the reference suggest that the exponential distribution is a reasonable 
assumption for PFS in CUP patients and, following this, we assume an estimated median PFS 
from randomization of 5 months for patients randomized to chemotherapy. 
Based on a two-sided 5% test, 330 events will give approximately 80% power to detect an HR 
of 0.7 (calculated using RPACT).  Randomizing 400 patients using a 3:1 ratio, and assuming a 
42-month recruitment period, the time to primary analysis will occur approximately 45 months 
from the time of first patient randomized. 
To allow for an estimated 15% dropout rate after randomization, a total of 472 patients will be 
randomized in the study.  Assuming a 60% disease control rate at the end of induction, it is 
estimated that approximately 790 patients with CUP will enroll.  If the actual number of patients 
who achieve a CR, PR, or SD during induction deviates from these estimates, the study will 
enroll patients until 472 patients have been randomized.  
In addition, if both the actual disease control and dropout rates differ from the protocol 
assumptions, the 330 PFS events may be reached before 790 patients are enrolled. In this 
case, screening will be stopped, when 330 PFS events have been observed. 
 
INTERIM ANALYSES 
No interim analyses of efficacy are planned. 
The iDMC will review safety and benefit-risk data periodically during the study. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
2-HG
R(−)-2-hydroxyglutarate 
AE
adverse event 
ALP
alkaline phosphatase 
ALT
alanine aminotransferase 
ANC
absolute neutrophil count 
aPTT
activated partial thromboplastin time 
AST
aspartate aminotransferase 
AUC
area under the concentration-time curve 
BID
twice daily 
BUN
blood urea nitrogen 
CCOD
Clinical Cut-off date 
CGP
CNA
comprehensive genomic profiling 
copy number alterations 
CNS
central nervous system 
COPD
chronic obstructive pulmonary disease 
CR
complete response 
CRO
CRS
contract research organization 
Cytokine Release Syndrome 
CT
computed tomography 
ctDNA
circulating tumor DNA 
CUP
cancer of unknown primary site 
DRESS
Drug Reaction with Eosinophilia and Systemic Symptoms 
EC
Ethics Committee 
ECG
electrocardiogram 
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic Case Report Form 
EDC
electronic data capture 
EMA
European Medicines Agency 
EQ-5D-5L
EuroQol 5-Dimension Questionnaire, 5-Level Version 
ERT
Eligibility Review Team 
ESMO
European Society for Medical Oncology 
EU
European Union 
FACT-G
Functional Assessment of Cancer Therapy–General 
Questionnaire 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 


 
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Abbreviation 
Definition 
HbA1c 
glycated hemoglobin 
HBcAb 
hepatitis B core antibody 
HbsAb 
hepatitis B surface antibody 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLH 
hemophagocytic lymphohistiocytosis 
HR QoL 
health-related quality of life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
infusion-related reaction 
ISH 
In-Situ Hybridization 
IV 
intravenous 
IxRS 
interactive voice or Web-based response system 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
MAS 
macrophage activation syndrome 
MRI 
magnetic resonance imaging 
MTB 
Molecular Tumor Board 
MUGA 
multiple-gated acquisition scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
next-generation sequencing 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-L1 
Programmed-death ligand 1 


 
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Abbreviation 
Definition 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PPI 
Proton Pump Inhibitors 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
QD 
once daily 
QTcF 
QT interval corrected through use of Fridericia’s formula 
RBR 
Research Biosample Repository 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
SC 
Steering Committee 
SCC 
squamous cell carcinoma 
SD 
stable disease 
TMB 
tumor mutational burden 
ULN 
upper limit of normal 
US FDA 
United States Food and Drug Administration 
VAS 
visual analog scale 
WBC 
white blood cell 
WES 
whole -exome sequencing 
WGS 
whole genome sequencing 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON CANCER OF UNKNOWN PRIMARY 
Cancer of unknown primary site (CUP) is defined as a histologically-confirmed 
metastatic cancer for which a standardized diagnostic work-up fails to identify the site of 
origin at the time of diagnosis (Pavlidis and Fizazi 2009; Massard et al. 2011; Fizazi et 
al. 2015).   
A standardized diagnostic work-up in this context includes mainly: 
 
A histopathological review of biopsy material using immunohistochemistry (IHC) 
 
A detailed medical history of the patient 
 
A complete physical examination (including pelvic and rectal examination) 
 
A full blood count and biochemistry analysis 
 
Urinalysis and stool occult blood tests 
 
A computed tomography (CT) scan of the thorax, abdomen and pelvis 
 
A mammography scan (female patients) 
 
Additional diagnostic tests oriented by signs and symptoms, tumor location and 
histopathological review, typically including: 
 
Breast MRI (in female patients with axillary lymph nodes)  
 
Serum prostate-specific antigen in male patients with bone metastases  
 
Endoscopies directed according to clinical and immunohistochemistry context 
 
(In the current protocol, if clinical and/or histopathological assessments in a recruited 
patient suggest a primary origin for the cancer, but the ESMO CUP guidelines have no 
guidance for its diagnosis, the most up-to-date guidance for a diagnostic work-up of the 
suspected tumor should apply). 
CUP accounts for 3% to 5% of all malignancies (Fizazi et al. 2015).  The disease has a 
median age of occurrence of approximately 60 years, is rare in children, and is 
marginally more frequent in males.  Survival of patients with CUP is poor, with a median 
overall survival (OS) of 8–11 months and a one-year survival rate of 25% (Massard et al. 
2011).  
No obvious risk factors have been identified for CUP (Pavlidis and Fizazi 2009; Massard 
et al. 2011; Fizazi et al. 2015).  By definition, early detection of patients with CUP is 
problematic, and screening programs for the disease are non-existent.  Autopsies are 
performed in only a minority of patients with CUP, but even thorough post-mortem 
evaluations identify only 55–85% of the primaries, usually small asymptomatic tumors in 
the pancreas, lung, gut, and kidney (Abrams et al. 1950; Didolkar et al. 1977; Jordan 
and Shildt 1985; Le Chevalier et al. 1988; Mayordomo et al. 1993; Jemal et al. 2008). 


 
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Two opposing hypotheses have been proposed for CUP pathogenesis (Busson et al. 
2006; Pentheroudakis et al. 2007).  One hypothesis considers CUP to be a single 
biological entity with unique molecular features that accounts for the absence of the 
primary site and for early metastatic disease.  The second hypothesis posits that CUP 
arises from different groups of unrelated tumors, each with a primary site that escapes 
detection. 
1.1.1 
Current Treatments for Cancer of Unknown Primary Origin 
The heterogeneity of CUP tumors, as well as their lack of an identified tissue of origin, 
imposes challenges on how the disease is treated.  The European Society for Medical 
Oncology (ESMO) has developed a treatment algorithm for CUP that consists of two 
general steps (Fizazi et al. 2015) (Figure 1):   
 
In the first step, if examination results including clinical features, 
immunohistochemistry, radiology, laboratory values and additional diagnostic 
measures beyond those of the standard diagnostic work-up strongly suggest a 
tissue of origin, treatment is initiated based on known site-specific therapies for the 
identified cancer type 
 
In the second step, patients for whom a likely tissue of origin cannot be posited are 
classified into distinct clinic-pathological subgroups (favorable and poor prognosis 
CUP).  Subsequent chemotherapeutic treatment is initiated based on this 
classification (see below) 
 


 
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Figure 1 Clinical Management of Patients With CUP 
 
CUP, cancer of unknown primary; IHC, immunohistochemistry; ECOG PS, Eastern Cooperative 
Oncology Group performance status; LDH, lactate dehydrogenase; OS, overall survival. 
Modified from (Fizazi et al. 2015). 
 
1.1.1.1 
Assessment of the Tissue of Origin 
To further evaluate the potential tissue of origin of CUP, as well as to exclude 
chemosensitive and potentially curable tumors (e.g., lymphomas and germ-cell tumors), 
high-quality tumor samples are subjected to extensive IHC on multiple antigenic markers 
(Abbruzzese et al. 1995; Oien 2009).  Patients with metastatic lesions that match one of 
the IHC profiles in Table 1 may be considered for treatment with standard site-specific 
regimens appropriate to the likely primary tissue of origin if the morphology and clinical 
picture are also pointing in this direction.  Patients with non-specific IHC profiles or 
clinical pictures that do not correlate with a specific IHC profiles are candidates for non-
tumor specific treatment regimens, as described in Section 1.1.1.2. 


 
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Table 1 
Examples of Immunohistochemical Work-Up to Identify Tissue of 
Origin 
 
CK 
PSA 
ER 
PgR 
CDX2+ 
CK20+ 
CK7– 
TTF1 
Napsin A 
CK7+ 
TGAB 
CT 
NSE, 
CG 
SYP 
AFP 
OCT4 
hCG 
PLAP 
LCA 
S100 
HMB45 
Vim 
Des 
Prostate cancer 
+ 
+ 
− 
− 
− 
− 
− 
− 
− 
− 
− 
Breast cancer 
+ 
− 
± 
− 
− 
− 
− 
− 
− 
− 
± 
Colorectal cancer 
+ 
− 
− 
+ 
− 
− 
− 
− 
− 
− 
− 
Lung 
adenocarcinoma 
+ 
− 
− 
− 
+ 
− 
− 
− 
− 
− 
− 
Thyroid cancer 
+ 
− 
− 
− 
± 
+ 
± 
− 
− 
− 
− 
Neuroendocrine 
+ 
− 
− 
− 
± 
± 
+ 
− 
− 
− 
− 
Germ-cell cancer 
+ 
− 
− 
− 
− 
− 
− 
+ 
− 
− 
± 
Lymphoma 
− 
− 
− 
− 
− 
− 
− 
− 
+ 
− 
− 
Melanoma 
− 
− 
− 
− 
− 
− 
− 
− 
− 
+ 
± 
Sarcoma 
− 
− 
− 
− 
− 
− 
− 
− 
− 
± 
+ 
AFP  alpha fetoprotein; CG  chromogranin; CK  cytokeratin; CT  calcitonin; DES  desmin; 
ER  estrogen receptor; hCG  human chorionic gonadotropin; LCA  leukocyte common antigen; 
NSE  neuron-specific enolase; PLAP  placental alkaline phosphatase; PgR  progesterone 
receptor; PSA  prostate-specific antigen; SYP  synaptophysin; TGAB  thyroglobulin;  
TTF-1  thyroid transcription factor 1; Vim  vimentin. 
The table shows general staining patterns but exceptions exist, especially for S100 and vimentin 
Thyroid and neuroendocrine cancers often positive with CK7 and TTF1 but not with Napsin A. 
Some lung cancers (up to 20%) may not be positive for TTF1 (Quint 2007; Travis et al. 2015). 
From (Fizazi et al. 2015). 
 
1.1.1.2 
Treatment of CUP  
CUP is defined as a tumor without a confirmed tissue of origin.  Two distinct subsets of 
CUP have been identified: favorable prognosis CUP, and poor prognosis CUP. 
Favorable Prognosis Cancer of Unknown Primary Site 
A minority (15%–20%) of patients with CUP, as defined by clinical and pathological 
criteria (Table 2), are referred to as having favorable prognosis disease (Fizazi et al. 
2015).  Within this subset, 30%–60% of patients can achieve long-term disease control if 
managed similarly to patients with a potentially equivalent metastatic cancer of known 
primary site.  Retrospective analyses confirm that the clinical behavior, biology, 
response to treatment and outcome of patients with favorable prognosis CUP parallel 
those observed with metastatic tumors from a known primary site (Hainsworth and Fizazi 
2009; Pavlidis et al. 2009; Spigel et al. 2009; Pentheroudakis et al. 2010; 
Pentheroudakis and Pavlidis 2010).   


 
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Treatment recommendations for favorable prognosis CUP, as provided in the ESMO 
guidelines, are shown below in Table 2. 
Table 2 
Therapy for Patients With Favorable Prognosis Cancer of 
Unknown Primary 
CUP Subtype 
Treatment 
Potential Equivalent Tumor 
Poorly differentiated 
neuroendocrine carcinomas of 
an unknown primary 
Platinum + etoposide 
combination chemotherapy 
Poorly differentiated 
neuroendocrine carcinomas with 
a known primary 
Well-differentiated 
neuroendocrine tumor of 
unknown primary 
Somatostatin analogs, 
streptozocin +5,-FU, sunitinib, 
everolimus 
Well-differentiated 
neuroendocrine tumor of a 
known primary site 
Peritoneal adenocarcinomatosis 
of a serous papillary histological 
type in females 
Optimal surgical debulking 
followed by platinum–taxane-
based chemotherapy 
Ovarian cancer 
Isolated axillary nodal 
metastases in females 
Axillary nodal dissection 
mastectomy or breast irradiation 
and adjuvant chemo/hormone 
therapy 
Breast cancer (found in 50%–
70% when breast MRI is 
performed) 
Squamous cell carcinoma 
involving nonsupraclavicular 
cervical lymph nodes 
Neck dissection and/or 
irradiation of bilateral neck and 
head–neck axis.  For advanced 
stages, induction chemotherapy 
with platinum-based combination 
or chemoradiation 
Head and neck squamous cell 
cancer 
CUP with a colorectal IHC (CK20 
+ CDX2 + CK7−) or molecular 
profile 
Systemic treatment used for 
colorectal cancer 
Metastatic colorectal cancer 
Single metastatic deposit from 
unknown primary 
Resection and/or RT ± systemic 
therapy 
Single metastasis 
Men with blastic bone 
metastases or IHC/serum PSA 
expression 
Androgen deprivation therapy ± 
RT 
Prostate cancer 
5-FU  5-fluorouracil; MRI  magnetic resonance imaging; IHC  immunohistochemistry; 
PSA  prostate-specific antigen; RT  radiotherapy; CK  cytokeratin. 
From (Fizazi et al. 2015). 
 
Poor-prognosis Cancer of Unknown Primary 
The remaining patients (80%–85%) have more limited sensitivity to therapy.  Two 
prognostic groups can be identified among patients with poor prognosis disease based 
on the following criteria (Culine et al. 2002): 
 
Good performance status (0–1) and a normal lactate dehydrogenase (LDH) level 
 
Poor performance status, elevated serum LDH, or both 
 


 
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The first prognostic group has a median OS of 1 year, while the second prognostic group 
has a median OS of about 4 months. 
Commonly used low-toxicity chemotherapy regimens for poor prognosis CUP, as 
described in the ESMO guidelines, are shown below in Table 3. 
Table 3 
Commonly Used Low-Toxicity Chemotherapy Regimens for 
Patients With Cancer of Unknown Primary in the Non-Specific 
Subset 
Chemotherapy (mg/m2) 
Time 
Interval 
Comments 
Cisplatin 60–75 +  
Gemcitabine 1000 
Day 1 
Day 1+8 
q3w 
Fit patients, adequate hydration 
Cisplatin 75 +  
Etoposide 100 
Day 1 
Day 1–3 
q3w 
Fit patients with neuroendocrine-
feature CUP, adequate hydration 
Paclitaxel 175 +  
Carboplatin AUC 5 
Day 1 
q3w 
Convenient outpatient regimen, 
monitor neurotoxicity 
Docetaxel 75 +  
Carboplatin AUC 5 
Day 1 
q3w 
Convenient outpatient regimen, 
monitor neurotoxicity 
Irinotecan 160 +  
Oxaliplatin 80 
Day 1 
q3w 
Outpatient regimen, monitor for 
neurotoxicity and diarrhea 
Oral capecitabine 2000 ±  
Oxaliplatin 85–130 
Days 1–14 
Day 1 
q3w 
Outpatient regimen risk for diarrhea 
and neurotoxicity 
Gemcitabine 1000/irinotecan 100 
Day 1+8 
q3w 
Convenient outpatient regimen, 
monitor diarrhea 
AUC  area under the concentration-time curve; q3w  once every 3 weeks. 
From (Fizazi et al. 2015). 
 
Clinical Studies of Treatment Regimens for Poor-Prognosis CUP 
A number of clinical studies/reviews have assessed the efficacy of various treatment 
regimens for poor-prognosis CUP.  Key publications in this area include, in chronological 
order: 
 
A review published in 2009 found that poor prognosis CUP had similar outcome 
whether treatment was based on platinum salts, taxanes or new-generation 
cytotoxic compounds (gemcitabine, vinca-alkaloids or irinotecan) (Golfinopoulos et 
al. 2009).  Hence, no single broad-based chemotherapy regimen had been identified 
at the time that was superior to others in this patient population.  Importantly, 
superiority of any chemotherapy regimen over best supportive care had never been 
formally demonstrated either.  Nevertheless, platinum-based doublet chemotherapy 
regimens became standard of care in the first-line treatment of poor prognosis CUP 
 
A meta-analysis published in 2013 confirmed the role of taxanes in the treatment of 
poor-prognosis CUP (Lee et al. 2013).  The review of available randomized 
controlled trials showed that the addition of platinum, taxane, or platinum and taxane 
to a regimen tended to extend the survival of CUP patients.  It also showed that 


 
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combinations containing a taxane agent demonstrated a prolongation of the median 
survival times and higher 1-year survival rates following first-line treatment of poor-
prognosis CUP compared with those without taxanes, although such a benefit did 
not seem to be sustained for 2 years 
 
An abstract published in 2019 described interim results from the GEFCAPI 04 study, 
a prospective randomized phase III trial that examined whether predicting the site of 
tumor origin by gene expression profiling (GEP), followed by site-specific treatment, 
was more effective than standard empiric treatment in patients with poor-prognosis 
CUP (Fizazi et al. 2019).  Eligible patients were randomly assigned to receive site-
specific treatment guided by GEP (n  123) or cisplatin and gemcitabine (n  120).  
Median PFS (primary endpoint) was 4.6 months in the site-specific treatment group 
and 5.3 months in the empiric group (HR   0.95 [0.72–1.25]; p  0.7).  Median OS 
(95% CI) was 10.68 (7.33–11.93) and 9.99 (7.06–11.96) months in the site-specific 
and empiric treatment groups, respectively 
 
A study published in 2020 described another prospective randomized phase II trial 
in which comprehensive GEP was performed to predict tumor origin in patients with 
poor prognosis CUP (Hayashi et al. 2019).  Following GEP, patients were randomly 
assigned to receive site-specific therapy (n  50) or paclitaxel and carboplatin 
(n  51).  One-year survival was 44.0% and 54.9% in the site-specific and empiric 
treatment groups, respectively (p  0.264).  Median OS and PFS were 9.8 and 5.1 
months, respectively, for site-specific treatment versus 12.5 and 4.8 months for 
empiric treatment, respectively (p  0.896 and 0.550 for the comparisons) 
 
A meta-analysis published in 2020 identified a trend towards improved OS in 
patients with poor-prognosis CUP who were treated with site-specific versus empiric 
treatment (HR  0.73; 95% CI: 0.52–1.02) (Rassy et al. 2020).  The test for overall 
effect for PFS was not statistically significant (HR  0.93; 95% CI:  0.74–1.17), with 
little heterogeneity between included studies  
 
In summary, the ESMO guidelines published in 2015 recommended various 
chemotherapy regimens (Table 3) for the treatment of poor-prognosis CUP, consistent 
with studies available at the time.  Newer studies examined whether genomic profiling to 
predict the potential origin of the tumor, followed by site-specific therapy, could provide 
benefit over empiric therapy.  Unfortunately, little to no improvement over the regimens 
recommended in 2015 has yet to be demonstrated by this approach.  Thus, a significant 
clinical need exists for new approaches that can be used to treat this relatively common 
and difficult-to-treat cancer type. 
1.2 
BACKGROUND ON TEST PRODUCTS 
Please refer to the investigator’s brochures for alectinib, atezolizumab, cobimetinib, 
entrectinib, ipatasertib, ivosidenib, pemigatinib, pertuzumab, trastuzumab, vemurafenib 
and vismodegib for details on nonclinical and clinical studies of the respective test 
products.  Refer also to the local packaging information for the investigational agents 
bevacizumab, erlotinib and olaparib and for the control agents cisplatin, carboplatin, 
paclitaxel and gemcitabine for details on their clinical studies. 


 
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1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Study Rationale 
Treatment of cancer is generally based on the specific neoplasm’s tissue of origin 
(National Comprehensive Cancer Network), an approach that is obviously problematic in 
patients with CUP.  ESMO recommends standard broad-based chemotherapeutic 
agents for non-specific subsets of CUP, but these regimens are suboptimal in poor-
prognosis disease, resulting in median OS values of 1 year in patients with good ECOG 
performance status (0–1) and normal LDH and approximately 4 months in patients with 
poor ECOG performance status (2–4), elevated LDH, or both (Fizazi et al. 2015).  
Whether these chemotherapy regimens prolong survival over best supportive care 
remains unknown.  The reason(s) for the low response is unclear but might reflect the 
fact that any case of CUP could originate from multiple types of primary lesions (each 
with its own susceptibility to specific anticancer agents) or that some other unique 
feature(s) of CUP biology blocks response.  In either case, it is clear that a high unmet 
need exists for new therapeutic approaches in patients with CUP who do not fall into the 
favorable prognosis subset. 
Precision medicine is an approach for disease treatment that takes into account 
individual variability in genes, environment, and lifestyle for each person 
(National Institutes of Health).  In the case of cancer, this approach typically involves: 
1) delineating a patient’s genetic profile via DNA sequencing methodologies (whole 
genome, exome, etc.); 2) using this information to identify underlying driver alterations; 
and 3) treating the disease with one or more of an expanding list of targeted agents that 
specifically counteract the effects of the identified, mutated or altered proteins. 
Given the therapeutic challenges imposed when the tissue of origin is unknown, CUP 
would appear to be especially well suited for a precision medicine/targeted therapy 
approach.  Indeed, beyond the theoretical underpinning described above, an increasing 
amount of published data suggest that such an approach may have important clinical 
benefits in patients with CUP, as summarized in the table below:  
 
Study 
Methodology 
Outcome 
(Ross et al. 2015) 
 Comprehensive genomic 
profiling on tissue samples 
from 200 CUP patients using 
the FoundationOne® FMI 
F1CDx (tissue) test 
 One or more potentially 
targetable alterations were 
identified in 169/200 (85%) of 
the specimens 


 
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Study 
Methodology 
Outcome 
(Varghese et al. 2017) 
 Next-generation sequencing 
of 410 cancer-associated 
genes in tissue samples from 
150 CUP patients 
 Thirty percent of patients 
carried at least one 
druggable level 2 and/or level 
3 alteration.  An additional 
25% of tumors harbored at 
least one potentially 
actionable level 4 aberration 
(Kato et al. 2017) 
 Next-generation sequencing 
of 54–70 cancer-associated 
genes in tissue samples from 
442 patients with CUP 
 Overall, 290/442 patients 
(66%) had one or more 
characterized genomic 
alterations (excluding 
variants of unknown 
significance).  Of these, 
289/290 (99.7%) exhibited 
targetable alterations 
(Clynick et al. 2017) 
 Genomic profiling on tumor 
tissue from 32 CUP cases 
 Biologically relevant or 
therapeutically druggable 
variants were detected in 
88% (n = 28) of cases.  There 
were potentially actionable 
targets in 14/32 (44%) cases 
(Krämer et al. 2018) 
 Genomic profiling of 315 
cancer-related genes in 
tumor tissue from 4650 CUP 
cases 
 3675 cases harbored ≥ 1 
genomic alterations that were 
druggable with a targeted 
therapy and/or an immune 
checkpoint inhibitor 
 An additional 485 had 
genomic alterations that were 
druggable alterations with 
investigational targeted 
therapies 
(Ross et al. 2020) 
 Hybrid capture-based 
comprehensive genomic 
profiling of 303 centrally-
reviewed CUP cases 
 32% of patients were 
potentially eligible for 
molecularly-guided therapy 
 
The data presented above demonstrate the high frequency of druggable alterations in 
CUP tumors, supporting the idea that targeted therapy may have significant potential as 
a treatment approach in this setting.  In further support of this hypothesis, the 
prospective precision oncology registry trial NCT/DKTK MASTER used a combination of 
whole genome sequencing, whole-exome sequencing and transcriptome analysis to 
examine the genetic profiles of 70 poor-prognosis CUP patients (Werner et al. 2020).  
Among the participants, 56 had alterations that were targetable and 20 subsequently 
received targeted therapy.  The median PFS in the latter group after targeted therapy 
was 183 (50–805) days.  This compared to a median PFS of 89 (31–304) days in the 


 
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same group during their last prior systemic therapy, which translated into a PFS ratio 
2.25 (0.16–16.43) for targeted versus systemic therapy. 
Despite the high frequency of genomic alterations in CUP, a significant percentage of 
patients still lacks specific targetable alterations and, hence, would not be expected a 
priori to respond to targeted therapies.  Several lines of evidence suggest that therapy 
with immune checkpoint inhibitors might have potential benefit in such cases, especially 
in patients with higher levels of tumor mutational burden (TMB): 
 
Tanizaki et al. performed a single-arm, non-randomized Phase II study to assess 
the effects of nivolumab, a PD-1 inhibitor, in 45 patients with previously treated, 
poor-prognosis CUP (Tanizaki et al. 2020).  In this study, ORR was 24.4% (95% CI: 
12.9-39.5%), DCR was 53.3% (95% CI: 37.9–68.3%), and median OS was 15.1 
months (95% CI: 8.3NR).  Although the study population was not assessed for 
TMB, the results nonetheless the potential benefit of immune checkpoint inhibitor 
therapy as a general treatment modality in patients with poor-prognosis CUP. 
 
Gay et al. assessed TMB in 6116 CUP tumor specimens, defining high, intermediate 
and low TMB as   20,   6 and   20, and   6 mutations/Mb, respectively (Gay et al. 
2017).  Significant numbers of patients within each tested tumor type (ACUP, CUP 
not otherwise specified [NOS], squamous cell CUP, neuroendocrine, neoplasm 
NOS, urothelial, GIST and small cell) had high TMB, with the exception of GIST.  
Overall, 23% of SCC tumors, 15% of malignant neoplasm NOS tumors and 13% of 
urothelial tumors had high TMB.  For ACUP or CUP, the most common tumors, 8–
11% had high TMB.  In addition, 1.6% of CUP cases were found to be MSI-H.  
Furthermore, Varghese et al. found that about 10% of CUP tumors harbor 
signatures of tobacco-related or ultraviolet-induced DNA damage (Varghese et al. 
2017). 
 
Gatalica et al. performed NGS on tumor samples from 389 CUP patients, analyzing 
592 genes and 52 gene fusions (Gatalica et al. 2018).  High levels of total mutation 
load (TML-H) were observed 11.8% (46/389) of tumors, while high levels of 
microsatellite instability (MSI-H) were detected in 7/384 (1.8%) of tumors.  PD-L1 
expression was detected in 80/362 samples (22%).  Overall, therefore, 28% of CUP 
tumors carried one or more predictive biomarkers (MSI-H, PD-L1 and/or TML-H) to 
the immune checkpoint blockade.  
 
In non-CUP settings, high levels of TMB have been associated with favorable 
outcomes following therapy with immune checkpoint inhibitors (Kim et al. 2019; 
Schrock et al. 2019; Alborelli et al. 2020; Klempner et al. 2020; Osipov et al. 2020).  
For instance, in one meta-analysis of 5712 patients aggregated from 26 studies, 
high TMB groups exhibited better OS (HR 0.53, 95% CI: 0.42–0.67) and PFS (HR 
0.52, 95% CI: 0.40–0.67) compared to low TMB groups (Kim et al. 2019).  In 
patients with high TMB, those who received therapy with immune checkpoint 
inhibitors had a better OS (HR 0.69, 95% CI: 0.50–0.95) and PFS (HR 0.66, 95% 
CI: 0.47–0.92) compared to those who received chemotherapy alone, while the 
same comparisons were not statistically significant in patients with low TMB. 
 


 
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Combined, the above considerations clearly suggest that patients with poor-prognosis 
CUP might benefit from targeted therapies or immunotherapy guided by genomic 
profiling, but prospective clinical studies evaluating this potentially promising approach 
are lacking.  Therefore, to test this hypothesis, Study MX39795 will directly assess 
whether molecularly-guided therapy based on comprehensive genomic profiling is 
superior to recommended systemic chemotherapy in patients with poor-prognosis CUP 
(non-specific subset as defined in the ESMO guidelines for CUP (Fizazi et al. 2015) who 
have received 3 cycles of platinum-doublet induction chemotherapy.  
Choice of molecularly-guided therapy in this study will be determined based on results 
from patient-specific FoundationOne® FMI F1CDx (tissue) test and/or 
FoundationOne® F1LCDx (Liquid) test reports (dependent on availability of one or 
both), according to the guidance provided in Table 5 (Section 3.1) and the Molecular 
Tumor Board Charter (see Sections 3.1 and 3.1.7 for a description of the Molecular 
Tumor Board [MTB]).  FoundationOne® FMI F1CDx (tissue) test is a validated, 
comprehensive genomic profiling tool that interrogates the entire coding sequence 
of > 300 cancer-related genes, as well as select introns from genes commonly 
rearranged or altered in solid tumor cancers.  As described above, the FoundationOne® 
FMI F1CDx (tissue) test has been shown to identify, with high selectivity and sensitivity, 
actionable alterations in CUP tumor specimens (Ross et al. 2015).  In addition to the 
tissue biopsy, all patients in the study will also have genomic profiling done via 
FoundationOne® F1LCDx (Liquid) test, a blood-based circulating tumor-DNA assay for 
solid tumors that interrogates   300 cancer-related genes.  The gene panels used for the 
tissue and liquid biopsy assays are updated regularly to integrate the results of new 
research in cancer genomic profiling and therapy-related biomarkers.  These changes 
are documented in the Molecular Tumor Board Charter.   
Patients for whom neither a FoundationOne® FMI F1CDx (tissue) test report nor a 
FoundationOne® F1LCDx (Liquid) test report could be generated will be discontinued 
from the study. 
The Molecular Tumor Board Charter provides guidance on the rationale and principles 
for choosing molecularly-guided therapies and on treatment assignment by the 
Molecular Tumor Board.  For this study it is expected that choice of molecularly-guided 
therapies may be ambiguous in some cases (e.g., for co-occurrence of genomic 
alterations). 
A detailed description of the study design of MX39795 is presented in Section 3.1.  In 
brief, eligible patients with poor prognosis, non-specific CUP will receive 3 cycles of 
standard platinum-based chemotherapy (Fizazi et al. 2015).  After this Induction Period, 
response to platinum-based chemotherapy will be evaluated by the investigator using 


 
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RECIST v1.1 (Appendix 5).  Based on these results, participants will be grouped into two 
categories:  
 
Category 1:  Patients with a CR, PR or SD after 3 cycles of platinum induction 
chemotherapy 
 
Category 2:  Patients with a documented PD during 3 cycles of platinum induction 
chemotherapy or at any time during the Induction Period 
 
Category 1 patients will be subsequently randomized in a 3:1 ratio to receive either 
molecularly-guided therapy until loss of clinical benefit or additional cycles of platinum-
based chemotherapy, respectively (see Section 4.3.4.7 for treatment duration).  The 
primary and secondary efficacy endpoints will be analyzed exclusively in Category 1 
patients.  Category 2 patients will receive molecularly-guided therapy until loss of clinical 
benefit, and efficacy and safety endpoints will be assessed on an exploratory basis.  
Rationales for individual features of the study design are described in Section 3.3, and 
include: 
 
Rationale for selection of CUP with poor-prognosis factors, for whom a likely tissue 
of origin cannot be posited (Section 3.3.1), with a restriction to cancers of epithelial 
origin 
 
Rationale for the Control Group (Section 3.3.2) 
 
Rationale for Three Cycles of Induction Chemotherapy (Section 3.3.3) 
 
Rationale for Sub-Dividing the Study Population into Two Categories of Patients 
(Section 3.3.4) 
 
Rationale for 3:1 Randomization in Category 1 Patients (Section 3.3.5) 
 
Rationale for Progression-Free Survival as the Primary Efficacy Endpoint 
(Section 3.3.6), and rationale for tumor assessments every 9 weeks  
 
Rationale for Combining Data from Different Experimental Treatment Cohorts for the 
Primary Endpoint Analysis (Section 3.3.7) 
 
Rationale for Investigational Medicinal Products Doses and Schedules 
(Section 3.3.8) 
 
Rationale for Patient-Reported Outcomes (Section 3.3.9) 
 
Rationale for Exploratory Biomarker Assessments (Section 3.3.10) 
 
1.3.2 
Benefit-Risk Assessment 
1.3.2.1 
Molecularly-Guided Therapy 
As described in Section 1, patients with poor-prognosis CUP (non-specific subset) have 
poor outcomes on currently recommended treatments and, hence, have a high unmet 
need for new therapeutic approaches.  Unfortunately, treatment options for CUP have 
not evolved in decades, and no drug has yet been registered specifically for the disease.  
This dearth of treatment options likely reflects the fact that, until recently, treatment of 
cancer has generally been based on the neoplasm’s tissue of origin, which is obviously 


 
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problematic in the case of CUP.  However, with the advent of large-scale DNA 
sequencing technologies, and the availability of a growing collection of targeted agents 
and immunotherapies, a new and rationally-designed treatment paradigm may now be 
possible for CUP that is independent of tissue of origin (see above, Study Rationale).  
The potential benefits of such a molecularly-guided treatment approach provide a strong 
medical rationale for carrying out the current study. 
With the exception of entrectinib, none of the molecularly-guided therapies examined in 
this study are indicated for CUP.  Most of them, however, have been approved for the 
treatment of other cancers or are in late clinical development for non-CUP cancer 
indications.  Consequently, all proposed treatments in this study have been shown to 
provide important clinical benefit in other cancers that carry the same genomic 
alterations examined in this study.  As the molecular pathways affected by the genomic 
alterations examined here have been shown to operate at the molecular level in a similar 
fashion across different cell types (and indeed across different organisms), it is 
reasonable to hypothesize that the targeted agents and immunotherapy regimens 
comprising this study’s IMPs may have significant benefit in patients with CUP. 
An advantage of using agents approved in other cancer indications or in late stage of 
development is that their safety profiles have been assessed in great detail, at least in 
other cancers.  Several steps will be taken to further limit the risk of participants in this 
study.  First, administration of all IMPs will be performed in a setting with emergency 
medical facilities and staff who are trained to monitor for and respond to medical 
emergencies.  Second, identified and potential risks associated with IMPs will be closely 
monitored throughout this study (Section 5.1).  Third, the study will have an independent 
data monitoring committee (iDMC) to assess benefit-risk profiles and safety signals.  
Fourth, key IMP-specific eligibility criteria relating to safety in other cancers will be 
assessed prior to starting treatment with molecularly-guided therapy (see 
Sections 4.1.1.2 and 4.1.3).  Finally, the study contains protocol-specified drug 
interruption and/or dose modification criteria designed to ensure safety (Section 5.1.2). 
In view of the biological and medical rationale for using molecularly-guided therapies in 
patients with CUP—and with the above safety precautions in place—a favorable 
benefitrisk proposition exists to support the conduct of this study.  This is especially 
true given the high unmet need for new therapeutic options in patients who have this 
difficult-to-treat disease. 
1.3.2.2 
The COVID-19 Pandemic 
In the setting of the coronavirus disease 2019 (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. 


 
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Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines 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 judgment.  If a diagnosis of SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
COVID-19 and Atezolizumab 
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 CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon- (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 
features for SARS-CoV-2-related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
If Atezolizumab is administered in combination with chemotherapy, neutropenia and 
lymphopenia associated with chemotherapy may increase the risk for developing an 
infection in patients receiving atezolizumab in combination with chemotherapy. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 


 
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immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination (Society 
for Immunotherapy of Cancer [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 consultation 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 Section 4.4.1). 
2. 
OBJECTIVES AND ENDPOINTS 
Study MX39795 will compare the efficacy and safety of molecularly-guided therapy 
versus standard platinum-containing chemotherapy in patients with poor prognosis 
cancer of unknown primary site (CUP; non-specific subset) who have achieved disease 
control (CR, PR, or SD) after 3 cycles of first-line platinum-based induction 
chemotherapy.  Molecularly-guided therapies will include 10 targeted cancer therapy 
regimens and 2 cancer immunotherapy regimens and will be chosen based on each 
patient’s comprehensive genomic profile (see below for further details). 
Specific objectives and corresponding endpoints for the study are outlined in Table 4, 
where “molecularly-guided therapy” refers to a pooled treatment group comprising 
patients who received a targeted agent or cancer immunotherapy. 


 
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Table 4 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
molecularly-guided therapy versus 
platinum chemotherapy in term of 
progression-free survival in patients 
with CUP whose best response to 
3 cycles of platinum induction 
chemotherapy was assessed CR, 
PR, or SD 
 
Progression-free survival (PFS1), defined in 
Category 1 patients as the time from 
randomization to the first occurrence of disease 
progression, as assessed by the investigator 
according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1), or death from 
any cause, whichever occurs first 
Secondary Efficacy Objectives 
Corresponding Endpoints 
 
To evaluate the efficacy of 
molecularly-guided therapy versus 
platinum chemotherapy in terms of 
overall survival, objective response 
rate, duration of response and 
disease control rate in patients with 
CUP whose best response to 
3 cycles of platinum induction 
chemotherapy was assessed CR, 
PR, or SD 
 
Overall survival (OS), defined as the time from 
randomization to death from any cause 
 
Objective response rate (ORR1), defined in 
Category 1 patients as the proportion of 
randomized patients who exhibit a CR or PR on 
two consecutive occasions   4 weeks apart 
 
Duration of response (DOR1), defined in Category 
1 patients with an objective response as the time 
from when response (CR or PR) is first 
documented to disease progression or death due 
to any cause, whichever occurs first 
 
Disease Control Rate (DCR1) defined as the 
proportion of Category 1 patients with confirmed 
CR, PR, SD, or NA, per RECIST v1.1 
 
Responses will be determined by the investigator 
according to RECIST v1.1 
Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety of 
molecularly-guided therapy in all 
patients with CUP who receive 
targeted therapy or cancer 
immunotherapy 
 Incidence and severity of adverse events (AEs), 
with severity determined according to NCI CTCAE 
v5.0 
 Incidence and reasons for any dose reductions, 
interruptions, or premature discontinuation of any 
component of study treatment 
 Change from baseline in targeted vital signs 
 Incidence in clinical laboratory abnormalities 
Exploratory Objectives 
Corresponding Endpoints 
 
To evaluate the efficacy of 
molecularly-guided therapy in 
patients with CUP who progressed 
(PD) during 3 cycles of platinum 
induction chemotherapy 
 
PFS2, OS2, ORR2, DOR2 and DCR2, assessed 
by the investigator in Category 2 patients 
according to RECIST v1.1 as described above 
 
To evaluate the mutagenic effects 
of 3 cycles of platinum induction 
chemotherapy in all patients with 
CUP 
 
Genomic profiles pre and post platinum induction 
chemotherapy, as assessed using 
FoundationOne® F1LCDx (Liquid) test 


 
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Primary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate clonal evolution of 
CUP during targeted or cancer 
immunotherapy treatment 
 
Genomic profiles pre-treatment and at disease 
progression in patients receiving targeted therapy 
or cancer immunotherapy 
 
To characterize CUP tumors and 
their microenvironment on a 
molecular level 
 
Molecular profiling by, e.g., gene expression and 
immunohistochemistry analyses, and tumor 
immune signatures 
 
To evaluate the HRQol effects of 
molecularly-guided therapy in 
patients with CUP whose best 
response to 3 cycles of platinum 
induction chemotherapy was 
assessed CR, PR or SD  
 
Absolute change from Treatment Period Cycle 1 
Day 1 in FACT-G score in Category 1 patients 
 
Absolute change from Treatment Period Cycle 1 
Day 1 in HADS score in Category 1 patients 
 
To evaluate health status utility of 
molecularly-guided therapy in 
patients with CUP whose best 
response to 3 cycles of platinum 
induction chemotherapy was 
assessed CR, PR or SD 
 
Absolute change from Treatment Period Cycle 1 
Day 1 in EQ-5D-5L index-based score in 
Category 1 patients 
CR, complete response; CUP, cancer of unknown primary; EQ-5D-5L, EuroQol 5-Dimensional 
5-Level questionnaire; FACT-G, Functional Assessment of Cancer Therapy: General; HADS, 
Hospital Anxiety and Depression Scale; HRQol, health-related quality of life; ORR, objective 
response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; 
RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1; SD, stable disease. 
NOTE:  Category 1 patients are those who achieved disease control (CR, PR or SD) after 
3 cycles of first-line platinum-based induction chemotherapy; Category 2 patients are those who 
experienced PD during 3 cycles of platinum induction chemotherapy (see Study Design [below] 
for more details). 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Study MX39795 is a phase II, randomized, open-label, active-controlled, multicenter trial.  
The study will consist of a Screening Period, an Induction Period including an End of 
Induction Visit, a Treatment Period, a Safety Follow-Up Visit occurring 30 ( 7) days from 
last treatment or at initiation of other systemic anticancer therapy (whichever occurs 
first), and a Follow-Up Period.  The first day of treatment during the Induction Period will 
be Day 1 (baseline) of the study.  
The overall study design is presented in Figure 2.  A Schedule of Activities is provided in 
Appendix 1.  A timeline of key study events is summarized in Appendix 2 and further 
detailed below. 


 
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Figure 2 Study Design 
 
CUP, cancer of unknown primary site; CR, complete response; ECOG PS, Eastern Cooperative 
Oncology Group performance status; EoT, End of Treatment; MTB, Molecular Tumor Board; PD, 
progressive disease; PR, partial response; R, randomization; SD, stable disease. 
a. Confirmation according to the 2015 ESMO Clinical Practice Guidelines for CUP (Fizazi et al. 
2015). 
b. A tumor tissue sample that is suitable for: 1) the initial diagnosis of CUP at the study site’s 
local laboratory, and 2) confirmation of diagnosis compatible with CUP and generation of a 
comprehensive genomic profile using FoundationOne® FMI F1CDx (tissue) test at a central 
reference pathology laboratory.  If, after local diagnosis of CUP, insufficient tumor tissue (in 
quantity or quality) remains for the central pathology laboratory to confirm the CUP diagnosis 
and generate profile using a FoundationOne® FMI F1CDx (tissue) test, then a fresh biopsy 
sample must be collected during the Screening Period that meets the study’s requirements 
(refer to the Laboratory Manual for suitability details and specimen collection instructions).  In 
exceptional cases where a repeat biopsy is not possible, or where a repeat biopsy would lead 
to significant delay in treatment start, the reason will be documented by the investigator and 
the patient will proceed through the eligibility review process without such new biopsy; in these 
cases, a blood sample will be used to generate a profile using the FoundationOne® F1LCDx 
(Liquid) test. 
 
3.1.1 
Screening Period 
The population to be included in this study corresponds to patients with CUP of epithelial 
origin with poor-prognosis, for whom a likely tissue of origin cannot be posited. 
To be eligible, patients must have a histological diagnosis compatible with CUP (non-
specific subset per 2015 ESMO guidelines), with available pathology report, as 
determined by the study site’s local laboratory on a contemporaneous tissue sample. 
Only patients with the histological subtypes and the poor-prognosis subsets of CUP 
allowed in the study should enter the Screening Period.  


 
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The diagnosis of poor prognosis CUP must be ascertained prior to entering the 
Screening Period of the study, following the 2015 ESMO Clinical Practice Guidelines for 
CUP (Fizazi et al. 2015) and any additional protocol-specific eligibility requirements for 
the diagnosis of CUP.  Where ESMO CUP guidelines are outdated or fail to provide 
guidance, an appropriate work-up using state-of the art diagnostic methods (per 
guidelines for the suspected tumor) should be used to exclude a potential primary origin 
for the cancer.  All tests/examinations (e.g., pathology, clinical and imaging work-up) 
performed to ascertain the diagnosis of CUP and exclude a tumor of known origin must 
be available when entering the Screening Period.  
The pre-screening tests/examinations performed to diagnose CUP will be re-assessed 
by an Eligibility Review Team, in consultation with a referent oncologist in complex 
cases (if necessary).  Potential participants will be excluded from the study if their clinical 
presentations and pathology work-ups (including IHC) indicate primary origins for their 
tumors (for further information, see below [“During Screening”]). 
The diagnosis of CUP according to the 2015 ESMO guidelines should have included:  
Minimal basic work-up:  
 
Thorough physical examination (including, e.g., head and neck, rectal, pelvic and 
breast examination) 
 
Basic blood and biochemical analyses 
 
Computed tomography (CT) scans of thorax, abdomen and pelvis  
 
Further work-up (including, but not limited to): 
 
Mammography in women  
 
Breast MRI in women with axillary disease 
 
Endoscopies guided by sign-, symptom- or laboratory abnormalities  
 
Serum assessment of α-fetoprotein, human chorionic gonadotropin, plasma 
chromogranin A and PSA suggested in male patients to exclude potentially curable 
extragonadal germ-cell tumors, neuroendocrine tumors and prostate cancers 
amenable to hormonal treatment 
 
Whole-body FDG–PET/CT suggested for patients with cervical adenopathies from 
CUP and those with a single CUP metastasis 
 
In situations, where clinical and histopathological pictures are suggestive of a 
specific primary origin for the cancer, an appropriate work-up to exclude this specific 
cancer should have been performed.  These situations include (but are not limited 
to) the following:  
 
Breast MRI in women with lymph nodes in the breast drainage areas in the 
context of IHC results suggestive of breast cancer 


 
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 
High-definition CT scan of the thorax in patients with TTF-1 negative IHC in the 
context of poorly characterized lung masses or in the context of hilar lesions (with 
or without lung masses) 
 
MRI in patients with one or few liver lesions presenting with no extra-hepatic 
disease or with extra-hepatic disease limited to lung metastases and/or lesions in 
the upper abdomen, in the context of IHC suggestive of cholangiocarcinoma or 
pancreatobiliary or upper gastrointestinal disease 
 
Adequate abdominal and pelvic imaging in the presence of high-grade serous 
carcinoma 
 
Bosniak classification of any kidney lesion in the context of IHC suggestive of 
renal cell carcinoma or other kidney malignancy 
 
ENT (Ear-Nose-Throat) examination and MRI and/or PET imaging in patients 
with IHC and/or a clinical picture suggestive of salivary gland carcinoma (this 
includes poorly defined masses in the neck or predominance of neck lymph 
nodes in the clinical presentation) 
 
Acceptable histology will include:  
 
Adenocarcinoma  
 
Poorly differentiated adenocarcinoma  
 
Poorly differentiated carcinoma  
 
The following patients will not be eligible: 
 
Patients with squamous cell CUP 
 
Patients with histology and immunohistology profiles (per ESMO guidelines) that are 
not adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma), such as 
but not limited to non-epithelial cancer, extragonadal germ-cell tumor, 
neuroendocrine tumors, sarcoma, melanoma, mesothelioma, hematologic 
malignancies 
 
Patients who can be assigned to a specific subset of CUP for which a specific 
treatment is recommended by the 2015 ESMO Clinical Practice Guidelines for CUP 
(Fizazi et al. 2015) or with a clinical and IHC profile indicative of a specific primary 
tumor (favorable prognosis CUP subsets).  These are: 
– 
Poorly differentiated carcinoma with midline distribution 
– 
Women with papillary adenocarcinoma of the peritoneal cavity 
– 
Women with adenocarcinoma involving only the axillary lymph nodes 
– 
Squamous cell carcinoma of the cervical lymph nodes 
– 
Poorly differentiated neuroendocrine tumors 
– 
Men with blastic bone metastases and elevated PSA 
– 
Patients with a single, small, potentially resectable tumor 


 
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– 
Colon cancer-type CUP with a CK7 negative, CK20 positive, CDX-2 positive 
immunohistochemistry profile 
– 
CK7 positive, CK20 negative and TTF-1 positive tumors in a context suggestive 
of lung adenocarcinoma or thyroid cancer (i.e., with lesions in the lung or thyroid 
or the lymph nodes in their drainage areas) 
– 
IHC profile definitely indicative of breast cancer OR an IHC profile indicative of 
breast cancer and either a history of breast cancer or lymph nodes in the 
drainage areas of the breast 
– 
High-grade serous carcinoma histology and elevated CA125 tumor marker 
and/or a mass in the gynecological tract or any tumor mass or lymph node in the 
abdominal cavity (i.e., below the diaphragm) 
– 
IHC profile suggestive of renal cell carcinoma and renal lesions, with a Bosniak 
classification higher than IIF 
– 
IHC profile compatible with cholangiocarcinoma or pancreatobiliary (or upper 
gastrointestinal carcinoma) AND 1 or 2 liver lesions without extrahepatic disease 
or with only pulmonary metastases and/or lymph nodes in the drainage areas of 
the liver 
 
 
Patients with a history of malignancy within 5 years prior to initiation of study 
treatment, with the exception of the cancer under investigation in this study and 
malignancies with a negligible risk of metastasis or death (e.g., 5-year OS 
rate   90%). 
General inclusion and exclusion criteria must also be satisfied for a patient to be 
considered for screening (Refer to Sections 4.1.1 and 4.1.2). 
3.1.1.1 
During Screening 
As this study aims to direct treatment according to genomic profiles, it is further 
mandated that participants are willing and able to provide: 
 
A tumor tissue sample for generation of a comprehensive genomic profile using the 
FoundationOne® FMI F1CDx (tissue) test at a central reference pathology 
laboratory (refer to the Laboratory Manual for suitability details and specimen 
collection instructions) 
 
Archival tumor FFPE block   4 months prior to screening will be acceptable for 
these central analyses.  However, if an acceptable archival tumor FFPE block is not 
available or is not suitable (in quantity and quality) at screening, an FFPE block from 
a freshly obtained biopsy sample must be provided that meets the study’s 
requirements 
In cases, where the first tissue sample sent to the central laboratory is 
considered unsuitable for generation of a comprehensive genomic profile using 
the FoundationOne® FMI F1CDx (tissue) test but allows for the confirmation 
of CUP (or the confirmation of CUP can be ascertained on a prior sample 
deemed suitable by the referent pathologist), and all other eligibility criteria are 
met for the study, the patient may start platinum-based induction chemotherapy 


 
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prior to a fresh biopsy sample being received by the central laboratory, 
providing that the fresh sample has been collected (e.g., when shipment could 
delay an urgent start of treatment) 
In exceptional cases where a repeat biopsy is not possible, or where a repeat 
biopsy would lead to significant delay in treatment start, the reason will be 
documented by the investigator and the patient will proceed through the 
eligibility review process without such new biopsy 
Tumor FFPE blocks are preferred.  In exceptional cases, 25 slides (4 m slide 
thickness each) may be accepted 
 
The local pathology reports confirming compatibility with CUP diagnosis and the 
associated slides used for the diagnosis (refer to the Laboratory Manual for further 
details) 
Expectations are that the histology and routine immunohistochemistry 
performed locally are compatible with CUP following the algorithm suggested in 
the 2015 ESMO guidelines for CUP, which recommends CK7 and CK20 as first 
step markers 
If the slides used for the local test confirming local CUP diagnosis are not 
available, the FFPE block submitted for genomic profiling must be sufficient to 
allow central confirmation of CUP diagnosis (i.e., performing relevant IHC and 
ISH if required) 
 
A central pathology laboratory will interpret the local histopathology results (including 
immunohistochemistry) and perform additional tests if required to confirm that the 
pathology and immunohistochemistry profiles are compatible with the diagnosis of poor 
prognosis CUP.  The assessment performed by the central pathology laboratory will be 
oriented by pathological and clinical features and the choice of immunohistochemistry 
markers (and in-situ hybridization if required) to be reviewed and additional tests to be 
performed will be in line with 2015 ESMO Clinical Practice Guidelines for CUP and with 
the Study Laboratory Manual. 
NOTE:  The Eligibility Review Team (ERT) will review pathology and 
immunohistology reports from central and local laboratories, and details of the 
CUP work-up (as reported in the eCRF) to determine patient eligibility.  
Identification of acceptable poor-prognosis CUP will be carried out according to 
ESMO guidelines and, in cases where these guidelines may be insufficient or 
outdated, by adequately excluding potential primary tumors via newer genetic, 
immunologic, etc., methodologies.  The ERT may not be able to confirm the 
diagnosis of poor prognosis CUP without a complete and proper pre-screening 
CUP work-up, i.e., one that was carried out to completion per ESMO guidelines 
(see beginning of this section).  Therefore, failure by the investigator to provide 
this necessary pre-screening CUP work-up information may lead to screen failure. 


 
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In order to enter the Induction Period (see below), patients must have completed Part 1 
and the RBR section of the Informed Consent Form (ICF).  Since the molecularly-guided 
therapy eventually assigned to a patient is unknown during the Screening Period, Part 1 
of the ICF will cover all aspects of the trial except for information related to any specific 
molecularly-guided therapies.  Information related to the specific molecularly-guided 
therapy eventually assigned to an individual patient (e.g., identified targetable alteration, 
background on selected agent, and tolerability profile) will be provided in Part 2 of the 
ICF, which must be completed prior to the first dose of molecularly-guided therapy (see 
below for more detail).  Patients who are randomly assigned to receive additional cycles 
of platinum chemotherapy will not be required to complete Part 2 of the ICF (see below). 
3.1.1.2 
Re-Screening and Extension of the Screening Period 
The Screening Period will be 28 days (from signature of the ICF until the first dose of 
study treatment).  Potential participants who are unable to fulfill all eligibility criteria 
within the Screening Period can be re-screened, provided that the reason for screen 
failure is one that can change over time and that all eligibility criteria will likely be fulfilled 
at the time of re-screening. 
The 28-day Screening Period may be extended in exceptional cases: 
 
Up to 42 days (extension by 2 weeks) in case the first tissue submitted was not 
suitable or insufficient per central pathology assessment and a fresh biopsy has to 
be taken (see above)  
 
Up to 35 days (extension by 1 week): 
- If there has been a delay in the shipment of the tissue sample 
- If escalation of the eligibility review to the referent oncologist and further 
information are requested, or further tests are needed to determine eligibility 
 
In cases where the Screening Period has been extended (see Section 3.1.1.2), 
screening assessments conducted during the initial Screening Period (e.g., CT scans) 
that met protocol requirements will remain valid during the Screening Period extension, 
with the following exceptions: 
 
Pregnancy tests and tests that should be repeated at baseline 
 
Imaging tests performed up to 49 days prior to first dose of study treatment are 
acceptable  
 
3.1.2 
Induction Period 
All patients fulfilling eligibility criteria will enter the Induction Period. 
A blood sample suitable for analysis of circulating tumor DNA using the 
FoundationOne® F1LCDx (Liquid) test (refer to the Laboratory Manual for specimen 
collection instructions) will be collected before initiation of chemotherapy. 


 
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Patients will receive 3 cycles of standard first-line platinum-based chemotherapy per 
investigator choice (carboplatin/paclitaxel, cisplatin/gemcitabine or 
carboplatin/gemcitabine) until the end of the Induction Period or documented early 
disease progression (Figure 2). 
Patients who cannot tolerate their initial platinum-based induction therapy will be 
managed until the end of the Induction Period or documented early disease progression 
as follows: 
 
Patients should undergo dose reductions or interruptions of one or both components 
of the chosen chemotherapy regimen per institutional standards 
 
If dose reductions and interruptions are not sufficient or if intolerant to the initial 
platinum-based therapy, patients may be switched to another protocol-mandated 
induction chemotherapy regimen, if judged clinically relevant by the investigator 
 
If intolerant of the second induction chemotherapy regimen, or if switching to 
another platinum induction therapy is not possible, the treatment may be continued 
with only one component of the induction chemotherapy regimen.  If treatment is 
reduced to one component and tolerance improves, then switching to another 
accepted platinum regimen will be possible if judged clinically relevant by the 
investigator 
 
If all options to manage intolerance to the induction chemotherapy are exhausted 
prior to Cycle 3 Day 1, the patient will discontinue from study treatment.  The patient 
will move directly to the Safety Follow-Up Visit, receive further treatment per 
institutional standards, and enter the Follow-up Period (see below) 
 
Also during the Induction Period, the patient’s tumor and blood samples will be analyzed 
to generate comprehensive genomic profiles based on the FoundationOne® FMI 
F1CDx (tissue) test and FoundationOne® F1LCDx (Liquid) test respectively.  Results 
from these analyses will be used to inform treatment decisions during the subsequent 
Treatment Period (see below).  
In exceptional situations, where the genomic profile based on the FoundationOne® FMI 
F1CDx (tissue) test and/or FoundationOne® F1LCDx (Liquid) test provides an 
indication of a non-epithelial tumor, the FoundationOne® team may inform the Sponsor. 
In this case, the investigator will be contacted and every effort should be made to verify 
the diagnosis of non-epithelial tumor. If this diagnosis is verified, the patient should be 
discontinued from the study. 
3.1.3 
End of Induction Visit 
For patients, who reach Cycle 3, the End of Induction Visit will occur between Cycle 3 
Day 14 and Day 21 ( 3 days).  
For patients who progress (PD) before Cycle 3, the End of Induction Visit will take place 
within 10 days of disease progression assessment.  


 
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Patients who permanently discontinue at or before the end of induction will not attend an 
End of Induction Visit, but instead will move directly to the Safety Follow-Up Visit. 
During the End of Induction Visit: 
 
Response to platinum induction chemotherapy will be evaluated by the investigator 
according to RECIST v1.1 (Appendix 5) based on disease assessment performed 
between Cycle 3 Day 7 and the End of Induction Visit (except for patients with 
documented PD prior to Cycle 3).  Based on these results, participants will be 
grouped into two categories (Synopsis Figure 1):  
– 
Category 1: Patients with a CR, PR or SD after 3 cycles of platinum induction 
chemotherapy 
– 
Category 2: Patients with a documented PD after 3 cycles of platinum induction 
chemotherapy or at any time during the Induction Period 
 
In exceptional cases, where response according to RECIST v1.1 would be Not 
Evaluable, the case will be referred to the referent radiologist for adjudication.  Patients 
without a RECIST v1.1 assessment at the End of Induction Visit will discontinue from the 
study. 
 
Selected inclusion and exclusion criteria will be re-evaluated in all patients at the 
End of Induction Visit.  This re-evaluation will include: 
– 
IMP-specific exclusions: to determine whether any IMP-specific restrictions 
have developed since Day 1, e.g., development of diabetes since start of 
chemotherapy, etc.  Since data from this re-assessment will be used at the 
MTB to assign treatment (see below), each patient will be re-evaluated for all 
IMP-specific exclusions at the End of Induction Work-up 
– 
Re-assessment of general safety criteria: the purpose of this re-assessment is 
not to limit choice of targeted therapy, but rather to delay start of treatment or 
elicit a treatment discontinuation if safety criteria are not met 
 
3.1.4 
MTB and Randomization 
The MTB must be scheduled to take place no later than 10 calendar days after the End 
of Induction Visit for all patients.  The MTB will be cancelled for Category 1 patients 
randomized to continue chemotherapy. 
Randomization (for Category 1 patients only) should occur between the End of Induction 
Visit and no less than 48 hours before the planned MTB meeting date. 
The MTB (for all patients) and randomization (for Category 1 patients) must be delayed 
after the End of Induction Visit if general safety criteria for entrance into the Treatment 
Period are not met, however the Sponsor’s study team must be informed of the delay. 
(See below and in Sections 4.1.1.2 and 4.2).  If the MTB is delayed, starting treatment in 
the Treatment Period of the study will be subject to verifying that the general safety 
criteria for entry into the study are met:  


 
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 
If the MTB is delayed up to Cycle 3 Day 42 (or until 42 days after Day 1 of the last 
induction treatment cycle for Category 2 patients who receive less than 3 cycles), 
only the general safety criteria previously not met will need verifying. 
 
If the MTB is delayed beyond Cycle 3 Day 42 (or until 42 days after Day 1 of the last 
induction treatment cycle for Category 2 patients who receive less than 3 cycles), all 
general safety eligibility criteria must be checked, and if they are still not met, the 
patient will not be eligible to receive further treatment in the study.  Instead, the 
patient will move directly to the Safety Follow-Up Visit and, then, proceed into the 
Follow-up Period, where he or she will receive non-IMP treatment outside of the 
study (see below). 
 
Figure 3 Summary of Events on and Between the End of Induction Visit 
and the Start of Treatment in the Treatment Period 
 
* If the patient experiences progressive disease before Cycle 3, the End of Induction Visit should 
occur within 10 days of the disease progression assessment. 
** The MTB and randomization should be postponed if any re-assessed general safety eligibility 
criteria are not met at the End of Induction Visit.   
***If start of treatment in the Treatment Period is delayed > 42 days post Cycle 3 Day 1 (or 42 
days post Day 1 of the last induction cycle for Category 2 patients who receive less than 3 
cycles), all general safety criteria must be checked and verified prior to starting treatment in the 
Treatment period. 
 
If the MTB is delayed to Day 15 or more after the End of Induction Visit, Investigator’s 
judgment will be exercised to determine which tests need repeating prior to the MTB. 
3.1.5 
Treatment Period 
3.1.5.1 
Pre-Treatment Work-Up 
As the efficacy and safety assessments for the main study endpoints are evaluated from 
randomization in Category 1 patients (including patients randomized to chemotherapy) 


 
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and from start of molecularly-guided therapy for Category 2 patients, Treatment Period 
baseline assessments for efficacy and safety data will be as follows: 
Tumor assessments:  
 
The End of Induction Visit assessment will be used for the Treatment Period 
baseline tumor assessment.   
In exceptional cases where the interval between end of Induction Period 
assessments and Day 1 of treatment in the Treatment Period are   42 days, 
tumor assessments would need repeating to ensure reliable baseline tumor 
assessments 
 
Investigators will review the CT scans and any other tests used for tumor 
assessment according to RECIST v1.1 to establish new baseline assessments.  The 
target and non-target lesions chosen for baseline in the Treatment Period may differ 
from those chosen at baseline for the Induction Period.  It is accepted that in 
patients with complete response and in some patients with partial response at the 
end of the Induction Period, there will/may not be any measurable lesion 
 
Physical examination, performance status, vital signs, weight and laboratory results 
at Day 1 of the first cycle of treatment in the Treatment Period will be used as 
baseline for the Treatment Period 
 
Any ongoing AEs from the induction chemotherapy and all concomitant medications 
will be reported at the End of Induction Visit and reassessed on Day 1 of the 
Treatment Period 
 
The pre-treatment work-up does not require a dedicated visit, as it combines 
examinations performed as part of the End of induction Visit and the Cycle 1 Day 1 visit 
in the Treatment Period.  
3.1.5.2 
Category 1 Patients: Treatment Assignment and Treatment 
The primary and secondary efficacy endpoints will be analyzed exclusively in Category 1 
patients.  Thus, patients with a CR, PR or SD during the Induction Period will be 
randomized in a 3:1 ratio to receive either molecularly-guided therapy or to continuation 
of the same chemotherapy regimen used during induction, respectively (Figure 2).  An 
assessment cycle will be considered to be 21 days for all treatment arms (including for 
cohorts with oral therapies), except for cobimetinib and vemurafenib, ipatasertib and 
paclitaxel, and ivosidenib, where the administration cycle will be 28 days.  Administration 
of therapy will be according to the treatment schedules specified in Section 4.3.  
To ensure balanced treatment groups, randomization will be stratified by the following 
factors: 
 
Gender 
 
Response to platinum induction chemotherapy (CR  PR vs. SD) 
 


 
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For patients randomized to the control arm:  the chemotherapy will be administered per 
Section 4.3.4.7 of the protocol. 
For patients randomized to the investigational arm, molecularly-guided therapy will be 
decided based on results from the FoundationOne® FMI F1CDx (tissue) test and/or 
FoundationOne® F1LCDx (Liquid) test reports (dependent on availability of one or 
both) during a virtual Molecular Tumor Board (MTB), consisting of the treating 
investigator (or their designee), referent pathologist, referent oncologist and 
FoundationOne® expert (if needed). 
A detailed description of the process for assigning molecularly-guided therapy is 
provided in the Molecular Tumor Board Charter.  In brief: 
 
Specific therapies for potentially actionable alterations in each patient’s 
FoundationOne® FMI F1CDx (tissue) test and/or FoundationOne® F1LCDx 
(Liquid) test reports (dependent on availability of one or both) will be categorized 
for their relevance to treatment decisions in consultation with an experienced 
FoundationOne® pathologist (if required)  
 
At the same time, the FoundationOne® FMI F1CDx (tissue) test and/or 
FoundationOne® F1LCDx (Liquid) test reports will be shared with the MTB 
standing members and, if required, will be discussed during preparatory MTB 
meetings in the absence of the investigator  
 
At a virtual MTB, the FoundationOne® FMI F1CDx (tissue) test and/or 
FoundationOne® F1LCDx (Liquid) test results and relevant patient information 
(including exclusions criteria for specific targeted therapies) will be reviewed by all 
members of the MTB, and a patient-specific treatment regimen will be decided upon 
by the treating investigator in consultation with other board members 
 
It is expected that choice of molecularly-guided therapies may be ambiguous in 
some cases.  Guidance and rationales for choosing therapy under such 
circumstances are presented in the Molecular Tumor Board Charter 
 
After the MTB, the investigator will have 24 hours to finalize the treatment choice, 
and if different from the MTB recommendations, a new MTB discussion will need to 
be organized to validate the choice 
  
During the above process, all treatment choices will be made according to the guidance 
provided in Table 5 and based on exclusions criteria for specific targeted therapies. 
Those Category 1 patients who are randomized to the investigational arm will complete 
Part 2 of the ICF and will then receive one of the molecularly-guided therapies in Table 5 
until loss of clinical benefit, unacceptable toxicity, patient or investigator decision to 
discontinue, or death (whichever occurs first).   
For Category 1 patients randomized to the investigational arm and receiving treatment 
given in combination with chemotherapy, the chemotherapy will be administered per 
Section 4.3.4.7 of the protocol. 


 
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Table 5 
Identified Genomic Alterations and Corresponding Molecularly-
Guided Therapies 
Molecularly-Guided Therapies 
Actionable Genomic Alterations 
Targeted Therapies 
 
 
Alectinib 
● 
ALK, RET fusions or rearrangements 
 
Entrectinib 
● 
NTRK gene fusions, ROS1 rearrangements 
 
Ivosidenib 
● 
IDH1 alterations 
 
Olaparib 
● 
BRCA1, BRCA2 
● 
PALB2 and RAD51B/C/D 
● 
gLOH (FMI score 20 or above)  
 
Pemigatinib 
● 
FGFR1, FGFR2 and FGFR3 alterations 
 
Vismodegib 
● 
Inactivating PTCH1, SMO alterations 
 
Erlotinib + bevacizumab 
● 
EGFR alterations 
 
Ipatasertib + paclitaxel 
● 
AKT1, PIK3CA, PTEN  
 
Vemurafenib + cobimetinib  
● 
BRAF V600 alterations, BRAF K601E 
 
Trastuzumab SC + pertuzumab + 
chemotherapy a 
● 
ERBB2/ERBB3 alterations  
Immunotherapy 
 
 
Atezolizumab 
● 
TMB–High (≥ 16 mutations/Mb) or MSI-High 
 
Atezolizumab + chemotherapy a 
● 
TMB–Low or Unknown (< 16 mutations/Mb) 
Other Treatment Options 
Potential Rationales  
for Other Options 
 
Alternative therapies  
 
(Only if the investigator in 
consultation with the MTB has strong 
evidence to support a therapy not 
represented in the investigational 
treatment arms above) 
● 
Strong suspicion of a primary tumor revealed 
by comprehensive genomic profiling 
● 
Strong rationale for alternative, commercially-
available, targeted therapy 
● 
Negative predictor of response to 
anti-PD-1/PD-L1 agents 
● 
Patients who do not have a genetic alteration 
allowing for assignment to a protocol-
mandated targeted therapy and who are 
contraindicated for atezolizumab 
TMB, tumor mutational burden; MSI, microsatellite instability. 
a. Platinum-based chemotherapy allowed per protocol (see other Sections for details). 
 
Alternative Therapy arm: 
If the investigator and MTB have strong evidence to support a therapy not represented in 
any of the investigational treatment arms, the investigator can choose to discontinue 
study treatment and allow the patient to receive an “alternative treatment option.”  
Examples of cases suitable for an alternative treatment option include: 
 
Patients with a defined treatment path revealed by comprehensive genomic profiling 
(CGP) (e.g., prostate cancer revealed by CGP) 


 
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 
Patients who have a strong rationale for an alternative targeted therapy and have 
access to that alternative (e.g., crizotinib for cancers with MET-amplification) 
 
Patients not eligible for atezolizumab plus chemotherapy (due to a safety 
contraindication to atezolizumab), for whom chemotherapy may remain the best 
treatment option 
 
Patients with a safety contraindication to the preferred molecularly-guided therapy 
and/or atezolizumab (at time of randomization) for whom chemotherapy may remain 
the best treatment option 
 
Patients for whom an alternative therapy is selected by the MTB will go off study 
treatment.  They will be managed per standard of care at their institution and will receive 
the alternative therapy outside of this study.  They will proceed to the Safety Follow-Up 
Visit and post-treatment follow-up (Refer to Section 3.1.6).  
Specific Scenarios: 
 
Reasons for a report not being generated include, but are not limited to, poor tumor 
tissue quantity or quality or other technical issues.  Patients for whom neither a 
FoundationOne® FMI F1CDx (tissue) test report nor a FoundationOne® F1LCDx 
(Liquid) test report could be generated will be discontinued from study treatment at 
the end of Induction Period. These patients will not be randomized. 
 
Category 1 patients with a valid result from the FoundationOne® FMI F1CDx 
(tissue) test and/or FoundationOne® F1LCDx (Liquid) test reports, but turn out to 
be ineligible for any molecularly-guided therapy will have the opportunity to receive 
the control therapy (i.e., the same platinum-based chemotherapy in place at the end 
of the Induction Period) for a minimum of 3 additional cycles. 
 
Patients who show evidence of clinical benefit after meeting RECIST v1.1 criteria for 
progressive disease will be permitted to continue treatment with molecularly-guided 
therapy until loss of clinical benefit, unacceptable toxicity, patient or investigator decision 
to discontinue, or death (whichever occurs first), if they meet all of the following criteria: 
 
Evidence of clinical benefit (i.e., in the absence of symptomatic deterioration 
attributed to disease progression, as determined by the investigator after an 
integrated assessment of radiographic data, biopsy results [if available], clinical 
status, and worsening of laboratory values)  
 
Absence of unacceptable toxicity 
 
No decline in ECOG performance status that can be attributed to disease 
progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions (refer to 
Section 4.4.1) 
 
Timelines for randomization, selection of treatment and start of treatment are described 
in Sections 4.2 and 4.3 and inAppendix 2. 


 
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3.1.5.3 
Category 2 Patients: Treatment Assignment and Treatment 
Category 2 patients, i.e., PD after or during 3 cycles of platinum induction chemotherapy, 
will be assigned molecularly-guided therapy by the investigator in consultation with the 
MTB, and will receive treatment as described for Category 1 patients, except for 
continuing induction chemotherapy in case of ineligibility for all molecularly-guided 
therapies (refer to Section 3.1.5.2).  
For Category 2 patients receiving treatment given in combination with chemotherapy will 
be administered per Section 4.3.4.7 of the protocol.  
3.1.6 
Follow-Up Period 
Following completion or discontinuation of all study treatments, (whether the patient 
discontinues after the Induction Period or After the Treatment Period), all patients will 
return to the clinic 30 ( 7) days from last treatment or at initiation of other systemic 
anticancer therapy (whichever occurs first) for a Safety Follow-Up Visit. 
After the Safety Follow-Up Visit, Patients in the control chemotherapy arm and patients 
who discontinue treatment for reason other than disease progression (including patient 
receiving alternative therapy) but who do not withdraw consent to follow-up will be 
assessed for progression as described during the Treatment Period (including scans) 
until disease progression per RECIST v1.1 (refer to Section 4.5.6).  
Thereafter, all patients will be contacted by the physician by phone for survival status 
every 3 ( 1) months until death, loss to follow-up, withdrawal of consent or end of the 
study.  Data on nature of and response to further anticancer therapies will also be 
collected during the survival follow-up (refer to Appendix 1 for additional details). 
3.1.7 
Study Committees 
A Steering Committee (SC), guided by a Steering Committee Charter, will be 
responsible for overseeing the general conduct of the study.  
An Eligibility Review Team (ERT), guided by Eligibility Review guidelines, will be 
responsible for ensuring that patients who enroll in the trial have the correct diagnosis of 
CUP (following ESMO guidelines) (See Section 3.1.1.1).  The ERT will be able to take 
advice from a referent oncologist, a referent radiologist and a referent pathologist, as 
appropriate.  In case the ERT cannot confirm a diagnosis of CUP due to an incomplete 
pre-screening work-up, the ERT will inform the investigator and provide the reason prior 
to declaring the patient ineligible. 
A Molecular Tumor Board (MTB) will provide guidance to the investigator regarding the 
choice of molecularly-guided therapy.  The MTB will be independent of the Sponsor, i.e., 
the Sponsor will not participate in the MTB meetings nor in the decision-making process.  
However, if there is a disagreement among MTB members regarding choice of 
molecularly-guided therapies or safety concerns associated with choice of such agents, 


 
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the Sponsor should be consulted for advice.  MTB members cannot grant any waiver 
from the protocol in regard to eligibility criteria or mandated study procedures.  Further 
information on the MTB and the MTB process are described in the Molecular Tumor 
Board Charter. 
An independent data monitoring committee (iDMC), guided by an iDMC Charter, will be 
responsible for evaluating the safety and ongoing efficacy data of trial patients at regular 
intervals throughout the study.  This includes an ongoing evaluation of the benefit-risk 
balance, based on accumulating safety and, as warranted, efficacy data.  The iDMC will 
make recommendations as to whether cohort recruitment should continue based on 
ongoing assessments.   
If applicable, an Independent Review committee (IRC) may perform a centralized, 
independent review of images, and other clinical data as needed, prior to the efficacy 
analyses. IRC membership and procedures would be detailed in an IRC charter (see 
Section 4.5.6.2 for conditions of centralized independent review implementation).  
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of study will occur when all enrolled patients have either died, withdrawn 
consent, are lost to follow-up, or have been followed for 18 months after the last study 
patient is enrolled, whichever occurs first.  
If the sufficient number of events for the OS follow-up analysis is not reached (Refer to 
Section 6.4.2.1 of the protocol) by time of the planned end of the study as defined 
above, the study will be prolonged until this number is reached. 
Recruitment is expected to occur over approximately 52 months.  It is therefore 
estimated that the study will last for a total of approximately 70 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Population Selection 
The inclusion and exclusion criteria for the study are aimed at specifically selecting 
patients with poor-prognosis CUP, for whom a likely tissue of origin cannot be posited 
with the following rational: 
 
These patients have no customized treatment available, as opposed to patients with 
favorable prognosis CUP, who should receive the therapy options for their potential 
equivalent tumor (see Table 2, Section 1.1.1.2).  It is therefore acceptable to have 
poor-prognosis CUP receiving a platinum-based therapy as a reference treatment in 
the study 
 
These patients have similar outcomes and constitute a rather homogeneous 
population, as opposed to favorable prognosis patients, among whom 30%–60% 
can achieve long-term disease control (see Section 1.1.1.2)  


 
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 
As the tissue of origin is unknown with no potential equivalent tumor suspected and 
the disease is inherently heterogeneous, a therapeutic approach based on 
molecular profiling is particularly relevant (see Section 1.3) 
 
Patients with squamous cell carcinoma have been excluded, as they have a different 
prognosis from adenocarcinoma and poorly differentiated carcinoma/adenocarcinoma of 
unknown primary.  
3.3.2 
Rationale for the Control Group 
The control group in this study (Category 1 patients only) will receive 3 cycles of pre-
randomization (induction) and at least 3 cycles of post-randomization platinum-based 
chemotherapy.  This regimen is recommended by ESMO for the treatment of patients 
with CUP (Fizazi et al. 2015) and, hence, reflects current standard of care in this patient 
population.  Although standard practice, superiority of chemotherapy over best 
supportive care has never been formally demonstrated. 
3.3.3 
Rationale for Three Cycles of Induction Chemotherapy  
Although targeted therapy and immunotherapy may have high potential in CUP patients, 
effects of molecularly-guided therapy are currently unknown in this setting.  In the 
absence of such data, the Steering Committee deemed that it was in the patient’s 
interest to receive 3 cycles of initial induction therapy followed by a response evaluation, 
consistent with ESMO guidelines for CUP, which also recommend 2 to 3 cycles of 
platinum-based chemotherapy followed by a response evaluation (Fizazi et al. 2015).  
Generally, a response in CUP patients to front-line platinum-based chemotherapy—if it 
is going to occur at all—is observed within 3 cycles, so the induction therapy used in this 
study should again be commensurate with standard of care in the study population. 
3.3.4 
Rationale for Sub-Dividing the Study Population Into Two 
Categories of Patients 
The primary and secondary efficacy endpoints will be analyzed exclusively in Category 1 
patients.  Thus, those patients who had a CR, PR, or SD after 3 cycles of induction 
chemotherapy will be allocated to either molecularly-guided therapy (investigational 
group) or to more cycles of platinum-based chemotherapy, as recommended by the 
ESMO guidelines (control group).  In effect, then, Study MX39795 will assess whether 
switching to therapy with targeted agents or cancer immunotherapy is beneficial relative 
to continuation of standard chemotherapy in Category 1 patients, using a standard 
randomized and comparative study design. 
It is anticipated that a portion of the study population will have progressive disease 
before or at the end of the Induction Period, i.e., 3 cycles of platinum-based 
chemotherapy will fail to generate a response or will produce an initial response that is 
followed by relapse.  Since response to chemotherapy is typically observed within 
3 cycles for CUP, it is not in the interest of the non-responsive patients to receive 
additional cycles of the same chemotherapy, especially given the potential efficacy of the 


 
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accessible, molecularly-guided therapies.  Consequently, since they cannot be 
randomized to control treatment (additional cycles of chemotherapy), patients who have 
progressive disease following induction chemotherapy will be assigned to a separate 
group of patients (Category 2) and will receive only targeted therapy or immunotherapy 
based on their genomic profiles.  Lacking a control comparator arm in the trial, or an 
appropriate historical control in the literature, these Category 2 patients will be analyzed 
on an exploratory basis. 
3.3.5 
Rationale for 3:1 Randomization in Category 1 Patients 
Based on prior genomic profiling studies, it is estimated that approximately one quarter 
to one-third of CUP patients randomized to receive molecularly-guided therapy will be 
actually eligible for molecularly-guided therapy, leading to approximately two-thirds to 
three-quarters of CUP patients being candidates to receive one of the two cancer 
immunotherapy treatments.  The number of patients in the targeted therapy cohorts will 
therefore be small.   
In order to draw more meaningful conclusions in the individual targeted therapy arms 
without increasing the overall sample size, Category 1 patients will be randomized in a 
3:1 fashion.  The higher likelihood of receiving molecularly-guided therapies is also 
expected to make the study more acceptable to patients and investigators 
3.3.6 
Rationale for Progression-Free Survival as the Primary 
Efficacy Endpoint and Frequency of Tumor Assessments 
The primary efficacy endpoint in this study is progression-free survival, defined as the 
time from randomization to the first occurrence of disease progression, as determined by 
the investigator according to RECIST v1.1, or death from any cause, whichever occurs 
first.  PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit, and its determination is not generally confounded by 
subsequent therapies.  Consequently, PFS provides an early readout of effect and is 
ideally suited to early-stage trials in new oncology indications. 
Considering the short median progression-free survival (around 5 months) observed in 
this poor prognosis CUP population (Hainsworth et al. 2015); see Section 6.1), tumor 
assessments are planned to be done every 9 weeks (equivalent of 3 cycles of most 
study treatments) in order to accurately assess the primary endpoint of the study (PFS). 
3.3.7 
Rationale for Combining Data from Different Experimental 
Treatment Cohorts for the Primary Endpoint Analysis 
Results will compare the pooled PFS of the different cohorts of molecularly-guided 
therapies plus 1 cohort of alternative therapies versus continuation of up to 3 cycles of 
chemotherapy in patients who exhibited disease control to an initial 3 cycles of platinum-
based induction chemotherapy.  Therefore, the study has been designed to assess the 
effects of profiling generally relative to standard chemotherapy, rather than effects within 
the individual therapy lines.  Nonetheless, it is possible that some of the molecularly-


 
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guided treatment regimens may have benefit, whereas others may not, so the benefit of 
individual regimens will also be determined.  The increase in statistical power afforded 
by combining treatment groups also made sense for this early-stage clinical trial in a new 
indication. 
3.3.8 
Rationale for Investigational Medicinal Products Doses and 
Schedules 
While none of the IMPs in this study have been approved for CUP, all but ipatasertib 
have been approved for the treatment of one or more cancer types, while their 
development programs have included multiple cancer indications (refer to the individual 
agents’ investigator’s brochures).  Consequently, a large and expanding knowledgebase 
of PK and safety information is available for each of the test agents in broad populations 
of cancer patients, allowing for reasonable extrapolation to a CUP population.   
The following test agents will be administered as monotherapies: alectinib, atezolizumab 
(also administered in combination, see below), entrectinib, ivosidenib, olaparib, 
pemigatinib and vismodegib.  All of these medications have been approved (pemigatinib 
and ivosidenib currently in the US only) for use in different non-CUP cancer indications 
and will be administered at the same dosages and schedules used in their currently 
approved indications, as described in the current investigator’s brochures and/or 
reference safety information for the individual IMPs: 
 
Alectinib will be administered as recommended for ALK-positive NSCLC in patients 
with ALK or RET alterations, i.e., at an oral dosage of 600 mg BID until loss of 
clinical benefit or unacceptable toxicity 
 
Atezolizumab will be administered as recommended for urinary carcinoma or 
NSCLC in patients with no actionable alterations and high TMB or MSI-high (also 
defined as mismatch repair (MMR)-deficient), i.e., as a 1200 mg intravenous 
infusion over 60 minutes every 3 weeks until loss of clinical benefit or unacceptable 
toxicity 
 
Entrectinib will be administered as recommended in its US label for patients with 
NTRK gene fusions or ROS1 gene rearrangements at an oral dosage of 600 mg QD 
(three 200-mg capsules per day) until loss of clinical benefit or unacceptable toxicity 
 
Ivosidenib will be administered as recommended in its US label for patients with 
newly diagnosed and relapsed or refractory acute myeloid leukemia with a 
susceptible IDH1 mutation, i.e., at an oral dose of 500 mg QD (with or without food) 
across a 28-day treatment cycle until loss of clinical benefit or unacceptable toxicity 
 
Olaparib will be administered until loss of clinical benefit or unacceptable toxicity, as 
recommended for patients with germline BRCA-mutated advanced ovarian cancer, 
i.e., at an oral dosage of: 
- 
400 mg BID if administered as capsules  
- 
or 300 mg BID if administered as film-coated tablets 
– 
Note:  After the film-coated tablets are available for use in the study,   


 
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▪ 
patients newly randomized should start olaparib treatment with 300 mg BID 
using film-coated tablets.  
▪ 
patients who already started treatment with 400 mg BID using capsules 
should only switch to 300 mg BID using film-coated tablets, after capsules 
are not any more available (when the last batch of capsules expires). 
 
Pemigatinib will be administered as recommended for advanced or metastatic 
cholangiocarcinoma with FGFR2 fusions or other rearrangements, i.e., at an oral 
dosage of 13.5 mg QD (given in the morning with water, with or without food) across 
a 21-day treatment cycle until loss of clinical benefit or unacceptable toxicity.  (As 
described in Appendix 10-11, pemigatinib may be up-titrated to 18 mg QD after one 
cycle of therapy if the patient does not reach the target serum phosphate level 
of   5.5 mg/dL at any time during Cycle 1, is compliant with taking study drug and 
does not experience an ongoing Grade 2 or higher treatment-related AE) 
 
Vismodegib will be administered as recommended for metastatic basal cell 
carcinoma in patients with PTCH1 or SMO alterations, i.e., at an oral dosage of 
150 mg QD until loss of clinical benefit or unacceptable toxicity 
 
Patients with AKT1-, PIK3CA- or PTEN-altered tumors will receive the 
investigational agent ipatasertib either in monotherapy or in combination with 
paclitaxel or unacceptable toxicity 
- 
Ipatasertib will be administered as recommended in the current Ipatasertib 
Investigator’s Brochure, i.e. orally at the dose of 400 mg QD on Days 1 to 21 of 
a 28-day cycle until loss of clinical benefit or unacceptable toxicity 
- 
Ipatasertib will be administered with paclitaxel at the dose of 80 mg/m2 IV on 
Days 1, 8, and 15 for 3 cycles.  If relevant and tolerated, it may be continued 
beyond 3 cycles 
- 
Patients (both Category 1 or 2) who have contraindications for paclitaxel, or 
Category 2 patients who were previously treated with paclitaxel, may receive 
ipatasertib monotherapy without paclitaxel at the discretion of the investigator.  
Likewise, patients who initiated ipatasertib without paclitaxel, as recommended 
in earlier versions of this protocol, may continue to receive ipatasertib 
monotherapy at the investigator’s discretion.  In all of these cases, single-agent 
ipatasertib will be administered as recommended in the current Ipatasertib 
Investigator’s Brochure for patients with AKT-, PTEN- or PIK3CA-altered tumors, 
i.e., at a once-daily dosage of 400 mg across a 21-day treatment cycle 
 
 
Patients with BRAF V600 or BRAF K601E mutations will receive 
vemurafenib/cobimetinib combination therapy.  The dosages and schedules for 
vemurafenib and cobimetinib will be the same as in the FDA- and EMA-approved 
melanoma indications, as described in the individual investigator’s brochures: 
- 
Vemurafenib will be administered at an oral dosage of 960 mg BID until loss of 
clinical benefit or unacceptable toxicity 


 
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- 
Cobimetinib will be administered at an oral dosage of 60 mg QD for the first 
21 days of a 28-day treatment cycle until loss of clinical benefit or unacceptable 
toxicity 
 
 
Patients with EGFR alterations will receive erlotinib/bevacizumab combination 
therapy.  The dosages and schedules for erlotinib and bevacizumab will be the 
same as in the EMA-approved NSCLC indications, as described in their respective 
EMA Summary of Product Characteristics (EU SmPC) 
- 
Erlotinib will be administered at an oral dosage of 150 mg QD (on an empty 
stomach) until loss of clinical benefit or unacceptable toxicity 
- 
Bevacizumab will be administered as a 15 mg/kg infusion every 3 weeks until 
loss of clinical benefit or unacceptable toxicity 
 
 
Patients with HER2 alterations will receive trastuzumab SC plus pertuzumab plus 
platinum-based chemotherapy (same as in the Induction Period) until loss of clinical 
benefit or unacceptable toxicity.  The dosages and schedules for pertuzumab and 
trastuzumab will be the same as in the EMA-approved breast indications, as 
described in the individual investigator’s brochures. 
- 
The initial loading dose of pertuzumab will be 840 mg administered as a 60 
(  10) minute intravenous infusion, followed every 3 weeks thereafter by a 
maintenance dose of 420 mg administered over a period of 30 to 60 ( 10) 
minutes.  When administered with pertuzumab, the dose of trastuzumab will be 
600 mg administered as a subcutaneous injection every 3 weeks.  If a dose is 
missed (i.e., the time between two sequential infusions is 6 weeks or more), a 
re-loading dose of pertuzumab (840 mg) should be given as described for 
loading dose 
 
 
Patients with no actionable alterations and who are not TMB-high or MSI-high will 
receive atezolizumab 1200 mg IV every 3 weeks until loss of clinical benefit and 
platinum-based chemotherapy (same as in the Induction Period) for 3 cycles.  
 
Patients for whom an alternative therapy is selected by the MTB will go off study 
treatment.  They will be managed per standard of care at their institution and will 
receive the alternative therapy outside of this study. 
 
Category 1 patients with a valid result from the FoundationOne® FMI F1CDx (tissue) 
test and/or FoundationOne® F1LCDx (Liquid) test reports, but turn out to be ineligible 
for any molecularly-guided therapy will have the opportunity to receive the control 
therapy, i.e., the same platinum-based chemotherapy in place at the end of the Induction 
Period, for a minimum of 3 additional cycles. 
During the course of study, the protocol might be amended to include new treatment 
cohorts if additional alterations and corresponding accessible targeted therapies are 
identified or if new immunotherapies (as monotherapy or in combination) are identified 
with a rationale to use in CUP patients. 


 
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The study will also incorporate a variety of measures to ensure the safety of participants, 
including emergency medical facilities and staff trained to monitor for and respond to 
medical emergencies, an iDMC to assess safety signals on an ongoing basis, and 
protocol-specified drug interruption criteria designed to ensure optimal dosing 
(Sections 4.6.1 and 5.1.2). 
3.3.9 
Rationale for Patient-Reported Outcomes 
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic adverse events.  Recent research has shown that clinicians may 
underreport the incidence and severity of symptoms experienced by patients receiving 
treatment for cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; 
Basch 2010; Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014).  Collecting 
adverse event information directly from patients can provide a better understanding of 
treatment characteristics and their effects.   
In order to evaluate the HRQol effects and the health status utility of molecularly-guided 
therapy in patients with CUP this study will employ the following instruments: 
 
The Functional Assessment of Cancer Therapy–General (FACT-G) is a widely used 
measure to assess health-related quality of life in patients undergoing cancer 
therapy (Cella et al. 1993; Luckett et al. 2011).  The current instrument has 
27 questions, each answered using a 5-point Likert scale.  Questions measure the 
respondent’s health status over the last 7 days in four subscales: Physical Well-
Being (7 questions), Social/Family Well-Being (7 questions), Emotional Well-Being 
(6 questions), and Functional Well-being (7 questions).  Scoring involves a simple 
sum of item scores 
 
The Hospital Anxiety and Depression Scale (HADS) is a validated self-report 
questionnaire used to assess patient anxiety and depression in the hospital 
outpatient-clinic setting (Zigmond and Snaith 1983).  The HADS is a fourteen-item 
scale that generates ordinal data, 7 items relating to anxiety, and 7 relating to 
depression.  This outcome measure was created to avoid reliance on symptoms of 
anxiety and depression that are also common symptoms of illness, e.g., fatigue, 
insomnia and hypersomnia.  Use of the HADS scale in quantifying psychological 
distress among cancer patients has been assessed in several recent meta-analyses 
(Vodermaier and Millman 2011; Yeh et al. 2014; Wakefield et al. 2015) 
 
The EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L) is a validated 
self-report health status questionnaire that is used to calculate a health status utility 
score for use in health economic analyses (EuroQol 1990; Brooks 1996; Herdman 
et al. 2011; Janssen et al. 2013).  There are two components to the EQ-5D-5L:  a 
five-item health state profile that assesses mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression, as well as a visual analog scale (VAS) that 
measures health state.  The EQ-5D-5L is designed to capture the patient’s current 
health status.  Published weighting systems allow for creation of a single composite 
score of the patient’s health status 
 


 
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PRO data will only be collected in Category 1 patients, i.e., in patients with a CR, PR or 
SD after 3 cycles of induction chemotherapy who are randomized to investigational 
therapy or control therapy. 
PROs being only analyzed at the time of primary analysis, these questionnaires will not 
be collected after the clinical cut-off date for the primary analysis (CCOD). 
3.3.10 
Rationale for Exploratory Biomarker Assessments 
Exploratory biomarker assessments in this study might include, but are not limited to, the 
following: 
 
PD-L1: Expression of PD-L1 on either tumor or infiltrating immune cells, verified 
predominantly by immunohistochemistry (IHC) in a variety of tumors, has suggested 
a role for the PD-1/PD-L1 axis as a prognostic trait and therapeutic target across 
multiple histotypes.  Several clinical studies have reported that PD-L1 
overexpression is positively correlated with response to PD-1/PD-L1 targeted 
therapy in various indications like NSCLC, urothelial bladder cancer or renal cell 
carcinoma (Zou et al. 2016).  Therefore, analyzing PD-L1 might elucidate PD-L1 
expression patterns in CUP and correlate expression patterns with response to 
atezolizumab. 
 
RNA sequencing: RNA sequencing has changed our ability to explore the molecular 
mechanisms underlying complex diseases.  Analyzing RNA expression will allow 
comprehensive molecular characterization of the underlying disease and potentially 
stimulate hypothesis generation on how RNA expression patterns correlate with 
response to targeted treatment in CUP. Gene expression analysis may also be used 
to predict the likely primary tumor type and how it may correlate with response to 
treatment. 
 
DNA methylation: Genome wide methylation analysis has been shown to improve 
classification of tumors and has the potential to predict the tissue of origin. Tumor 
DNA methylation analyses also allows for profiling of DNA copy number alterations 
(CNAs) which has been proposed as a potential predictive marker. Analyzing tumor 
DNA methylation profiles may allow for further classification of CUP at multiple 
molecular levels, assessment of potential primary tumor site and how these 
signatures might relate treatment response. 
 
Proteome analysis: Many cancer drugs specifically target proteins.  Alterations on 
the DNA, RNA and methylation levels ultimately affect the abundance and activity of 
proteins expressed in tumors.  Analysis of CNAs has shown relatively strong 
correlation with mRNA abundance, however variation in mRNA levels has shown to 
correlate poorly with variation in protein expression.  Evolving proteome profiling 
technologies might help to understand posttranslational modifications of proteins 
much better in the future and reveal proteins whose genetic information is intact but 
pathogenic alterations impact functionality of respective proteins (e.g., more stable 
or more prone to degradation).  No data are available on protein modifications and 
their potential relevance in CUP (Dermawan and Rubin 2020, Hayashi et al. 2020) 
and therefore it can be important to analyse protein expression directly in both tumor 


 
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tissue and blood to identify potential predictive and prognostic proteome signatures 
(Dova et al. 2008).  
 
Immune cell infiltration: Cancer cells are heterogeneous and dynamic 
microenvironments that communicate with the immune system, and the immune 
system context of the tumor microenvironment has been shown to influence the 
course of the disease.  Characterization of immune cell infiltration and quantification 
of immune cell density indicated that cytotoxic and memory T cells predict clinical 
outcome (Galon et al. 2006).  Immune cells will be characterized (e.g., CD8-positive 
cells) to better understand the expression patterns in CUP. 
 
Germline mutation/variants: A previous genome-wide association study on CUP 
suggested that various germline genes (e.g., LTA4H, TIAM1) may contribute to the 
risk of CUP (Hemminki et al. 2016).  As little is known about germline genetics in 
CUP, this study might help to increase the understanding of genetic variants. 
 
It is possible that by the time tumor samples are analyzed in this study, additional 
molecular markers for disease characterization or efficacy correlation will emerge.  Thus, 
during the course of this study, it may become necessary to investigate additional 
markers associated with disease or target signaling pathways and to reprioritize the 
above biomarkers. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target sample for this study is 472 randomized patients with CUP who exhibited 
disease control (CR, PR, or SD) after 3 cycles of platinum induction chemotherapy 
(Category 1 patients).  Assuming a 60% disease control rate at the end of induction and 
a 15% dropout rate, it is estimated that approximately 790 patients with CUP will need to 
be enrolled.   
If the actual number of patients who achieve a CR, PR, or SD during induction deviates 
from these estimates, the study will enroll patients until 472 patients have been 
randomized.  
In addition, if both the actual disease control and dropout rates differ from the protocol 
assumptions, the 330 PFS events may be reached before 790 patients are enrolled. In 
this case, screening will be stopped, when 330 PFS events have been observed. 
4.1.1 
General Inclusion Criteria 
4.1.1.1 
At Study Entry 
Prior to eligibility review, as assessed during the Screening Period enrollment and 
initiation of platinum doublet chemotherapy, patients must meet the following main 
inclusion criteria for study entry: 
 
Signed Informed Consent Form 
 
Able and willing to comply with the study protocol 


 
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 
Age   18 years at time of signing Informed Consent Form 
 
Histologically-confirmed unresectable CUP diagnosed according to the criteria 
defined in the 2015 ESMO Clinical Practice Guidelines for CUP (Fizazi et al. 2015).  
Acceptable disease includes:  
- 
Adenocarcinoma 
- 
Poorly differentiated adenocarcinoma 
- 
Poorly differentiated carcinoma 
 
Disease should not be amenable to resection and/or irradiation with curative intent 
during the course of the study 
 
At least one lesion that is measurable according to RECIST v1.1 (Appendix 5) 
- 
If a fresh biopsy is needed during Screening, the biopsy procedure must not 
affect measurability of disease 
 
 
Availability of a tumor FFPE block   4 months old at the start of screening that is 
expected to be sufficient and suitable (in quantity and quality) for generation of a 
comprehensive genomic profile using the FoundationOne® FMI F1CDx (tissue) 
test at a central reference pathology laboratory (refer to the Laboratory Manual for 
suitability details and specimen collection instructions) 
 
Availability of local pathology reports confirming compatibility with CUP diagnosis 
and the associated slides used for the diagnosis (histology and routine 
immunohistochemistry compatible with CUP; refer to the Laboratory Manual for 
details).  If the slides used for the local test confirming CUP diagnosis are not 
available, an FFPE block must be submitted that is sufficient to allow for central 
confirmation of CUP diagnosis, i.e., performing relevant IHC and ISH if required 
- 
If the available tumor sample is insufficient or not suitable (in quantity and 
quality) to enable the above assessments, a fresh biopsy sample must be 
collected during the Screening Period that meets the study’s requirements (refer 
to the Laboratory Manual for suitability details and specimen collection 
instructions and to Section 3.1.1 for special circumstances).  There is no 
restriction in the number of repeat biopsies performed locally to obtain a suitable 
sample for a submission to the central laboratory 
 
 
No prior systemic therapy for the treatment of CUP 
- 
Prior local intratumoral therapy may be accepted.  If prior local intratumoral 
therapy, at least one of the measurable lesion(s) must have not benefited from 
local intratumoral therapy  
- 
Patients who have received prior surgery and/or radiotherapy (including 
radioembolization of tumor) are eligible.  If the patient had prior radiotherapy, the 
measurable lesion(s) must not have been irradiated 
- 
The last dose of radiotherapy must have been administered at least one week 
prior to the first dose of study treatment and the patient must have recovered to 
Grade 1 or less from any toxicity of radiotherapy 


 
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In cases where radiotherapy has been administered for post brain surgery 
adjuvant treatment or as definitive intervention (e.g., stereotactic 
radiosurgery) for brain metastases, there must be at least 4 weeks 
between the end of the radiotherapy and start of study treatment 
 
 
ECOG performance status of 0 or 1 
 
Life expectancy   12 weeks 
 
Eligible for platinum-based chemotherapy (according to the reference information for 
the intended chemotherapy) 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 14 days prior to initiation of study treatment: 
- 
Absolute neutrophil count (ANC)   1  109 cells/L (1000/L) (without granulocyte 
colony-stimulating factor [G-CSF] support within 2 weeks prior to the first study 
treatment) 
- 
Platelet count   100  109 cells/L (100,000/L) (without transfusion within 
2 weeks prior to the first study treatment) 
- 
Hemoglobin   90 g/L (9.0 g/dL)  
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT)   2.5 times the 
upper limit of normal (ULN), with the following exceptions: 
Patients with documented liver metastases: AST and/or ALT   5  ULN 
- 
Serum bilirubin   1.5  ULN  
Patients with known Gilbert disease who have serum bilirubin   3  ULN 
may be enrolled 
- 
Creatinine clearance   30 mL/min (calculated through use of the Cockcroft-Gault 
formula) 
In patients who receive cisplatin, creatinine clearance must be   60 mL/min  
- 
For patients not receiving therapeutic anticoagulation: International normalized 
ratio (INR) or activated partial thromboplastin time (aPTT)   1.5  ULN 
Patients receiving heparin treatment should have an aPTT between 1.5 to 
2.5  ULN (or patient value before starting heparin treatment).  Patients 
receiving coumarin derivatives should have an INR between 2.0 and 3.0 
assessed in two consecutive measurements 1 to 4 days apart 
 
 
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception with a failure rate of   1% per year 
during the Induction and Treatment Periods and after the final dose of study 
treatment for at least: 
- 
2 weeks for erlotinib 
- 
1 month for ipatasertib and olaparib 


 
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- 
5 weeks for entrectinib and pemigatinib 
- 
3 months for alectinib and ivosidenib 
- 
5 months for atezolizumab 
- 
6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, cisplatin, 
paclitaxel and gemcitabine 
- 
7 months for trastuzumab and pertuzumab 
- 
24 months for vismodegib 
 
 
Women must refrain from donating eggs during this same period 
- 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
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 
- 
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.  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 not adequate methods of contraception 
- 
If required per local guidelines or regulations, locally recognized adequate 
periods and methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form 
- 
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to first dose.  If the serum pregnancy test is 
uninterpretable (e.g., beta-HCG is elevated in the absence of other signs of 
pregnancy), the reason for non-interpretability should be adequately 
documented, and intra- or extra-uterine pregnancy should be ruled out by 
ultrasound within 7 days prior to the first administration of study treatment 
 
 
For male patients: acceptance that most of the study treatments require specific 
reliable and effective contraception measures, as well as measures related to sperm 
donation.  This includes agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraception, and agreement to refrain from donating sperm, as 
defined below: 
- 
With a female partner of childbearing potential who is not pregnant, men must 
remain abstinent or use a condom plus an additional contraceptive method that 


 
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together result in a failure rate of   1% per year during the Induction and 
Treatment Periods and after the final dose of study treatment for at least: 
▪ 
2 weeks for erlotinib 
▪ 
1 month for ipatasertib 
▪ 
2 months for vismodegib 
▪ 
3 months for alectinib, olaparib, entrectinib, ivosidenib and pemigatinib 
▪ 
6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, 
cisplatin, paclitaxel and gemcitabine 
▪ 
7 months for trastuzumab and pertuzumab 
 
– 
Men must refrain from donating sperm during this same period 
 
- 
With pregnant female partners, men must remain abstinent or use a condom to 
avoid exposing the embryo during the Induction and Treatment Periods and for 
at least: 
▪ 
2 weeks for erlotinib 
▪ 
1 month for ipatasertib 
▪ 
2 months for vismodegib 
▪ 
3 months for alectinib, olaparib, entrectinib, ivosidenib and pemigatinib 
▪ 
6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, 
cisplatin, paclitaxel and gemcitabine 
▪ 
7 months for trastuzumab and pertuzumab 
 
- 
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 not adequate methods of contraception  
- 
If required per local guidelines or regulations, locally recognized adequate 
periods and methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form 
 
4.1.1.2 
Prior to Start of Therapy in the Treatment Period 
If any of the below criteria are NOT met, randomization and/or the MTB will be delayed 
or study treatment will be discontinued (see Section 3.1.3): 
 
Head CT or MRI scans must meet the following criteria: 
- 
Category 1 patients: 
o No change from baseline 
 
- 
Category 2 patients: 
o No change from baseline, OR: 


 
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o Asymptomatic brain metastases (if necessary, concomitant treatment to 
control CNS involvement and/or provide symptom prophylaxis is allowed)  
o Patients who have had a resection of brain metastases by, for example, 
conventional surgery or stereotactic radiosurgery may continue into the 
Treatment Period, provided they have recovered from the surgery (see 
below) and any ongoing symptomatic therapy or prophylaxis is 
compatible with the treatment-specific exclusion criteria described in 
Section 4.1.3 
 
 
Recovery to Grade   1 of significant toxicities attributable to induction 
chemotherapy, with the following exceptions: 
- 
Alopecia of any grade is allowed 
- 
Neurosensory toxicity must have recovered to   Grade 2 
- 
Laboratory values must be as per inclusion criteria described below 
 
 
With the exception of resection of brain metastases by conventional surgery or 
stereotactic radiosurgery (see prior inclusion criterion), the patient must not have 
had a major surgical procedure within 2 weeks prior to initiation of the Treatment 
Period and/or there must be no anticipation of a need for a major surgical procedure 
during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that 
occurred   2 weeks before initiation of the Treatment Period, including sufficient 
wound healing, with the following exceptions: 
Patients assigned to erlotinib in combination with bevacizumab, to ipatasertib (in 
combination with paclitaxel or as monotherapy), or to ivosidenib must have 
recovered from any major surgical procedure that occurred ≥ 4 weeks before 
initiation of the Treatment Period, including sufficient wound healing 
 
 
No history or known presence of leptomeningeal disease 
 
ECOG performance status of 0 or 1 for Category 1 patients 
 
ECOG performance status of 0, 1 or 2 for Category 2 patients 
 
Adequate hematologic function, defined by the following laboratory results (criteria 
must be verified and fulfilled prior to first dose in the Treatment Period, but will not 
delay randomization): 
- 
ANC   1.0  109 cells/L (1000/µL) (without granulocyte colony-stimulating [G-
CSF] factor support within 2 weeks prior to planned study treatment date) 
- 
Platelet count   100  109 cells/L (100,000/µL) (without transfusion within 
2 weeks prior to the planned treatment date) 
- 
Hemoglobin   90 g/L (9.0 g/dL)  
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion 
 
Adequate end-organ function, defined by the following laboratory results: 


 
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- 
AST and ALT   2.5  ULN, with the following exceptions: 
Patients with documented liver metastases: AST and/or ALT   5  ULN 
- 
Serum bilirubin   1.5  ULN  
Patients with known Gilbert disease who have serum bilirubin   3  ULN may 
be randomized (Category 1 patients) or considered for molecularly-guided 
therapy (Category 2 patients) 
- 
Creatinine clearance ≥ 30 mL/min (calculated through use of the Cockcroft-
Gault formula) 
In patients who receive cisplatin, creatinine clearance must be   60 mL/min 
- 
For patients not receiving therapeutic anticoagulation: International normalized 
ratio (INR) or activated partial thromboplastin time (aPTT)   1.5  ULN 
Patients receiving heparin treatment should have an aPTT between 1.5 to 
2.5  ULN (or patient value before starting heparin treatment) 
Patients receiving coumarin derivatives should have an INR between 2.0 and 
3.0 assessed in two consecutive measurements 1 to 4 days apart 
 
 
At least 2 weeks between the last dose of radiotherapy administered during the 
Induction Period and the first dose of study treatment administered during the 
Treatment Period.  
- 
Patients must have recovered from all radiation-related toxicities, must not 
require corticosteroids and must not have had radiation pneumonitis 
 
 
Recovery from active infections requiring intravenous antibiotics, with antibiotic 
therapy ceased for   7 days prior to planned start of therapy 
 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to the first dose.  If the serum pregnancy test is uninterpretable 
(e.g., beta-HCG is elevated in the absence of other signs of pregnancy), the reason 
for non-interpretability should be adequately documented, and intra- or extra-uterine 
pregnancy should be ruled out by ultrasound within 7 days prior to the first 
administration of study treatment 
 
4.1.2 
Main Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Squamous cell CUP 
 
Patients with histology and immunohistology profiles (per 2015 ESMO guidelines) 
that are not adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma), 
i.e., non-epithelial cancer, extragonadal germ-cell tumor, neuroendocrine tumors, 
sarcoma, melanoma, mesothelioma, hematologic malignancies (this list is not 
limitative) 
 
Patients who can be assigned to a specific subset of CUP for which a specific 
treatment is recommended by the 2015 ESMO Clinical Practice Guidelines for CUP 


 
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(Fizazi et al. 2015) or with a clinical and IHC profile indicative of a specific primary 
tumor are also excluded (favorable prognosis CUP subsets).  These are: 
- 
Poorly differentiated carcinoma with midline distribution 
- 
Women with papillary adenocarcinoma of the peritoneal cavity 
- 
Women with adenocarcinoma involving only the axillary lymph nodes 
- 
Squamous cell carcinoma of the cervical lymph nodes 
- 
Poorly differentiated neuroendocrine tumors 
- 
Men with blastic bone metastases and elevated PSA 
- 
Patients with a single, small, potentially resectable tumor 
- 
Colon cancer-type CUP with a CK7 negative, CK20 positive, CDX-2 positive 
immunohistochemistry profile 
- 
CK7 positive, CK20 negative and TTF-1 positive tumors in a context suggestive 
of lung adenocarcinoma or thyroid cancer (i.e., with lesions in the lung or thyroid 
or the lymph nodes in their drainage areas) 
- 
IHC profile definitely indicative of breast cancer OR an IHC profile indicative of 
breast cancer and either a history of breast cancer or lymph nodes in the 
drainage areas of the breast 
- 
High-grade serous carcinoma histology and elevated CA125 tumor marker 
and/or a mass in the gynecological tract or any tumor mass or lymph node in the 
abdominal cavity (i.e., below the diaphragm) 
- 
IHC profile suggestive of renal cell carcinoma and renal lesions, with a Bosniak 
classification higher than IIF 
- 
IHC profile compatible with cholangiocarcinoma or pancreatobiliary (or upper 
gastrointestinal carcinoma) AND 1 or 2 liver lesions without extrahepatic disease 
or with only pulmonary metastases and/or lymph nodes in the drainage areas of 
the liver 
 
Note:  For the aforementioned patients, but not limited to them, an escalation to a 
referent oncologist or radiologist may be required by the study team for adjudication 
 
 
Known presence of brain or spinal cord metastasis (including metastases that have 
been irradiated only), as determined by CT or magnetic resonance imaging (MRI) 
evaluation during screening 
- 
Patients who had a complete resection of brain metastases by surgery with or 
without a combination of stereotactic radiotherapy, whole-brain irradiation or 
intensity-modulated radiation therapy may be accepted, provided that there were 
3 (at maximum) or less metastases resected or treated and that an MRI or high 
resolution CT scan of the brain not older than 3 months post intervention shows 
the absence of residual disease at least, no other ongoing brain metastases and 
no leptomeningeal carcinomatosis.  Benign lesions such as meningiomas may 
be accepted if it can be demonstrated that they may not affect the interpretation 


 
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of the study results or render the patient at high-risk from treatment 
complications 
 
 
History or known presence of leptomeningeal disease 
 
Known clinically significant history of liver disease consistent with Child-Pugh Class 
B or C, including active viral or other hepatitis, current alcohol abuse, or cirrhosis  
 
Human immunodeficiency virus (HIV) infection 
 
Positive for hepatitis C virus (HCV) antibody at screening 
- 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed.  A patient will be excluded from the study only if the 
HCV antibody and the HCV RNA test are positive.  If the HCV antibody test is 
positive, but the HCV RNA test is negative, the patient may enroll in the study 
 
 
Positive for hepatitis B surface antigen (HBsAg) at screening 
- 
If the HBsAg test is negative but the total hepatitis B core antibody (HbcAb) test 
is positive, assessment of HBV DNA must be performed.  If the resulting HBV 
DNA test is positive, the patient will be excluded from the study 
 
Active tuberculosis at screening 
 
Active infections requiring intravenous antibiotics.  If prior infection required IV 
antibiotic therapy, antibiotic therapy must have ceased   2 days prior to planned 
start of study treatment 
 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
3 months prior to initiation of study treatment, unstable arrhythmia (including active 
ventricular arrhythmia requiring medication), or unstable angina  
 
History of malignancy within 5 years prior to initiation of study treatment, with the 
exception of the cancer under investigation in this study and 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 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high-risk from treatment 
complications 
 
Treatment with investigational therapy within 28 days or the equivalent of 5 half-lives 
(whichever is the longest) prior to initiation of study treatment 
 
Known allergy or hypersensitivity to any component of the platinum-based 
chemotherapy 
 
Pregnant or breastfeeding, or intending to become pregnant during study treatment 
or for up to 24 months after the final dose of treatment 
 


 
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4.1.3 
Exclusion Criteria Specific to Molecularly-Guided Therapies 
Details of exclusion criteria described below will be collected prior to study entry and re-
assessed at the End of Induction Visit to capture any exclusion criteria that may have 
developed during the Induction Period.  Meeting any of these exclusion criteria will not 
prevent patients from entering the study, a Category 1 patient from being randomized, or 
a Category 2 patient from proceeding to study treatment.  Rather, if a patient does meet 
an exclusion criterion for a particular molecularly-guided therapy, then only that specific 
therapy will be excluded as a choice for this patient.  This will be clearly notified to the 
investigator and the MTB and no patient will be allowed to start treatment with a therapy 
he/she is not eligible to receive within the study. 
4.1.3.1 
All Molecularly-Guided Therapies 
 
Known allergy or hypersensitivity to any component of the molecularly-guided 
agents 
– 
This includes history of severe allergic anaphylactic reactions to chimeric or 
humanized antibodies or fusion proteins and to Chinese hamster ovary cell products 
or other recombinant human or humanized antibodies for atezolizumab, 
bevacizumab, pertuzumab and trastuzumab. 
 
4.1.3.2 
All Oral Therapies 
 
History of malabsorption syndrome, lack of physical integrity of the upper 
gastrointestinal tract, or other condition that would interfere with enteral absorption 
or results in the inability or unwillingness to swallow pills 
 
4.1.3.3 
Alectinib 
 
Hereditary galactose intolerance, a congenital lactase deficiency or glucose-
galactose malabsorption 
 
Symptomatic bradycardia 
 
4.1.3.4 
Vismodegib 
 
Males unwilling to use condoms (with spermicide, where available), even after a 
vasectomy, during heterosexual intercourse while being treated with vismodegib, 
and for 2 months after the final dose (men must refrain from donating sperm during 
this same period). 
 
4.1.3.5 
Ipatasertib in Combination with Paclitaxel (or Ipatasertib 
Monotherapy in Patients who are not Receiving the 
Combination) 
 
Fasting total serum glucose   150 mg/dL 
 
Glycated hemoglobin (HbA1C)   7.5% 
 
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 
 


 
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 
Creatinine clearance   50 mL/min (calculated through the use of the Cockcroft-Gault 
formula) 
 
Ongoing corticosteroid therapy (use of topical steroids or inhaled steroids is 
acceptable) or immunosuppressants for a chronic disease 
 
Active small or large intestine inflammation (such as Crohn’s disease or ulcerative 
colitis) 
 
With the exception of resection of brain metastases by conventional surgery or 
stereotactic radiosurgery, the patient must not have had a major surgical procedure 
within 4 weeks prior to initiation of the Treatment Period and/or there must be no 
anticipation of a need for a major surgical procedure during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that 
occurred   4 weeks before initiation of the Treatment Period, including sufficient 
wound healing 
- 
Patients who have received palliative radiation treatment to peripheral sites 
(e.g., bone metastases) for pain control and whose last treatment was 
completed 14 days prior to Day 1 of Cycle 1 may be enrolled in the study if they 
have recovered from all acute, reversible effects (e.g., resolved to Grade   1 by 
enrolment) 
- 
More guidance on permitted therapies, including palliative radiotherapy, can be 
found in Section 4.4 
 
4.1.3.6 
Ivosidenib 
 
ANC   1.5   109 cells/L (1500/L) 
 
Creatinine clearance   50 mL/min (calculated through the use of the Cockcroft-Gault 
formula) 
 
Known medical history of progressive multifocal leukoencephalopathy (PML) 
 
Ongoing treatment with drugs known to be strong cytochrome P450 (CYP) 3A4 
inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic 
window, unless they can be switched to other medications within   5 half-lives prior 
to dosing 
 
Ongoing treatment with P-glycoprotein (P-gp) transporter-sensitive substrate 
medications with a narrow therapeutic window, unless they can be transferred to 
other medications within   5 half-lives prior to administration of study treatment 
 
LVEF   40% by ECHO scan (or by other methods according to institutional practice) 
obtained within 28 days prior to the start of study treatment 
 
Heart rate corrected QT interval (using Fridericia’s formula) (QTcF)   450 msec or 
other factors that increase the risk of QT prolongation or arrhythmic events 
(e.g., heart failure, hypokalemia, family history of long QT interval syndrome).  
Bundle branch block are permitted 
 
Concomitant medications that are known to prolong the QT interval, unless they can 
be transferred to other medications within   5 half-lives prior to dosing or unless the 


 
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medications can be properly monitored during the study.  (If equivalent medication is 
not available, QTcF should be closely monitored) 
 
With the exception of resection of brain metastases by conventional surgery or 
stereotactic radiosurgery, the patient must not have had a major surgical procedure 
within 4 weeks prior to initiation of the Treatment Period and/or there must be no 
anticipation of a need for a major surgical procedure during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that 
occurred   4 weeks before initiation of the Treatment Period, including sufficient 
wound healing 
 
4.1.3.7 
Olaparib 
 
None 
 
4.1.3.8 
Pemigatinib 
 
Current evidence of clinically significant corneal (including, but not limited to, 
bullous/band keratopathy, corneal abrasion, inflammation/ulceration, 
keratoconjunctivitis) or retinal disorder (including, but not limited to, macular/retinal 
degeneration, diabetic retinopathy, retinal detachment) as confirmed by 
ophthalmologic examination 
 
Serum phosphate   ULN 
 
Serum calcium outside of normal range, or serum-albumin-corrected calcium 
outside of the normal range when serum albumin is outside of the normal range 
 
History of calcium and phosphate homeostasis disorder or systemic mineral 
imbalance with ectopic calcification of soft tissues (exception: commonly observed 
calcifications in soft tissues such as the skin, kidney tendon, or vessels due to injury, 
disease, or aging in the absence of systemic mineral imbalance)  
 
Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers 
within 14 days or five half-lives (whichever is longer) before the first dose of 
pemigatinib 
- 
Note:  Moderate CYP3A4 inhibitors are not prohibited 
 
4.1.3.9 
Atezolizumab Monotherapy or in Combination with Platinum-
Based Chemotherapy 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, myocarditis, systemic 
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-
phospholipid antibody syndrome, granulomatosis with polyangiitis, Sjögren 
syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix 4 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 thyroid-
replacement hormone are eligible for the study. 
 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for treatment with atezolizumab. 


 
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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 treatment with atezolizumab provided all of following conditions are 
met: 
- 
Rash must cover   10% of body surface area 
- 
Disease is well controlled on Day 1 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 
 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti− tumor necrosis factor–TNF- agents) within 4 weeks or 5 drug-elimination 
half-lives (whichever is longer) prior to initiation of atezolizumab and during 
treatment with atezolizumab, 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 or anti-emetic prophylaxis for 
chemotherapy) are eligible 
- 
Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-
dose corticosteroids for chronic obstructive pulmonary disease (COPD) or 
asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal 
insufficiency are eligible for the study 
 
In patients who receive concomitant chemotherapy, all criteria for administration of 
chemotherapy must be verified 
 
Alkaline phosphatase (ALP)   2.5  ULN, with the following exception: 
- 
Patients with documented liver or bone metastases must have ALP   5  ULN 
- 
Uncontrolled or symptomatic hypercalcemia (ionized calcium   1.5 mmol/L, 
calcium > 12 mg/dL, or corrected serum calcium   2.9 mmol/L) 
 
4.1.3.10 
Erlotinib in Combination With Bevacizumab 
 
Poorly controlled hypertension (e.g., systolic   140 mm Hg or diastolic   90 mm Hg) 
 
History or evidence of inherited bleeding diathesis or coagulopathy with the risk of 
bleeding 
 
History of thrombotic disorders within the last 6 months prior first dose of 
bevacizumab 


 
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 
Patients discovered to have   2  proteinuria on dipstick urinalysis at end of 
induction work-up or at Cycle 1 Day1 assessment should undergo a 24-hour urine 
collection and must demonstrate   1 g of protein in 24 hours prior to first 
administration of bevacizumab 
 
Non-healing wound, active peptic ulcer or bone fracture at Cycle 3 of induction 
chemotherapy 
 
History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess 
within 6 months of planned study treatment 
 
Recent pulmonary hemorrhage/hemoptysis ( 1/2 teaspoon red blood) 
 
Unwillingness to stop smoking and vaping 
 
With the exception of resection of brain metastases by conventional surgery or 
stereotactic radiosurgery, the patient must not have had a major surgical procedure 
within 4 weeks prior to initiation of the Treatment Period and/or there must be no 
anticipation of a need for a major surgical procedure during the rest of the study 
- 
The patient must have recovered from any major surgical procedure that 
occurred   4 weeks before initiation of the Treatment Period, including sufficient 
wound healing 
 
4.1.3.11 
Vemurafenib in Combination With Cobimetinib 
 
LVEF below institutional LLN or below 50%, whichever is lower  
 
QTc   500 msec at Cycle 3 of induction chemotherapy 
 
Long QT syndrome 
 
Uncorrectable electrolyte abnormalities 
 
Known risk factors for ocular toxicity, consisting of any of the following: 
 
History of serous retinopathy 
 
History of retinal vein occlusion (RVO) 
 
Evidence of ongoing serous retinopathy or RVO at screening 
 
Any Grade   3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1 
 
Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 
enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during 
study treatment 
- 
These include St. John’s wort or hyperforin (strong CYP3A4 enzyme inducer) 
and grapefruit juice (strong cytochrome P450 CYP3A4 enzyme inhibitor) 
 
Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic 
baseline hypertension consistently above systolic   140 mm Hg or diastolic 
 90 mmHg despite optimal medical management 
 
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 


 
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 
Hereditary galactose intolerance, a congenital lactase deficiency or glucose-
galactose malabsorption 
 
4.1.3.12 
Trastuzumab SC Plus Pertuzumab Plus Platinum-Based 
Chemotherapy 
 
Serious cardiac illness or medical conditions including but not confined to: 
- 
History of documented congestive heart failure or systolic dysfunction (baseline 
LVEF   55% at Cycle 3 of induction chemotherapy, measured by 
echocardiography or multiple-gated radionuclide angiography (MUGA) scan 
prior to first dose of trastuzumab) 
- 
High-risk uncontrolled arrhythmias i.e., atrial tachycardia with a heart rate 
 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or 
higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third 
degree AV-block) 
- 
Angina pectoris requiring anti-anginal medication 
- 
Clinically significant valvular heart disease 
- 
Evidence of transmural infarction on ECG 
- 
Poorly controlled hypertension (e.g., systolic   140 mm Hg or diastolic 
 90 mm Hg) 
 
Dyspnea at rest or other diseases that require continuous oxygen therapy 
 
Current chronic daily treatment with corticosteroids (dose   10 mg 
methylprednisolone or equivalent [excluding inhaled steroids]) 
 
Current severe, uncontrolled systemic disease that may interfere with planned 
treatment (e.g., clinically significant cardiovascular, pulmonary, or metabolic 
disease; wound-healing disorders) 
 
Type 1 or Type 2 diabetes mellitus requiring insulin 
- 
Patients who are on a stable dose of oral diabetes medication   4 weeks prior to 
initiation of trastuzumab plus pertuzumab may be eligible for treatment.  Fasting 
total serum glucose must be   150 mg/dL and glycated hemoglobin (HbA1c) 
must be   7.5% at Cycle 3 of induction chemotherapy 
 
History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), 
active bowel inflammation (e.g., diverticulitis) 
 
In patients who receive concomitant chemotherapy, all criteria for administration of 
chemotherapy must be verified 
 
4.1.3.13 
Entrectinib 
 
History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval 
 450 milliseconds from ECGs performed at least 24 hours apart) 
 
History of additional risk factors for torsade de pointes (e.g., family history of long 
QT syndrome) 


 
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 
History of recent (within 3 months from MTB) symptomatic congestive heart failure 
or ejection fraction   50%  
 
Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase 
inhibitor-induced pneumonitis 
 
Peripheral sensory neuropathy Grade   2 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This will be an open-label trial.  Following screening and confirmation of the CUP 
diagnosis by the Eligibility Review Team, approximately 790 eligible patients will receive 
3 cycles of standard first-line platinum-based induction chemotherapy 
(carboplatin/paclitaxel, cisplatin/gemcitabine or carboplatin/gemcitabine).  If both the 
actual disease control and dropout rates differ from the protocol assumptions (see 
Section 4.1), all patients who are screened before 330 PFS events have been observed 
and who are eligible for the study, will start the 3 cycles induction chemotherapy. 
At the end of the 3 cycles of induction chemotherapy, antitumor response will be 
evaluated in each patient according to RECIST v1.1 (between Cycle 3 Day 7 and 
Cycle 3 Day 21).  The response assessment must be available at the End of Induction 
Visit. 
 
Category 1:  It is estimated that approximately 60% of patients will have a CR, PR, 
or SD at the end of 3 cycles of induction chemotherapy.  These patients will be 
randomly assigned in a 3:1 allocation ratio via a block-stratified randomization 
procedure to receive either molecularly-guided therapy or additional cycles of the 
same chemotherapy used during initial induction chemotherapy treatment, 
respectively.  To assist balance, guard against systematic selection bias, and 
ensure comparability of treatment groups, randomization will be stratified by gender 
and response to platinum induction chemotherapy (CR  PR vs. SD) 
 
Category 2:  It is estimated that approximately 40% of patients will have PD before 
or at the end of 3 cycles of the induction chemotherapy.  These patients will have 
the possibility to receive molecularly-guided therapy 
 
Central randomization and drug pack number allocations will be performed and 
managed by an interactive response system (IxRS; further details provided in the IxRS 
manual). 
Choice of molecularly-guided therapy in Category 1 and Category 2 patients will be 
determined by the investigator in consultation with the MTB, as described in Section 3.1. 
To maintain the scientific integrity of the study and the primary endpoint, genomic 
profiling results (FoundationOne® FMI F1CDx (tissue) test and/or FoundationOne® 
F1LCDx (Liquid) test reports) will only be disclosed to the investigator: 
 
After randomization for Category 1 patients assigned to molecularly-guided therapy  


 
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 
Only After disease progression per RECIST v1.1 during the Treatment Period for 
Category 1 patients randomized to continuing platinum-based chemotherapy 
 
After disease progression on platinum induction chemotherapy for Category 2 
patients 
 
In exceptional situations during the induction period, where the genomic profile 
based on the FoundationOne® FMI F1CDx (tissue) test and/or FoundationOne® 
F1LCDx (Liquid) test provides an indication of a non-epithelial tumor (see 
Section 3.1.2). 
 
4.3 
STUDY TREATMENT 
4.3.1 
Induction Period 
Platinum-based induction chemotherapy will start after the CUP diagnosis and the 
availability of suitable tumor tissue have been reviewed and confirmed by the Eligibility 
Review Team. 
4.3.2 
Treatment Period 
Initiation of therapy should occur within 21 calendar days after the End of Induction Visit 
If any of the Day 1 of the Treatment Period assessments do not meet safety criteria for 
starting treatment, study drug administration should be held and the tests repeated 
(timing of repeat testing should be based on clinical judgment). 
Investigational medicinal products (IMPs) in this study include: 
 
Alectinib 
 
Atezolizumab 
 
Entrectinib 
 
Ivosidenib 
 
Olaparib 
 
Pemigatinib 
 
Vismodegib 
 
Atezolizumab  platinum-based chemotherapy 
 
Erlotinib  bevacizumab 
 
Ipatasertib  paclitaxel 
 
Trastuzumab  pertuzumab  platinum-based chemotherapy 
 
Vemurafenib  cobimetinib 
 
Carboplatin  paclitaxel 
 
Cisplatin  gemcitabine 
 
Carboplatin  gemcitabine 
 
Paclitaxel  gemcitabine (only after induction and in exceptional circumstances) 


 
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Note:  Patients for whom an alternative therapy is selected by the MTB will go off study 
treatment.  They will be managed per standard of care at their institution and will receive 
the alternative therapy outside of this study. 
4.3.3 
Study Treatment Formulation and Packaging 
Alectinib, atezolizumab, bevacizumab, carboplatin, cisplatin, cobimetinib, erlotinib, 
gemcitabine, ivosidenib, olaparib, paclitaxel, pertuzumab, trastuzumab, vemurafenib and 
vismodegib will be supplied by the Sponsor as commercially-available formulations.  For 
information on the formulation and packaging of these marketed IMPs, refer to their 
respective investigator’s brochures and/or reference safety information. 
Ipatasertib will be supplied as 100- and 200-mg tablets.  For information on the 
formulation and packaging of ipatasertib, refer to the Ipatasertib Investigator’s Brochure. 
Entrectinib will be supplied as 200-mg hard capsules.  For information on the formulation 
and packaging of entrectinib, refer to the Entrectinib Investigator’s Brochure. 
Pemigatinib will be supplied as oral 4.5-mg tablets.  For information on the formulation 
and packaging of pemigatinib, refer to the Pemigatinib Investigator’s Brochure. 
Alternative therapies are not part of study treatment; the patient will be discontinued from 
study treatment if this option is selected. 
4.3.4 
Study Treatment Dosage, Administration, and Compliance 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error (for IMPs site administered), overdose, medication error, 
drug abuse or drug misuse (for IMPs not site administered) along with any associated 
adverse events should be reported as described in Section 5.3.5.12. 
Guidelines for dose reduction and management of specific adverse events, and 
treatment interruption or discontinuation for patients who experience adverse events, are 
available as follows (refer to Section 5.1.2 for further detail): 
 
The subsection of Appendix 10 (IMP-Specific Safety and Administration Information) 
applicable to the assigned molecularly-guided therapy 
 
Investigator’s brochures for alectinib, atezolizumab, cobimetinib, entrectinib, 
ipatasertib, ivosidenib, pemigatinib, pertuzumab, trastuzumab, vemurafenib and 
vismodegib 
 
European Medicines Agency (EMA) Summary of Product Characteristics or local 
prescribing information for bevacizumab, erlotinib, olaparib, cisplatin, carboplatin, 
gemcitabine, and paclitaxel  
 


 
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4.3.4.1 
Alectinib, Atezolizumab, Entrectinib, Ivosidenib, Olaparib, 
Pemigatinib and Vismodegib Monotherapy 
These treatments will be administered, per results from comprehensive genomic profiling 
(see Section 3.1 and the Molecular Tumor Board Charter), as recommended in their 
respective investigator’s brochures and/or reference safety information for currently 
approved (non-CUP) indications.  With the exception of entrectinib, none of these agents 
are approved for the treatment of CUP, although all have been approved for other 
cancer indications: 
 
Alectinib will be administered as recommended for ALK-positive NSCLC (i.e., at an 
oral dosage of 600 mg BID) until loss of clinical benefit or unacceptable toxicity 
 
Atezolizumab will be administered as recommended for urinary carcinoma or 
NSCLC, i.e., as a 1200 mg intravenous infusion over 60 minutes every 3 weeks until 
loss of clinical benefit or unacceptable toxicity 
 
Entrectinib will be administered as recommended in its US label for patients with 
NTRK gene fusions or ROS1 gene rearrangements at an oral dosage of 600 mg QD 
(three 200-mg capsules per day) until loss of clinical benefit or unacceptable toxicity 
 
Ivosidenib will be administered as recommended in its US label for patients with 
newly-diagnosed or relapsed/refractory acute myeloid leukemia with a susceptible 
IDH1 mutation, i.e., at an oral dose of 500 mg QD (with or without food) across a 28-
day treatment cycle until loss of clinical benefit or unacceptable toxicity 
 
Olaparib will be administered until loss of clinical benefit or unacceptable toxicity, as 
recommended for patients with germline BRCA-mutated advanced ovarian cancer, 
i.e., at an oral dosage of: 
- 400 mg BID if administered as capsules 
- or 300 mg BID if administered as film-coated tablets 
Note: After the film-coated tablets are available for use in the study,   
▪ 
patients newly randomized should start olaparib treatment with 300 mg 
BID using film-coated tablets.  
▪ 
patients who already started treatment with 400 mg BID using capsules 
should only switch to 300 mg BID using film-coated tablets, after 
capsules are not any more available (when the last batch of capsules 
expires). 
 
Pemigatinib will be administered as recommended for advanced or metastatic 
cholangiocarcinoma with FGFR2 fusions or other rearrangements, i.e., at an oral 
dosage of 13.5 mg QD (given in the morning with water, with or without food) across 
a 21-day treatment cycle until loss of clinical benefit or unacceptable toxicity.  (As 
described in Appendix 10-11, pemigatinib may be up-titrated to 18 mg QD after one 
cycle of therapy if the patient does not reach the target serum phosphate level 
of   5.5 mg/dL at any time during Cycle 1, is compliant with taking study drug, and 
does not experience an ongoing Grade 2 or higher treatment-related AE) 


 
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 
Vismodegib will be administered as recommended for metastatic basal cell 
carcinoma, i.e., at an oral dosage of 150 mg QD until loss of clinical benefit or 
unacceptable toxicity 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
alectinib, atezolizumab, entrectinib, ivosidenib, olaparib, pemigatinib and vismodegib are 
provided in their respective investigator’s brochures and/or reference safety information.  
Summaries are provided in Appendices 10-1, 10-2, 10-5, 10-9, 10-10, 10-11 and 10-14, 
respectively. 
4.3.4.2 
Erlotinib/Bevacizumab Combination Therapy 
Erlotinib plus bevacizumab will be administered in patients with EGFR alterations (see 
Section 3.1).  While neither of these agents are approved for the treatment of CUP, the 
combination has been approved by the EMA in patients with advanced EGFR-positive 
NSCLC. 
Erlotinib and bevacizumab will be administered as recommended in their respective 
European Medicines Agency (EMA) Summary of Product Characteristics (EU SmPC) 
for advanced NSCLC: 
 
Erlotinib will be administered at an oral dosage of 150 mg QD (on an empty 
stomach) until loss of clinical benefit or unacceptable toxicity 
 
Bevacizumab will be administered as a 15 mg/kg Q3W intravenous infusion until 
loss of clinical benefit or unacceptable toxicity 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
erlotinib and bevacizumab are provided in their respective  reference safety information.  
Summaries are provided in Appendices 10-6 and 10-3, respectively. 
In exceptional cases of patients with a contraindication to bevacizumab but not to 
erlotinib, erlotinib may be administered as a monotherapy.  
4.3.4.3 
Ipatasertib/Paclitaxel Combination Therapy 
The investigational therapy ipatasertib plus paclitaxel will be administered in patients 
with AKT1, PTEN or PIK3CA alterations (see Section 3.1). 
Ipatasertib will be administered as recommended in the current Ipatasertib Investigator’s 
Brochure for patients with AKT-, PIK3CA- or PTEN-altered tumors, i.e., at an oral once-
daily dosage of 400 mg.  In combination with paclitaxel, the dosages and schedule of 
administration will be: 
 
Ipatasertib will be administered orally at a dose of 400 mg QD on Days 1 to 21 of a 
28-day cycle (21 days "on", 7 days "off") until loss of clinical benefit or unacceptable 
toxicity.  Ipatasertib will continue to be dosed as a monotherapy with the same 
schedule after the final administration of paclitaxel (see next bullet) until loss of 
clinical benefit or unacceptable toxicity 


 
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 
Paclitaxel will be administered at a dose of 80 mg/m2 IV over 1 hour on Days 1, 8, 
and 15 of a 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can be given 
on Day 22.  Paclitaxel will be given for 3 cycles.  If tolerated, it may be continued 
beyond 3 cycles (refer to Section 4.3.4.7) 
 
Note:  Ipatasertib should be administered before paclitaxel on days when patients 
receive both medications. 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
ipatasertib are provided in the Ipatasertib Investigator’s Brochure.  A summary of dose 
reductions, interruptions and discontinuation for ipatasertib and paclitaxel in combination 
is provided in Appendix 10-8. 
Any patient who started ipatasertib monotherapy under Versions 2–5 of the protocol can 
be switched to ipatasertib combined with paclitaxel if judged clinically appropriate by the 
investigator and accepted by the patient.  
Patients (both Category 1 or 2) who have contraindications for paclitaxel, or Category 2 
patients who were previously treated with paclitaxel, may receive ipatasertib 
monotherapy without paclitaxel at the discretion of the investigator.  Likewise, patients 
who initiated ipatasertib without paclitaxel, as recommended in earlier versions of this 
protocol, may continue to receive ipatasertib monotherapy at the investigator’s 
discretion.  In all of these cases, single-agent ipatasertib will be administered as 
recommended in the current Ipatasertib Investigator’s Brochure for patients with AKT-, 
PTEN-, or PIK3CA-altered tumors, i.e., at a once-daily dosage of 400 mg across a 
21-day treatment cycle. 
4.3.4.4 
Vemurafenib/Cobimetinib Combination Therapy 
Vemurafenib plus cobimetinib will be administered in patients with BRAF mutations (see 
Section 3.1).  While neither of these agents are approved for the treatment of CUP, the 
combination has been approved by the FDA in patients with advanced BRAF-positive 
melanoma. 
Vemurafenib and cobimetinib will be administered as recommended in their respective 
investigator’s brochures for advanced melanoma: 
 
Vemurafenib will be administered at an oral dosage of 960 mg BID until loss of 
clinical benefit or unacceptable toxicity 
 
Cobimetinib will be administered at an oral dosage of 60 mg QD for the first 21 days 
of a 28-day treatment cycle until loss of clinical benefit or unacceptable toxicity 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
vemurafenib and cobimetinib are provided in their respective investigator’s brochures 
and/or reference safety information.  Summaries are provided in Appendices 10-13 and 
10-4, respectively. 


 
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In exceptional cases of patients with a contraindication to cobimetinib but not to 
vemurafenib, vemurafenib may be administered as monotherapy. 
4.3.4.5 
Trastuzumab/Pertuzumab/Platinum-Based Chemotherapy 
Combination 
Trastuzumab SC plus pertuzumab plus platinum-based chemotherapy will be 
administered in patients with HER2 alterations. 
While neither trastuzumab SC nor pertuzumab are approved for the treatment of CUP, 
the combination has been approved by the EMA in metastatic breast cancer patients 
with HER2 alterations, while the combination of trastuzumab, pertuzumab and 
chemotherapy has been approved by the EMA for the neoadjuvant treatment of adult 
patients with HER2-positive, locally advanced, inflammatory, or early stage breast 
cancer at high-risk of recurrence. 
Trastuzumab SC and pertuzumab will be administered as recommended in their 
respective investigator’s brochures and/or reference safety information for advanced 
breast cancer with HER2 alterations: 
 
Pertuzumab: Initial loading dose of 840 mg administered as a 60-minute IV infusion, 
followed every 3 weeks thereafter by a maintenance dose of 420 mg administered 
over a period of 30 to 60 minutes.  An observation period of 30–60 minutes is 
recommended after completion of each pertuzumab infusion.  If a dose is delayed 
(i.e., the time between two sequential infusions is less than 6 weeks), the 420-mg 
dose of pertuzumab should be administered.  If a dose is missed (i.e., the time 
between two sequential infusions is 6 weeks or more), a re-loading dose of 
pertuzumab (840 mg) should be given as described for a loading dose 
 
Trastuzumab: 600 mg fixed dose SC injection every 3 weeks 
 
Chemotherapy will be administered for a minimum of 3 additional cycles.  If relevant 
and tolerated, the chemotherapy may be continued beyond 3 cycles with one or 
both drugs.  Refer to Section 4.3.4.7 for details 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
pertuzumab and trastuzumab are provided in their respective investigator’s brochures.  
A summary is provided in Appendix 10-12. 
4.3.4.6 
Atezolizumab/Platinum-Based Chemotherapy Combination 
Atezolizumab plus platinum-based chemotherapy will be administered in patients with no 
actionable alterations and who are not TMB high or MSI-high. 
The combination of atezolizumab and a platinum-based chemotherapy has been 
investigated in several clinical trials, including a Phase 3 study (NCT02807636) 
assessing the combination of atezolizumab with gemcitabine and cisplatin or carboplatin, 
and a Phase 3 study (NCT02367794) assessing the combination of atezolizumab with 
carboplatin and paclitaxel.  


 
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Atezolizumab will be administered as recommended in its investigator’s brochure and/or 
reference safety information for urinary carcinoma or NSCLC: 
 
Atezolizumab:  1200 mg IV infusion over 60 minutes every 3 weeks 
 
Chemotherapy will be administered for a minimum of 3 additional cycles.  If 
relevant and tolerated, the chemotherapy may be continued beyond 3 cycles with 
one or both drugs.  Refer to Section 4.3.4.7 for details 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
atezolizumab are provided in the Atezolizumab Investigator’s Brochure.  A summary is 
provided in Appendix 10-2. 
4.3.4.7 
Platinum-Based Chemotherapy 
All patients in this study will initially receive 3 cycles of platinum-based induction 
chemotherapy. 
Three platinum-based chemotherapy regimens will be permitted in this study: 
 
Carboplatin/paclitaxel:  
 
Paclitaxel 175 mg/m2   carboplatin AUC 5–6 on Day 1 of a 3-week cycle, 
monitoring for neurotoxicity (Fizazi et al. 2015).   
 
Carboplatin AUC dose will be calculated by the Calvert formula 
(http://reference.medscape.com/calculator/carboplatin-auc-dose-calvert) 
(Calvert et al. 1989) 
 
 
Cisplatin/gemcitabine:  
 
Cisplatin 60–75 mg/m2 on Day 1 
 
Gemcitabine 1000 mg/m2 on Day 1 and Day 8 of a 3-week cycle, ensuring 
adequate hydration (Fizazi et al. 2015) 
 
 
Carboplatin/gemcitabine:  
 
Gemcitabine 1000 mg/m2 on Day 1 and Day 8 with carboplatin AUC 56 on Day 
1 of a 3-week cycle (Pittman et al. 2006).   
 
Carboplatin AUC dose will be calculated by the Calvert formula 
(http://reference.medscape.com/calculator/carboplatin-auc-dose-calvert) (Calvert 
et al. 1989) 
 
The carboplatin/paclitaxel or cisplatin/gemcitabine regimens may be administered using 
weekly schedules as follows: 
 
Paclitaxel 60 mg/m2 with carboplatin AUC 2 mg/mL every week for 9 weeks 
(equivalent to 3 cycles of 21 days) (Pignata et al. 2014) 
 
Carboplatin AUC dose will be calculated by the Calvert formula  
 
Cisplatin 25 mg/m² on Day 1 and Day 8 with gemcitabine 1000 mg/m² on Day 1 
and Day 8 of a 3-week cycle, ensuring adequate hydration (Valle et al. 2010) 


 
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The following alternative regimen may be administered as follows (Albers et al. 2011): 
 
Paclitaxel:  175 mg/m2 on Day 1 only 
 
Gemcitabine:  1000 mg/m2 on Day 1 and 8  
 
This regimen is only possible after the Induction Period, in exceptional circumstances, if 
the patient has contraindication to platinum-based regimens, and in association with 
either trastuzumab  pertuzumab or atezolizumab (not allowed for patients in the 
chemotherapy arm). 
If an investigating site typically uses slightly different dosages or schedule of 
administration for a chemotherapy regimen authorized in the study 
(carboplatin/paclitaxel, cisplatin/gemcitabine, carboplatin/gemcitabine or 
paclitaxel/gemcitabine), the local regimen may be used if sufficiently close to the 
regimen described in the protocol (similar dose intensity and similar efficacy and safety 
profiles).  The regimen will be used for all patients at a given site, except for 
management of intolerance as described in Section 3.1.2. 
For Category 1 patients (randomized to the control arm, or randomized to the 
investigational arm and receiving treatment given in combination with 
chemotherapy), the same chemotherapy regimen in place at the end of the Induction 
Period will be continued for a minimum of 3 additional cycles: 
 
In exceptional circumstances, the chemotherapy may be changed, but only upon 
the recommendation of the MTB.  Such changes in chemotherapy will be limited 
to the chemotherapy regimens allowed per protocol, or to any of their individual 
components used as single agents   
 
Any intolerance to the chemotherapy will be managed similarly to intolerance 
during the Induction Period 
 
After completion of 3 additional cycles, if relevant and tolerated, one of the 
components of the platinum-doublet therapy may be removed, and the single 
remaining agent may be continued beyond 3 cycles 
 
In selected cases, where the local practice is to give more than 6 cycles of 
chemotherapy for the treatment of CUP, 3 or more additional cycles of 
chemotherapy (same regimen as used for prior cycles, unless change is required 
for management of intolerance; see Section 3.1.2) may be administered, if 
tolerated and there is no disease progression per RECIST v1.1 
 
For Category 2 patients receiving treatment given in combination with 
chemotherapy, the chemotherapy regimen in place at the end of the Induction 
Period may be switched to another chemotherapy regimen or continued for a 
minimum of 3 additional cycles. Such changes in chemotherapy regimen must be 
limited to the chemotherapy regimens allowed per protocol, or to any of their 
individual components used as single agents. 


 
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 
Any intolerance to the chemotherapy will be managed similarly to intolerance 
during the Induction Period 
 
After completion of 3 additional cycles, if relevant and tolerated, one of the 
components of the platinum-doublet therapy may be removed, and the single 
remaining agent may be continued beyond 3 cycles 
 
In selected cases, where the local practice is to give more than 6 cycles of 
chemotherapy for the treatment of CUP, 3 or more additional cycles of 
chemotherapy (same regimen as used for prior cycles, unless change is required 
for management of intolerance; see Section 3.1.2) may be administered, if 
tolerated and there is no disease progression per RECIST v1.1 
 
Dosage modification, treatment interruption, and treatment discontinuation guidelines for 
cisplatin, carboplatin, gemcitabine and paclitaxel are indicated in their respective 
reference information.  This includes any dose or schedule adjustments at baseline that 
are suggested for elderly patients or any special population.  
4.3.4.8 
Alternative Therapy 
Patients for whom an alternative therapy is selected by the MTB will go off study 
treatment.  They will be managed per standard of care at their institution and will receive 
the alternative therapy outside of this study.  They will proceed to the Safety Follow-Up 
Visit and post treatment Follow-up Period (Refer to Section 3.1.6).  
4.3.5 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) 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 
IMP 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 labelled 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. 


 
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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 Investigator's Brochure and/or or local prescribing information of each given 
IMP for information on IMP handling, including preparation and storage, and 
accountability.  
4.3.6 
Continued Access to Investigational Medicinal Products 
After study discontinuation, the Sponsor will offer continued access to study drugs 
(alectinib, atezolizumab, bevacizumab, cobimetinib, entrectinib, erlotinib, ipatasertib, 
ivosidenib, olaparib, pemigatinib, pertuzumab, trastuzumab, vemurafenib and 
vismodegib) free of charge to eligible patients in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, as outlined below.  
Access will only be given to the IMP/IMPs the patient was receiving in the study. 
A patient will be eligible to receive study drugs after completing the study if all of the 
following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Sponsor study drug treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
Treatment with study drug/drugs has not been discontinued 
 
A patient will not be eligible to receive study drugs after completing the study if any of 
the following conditions are met: 
 
The Sponsor study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the drug or data suggest that the 
drug is not effective for cancer of unknown primary site 
 
The Sponsor has reasonable safety concerns regarding the drug as treatment for 
cancer of unknown primary site 
 
Provision of the drug is not permitted under the laws and regulations of the patient's 
country 
 


 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
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 drug until the Safety Follow-Up Visit.  All such medications should be reported to 
the investigator and recorded on the Concomitant Medications eCRF according to the 
rules described in Section 4.5.2.  
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
Vaccinations (such as influenza, COVID-19) are allowed during the course of this 
study while live, attenuated vaccines are prohibited (Section 4.3.3).  SARS-CoV-2 
vaccines should be administered in accordance with the approved vaccine label 
 
Oral contraceptives with a failure rate of   1% per year 
 
Hormone-replacement therapy 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain), that does not interfere with the assessment of tumor target lesions, as 
outlined below: 
- 
At any time during platinum-based induction chemotherapy, providing that the 
lesion to be irradiated is not a target lesion  
- 
After Cycle 3 of study treatment in the Treatment Period for Category 1 
patients, providing that the lesion to be irradiated is not the only target lesion 
- 
At any time as soon as the patient has been assessed as Category 2 
There must be a 2-weeks interval between the last dose of palliative 
radiotherapy administered during the Induction Period and the first dose of 
study treatment administered during the Treatment Period. Patients must 
have recovered from all radiation-related toxicities, must not require 
corticosteroids and must not have had radiation pneumonitis 
Study drug treatment may be continued during palliative radiotherapy unless 
radiotherapy is part of the prohibited therapy for a specific IMP (see 
Appendix 10).  Treatment with ipatasertib and entrectinib should be 
temporarily held before and after radiotherapy treatment.  Please refer to the 
corresponding Appendix 10 for dose interruptions and specific measures for 
a specific IMP 
 
 
Local therapy (e.g., surgery, stereotactic radiosurgery, radiofrequency ablation) as 
outlined below: 


 
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After disease progression has been reached, patients experiencing a mixed 
response requiring local therapy for control of three or fewer lesions may still 
be eligible to continue study treatment at the investigator’s discretion.  These 
patients may then receive local therapy directed at a target lesion.  Local 
therapy is not permitted until disease progression  
 
 
Bone-sparing agents (e.g., bisphosphonates) for palliation of bone metastases or for 
the treatment of osteoporosis/osteopenia are allowed 
 
Prophylactic use of 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. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
at the discretion of the investigator. 
Guidelines for use of premedications are described in the respective investigator’s 
brochures for each IMP and are summarized in Appendix 10 (if any).  In general, 
investigators should manage a patient’s care with supportive therapies 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). 
4.4.2 
Cautionary Therapy 
4.4.2.1 
Medications Given with Precaution due to Effects Related to 
CYP Enzymes 
Medications to be administered with precaution due to effects related to 
cytochrome P450 enzymes as well as to other potential drug interactions are presented 
in the individual investigator’s brochures and summarized in Appendix 10 for each IMP.  
It is the responsibility of the investigator to identify potential drug interactions.  
Treatment with strong CYP inhibitors or strong CYP inducers is to be excluded for some 
IMPs.  It is the responsibility of the investigator to verify that none of a patient’s long-term 
therapies are contraindicated when co-administered with a potential IMP and to 
communicate all contraindications at the time of the MTB. 
4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer, with the 
exception of those prohibited for a specific IMP (see Section 4.4.3), may be used during 
the study at the discretion of the investigator. 


 
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4.4.2.3 
Medications Given with Precaution Due to Potential Additive 
Nephrotoxicity and Ototoxicity with Platinum-Based 
Chemotherapy 
Concomitant administration of nephrotoxic (e.g., cephalosporins, aminoglycosides, 
amphotericin B or contrast media) or ototoxic (e.g., aminoglycosides) medicinal products 
will potentiate the toxic effect of cisplatin or carboplatin on the kidneys and the auditory 
system and should be used with caution with platinum-based chemotherapy. 
4.4.2.4 
Medications Given with Precaution with Atezolizumab 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with 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. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 10-2 for details). 
4.4.2.5 
Medications Given with Precaution with Ipatasertib 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events (refer to Appendix 10-7 and 10-8 for details).  
Ipatasertib treatment should be temporarily held during systemic corticosteroids 
treatment. 
4.4.2.6 
Medications Given with Precaution with Entrectinib 
Use of concomitant medications that increase or possibly increase the risk of QTc 
prolongation and/or induce torsades de pointes ventricular arrhythmia, congestive heart 
failure, syncope and cognitive disturbances (See Appendix 10-5 for details) must be 
used with caution or avoided if possible during treatment with entrectinib 
Entrectinib should be administered with caution with cytochrome P450 enzyme-specific 
substrates: 
CYP450 Enzyme 
Sensitive Substrates 
Substrates with Narrow 
Therapeutic Ranges 
CYP2C9 
Celecoxib 
Warfarin 
CYP2D6 
Atomoxetine, desipramine, 
dextromethorphan, metoprolol, 
nebivolol, perphenazine, 
tolterodine, venlafaxine 
Thioridazine, pimozide 


 
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CYP450 Enzyme 
Sensitive Substrates 
Substrates with Narrow 
Therapeutic Ranges 
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 
 
4.4.2.7 
Medications Given with Precaution with Pemigatinib 
Pemigatinib is predominantly metabolized by CYP3A4.  The use of moderate CYP3A4 
inhibitors is not prohibited but should involve careful monitoring, especially in relation to 
safety, while moderate CYP3A4 inducers and potent CYP3A4 inhibitors and inducers 
are prohibited (see Section 4.4.3).  
Careful monitoring is required when pemigatinib is concomitantly administered with 
OCT2 substrates, such as dofetilide and metformin.  
Proton pump inhibitors (PPIs) should be avoided with pemigatinib. 
Close clinical surveillance is recommended when pemigatinib is administered with 
CYP2B6 substrates (e.g. methadone, efavirenz). 
Co-administration of pemigatinib with P-gp substrates (e.g. digoxin, dabigatran, 
colchicine) may increase their exposure and thus their toxicity. Pemigatinib 
administration should be separated by at least 6 hours before or after administration of 
P-gp substrates with a narrow therapeutic index. 
4.4.2.8 
Medications Given with Precaution with Ivosidenib 
Cytochrome P450 (CYP)-phenotyping of ivosidenib metabolism performed in human 
liver microsomes and recombinant CYP enzymes suggest that CYP3A4 played a major 
role in the oxidative metabolism of ivosidenib, while other CYP enzymes such as 
CYP2B6 and CYP2C8 play a minor role. 
Ivosidenib induced CYP2B6, CYP2C8, CYP2C9, and CYP3A4 but not CYP1A2 in 
cultured human hepatocytes, and therefore, there is the possibility of drug-drug 
interactions upon co-administration with sensitive substrates of CYP2B6, CYP2C8, 
CYP2C9 and CYP3A4/5. 
Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 
substrates and may decrease concentrations of drugs that are sensitive CYP2C9.  Use 
alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during 
ivosidenib treatment.   


 
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Do not administer ivosidenib with itraconazole or ketoconazole (CYP3A4 substrates) due 
to expected loss of antifungal efficacy.   
Co-administration of ivosidenib may decrease the concentrations of hormonal 
contraceptives, consider alternative methods of contraception in patients receiving 
ivosidenib. 
If co-administration of ivosidenib with sensitive CYP3A4 substrates or CYP2C9 
substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs. 
Caution should be used in case of co-administration of ivosidenib with sensitive 
substrates of CYP2B6, CYP2C8. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited for all treatment arms as 
described below: 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 4 weeks prior to initiation of study treatment and during study treatment. 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, surgery [including radiofrequency ablation and stereotactic radiosurgery], 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy) is prohibited for various time periods prior to starting study treatment, 
depending on the agent (see Section 4.1.2 and Appendix 10), and during study 
treatment, until disease progression is documented and the patient has discontinued 
study treatment with the exception of palliative radiotherapy under certain 
circumstances (see Section 4.4.1 for details). 
 
Live, attenuated vaccine:  
- Within 4 weeks prior to planned date for start of molecularly-guided therapy 
(this restriction is preventive, i.e., it is not designed to delay start of treatment; 
rather, this restriction is included in case a patient is subsequently found to be 
a candidate for an IMP that cannot be administered in combination with a live 
vaccine).  If the selected therapies are atezolizumab or paclitaxel, carboplatin, 
cisplatin or gemcitabine and a live attenuated vaccine has been administered, 
start of treatment will be withheld until 4 weeks after the administration of the 
vaccine.  Other therapies may start without waiting until the 4-week interval has 
elapsed 
- At any time during the study treatment and within 5 months after the final dose 
of atezolizumab  
- During study treatment for entrectinib 
- At any time during the study treatment for paclitaxel-, carboplatin-, cisplatin- or 
gemcitabine-containing regimens, and within 3 months after the final dose of 
paclitaxel, carboplatin, cisplatin, or gemcitabine 
 


 
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 
St John's wort (Hypericum perforatum) 
At any time during study treatment with vismodegib, entrectinib or pemigatinib 
 
 
Concomitant use of moderate to strong CYP3A inhibitor and inducer medications 
should be avoided.  This includes: 
Strong Inhibitors 
Strong Inducers 
Boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole 
Alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus 
 
 
Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) are prohibited with entrectinib 
- 
Carbamazepine  
- 
Oxcarbazepine  
- 
Phenytoin  
- 
Fosphenytoin  
- 
Phenobarbital  
- 
Primidone 
 
 
Calcium-based phosphate–binding medications are prohibited with pemigatinib, due 
to a concern for soft tissue mineralization. Soft tissue mineralization, including 
cutaneous calcification and calcinosis, may be associated with hyperphosphatemia 
and has been observed with pemigatinib. 
 
Potent CYP3A4 inhibitors and inducers and moderate CYP3A4 inducers are 
prohibited with pemigatinib. 
 
Based on the low overall bioavailability of topical ketoconazole, there are no 
restrictions on topical ketoconazole. 
 
Therapies prohibited for specific IMPs are described in the respective investigator’s 
brochures for each IMP and summarized in Appendix 10 in subsections Prohibited 
Therapies and Drug Interactions. 
4.4.4 
Prohibited Food 
Use of the following foods is prohibited as described below: 
 
Consumption of grapefruit or grapefruit juice, Seville oranges, pomelos, exotic citrus 
fruits, grapefruit hybrids or fruit juices is prohibited for 7 days before the start of the 
study until 30 days after the final dose of study treatment 


 
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 
Patients assigned to ivosidenib or pemigatinib treatments should also refrain from 
consumption of red wine for 7 days before the start of study treatment until 30 days 
after the final dose of study treatment (see Appendices 10-9 and 10-11) 
 
Foods prohibited for specific IMPs are described in the respective investigator’s 
brochures and summarized in Appendix 10 
 
4.4.5 
Additional Restrictions 
Patients should not donate blood while taking vismodegib and for 24 months after the 
final dose. 
Additional restrictions prohibited for specific IMPs are described in the respective 
investigator’s brochures and summarized in Appendix 10 . 
4.5 
STUDY ASSESSMENTS  
A Schedule of Activities to be performed during the study is provided in Appendix 1.  
A timeline of key study events is summarized in Appendix 2 and further described in 
Section 3.1. 
All activities should be performed and documented for each patient.  
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. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  An Eligibility Review Team (ERT), guided by 
Eligibility Review guidelines, will be responsible for ensuring that patients who enroll in 
the trial have the correct diagnosis of CUP (following ESMO guidelines).  The Eligibility 
Review Team will maintain a screening log to record details of all patients screened and 
to confirm eligibility or record reasons for screening failure, as applicable. 
This study will have a two-part consent process.  All patients must complete Part 1 of the 
ICF during the Screening Period and the RBR informed consent (RBR ICF).  Since the 
molecularly-guided therapy that will eventually be assigned to a patient is unknown at 
this time, Part 1 of the ICF will cover all aspects of the trial except for information related 
to any specific molecularly-guided therapies.  Prior to post-induction study treatment, 
Category 1 patients who are randomized to molecularly-guided therapy, as well as all 
Category 2 patients, must then complete Part 2 of the ICF.  Part 2 of the ICF will provide 
information related to the specific molecularly-guided therapy assigned to an individual 
patient (e.g., identified targetable alteration, background on selected agent, and 
tolerability profile).  Category 1 patients who are randomized to 3 more cycles of 
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4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including smoking history, clinically significant diseases, surgeries, 
cancer history (including prior cancer therapies and procedures) and reproductive status, 
will be recorded during screening.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) will be recorded according to the following guidelines: 
 
At Screening: Any medications used by the patient within 7 days prior to initiation of 
study drug should be documented  
 
During the Induction Period: Only the medications related to the captured adverse 
reactions and changes to medications existing at baseline should be collected (See 
Section 5.2.1 for a detail of collected adverse reactions) 
 
At the End of Induction Visit: All ongoing medications should be collected (to allow 
for an appropriate assessment of the general inclusion criteria in the Treatment 
Period and to comply with the re-baselining activities at the start of the Treatment 
Period) 
 
At Subsequent Visits (During the Treatment Period): Changes to current 
medications or medications used since the last documentation of medications 
should be recorded 
 
At the time of each follow-up physical examination, an interval medical history (to 
capture new adverse events) should also be obtained. 
Demographic data will include age, sex, and self-reported race/ethnicity. Race/ethnicity 
will be collected (if allowed per local regulation) to allow for the assessment of potential 
racial or regional differences in responses or tolerance of treatment (e.g., possible 
differences in the toxicity of any of the IMPs relating to known differences in drug 
elimination). 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified during screening 
should be recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified visits 
during the Induction Period, the Treatment Period and as clinically indicated (see 
Appendix 1).  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. 


 
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Patients who are assigned to vemurafenib will have additional assessments beyond 
those occurring during the above-mentioned complete and limited physical 
examinations.  These additional assessments will include: 
 
Head and neck examination, consisting of at least a visual inspection of oral mucosa 
and lymph node palpation, prior to initiation of treatment and every 3 months during 
treatment 
 
Monitoring for non-cutaneous squamous cell carcinoma (SCC) for up to 6 months 
after end of treatment or until initiation of another anti-neoplastic therapy 
 
Dermatologic evaluation prior to initiation of therapy and, then, examination for 
cutaneous SCC at each study visit until end of study treatment; thereafter, 
evaluation should occur monthly up to six months after treatment or until initiation of 
another anti-neoplastic therapy   
 
Routine monitoring of ophthalmologic reactions at each cycle (including prior to 
starting the first administration of vemurafenib)  
 
Anal examinations (for all patients) and pelvic examinations (for women) before and 
at the end of treatment or when considered clinically indicated 
 
Patients who are assigned to entrectinib will have ophthalmologic exams, including at 
least the visual acuity and slit-lamp tests (which may be performed by an optometrist), 
prior to starting the first administration of entrectinib, at Day 1 of the second cycle of 
treatment with entrectinib, at end of treatment, and as clinically indicated. 
Patients who are assigned to pemigatinib will have additional assessments beyond 
those occurring during the above-mentioned complete and limited physical 
examinations.  These additional assessments will include: 
 
Comprehensive eye examination should be performed by a qualified 
ophthalmologist.  The eye examination should include a visual acuity test, slit-lamp 
examination, and fundoscopy with digital imaging and optical coherence 
tomography, and is required prior to the first administration of pemigatinib, once 
every 3 cycles ( 7 days, starting at Cycle 3), at end of treatment (not needed if 
completed within 28 days before the end of treatment), and more often if 
participants report any visual adverse events or change in visual acuity (see 
Appendix 10-11).  An optometrist can perform the assessments if adequately trained 
and qualified; however, the optometrist should be supervised by an ophthalmologist, 
if possible, to provide the requisite clinical assessment.  Every effort should be 
made to ensure that all subsequent examinations are performed by the same 
ophthalmologist 
 
Nail check, due to potential nail toxicity 
 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature. 


 
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Abnormalities observed at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits, new or worsened clinically 
significant abnormalities should be recorded on the Adverse Event eCRF. 
4.5.5 
Performance Status 
The patient’s ability to carry out daily activities will be evaluated using the Eastern 
Cooperative Oncology Group (ECOG) performance status scale (Appendix 6). 
4.5.6 
Tumor and Response Evaluations 
4.5.6.1 
Screening and Induction Periods 
All known sites of disease must be documented at screening and re-assessed at the end 
of the Induction Period to orientate patients toward Category 1 or Category 2 for the 
Treatment Period. 
Screening and End of Induction Period assessments must include CT scans (with oral or 
IV contrast unless contraindicated) of the chest, abdomen, and pelvis.  CT scans of 
the neck should be included if clinically indicated.  A spiral CT scan of the chest may be 
obtained but is not a requirement.  MRI scans may be performed in lieu of CT scans, if 
appropriate.  At the investigator’s discretion and if clinically indicated, other methods of 
assessment of measurable disease per RECIST v1.1 may be used in addition to those 
listed above.  All procedures for tumor assessment should be performed according to 
RECIST v1.1 (refer to Appendix 5). 
Bone imaging may be done during the screening part of the work-up of CUP according 
to the 2015 ESMO Clinical Practice Guidelines for CUP. 
All patients must undergo an MRI or CT scan (with contrast) of the brain at screening.  In 
the event of an equivocal CT scan at screening, an MRI scan of the brain is required to 
confirm or refute the diagnosis of CNS metastases at baseline (refer to Section 4.1.2 for 
CNS-related exclusions).  
Before start of the Treatment Period, a CT (with contrast) or MRI scan of the head must 
be included in the End of Induction tumor assessments, and results must be available at 
the End of Induction Visit, to exclude any CNS progression (in this case, the patient 
would be Category 2). 
4.5.6.2 
Treatment Period  
All known sites of disease must be documented at the start of the Treatment Period and 
at each subsequent tumor evaluation.  The tumor assessments obtained at the end of 
the Induction Period will be used for the start of Treatment Period assessments. 
As with the Screening Period assessments, start of Treatment Period assessments must 
include CT scans (with oral/IV contrast unless contraindicated) of the chest, abdomen, 
and pelvis.  CT scans of the neck should be included if clinically indicated.  A spiral CT 


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scan of the chest may be obtained but is not a requirement.  MRI scans may be 
performed in lieu of CT scans, if appropriate.  At the investigator’s discretion and if 
clinically indicated, other methods of assessment of measurable disease per RECIST 
v1.1 may be used in addition to those listed above. 
During the Treatment Period, tumor assessments should occur every 9 weeks ( 3 days, 
with first assessment during the Treatment Period being made 9 weeks post C1D1) 
regardless of dose interruptions. 
Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 should be monitored with a follow-up scan every 9 weeks until treatment 
discontinuation. Based on clinical judgment, the investigator can extend this period to 
every 12 weeks.  The results from the scans from patients continuing treatment beyond
progression being only analyzed at the time of primary analysis, these scans will not be 
collected after the clinical cut-off date for the primary analysis (CCOD).
The same radiographic procedure used to assess disease sites at screening (or for 
imaging test added at the End of Induction/start of Treatment Period assessment) should 
be used throughout the study (e.g., the same contrast protocol for CT scans).  If the 
baseline imaging methods cannot be used at any point of time due to safety issues (e.g., 
allergy to contrast media), then every effort must be made to review all existing tumor 
assessments using comparable images to evaluate response (e.g., if a CT scan cannot 
be done with contrast, CT-images without contrast should be used from baseline until 
the time point at which allergy to contrast media occurs) and further assessment 
methods should be aligned accordingly.   
At the investigator’s discretion, CT scans may be repeated at any time if progressive 
disease is suspected.  Assessments should be performed by the same individual to 
Response will be assessed by the investigator on the basis of physical examinations, CT 
scans, and magnetic resonance imaging (MRI), according to RECIST v1.1 criteria as 
described in Appendix 5.  An objective response should be confirmed by repeat 
assessments after initial documentation.  The confirmatory assessment will be the next 
per protocol assessment (i.e., 9 weeks later, which complies with RECIST v1.1 criteria 
mandating a minimum of 4 weeks for a confirmation of response). 
Evaluation of tumor response (e.g., for estimation of PFS, PFS rate, ORR, DoR and 
CBR) will be completed per RECIST v1.1 per investigator’s assessment.  All primary 
imaging data used for tumor assessment may be collected by the Sponsor to enable 
centralized review of response endpoints by an Independent Review Committee (IRC) 
(e.g., to meet potential requests by a reviewing Regulatory Health Authority). 
ensure internal consistency across visits (refer toAppendix 5).  


 
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All scans and other data supporting efficacy measurements will be stored at the study 
site and available for subsequent collection, if necessary, for review by the Sponsor 
and/or independent external reviewer(s).  
4.5.7 
Laboratory, Biomarker, and Other Biological Samples 
Refer to the Laboratory Manual for minimum tissue specification and needs, sampling 
procedures, storage conditions and shipment instructions. 
Refer to Appendix 3 for a summary table providing an overview of collected samples and 
collection time points. 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
 
Chemistry panel (serum or plasma): sodium, potassium, chloride, bicarbonate or 
total carbon dioxide (both optional and if considered standard of care for the region), 
glucose, BUN or urea, creatinine and creatinine clearance (calculated through use 
of Cockcroft-Gault formula), total protein, albumin, phosphorus, calcium, total and 
direct bilirubin, alkaline phosphatase, ALT, AST, urate and LDH.   
At the End of Induction Visit, the panel will also include CPK, fasting lipid profile (total 
cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and 
triglycerides; all performed following   4-hour fast prior to testing), amylase and lipase 
and glycated hemoglobin (HbA1c).  During the Treatment Period, the panel may also 
include some IMP-specific exam at the timepoints indicated in the footnote r of the 
Schedule of Activities (Appendix 1) 
 
Coagulation: INR, aPTT 
 
Viral serology:  
- 
HIV  
HIV testing is mandatory for participation in the study 
 
- 
Hepatitis B surface antigen (HBsAg) and total hepatitis B core antibody (HBcAb) 
If the HBsAg test is negative but the total HBcAb test is positive, 
assessment of HBV DNA must be performed.  If the resulting HBV DNA 
test is positive, the patient will be excluded from the study 
 
- 
HCV antibody serology: hepatitis C virus (HCV) antibody 
If a patient has a positive HCV antibody test at screening, an HCV RNA 
test must also be performed.  A patient will be excluded from the study only 
if the HCV antibody and the HCV RNA test are positive.  If the HCV 
antibody test is positive, but the HCV RNA test is negative, the patient may 
enroll in the study 


 
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 
Thyroid function panel: thyroid-stimulating hormone (TSH), free T3 (or total T3 for 
sites where free T3 is not performed), and free T4 
 
Lipids: cholesterol, LDL (low-density lipoprotein) cholesterol, HDL (high-density 
lipoprotein) cholesterol, and triglycerides 
 
Urinalysis: including dipstick (specific gravity, pH, glucose, protein, ketones, and 
blood) 
 
Pregnancy test (all study drugs except for vismodegib):  
- 
All women of childbearing potential will have a serum pregnancy test   7 days: 
- 
Prior to study treatment initiation  
- 
Prior to starting treatment with molecularly-guided therapy 
 
– 
Urine pregnancy tests will be performed  
- 
At each study visit (every 21 days   3 days or every 28 days   3 days depending 
on the schedule of administration of the IMP) during both Induction and 
Treatment Periods and no less than monthly if a study visit is delayed.  If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test 
 
- 
At the Safety Follow-Up Visit  
- 
At the end of each contraception period, which corresponds to the following time 
points after the final dose of study treatment: 
2 weeks for erlotinib 
1 month for ipatasertib and olaparib 
5 weeks for entrectinib and pemigatinib 
3 months for alectinib and ivosidenib 
5 months for atezolizumab 
6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, cisplatin, 
paclitaxel and gemcitabine 
7 months for trastuzumab and pertuzumab 
 
 
Pregnancy test (for women of childbearing potential assigned to treatment with 
vismodegib): 
- 
A blood test should be performed within 7 days prior to initiating treatment  
- 
A supervised pregnancy test, conducted by a health care provider, should be 
performed:  
At each study visit during treatment.  If study visits are delayed, the 
pregnancy tests must be performed independently of the visits and no less 
than monthly 
2 months and 24 months after the last administration 
 


 
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- Pregnancy tests should have a minimum sensitivity of 25 mIU/mL, as per local 
availability 
- Patients who present with amenorrhea during treatment with vismodegib should 
continue monthly pregnancy testing while on treatment 
 
Samples for the following laboratory tests will be sent to a Sponsor-designated central 
testing laboratory for analysis: 
 
Archival FFPE tumor tissue sample collected during screening for CUP confirmation 
and comprehensive genomic profiling using a FoundationOne® FMI F1CDx 
(tissue) test.  If the archival tumor tissue is insufficient or not suitable (in quantity 
and quality) for CUP confirmation, per the specimen collection instructions provided 
in the Laboratory Manual, then a fresh biopsy must be collected  
 
Blood samples collected for FoundationOne® F1LCDx (Liquid) test genomic 
profiling at the timepoints indicated in the Schedule of Activities (Appendix 1) 
 
Optional whole blood sample on Day 1 for exploratory germline mutation analyses 
 
Serum sample on Day 1 for exploratory research 
 
Plasma blood sample at the Safety Follow-Up Visit for exploratory research  
 
Exploratory analyses at the Sponsor-designated central testing laboratory will include 
the following (refer to Section 3.3.10 for rationales for choosing these biomarkers): 
 
PD-L1 
 
RNA sequencing 
 
DNA methylation  
 
Proteome analysis 
 
Immune cell infiltration  
 
Germline mutation/variants (optional) 
 
Analysis of tumor mutations will be performed using the investigational 
FoundationOne® FMI F1CDx (tissue) and FoundationOne® F1LCDx (Liquid) tests.  
Additional information about the use of this assay can be found in the clinical 
performance study protocol (PLAN-00024 [FoundationOne® FMI F1CDx (tissue) test] 
and PLAN-00025 [FoundationOne® F1LCDx (Liquid) test]). 
It is possible that by the time of tumor sample analysis in this study, additional molecular 
markers for disease characterization or efficacy correlation will emerge.  Thus, during 
the course of this study, it may become necessary to investigate additional markers 
associated with disease or with target signaling pathways and to reprioritize the above 
biomarkers. 
Unless the patient gives specific consent for his or her leftover samples from Sponsor-
designated central laboratories to be stored for optional exploratory research (see 
Section 4.5.10), biological samples will be destroyed 5 years after the final Clinical Study 


 
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Report has been completed.  Samples and derivatives thereof from patients who signed 
the RBR will be stored for up to 15 years or indefinitely after the final study results report 
has been completed (refer to Section 4.5.10). 
Genomic research will aim at exploring inherited characteristics.  NGS methods will not 
include whole genome sequencing (WGS) or whole exome sequencing (WES).   
Screening 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.  Although remaining tissue blocks from screening failure patients will be returned 
to sites, the slides prepared from those samples and the data obtained can be used for 
future research and/or disease-related analysis and assay validations. 
All the exploratory analyses specified above performed on screening samples may also 
be applicable for tissue samples of screening failure patients.  The exploratory analysis 
on blood samples are not applicable for screening failure patients, as all blood samples 
collected for exploratory analysis are taken after enrolment. 
NGS may be performed by FoundationOne®.  If performed by FoundationOne®, the 
investigator may obtain an NGS report through one of the study-specific HIPAA-
compliant tools (e.g., Navify).  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 enrolled patients, remaining archival 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.  For patients who are not enrolled, remaining archival 
tissue blocks will be returned to the site no later than 3 months after eligibility 
determination. 
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 should 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 germline mutations, will be subject 
to the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of the 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 reports from 
FoundationOne®).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 


 
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4.5.8 
Electrocardiograms and Cardiac Function Assessment 
Single electrocardiogram (ECG) recordings will be obtained at specified time points, as 
outlined in the Schedule of Activities (Appendix 1), and may be obtained at unscheduled 
time points 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 position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws).  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 
reports.  Paper copies of ECG tracings and digital recordings will be kept as part of the 
patient's permanent study file at the site.  
The following should be recorded in the appropriate eCRF: heart rate, RR interval, QRS 
interval, PR duration, uncorrected QT interval, and QTcF based on the machine 
readings of the individual ECG tracings.  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 any ECG abnormality is associated with an adverse event, it must be recorded and 
managed as described in the reference safety information of the respective IMP. 
If at a particular post-dose time point the mean QTcF is   500 ms (450 ms for 
entrectinib) 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.  A decision on study drug discontinuation 
should be made, as described in Section 4.6.1.  The 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). 
Cardiac function assessment by echocardiogram or MUGA will be obtained at specified 
time points, as outlined in the Schedule of Activities (see Appendix 1) and may be 
obtained at unscheduled time points as indicated. 
4.5.9 
Clinical Outcome Assessments 
Patient-reported outcome (PRO) instruments will be completed to assess the treatment 
benefit of targeted therapy/cancer immunotherapy in patients with CUP.  In addition, 


 
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PRO instruments will enable the capture of each patient's direct experience with targeted 
therapy/cancer immunotherapy or platinum-based chemotherapy. 
PRO data will be collected through use of the following instruments: FACT-G and HADS 
to assess HR QoL and EQ-5D-5L to assess health status utility.  Rationales for using 
these specific instruments and descriptions of the individual questionnaires are 
presented in Section 3.3.8 and Appendix 7, Appendix 8 , and Appendix 9. 
PRO instruments translated into the local language as appropriate, will be provided by 
the Sponsor in pre-printed booklets to enable the instrument to be administered in the 
correct order at each specified timepoints during the study.  The booklets will be labelled 
with the timepoint of administration.  
PRO instruments will be self-administered at specified time points during the study (see 
Schedule of Activities in Appendix 1).  At the clinic, instruments will be administered 
before the patient receives any information on disease status, prior to the performance 
of non-PRO assessments, and prior to the administration of study treatment, unless 
otherwise specified.  PROs being only analyzed at the time of primary analysis, these 
questionnaires will not be collected after the clinical cut-off date for the primary 
analysis (CCOD). 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 1015 minutes at each specified visit 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers 
 
Site staff should not interpret or explain questions but may read questions verbatim 
upon request 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments 
 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank 
 


 
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4.5.10 
Optional Samples for Research Biosample Repository 
4.5.10.1 
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 biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens 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. 
RBR specimens will be used to achieve the following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
 
To increase knowledge and understanding of disease biology 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop new biomarker or diagnostic assays and/or validate existing diagnostic 
assays and to establish the performance characteristics of these assays 
 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR 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 RBR sampling, this section of the protocol (Section 4.5.10) will not be 
applicable at that site. 
4.5.10.3 
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 CUP: 
 
Leftover or unused blood or 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, slides, TMAs) 
 
Leftover or unused blood samples collected for optional germline mutation analyses 
 
Note:  Fresh biopsy collected as screening samples from patients who do not enroll in 
the study may also be stored in the RBR for future research and/or development of 
disease-related tests or tools.  Archival tumor samples slides cut during the Screening 
Period may also be stored and used for future research if patient consents for the RBR 
ICF 


 
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The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing (NGS), or other exploratory 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.  Data 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 of important pathways, 
guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
Laboratory Manual.   
RBR specimens are to be stored by the Sponsor for up to 15 years after the final study 
results or indefinitely.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable local laws (e.g., health 
authority requirements). 
4.5.10.4 
Confidentiality 
Specimens and associated data will be labelled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens 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. 
Given the complexity and exploratory nature of the analyses of RBR specimens, 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 specimens 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. 
4.5.10.5 
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 


 
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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 specimens.  
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/Withdrawal eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.10.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  However, if RBR specimens 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 
specimens, the investigator must inform the Medical Monitor in writing of the patient's 
wishes through use of the appropriate RBR Subject Withdrawal Form and, if the trial is 
ongoing, must enter the date of withdrawal on the Sample Informed Consent/Withdrawal 
eCRF.  If a patient wishes to withdraw consent to the testing of his or her RCR samples 
after closure of the study 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 
A patient's withdrawal from Study MX39795 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study MX39795. 
4.5.10.7 
Monitoring and Oversight 
RBR specimens 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 specimens 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, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patient Discontinuation from the Treatment: 


 
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Note:  Disease progression during induction therapy is a study requirement for 
Category 2 patients and will not lead to study treatment discontinuation. 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues to receive study treatment.  This includes 
discontinuations due to adverse events as described in Appendix 10 
 
Investigator determines it is in the best interest of the patient, which includes but is 
not limited to: 
- 
Exceptional cases, where the genomic profile based on the FoundationOne® 
FMI F1CDx (tissue) test and/or  the FoundationOne® F1LCDx (Liquid) test 
provides an indication of a non-epithelial tumor (see Section 4.2) and the 
diagnosis of non-epithelial tumor is verified clinically or on histopathology (e.g. 
prior to the end of induction visit or randomization) 
 
Pregnancy 
 
Use of an anticancer therapy not required per protocol 
 
Symptomatic deterioration attributed to disease progression 
 
Confirmed disease progression per investigator assessment according to 
RECIST v1.1, unless the patient may benefit of treatment beyond progression as 
described below: 
 
Patients receiving molecularly-guided therapy who show evidence of clinical benefit 
at any time point after meeting RECIST v1.1 criteria for progressive disease will be 
permitted to continue treatment until loss of clinical benefit, unacceptable toxicity, 
patient or physician decision to discontinue, or death (whichever occurs first), if they 
meet all of the following criteria: 
Evidence of clinical benefit (i.e., in the absence of symptomatic deterioration 
attributed to disease progression, as determined by the investigator after an 
integrated assessment of radiographic data, biopsy results [if available], 
clinical status, and worsening of laboratory values)  
Absence of unacceptable toxicity 
No decline in ECOG performance status that can be attributed to disease 
progression 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced. 
Following completion or discontinuation of all study treatments, (whether the patient 
discontinues after the Induction Period or After the Treatment Period) all patients will 


 
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return to the clinic 30 ( 7) days from last treatment or at initiation of other systemic 
anticancer therapy (whichever occurs first) for a Safety Follow-Up Visit.  
After the Safety Follow-Up Visit, patients in the control chemotherapy arm and patients 
who discontinue for reason other than disease progression (including patient receiving 
alternative therapy) but who do not withdraw consent to follow-up will be assessed for 
progression as described during the Treatment Period (including scans) until disease 
progression per RECIST v1.1 (refer to Section 4.5.6). 
Thereafter, patients will be contacted by the physician by phone for survival status every 
3 ( 1) months until death, loss to follow up, withdrawal of consent or end of the study.  
Data on nature of and response to further anticancer therapies will also be collected 
during the survival follow up.   
Refer to the Schedule of Activities (Appendix 1) for details on follow-up assessments to 
be performed on patients who permanently discontinue study treatment.  If a patient 
requests to be withdrawn from treatment or follow-up assessments, this request must be 
documented in the source documents and signed by the investigator. 
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 
 
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 
may request to withdraw from treatment without withdrawing from the study (i.e., 
accepting study follow up).  If so, this request must be documented in the source 
documents and signed by the investigator. 
Patients who withdraw from the study (or from treatment only) will not be replaced.  


 
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If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
4.6.2 
Study Discontinuation 
The Sponsor has the right to terminate this study (or to close any of the molecularly-
guided therapy cohorts) at any time.  Reasons for terminating the study (or closing a 
molecularly-guided therapy cohort) 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 
(or any of the molecularly-guided therapy cohorts). 
4.6.3 
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 or absence of recruitment 
 
Poor protocol adherence 
 
Inaccurate, repeatedly delayed 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 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Study medications, or the combination of study medications, analyzed in this study have 
not been approved for the treatment of CUP.  Thus, the entire safety profile of all study 
medications (or their combinations) and their use by the Molecular Tumor Board are not 
known at this time in patients with CUP.  The safety plan for this study is designed to 
ensure patient safety and will include specific eligibility criteria and monitoring 
assessments as detailed below. 
Patients will be assessed by prior medical history, vital signs, weight, physical 
examination, AEs and concomitant medications.  A complete medical history (including 
prior treatments for cancer) will be documented at Screening.  A complete physical exam 
will be performed at Screening, with symptom-directed physical exams performed 
throughout induction and study treatment.  Changes in concomitant medication will be 
recorded at each study visit.  Concomitant medications for treatment of AEs related to 
study medication will continue to be recorded while the AE is being followed.  AEs will be 


 
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monitored and documented continuously during the study and SAEs will also be 
documented and reported.  See Sections 5.2.1 and 4.5.2 for a description of adverse 
events and concomitant medications collected during the study.  
All AEs will be graded according to NCI CTCAE v5.0.  
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe SARS-CoV-2 infection appears to be associated with a Cytokine Release 
Syndrome (CRS) involving the inflammatory cytokines 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 judgment.  If a diagnosis of 
SARS-CoV-2 infection is confirmed, the disease should be managed as per local or 
institutional guidelines. 
5.1.1 
Risks Associated with Test Agents 
5.1.1.1 
Alectinib, Atezolizumab, Entrectinib, Ivosidenib, Olaparib, 
Pemigatinib and Vismodegib Monotherapy 
Alectinib, atezolizumab, entrectinib, ivosidenib, olaparib, pemigatinib and vismodegib will 
be administered as monotherapies in patients with the appropriate molecular profiles, as 
per results from comprehensive genomic profiling (see Section 3.1).  
The identified and potential risks associated with alectinib, atezolizumab, entrectinib, and 
vismodegib are detailed in Sections 6.4 and 6.5 of their respective Investigator’s 
Brochures.  For pemigatinib, these risks can be found in Section 6 of the Pemigatinib 
Investigator’s Brochure, for ivosidenib in Sections 6.6 and 6.7 of the Ivosidenib 
Investigator’s Brochure, and for olaparib in Section 4.8 of the Olaparib EU-SmPC.  
Please refer to the respective reference safety information for risks associated with 
these IMPs in healthy volunteers and patients with diverse, non-CUP cancers.  
5.1.1.2 
Ipatasertib/Paclitaxel Combination Therapy 
Ipatasertib plus paclitaxel will be administered in patients with AKT1, PIK3CA or PTEN 
alterations.  The identified and potential risks associated with ipatasertib are detailed in 
Sections 6.4 and 6.5 of the Ipatasertib Investigator’s Brochure.  Please refer to the 
Ipatasertib Investigator’s Brochure and local prescribing information for paclitaxel for 
risks associated with the individual components of this combination therapy in healthy 
volunteers and patients with diverse, non-CUP cancers.   


 
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Ipatasertib has been administered in combination with paclitaxel in a Phase I/II study of 
25 patients (Study GO28341), in two Phase II studies of 62 patients (Study GO29227) 
and 75 patients (Study GO29505).  The combination is currently being tested in a large 
Phase 3 trial (Study CO40016) of 450 patients, with half of the study population due to 
receive the combination.  The data currently available show no major additional risks 
potentially associated with the combination (see the Ipatasertib Investigator’s Brochure). 
Patients (both Category 1 or 2) who have contraindications for paclitaxel, or Category 2 
patients who were previously treated with paclitaxel, may receive ipatasertib 
monotherapy without paclitaxel at the discretion of the investigator.  Likewise, patients 
who initiated ipatasertib without paclitaxel, as recommended in earlier versions of this 
protocol, may continue to receive ipatasertib monotherapy at the investigator’s 
discretion.  In all of these cases, single-agent ipatasertib will be administered as 
recommended in the current Ipatasertib Investigator’s Brochure for patients with AKT-, 
PTEN- or PIK3CA-altered tumors, i.e., at a once-daily dosage of 400 mg across a 
21-day treatment cycle. 
5.1.1.3 
Erlotinib/Bevacizumab Combination Therapy 
Erlotinib plus bevacizumab will be administered in patients with EGFR alterations (see 
Section 3.1).  The identified and potential risks associated with erlotinib and 
bevacizumab are detailed in Sections 4.4 Special warnings and precautions for use and 
4.8 Undesirable effects of their respective EMA Summary of Product Characteristics.  
Please refer to the Erlotinib and the Bevacizumab EMA Summary of Product 
Characteristics for risks associated with the individual components of this combination 
therapy in healthy volunteers and patients with diverse, non-CUP cancers. 
There are no major additional risks potentially associated with the combination of 
therapies. 
5.1.1.4 
Vemurafenib/Cobimetinib Combination Therapy 
Vemurafenib plus cobimetinib will be administered in patients with BRAF mutations (see 
Section 3.1).  The identified and potential risks associated with vemurafenib and 
cobimetinib are detailed in Sections 6.4 and 6.5 of their respective Investigator’s 
Brochures.  Please refer to the vemurafenib Investigator’s Brochure and the cobimetinib 
Investigator’s Brochure for risks associated with the individual components of this 
combination therapy in healthy volunteers and patients with diverse, non-CUP cancers. 
There are no known major additional risks potentially associated with the combination of 
vemurafenib and cobimetinib. 
5.1.1.5 
Trastuzumab/Pertuzumab/Platinum-Based Chemotherapy 
Combination 
Trastuzumab SC plus pertuzumab plus platinum-based chemotherapy will be 
administered in patients with HER2 alterations.  The identified and potential risks 


 
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associated with trastuzumab and pertuzumab are detailed in the Sections 6.4 and 6.5 of 
their respective Investigator’s Brochures.  Please refer to the Trastuzumab Investigator’s 
Brochure, the Pertuzumab Investigator’s Brochure and local prescribing information for 
paclitaxel, carboplatin, cisplatin or gemcitabine (whichever are relevant) for risks 
associated with the individual components of this combination therapy in healthy 
volunteers and patients with diverse, non-CUP cancers.   
There are no known additional risks potentially associated with the combination of 
trastuzumab, pertuzumab and platinum-based chemotherapies. 
5.1.1.6 
Atezolizumab/Platinum-Based Chemotherapy Combination 
Atezolizumab plus platinum-based chemotherapy will be administered in patients with no 
actionable alterations and who are not TMB-high or MSI-high.  Please refer to the 
Atezolizumab Investigator’s Brochure and local prescribing information for paclitaxel, 
carboplatin, cisplatin or gemcitabine (whichever are relevant) for risks associated with 
the individual components of this combination therapy in healthy volunteers and patients 
with diverse, non-CUP cancers.  
To date, no additional risks/adverse drug reactions specific to the combination of 
atezolizumab and other therapeutic agents have been identified. 
5.1.1.7 
Platinum-Based Chemotherapy 
Platinum-based chemotherapy will be administered for 3 cycles in all patients and for a 
minimum of 3 additional cycles in patients responding to induction who are randomly 
allocated to the control arm.  Please refer to the local prescribing information for 
paclitaxel, carboplatin, cisplatin or gemcitabine (whichever are relevant) for risks 
associated with the individual components of the platinum-based chemotherapy in 
patients with non-CUP cancers.   
5.1.2 
Management of Patients Who Experience Adverse Events 
5.1.2.1 
Dose Modifications 
Refer to Appendix 10 and to the individual IMPs’ investigator’s brochures for dose 
modification, dose discontinuation and specific management guidance. 
5.1.2.2 
Treatment Interruption 
Study drug may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug.  Refer to Appendix 10 and to the individual IMPs’ 
investigator’s brochures for treatment interruption and dose discontinuation. 
Study drug may be suspended for reasons other than toxicity (e.g., surgical procedures).  
The investigator may take advice from the Medical Monitor to determine the relevant 
length of treatment interruption. 


 
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5.1.2.3 
Management Guidelines 
Specific adverse events requiring management and their management regimens are 
provided for each IMP in the reference safety information.  Appendix 10 lists the specific 
adverse events for each study treatment as of the date of this version of the protocol. 
For specific adverse events for all IMPs, the following general rules should apply: 
 
Investigate etiology (see relevant investigator’s brochure(s) for specificities) 
 
Initiate treatment as per institutional guidelines and check the relevant investigator’s 
brochure(s) for any specific management 
 
Contact the Medical Monitor for advice as appropriate and as per investigator’s 
brochure guidance 
 
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 on 
Day 1 
 
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) 
 


 
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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 National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 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: 
 
All products: 
- 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 a study drug, as defined below 


 
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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 
 
 
Individual IMPs  
- Refer to Appendix 10 for a list of additional AESIs that must be reported for 
individual study drugs 
 
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 Section 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 drug: Only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies) should be reported (see Section 5.4.2 for instructions for 
reporting serious adverse events).   
During the Induction Period: Only adverse events leading to dose modifications, 
interruption or discontinuation of the platinum-based chemotherapy and all SAEs will be 
captured. 
At the End of Induction Visit: All ongoing adverse events will be collected (to allow for an 
appropriate assessment of the general inclusion criteria in the Treatment Period and to 
comply with the re-baselining activities at the start of the Treatment Period). 
After initiation of molecularly-guided therapy (including the control arm for Category 1 
patients): All adverse events, serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 30 days after the 
final dose of study drug or initiation of new systemic anticancer therapy, whichever 
occurs first, for all drugs except atezolizumab, where it will be 90 days. 


 
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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
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 time points.  Examples of non-
directive 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 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 6 
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 self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = 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 7): 
 
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 7 
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 re-challenge. 
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., pre-existing 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/Administration-Related Reactions 
and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and cytokine-release 
syndrome (CRS).  While IRRs occur during or within 24 hours after treatment 
administration, time to onset of CRS may vary.  Differential diagnosis should be applied, 


 
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particularly for late-onset CRS (occurring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 
sepsis or infections, HLH, tumor lysis syndrome, early disease progression, or other 
manifestations of systemic inflammation 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion/injection should be captured on 
the Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" or "cytokine-
release syndrome").  Avoid ambiguous terms such as "systemic reaction."  Cases of 
late-onset CRS should be reported as "cytokine-release syndrome" on the Adverse 
Event eCRF.  Associated signs and symptoms of an IRR or a CRS should be recorded 
as free text on the additional case details section of the AE page of the eCRF. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms of an IRR also recorded as free text on the 
additional case details section of the AE page of the eCRF. 
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 10-2 specifically for atezolizumab. 
5.3.5.2 
Diagnosis Versus Signs and Symptoms 
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 


 
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 
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 
 
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 time points.  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 time points 
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. 


 
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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP 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 
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 (e.g., 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  ULN) 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 


 
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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  ULN in combination with total 
bilirubin > 2 x ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.3) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  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 of unknown primary site 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 Sponsor will consider fatal serious adverse reactions (SARs) as 
unexpected for regulatory reporting purpose. 
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 
Pre-existing Medical Conditions 
A pre-existing 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 pre-existing 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 pre-existing condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 


 
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5.3.5.10 
Lack of Efficacy or Worsening of Cancer of Unknown Primary 
Site 
Deterioration that is judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature (i.e., deterioration beyond the expected 
pattern of progression of the underlying disease) should be recorded as an adverse 
event.  When recording an unanticipated worsening of CUP on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated worsening of cancer of unknown primary”).   
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 v1.1.  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. 
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 
or insertion of access device for study drug administration) 
 
Hospitalization for a pre-existing 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 
 


 
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There are some hospitalization scenarios that do not require reporting as a serious 
adverse event when there is no occurrence of an adverse event.  These scenarios 
include a planned hospitalization or prolonged hospitalization to:  
 
Perform an efficacy measurement for the study  
 
Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
 
Receive scheduled therapy for the target disease of the study 
 
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 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 event; see 
Section 5.4.2). 
For alectinib, atezolizumab, bevacizumab, cobimetinib, entrectinib, erlotinib, ipatasertib, 
ivosidenib, olaparib, pemigatinib, pertuzumab, trastuzumab, vemurafenib and 
vismodegib, 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 


 
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 
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 alectinib, atezolizumab, bevacizumab, 
cobimetinib, entrectinib, erlotinib, ipatasertib, ivosidenib, olaparib, pemigatinib, 
pertuzumab, trastuzumab, vemurafenib and vismodegib, 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 
 
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 


 
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 
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. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor.  In addition, 
the Sponsor will make no attempt to reconcile patient reports of treatment-related 
symptoms (via PRO) with investigator reports of adverse events.  Sites are not expected 
to review the PRO data for adverse events. 
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 


 
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 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
be available 24 hours per day, 7 days per week, in case the Roche Medical contacts 
cannot be reached.  The Emergency Medical Call Center will connect the investigator 
with an Emergency Medical Contact, provide medical translation service if necessary 
and track all calls.  Contact information, including toll-free numbers for the Emergency 
Medical Call Center, will be distributed to investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
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 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse Event/ 
Special Situations 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.   
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 (e.g., invasive 
procedures such as biopsies) should be reported. 
5.4.2.2 
Events That Occur After Study Drug Initiation 
During the Induction Period: Only adverse events leading to dose modifications, 
interruption or discontinuation of the platinum-based chemotherapy and all SAEs will be 
captured. 
After initiation of molecularly-guided therapy (including the control arm for Category 1 
patients): All serious adverse events and adverse events of special interest, regardless 
of relationship to study drug, will be reported until 30 days after the final dose of study 
drug or until initiation of new systemic anticancer therapy, whichever occurs first, for all 
drugs except atezolizumab, where it will be 90 days.  


 
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Instructions for reporting serious adverse events that occur after the adverse event 
reporting period are provided in Section 5.6. 
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 or 
for up to 24 months after the final dose of treatment.  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.   
In order to learn more about the effects of study drugs on pregnancy, additional 
information on any study drugs -exposed pregnancy and infant will be requested by 
Roche/Genentech Drug Safety at specific time points (i.e., after having received the 
initial report during the first trimester, at the end of the second trimester, 2 weeks after 
the expected date of delivery, and at 3, 6, and 12 months of the infant’s life).  In case of 
a report of pregnancy or congenital abnormality, a guided questionnaire will be sent out 
by Roche/Genentech Drug Safety. 
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 for up to 7 
months after the final dose of study drug.  There is no requirement for such report for 
atezolizumab monotherapy.  The investigator should 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.  There is no requirement for such report for male 
patients treated with atezolizumab monotherapy.  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 the 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 


 
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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. 
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 or the female partner of a male 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). 
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 adverse event reporting period (defined in Section 5.3.1), 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. 


 
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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 
After the end of the adverse event reporting period (defined as 30 days after the final 
dose of study drug or until initiation of new systemic anticancer therapy for all IMPs with 
the exception of atezolizumab, where it will be defined as 90 days), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival Follow-
Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event 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 Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
Additional specific molecule-related reporting time windows for AEs after the AE 
reporting period (as defined above) are: 
 
Trastuzumab:  
- Cardiac AEs should be reported between the end of the adverse event reporting 
period until the end of the study 
- SAEs considered to be unrelated to trastuzumab therapy should be reported for 
up to 6 months after the final dose of trastuzumab, unless the patient went off 
study and started a new systemic anticancer treatment 
 
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. 


 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the following reference 
documents: 
 
Investigator's brochure for alectinib, atezolizumab, cobimetinib, entrectinib, 
ipatasertib, ivosidenib, pemigatinib, pertuzumab, trastuzumab, vemurafenib and 
vismodegib 
 
EMA Summary of Product Characteristics or locally approved label for bevacizumab, 
erlotinib, olaparib, cisplatin, carboplatin, gemcitabine, paclitaxel or any alternative 
therapy commercially sourced 
 
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 
This is an open-label, randomized, multicenter study to compare the efficacy of 
molecularly-guided therapy versus platinum chemotherapy in patients with CUP who 
have received 3 cycles of platinum-based induction chemotherapy. 
The analysis populations are defined as follows: 
 
All enrolled patients population: all patients enrolled in the study 
 
Intention-to-treat (ITT) population: all randomized patients, whether or not the 
assigned study treatment was received 
 
Efficacy analysis population for Category 2 patients: defined in the same way as the 
Safety-evaluable population:  All non-randomized participants who received at least 
one dose of any component of study drug during the treatment period.  Patients who 
received an alternative therapy are not part of this population 
 
Safety population: all patients who received at least one dose of any component of 
study drug 
 
PRO-evaluable population: all patients in the ITT population with the relevant 
baseline and at least one post-treatment PRO assessment 
 
For all analyses of the ITT population, patients will be grouped according to the 
treatment arm assigned at randomization.  For all analyses of the Safety population, 
patients will be grouped according to treatment actually received. 
Hypothesis tests will be two-sided unless otherwise indicated.  The type I error () for 
this study is 0.05 (two-sided).  
Further details of the analyses will be provided in the Statistical Analysis Plan (SAP). 


 
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6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size has been estimated based on assumptions derived from Hainsworth et 
al. (Hainsworth et al. 2015), giving an estimated median PFS of 5 months for CUP 
patients.  Kaplan-Meier plots in the reference suggest that the exponential distribution is 
a reasonable assumption for PFS in CUP patients and, following this, we assume an 
estimated median PFS from randomization of 5 months for patients randomized to 
chemotherapy. 
Based on a two-sided 5% test, 330 events will give approximately 80% power to detect 
an HR of 0.7 (calculated using RPACT).  Randomizing 400 patients using a 3:1 ratio, 
and assuming a 42-month recruitment period, the time to primary analysis will occur 
approximately 45 months from the time of first patient randomized. 
To allow for an estimated 15% dropout rate after randomization, a total of 472 patients 
will be randomized in the study.  Assuming a 60% disease control rate at the end of 
induction, it is estimated that approximately 790 patients with CUP will enroll.  If the 
actual number of patients who achieve a CR, PR, or SD during induction deviates from 
these estimates, the study will enroll patients until 472 patients have been randomized. 
In addition, if both the actual disease control and dropout rates differ from the protocol 
assumptions, the 330 PFS events may be reached before 790 patients are enrolled. In 
this case, screening will be stopped, when 330 PFS events have been observed. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and other baseline characteristics (at patient and disease level) will be 
summarized using means, standard deviations (SDs), medians, inter-quartile range, 
minimum and maximum for continuous variables and proportions for categorical 
variables, as appropriate.  Medical history, prior and concomitant treatments (study and 
non-study condition related) will also be presented. 
6.4 
EFFICACY ANALYSES 
The primary efficacy analysis population will consist of all randomized patients, with 
patients grouped according to their assigned treatment arm. 


 
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6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study, PFS, is defined as the time from 
randomization to the first occurrence of disease progression, as determined by the 
investigator according to RECIST v1.1, or death from any cause, whichever occurs first. 
The primary analysis of PFS will be based on the ITT population to evaluate the efficacy 
of patients randomized to molecularly-guided therapy versus patients randomized to 
platinum chemotherapy in patients with CUP whose response to 3 cycles of platinum 
induction chemotherapy was CR, PR or SD.  Stratified analysis of the primary endpoint 
will be completed according to the pre-defined randomization stratification factors 
(gender and response to platinum induction chemotherapy).  Results from an unstratified 
analysis will also be provided as a sensitivity analysis. 
Data for patients without disease progression or death will be censored at the last tumor 
assessment date.  If no tumor assessment was performed after randomization, data will 
be censored at the date of randomization +1 day. 
Kaplan-Meier methodology will be used to estimate the median PFS for each treatment 
arm, together with the 95% confidence interval, and Kaplan-Meier curves will be 
produced.  PFS will be compared between treatment arms by the stratified log-rank test. 
Estimates and the corresponding 95% confidence intervals will also be reported by 
treatment arm for the 6- and 12-month survival rates.  The hazard ratio (HR) for PFS will 
be estimated using a Cox proportional hazards model, and the 95% confidence interval 
for the HR will be provided. 
Additional sensitivity analyses of PFS may be conducted to assess: 
 
The impact of missing tumor assessments, depending on the number of patients 
with one or more missing tumor assessments prior to documented disease 
progression.  
 
The impact of non-protocol-specified anticancer therapy depending on the number 
of patients receiving a non-protocol therapy prior to a PFS event. 
 
Details will be provided in the SAP. 
Additionally, first-line PFS will be described by Kaplan-Meier methodology for each 
molecularly-guided therapy (targeted therapy or cancer immunotherapy) and/or for each 
genomic alteration, where relevant, based on the patients in the cohort-specific safety 
population. 
The clinical cut-off date for the primary endpoint analysis will occur when approximately 
330 PFS events have been observed in the ITT population. In case the recruitment is 
still ongoing when 330 PFS events have been observed, all patients still in screening will 
proceed to enrollment, if eligible, and will be included in the primary endpoint analysis. 


 
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In that scenario, the clinical cut-off date for the primary endpoint analysis will be the date 
of randomization (or assignment in to Category 2) of the last patient enrolled.  
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy objectives for this study are described below. All secondary 
analyses will be descriptive only. 
6.4.2.1 
Overall Survival 
Overall survival (OS) is defined as the time from randomization to death from any cause. 
Data for patients with no record of death will be censored at the last date they were 
known to be alive.  The analysis of OS will follow the same methodology as the primary 
endpoint. 
Additional sensitivity analyses of OS will be outlined in the SAP. 
A preliminary analysis of OS will be performed at the time of the primary analysis of 
PFS.  A survival follow-up analysis will be performed once a sufficient number of death 
events have been observed, specifically when at least 55% of Category 1 patients 
(approximately 260 patients) have died. 
6.4.2.2 
Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of randomized patients who 
exhibit a complete response or partial response on two consecutive per protocol disease 
assessment (i.e., 9 weeks later, which complies with RECIST v1.1 criteria mandating a 
minimum of 4 weeks for a confirmation of response), as determined by the investigator 
according to RECIST v1.1. 
An estimate of ORR will be calculated for each treatment arm, and its 95% CI will be 
calculated using the Clopper-Pearson method. 
ORR will be compared between treatment arms using the stratified Cochran-Mantel-
Haenszel test.  The stratification factors will be the same as those described for the 
analysis of the primary endpoint of PFS.  The difference in ORR between treatment 
arms will be calculated, and its 95% CI will be calculated using the normal approximation 
to the binomial distribution.  
6.4.2.3 
Duration of Response 
Duration of Response (DOR) will be assessed in randomized patients who had an 
objective response as determined by the investigator according to RECIST v1.1. DOR is 
defined as the time from the first post-randomization occurrence of a confirmed CR or 
confirmed PR (whichever status is recorded first) until the first date progressive disease 
or death is documented, whichever occurs first. Patients who have not progressed and 
who have not died at the time of analysis will be censored at the time of last tumor 
assessment date. If no tumor assessments were performed after the date of the first 


 
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occurrence of a CR or PR, DOR will be censored at the date of the first occurrence of a 
CR or PR plus 1 day. DOR is based on a non-randomized subset of patients 
(specifically, patients who achieved an objective response); therefore, formal hypothesis 
testing will not be performed for this endpoint. Comparisons between treatment arms will 
be made for descriptive purposes. The methodologies detailed for the PFS analysis will 
be used for the DOR analysis. 
6.4.2.4 
Disease Control Rate 
DCR is defined as the rate of patients with confirmed CR or confirmed PR or SD, or Not 
Applicable (NA), as best overall response per RECIST 1.1.  The analysis of DCR will 
follow the same methodology as ORR. 
Not Applicable corresponds to patients that have Complete Response (CR) at the end of 
Induction.  The re-baseline assessment for these patients is Not Applicable as there are 
no lesions to be measured anymore. 
6.4.3 
Exploratory Endpoints 
Analyses of exploratory endpoints will be descriptive only. 
Efficacy Analysis for Non-Randomized Patients Who Received Molecularly-Guided 
Therapy in Second Line 
For Category 2 patients who received molecularly-guided therapy in second line, PFS1-  
cat2 will be defined as the time from first dose of any component of platinum-based 
induction chemotherapy to the first occurrence of disease progression, as determined by 
the investigator according to RECIST v1.1.  PFS2-cat2 will be defined as the time from 
first dose of molecularly-guided therapy to the first occurrence of disease progression, 
as determined by the investigator according to RECIST v1.1, or death from any cause, 
whichever occurs first.  For the patients in the cohort-specific safety population, 
second-line PFS (PFS2-cat2) will be described by Kaplan-Meier methodology for each 
molecularly-guided therapy (targeted therapy or cancer immunotherapy) and a summary 
of PFS2-cat2/PFS1-cat2 will be presented. 
For non-randomized patients who received molecularly-guided therapy in second-line, 
second-line OS will be defined as the time from first dose of molecularly-guided therapy 
to death from any cause.  For the patients in the cohort-specific safety population, 
second-line OS will be described by Kaplan-Meier methodology for each molecularly-
guided therapy (targeted therapy or cancer immunotherapy). 
For non-randomized patients who received molecularly-guided therapy in second line, 
ORR will be defined as the proportion of patients who exhibit a CR or PR on two 
consecutive occasions   4 weeks apart, as determined by the investigator according to 
RECIST v1.1.  An estimate of ORR will be calculated for each molecularly-guided 
therapy, and its 95% CI will be calculated using the Clopper-Pearson method.  DOR and 
DCR will also be analyzed as described above for Category 1 patients. 


 
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6.4.4 
Exploratory PRO Endpoints  
The exploratory PRO objectives for this study will be assessed using the following: 
 
FACT-G questionnaire score 
 
HADS questionnaire score 
 
EQ-5D-5L index-based score 
 
Analyses will be descriptive only. 
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) of linear 
transformed scores will be reported for all scales of the questionnaires according to the 
scoring guidelines for each assessment time point.  The mean change of the linear 
transformed scores from baseline (and 95% CI using the normal approximation) will also 
be reported.  Graphs depicting the mean changes (and standard errors) of items and 
scales over time will be provided for each treatment arm from the baseline assessment.  
Completion and compliance rates will be summarized at each time point by treatment 
arm with reasons for missing data.  Only patients with a baseline assessment and at 
least one post-treatment assessment will be included in the analyses.  
The number and proportion of patients who improved, worsened, or remained stable for 
all of the scales of the questionnaires will be summarized at each time point. 
PROs being only analyzed at the time of primary analysis, these questionnaires will not 
be collected after the clinical cut-off date for the primary analysis (CCOD). 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all patients who received at least one dose 
of any component of study drug, with patients grouped according to actual treatment 
received.  Safety will be presented by the relevant study phase: induction treatment, 
treatment started in first-line post-randomization (Category 1 patients), treatments 
started in second-line (Category 2 patients). 
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 NCI CTCAE v5.0. 
Safety endpoints will include: 
 
Incidence, nature and severity of adverse events (AEs) and SAEs with severity 
determined according to NCI CTCAE v5.0 
 
Incidence and reasons for any dose reductions, interruptions, or premature 
discontinuation of any component of study treatment 
 
Clinically significant laboratory values, ECGs and vital signs 
 


 
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The incidence of AEs will be summarized by frequency tables.  
Dose reductions, interruptions, or premature discontinuation of any component of study 
treatment will be analyzed by frequency tables.  Median duration of follow up and 
median time on treatment, with 95% CI, will be estimated by the Kaplan-Meier approach 
or using univariate statistics, presenting mean, median, quartiles, minimum, maximum 
and standard deviation. 
Worst grades for laboratory parameters, and newly occurring Grade 3 and 4 laboratory 
values during treatment will be summarized by frequency tables.  Shift in grade from 
baseline to worst grade during treatment will be presented in summary tables. 
Changes in vital signs and physical findings from baseline will be tabulated and 
presented graphically when applicable. 
6.6 
INTERIM ANALYSES 
6.6.1 
Planned Interim Analysis 
No interim analyses of efficacy are planned. 
The iDMC will review safety data periodically during the study. 
6.6.2 
Optional Interim Analysis 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct an interim efficacy analysis, e.g., based on a recommendation 
from the iDMC and in consultation with the Steering Committee.  If an interim analysis is 
conducted, it will be prospectively described in the SAP, and the Sponsor will remain 
blinded.  
Provisions will be in place to ensure the study continues to meet the highest standards 
of integrity when an optional interim analysis is executed.  The decision to conduct the 
optional interim analysis, along with the rationale, timing and statistical details for the 
analysis, will be documented in the SAP, which will be submitted to relevant health 
authorities at least two months prior to the conduct of the interim analysis.  In addition, 
the iDMC charter will be updated to document potential recommendations the iDMC can 
make to the Sponsor based on the results of the analysis.  The iDMC charter will also be 
made available to relevant health authorities. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The CRO will produce eCRF Specifications for the study based on Sponsor templates, 
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 


 
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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 CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data and vendor data, including 
FoundationOne® FMI F1CDx (tissue) test reports, FoundationOne® F1LCDx (Liquid) 
test reports and IxRS, will be sent directly to the Sponsor using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at 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.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the CRO. 
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, patient-reported outcomes, 
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. 


 
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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 
acceptable computerized data collection system allows preservation of the original entry 
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, paper PRO data, Informed Consent Forms, laboratory test 
results, medication inventory records, and images, 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. 
The Sponsor 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. 


 
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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. 
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 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) to 
communicate information that might affect a patient's willingness to continue in the 


 
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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.  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. 
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.  
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 9.6). 
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 (including 
comprehensive genomic profiling services provided by the central laboratory).  This 
means that patient names are not included in data sets that are transmitted to any 
Sponsor location. 


 
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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.  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. 
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 


 
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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 has implemented 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 initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks.  
Risk evaluation and control included the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters.  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 are 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 F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 150 sites globally will participate to enroll approximately 790 patients.  
Enrollment and randomization will occur through an IxRS.  The total number of patients 
enrolled may differ, if both the actual disease control and dropout rates differ from the 
protocol assumptions, as indicated in Sections 4.1 and 6.1. 
Central facilities will be used for certain study assessments throughout the study (e.g., 
specified laboratory tests and biomarker analyses), as specified in Section 4.5.  


 
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Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
An iDMC will be employed to monitor and evaluate patient safety throughout the study. 
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 
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. 


 
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9.7 
PROTOCOL AMENDMENTS 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
participants. 
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. 
 


 
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Appendix 1
Schedule of Activities 
A1–1
SCHEDULE OF ACTIVITIES AFTER THE PRIMARY ANALYSIS CUT-OFF DATE (CCOD) 
Treatment Period 
Safety Follow-Up Visit b 
Follow-up Period 
First day of each 21-day or 28-day cycle 
(± 3 days) 
Dosing schedule per RSI a 
30 (±7) days from last treatment 
or at initiation of other 
systemic anticancer therapy 
(whichever occurs first) 
Every 3 (± 1) months 
(Starting 3 months post final 
dose of study treatment) 
Weight 
X 
X 
Complete physical examination c 
X 
Limited physical examination d 
X 
Specific physical examination e 
X 
(vemurafenib patients only) 
ECOG performance status d
X 
X 
Vital signs f 
X 
X 
12-lead ECG d, g
As clinically indicated or as indicated for 
each individual IMP 
As indicated for each individual 
IMP 
Left ventricular ejection fraction 
(LVEF) 
As clinically indicated or as indicated for 
each individual IMP 
As clinically indicated or as 
indicated for each individual IMP 
As indicated  
for each individual IMP 
Ophthalmologic 
exams h 
X 
(entrectinib, pemigatinib and vemurafenib 
only) 
X 
Hematology d, i 
X
X 
Coagulation (aPTT, INR) d 
X 
X 
Thyroid function panel d, j 
Every 9 weeks 
(atezolizumab only) 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
184/Protocol MX39795, Version 11 
Treatment Period 
Safety Follow-Up Visit b 
Follow-up Period 
First day of each 21-day or 28-day cycle 
(± 3 days) 
Dosing schedule per RSI a 
30 (±7) days from last treatment 
or at initiation of other 
systemic anticancer therapy 
(whichever occurs first) 
Every 3 (± 1) months 
(Starting 3 months post final 
dose of study treatment) 
Chemistry panel d, k 
X 
X 
Chemistry panel (IMP-specific) d, l 
As indicated  
for each individual IMP 
Urinalysis d, m 
X
X 
Pregnancy test n 
Refer to Footnote n 
(urine) 
X 
Refer to Footnote n 
(urine) 
Tumor assessment o 
Every 9 weeks ± 3 days until PD 
X p 
(as per comment) 
Plasma blood sample for exploratory 
research  
X 
Concomitant medications q 
X 
X 
Adverse events r 
X 
X 
X 
Additional safety visits 
Ipatasertib + paclitaxel only Days 4, 8, 15 
and  22 of Cycle 1 
D8 and 15 of Cycle 2 
Then D15 of all cycles until paclitaxel is 
stopped  
Collection of information on survival 
and anticancer therapy s 
X 
X 
Study treatment 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
185/Protocol MX39795, Version 11 
Treatment Period 
Safety Follow-Up Visit b 
Follow-up Period 
First day of each 21-day or 28-day cycle 
(± 3 days) 
Dosing schedule per RSI a 
30 (±7) days from last treatment 
or at initiation of other 
systemic anticancer therapy 
(whichever occurs first) 
Every 3 (± 1) months 
(Starting 3 months post final 
dose of study treatment) 
Molecularly-guided therapy in patients 
with a CR, PR or SD during induction 
X r 
Platinum-based chemotherapy in 
patients with a CR, PR or SD during 
induction 
X r 
(at least 3 cycles) 
Molecularly-guided therapy in patients 
with PD during induction (Category 2 
patients) 
X r 
Abbreviations: aPTT = activated partial thromboplastin time; C = cycle; chemo = chemotherapy; CR = complete response; CUP = cancer of 
unknown primary site; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; IMP = Investigational Medicinal 
Product; INR, international normalized ratio; PD = progressive disease; PR = partial response; RSI= reference safety information; SD = stable 
disease. 
Note: Unless otherwise indicated, assessments scheduled on the study treatment days should be performed prior to initiation of st udy treatment. 
a 21-day cycles for all treatment arms (including for cohorts with oral therapies), except for cobimetinib and vemurafenib, ipatasertib and 
paclitaxel, and ivosidenib, where the administration cycle will be 28 days: 
– Assessments must be performed within 72 hours of first study treatment (Cycle 1 Day 1) and of first administration of treatme nt in the
Treatment Period.  If any of the assessments occurring within 72 hours of Cycle 1 Day 1 and of first administration of treatment in the
Treatment Period are abnormal, all assessments must be repeated on the first day of study treatment and of first administrati on of
treatment in the Treatment Period, respectively
b If the timing of the Safety Follow-Up Visit overlaps with a visit already completed, e.g., the End of Induction Visit, then the Safety Follow -
Up Visit may not be performed. The Safety Follow-Up Visit is applicable for all patients, whether they discontinued permanently the 
treatment in the Induction or in the Treatment Period. 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
186/Protocol MX39795, Version 11 
c A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascula r, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality identified at baselin e should be 
recorded on the General Medical History and Baseline Conditions eCRF.  At subsequent visits (or as clinical ly indicated), limited, symptom-
directed physical examinations should be performed (see next footnote).  Changes from baseline abnormalities should be record ed in patient 
notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
d Limited physical examination, ECOG performance status, ECG, urinalysis, and local laboratory assessments (hematology, coagula tion, 
chemistry and thyroid function panel [when mandated]) may be obtained ≤ 72 hours before Day 1 of each cycle.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded a s adverse events 
on the Adverse Event eCRF. 
e In patients who are assigned vemurafenib treatment: head and neck examination, consisting of at least a visual inspection of oral mucosa and 
lymph node palpation, should occur prior to initiation of treatment and every 3 months during treatment.  Anal examinations ( for all 
patients) and pelvic examinations (for women) should occur before and at the end of treatment or when considered clinically indicated.  
Monitoring for non-cuSCC should continue for up to 6 months after end of treatment or until initiation of another anti-neoplastic therapy.  
Dermatologic evaluation should occur prior to initiation of therapy, and then examination for cuSCC should occur at each stud y visit until 
end of study treatment; thereafter, evaluation should occur monthly up to six months after treatment or until initi ation of another anti-
neoplastic therapy.  
f Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressures while the patient is in a seated pos ition, and 
temperature.  Vital sign assessments performed on the first day of a treatment cycle should be done prior to IV study treatment (if 
applicable).  
g ECG recordings will be obtained when clinically indicated.  Patients should be resting and in a supine position for at least 10 minutes prior 
to each ECG collection. 
h Ophthalmologic exams should only occur in patients who are assigned to entrectinib, pemigatinib or vemurafenib treatment:  
– In patients assigned to entrectinib: Ophthalmologic exams, including at least visual acuity and slit-lamp tests (which may be performed by
an optometrist), should be performed prior to starting the first administration, at Day 1 of the second cycle of treatment, at the e nd of
treatment, and as clinically indicated
– In patients assigned to pemigatinib: A comprehensive eye examination should be performed by a qualified ophthalmologist. The eye
examination should include a visual acuity test, slit-lamp examination, and fundoscopy with digital imaging and optical coherence
tomography, and is required prior to the first administration of pemigatinib, onc e every 3 cycles (± 7 days, starting at Cycle 3), at end of
treatment (not needed if completed within 28 days before the end of treatment), and more often if participants report any vis ual adverse
events or change in visual acuity.  An optometrist can perform the assessments if adequately trained and qualified; however, the
optometrist should be supervised by an ophthalmologist, if possible, to provide the requisite clinical assessment.  Every eff ort should be
made to ensure that all subsequent examinations are performed by the same ophthalmologist.


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
187/Protocol MX39795, Version 11 
– In patients assigned to vemurafenib: Routine monitoring of ophthalmologic reactions should occur at each cycle 
 
i Hematology consists of CBC (including RBC count), hemoglobin, hematocrit, WBC count with differe ntial (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential may be done if clinically ind icated. 
j Thyroid function panel includes: thyroid-stimulating hormone (TSH), free T3 (or total T3 for sites where free T3 is not performed), and free 
T4 
k Chemistry panel (serum or plasma): sodium, potassium, chloride, bicarbonate or total carbon dioxide (both optional and if considered 
standard of care for the region), glucose, BUN or urea, creatinine + creatinine clearance (calculated through use of Cockcroft-Gault formula), 
total protein, albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, urate and LDH.   
At the End of Induction Visit, the panel will also include CPK, fasting lipid profile (total cholesterol, high-density lipoprotein cholesterol, 
low-density lipoprotein cholesterol, and triglycerides; all performed following ≥ 4-hour fast prior to testing), amylase and lipase and glycated 
hemoglobin (HbA1c).  
During the Treatment Period, the panel may also include some IMP-specific exam at the timepoints indicated in the footnote r. 
l The following should be tested for specific IMPs only 
(Note: Assessments that do not coincide with planned study visits may be performed within ± 3 days of the timing described below for tests 
planned at intervals ≤ 3-weekly and within ± 7 days of the timing for tests planned at monthly or greater intervals):  
 
– Alectinib: CPK levels, and liver function tests (ALT, AST, total bilirubin, alkaline phosphatase) every two weeks for 12 weeks of treatment, 
then every 6 weeks between weeks 12 and 48 and every 12 weeks thereafter, until week 96 (during the Treatment Period only)  
 
– Atezolizumab: Thyroid function panel: thyroid-stimulating hormone (TSH), free T3 (or total T3 for sites where free T3 is not performed), 
and free T4 every 9 weeks; ECG as clinically indicated 
 
– Cobimetinib: LVEF after the first month of treatment and at least every 3 months or as clinically indicated until treat ment discontinuation.  
CPK levels every 4 weeks during treatment and as clinically indicated in patients reporting severe myalgias  
 
– Entrectinib: LVEF at Cycle 3 Day 1 (± 7 days), as clinically indicated, and at the Safety Follow-Up Visit (if patient experienced Grade 2 or 
higher ejection fraction decrease at Cycle 3 or at any time during treatment, or if clinically indicated).  Safety Follow -Up LVEF is not 
necessary if the last LVEF assessment was performed within 1 week prior to the Safety Follow-Up Visit and if the investigator deems it not 
clinically indicated.  Evaluation of LVEF must be performed by the same method (echocardiogram or MUGA) for each patient.  It  is 
strongly recommended that the same laboratory and operator perform echocardiogram/MU GA scans for each individual patient. 
ECGs:  
- At Day 1 of Cycles 1 to 5 of treatment with entrectinib with a single 12-Lead ECG assessment performed pre-dose and 4 hours 
(± 15 minutes) post-dose,  


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
188/Protocol MX39795, Version 11 
- At end of treatment, and 
- As clinically indicated. 
In case of an event of QTc prolongation (Grade > 1), patient should be followed more closely.  In addition, the ECG should be read over 
for confirmation, and continuous ECG monitoring may be implemented as clinically indicated  
 
– Erlotinib + bevacizumab: No additional assessments 
 
– Ipatasertib (only if administered without paclitaxel [see next bullet if ipatasertib is administered with paclitaxel]) :  
Every 3 weeks, on Day 1 of each cycle and on Day 8 of Cycle 1: Fasting blood glucose and fasting lipid profile (total cholesterol, high-
density lipoprotein, low-density lipoprotein and triglycerides, all performed following ≥ 4-hour fast prior to testing); amylase and 
lipase; and glycosylated hemoglobin (HbA1c). In addition, on Days 4, 15 of Cycle 1 and Days 8 and 15 of Cycle 2: fasting blood 
glucose (patients should fast  4 hours prior to testing) 
 
– Ipatasertib and paclitaxel:  
On Day 1 and 15 of each 28-day cycle, on Days 4, 8 and 22 of Cycle 1 and on Day 8 of Cycle 2: fasting blood glucose and fasting lipid 
profile (total cholesterol, high-density lipoprotein, low-density lipoprotein and triglycerides; all performed following ≥ 4-hour fast 
prior to testing), amylase and lipase, and glycosylated hemoglobin (HbA1c) 
On Days 1, 8 and 15 of each 28-day cycle (until paclitaxel is stopped): hematology including WBC count, WBC differential count 
(including absolute neutrophil counts, lymphocytes), hemoglobin, hematocrit, and platelet count.  
On paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of the infusion 
Additional safety visits at Day 15 of each cycle should coincide with paclitaxel administration. These visits are necessary o nly until 
paclitaxel is stopped 
 
– Ivosidenib: 
ECGs: On Day 1 of each 28-day cycle, on Cycle 1 Day 15, and at the Safety Follow-Up Visit 
LVEF: As clinically indicated and at the Safety Follow-Up Visit (ECHO or other method per institutional practice) 
 
– Olaparib: No additional assessments 
 
– Pemigatinib:  
Parathyroid hormone at Cycle 1 Day 1, every 3 cycles on Day 1 starting with Cycle 3, and at the Safety Follow -Up Visit  
Serum phosphorus levels at: 
- Day 1, Day 8 and Day 15 of Cycle 1 


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
189/Protocol MX39795, Version 11 
- Day 1 of Cycle 2 and the first day of every cycle thereafter until end of treatment 
- Safety Follow-Up Visit 
 
 Note: Any patient assigned to pemigatinib who does not reach a target serum phosphate level of > 5.5 mg/dL at any time during 
Cycle 1, is compliant with taking study drug, and does not experience an ongoing Grade 2 or higher treatment-related AE will 
increase the daily dose to 18 mg QD starting from Cycle 2 Day 1.  Hyperphosphatemia in Cycle 1 requires Day 8 testing of serum 
phosphate in Cycle 2+ until phosphate is < 7 mg/dL on Day 8 for at least 2 consecutive cycles on stable dose of binders.   
 
ECGs on the first day of every cycle and at the Safety Follow-Up Visit 
Nail check, as part of the physical exam, on the first day of every cycle and at the Safety Follow-Up Visit 
 
– Trastuzumab + pertuzumab (± chemotherapy): LVEF at Cycle 3 Day 1, then every 3 cycles during treatment.  Patients who develop 
asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g., every 6 –8 weeks).  LVEF every 6 months following 
discontinuation of treatment until 24 months from the last administration of trastuzumab 
 
– Vemurafenib: Amylase and lipase at each cycle; ECG and electrolytes (including magnesium) must be monitored in all patients before 
treatment, monthly for 3 months, then every third month while on study treatment and after dose modification.  Note: Patients who are 
assigned vemurafenib will also have additional assessments during their ongoing physical examinations, as described in Footnote  j 
 
– Vismodegib: No additional chemistry laboratory assessments 
 
m Urinalysis including dipstick: specific gravity, pH, glucose, protein, ketones, and blood. 
n A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed  prior to the 
first dose in the Treatment Period (see specific requirements for vismodegib).  Pregnancy tests (urine) should be conducted at each study visit 
(every 21 days ± 3 days or every 28 days ± 3 days depending on the IMP schedule of administration) during both Induction and Treatment 
Periods and no less than monthly if a study visit is delayed.  For all treatments, pregnancy tests should be conducted at the Safety Follow-Up 
Visit and at the end of each contraception period, which corresponds to the following time points after their final dose of s tudy treatment: 2 
weeks for erlotinib, 1 month for ipatasertib and olaparib, 5 weeks for entrectinib and pemigatinib; 3 months for alectinib and ivosidenib; 5 
months for atezolizumab; 6 months for bevacizumab, cobimetinib, vemurafenib, carboplatin, cisplatin, paclitaxel and gemcitabi ne; 7 months 
for trastuzumab and pertuzumab.  
Note: For vismodegib, a blood pregnancy test should be performed within 7 days prior to initiating treatment and a supervised pregnancy 
test, conducted by a healthcare provider, should be performed at each study visit during treatment and 2 months and 24 months after their 
final dose of study treatment (the 2 and 24 months post treatment tests can be performed by a local health practitioner and r eported to the 
investigator).  If study visits are delayed, the pregnancy tests must be performed independently of the visits and no less than monthly.  


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
190/Protocol MX39795, Version 11 
Pregnancy tests should have a minimum sensitivity of 25 mIU/mL, as per local availability.  Patients who present with amenorr hea during 
treatment with vismodegib should continue monthly pregnancy testing while on treatment. 
o The same radiographic procedure should be used throughout the study for each patient:
– Treatment Period: During the Treatment Period, tumor assessments should occur every 9 weeks (± 3 days, with first assessment during the
Treatment Period being made 9 weeks post C1D1) regardless of dose interruptions.  Results must be reviewed by the investigator before
dosing at the next cycle
p Patients who enter the Follow-up Period before PD should continue to be assessed, per protocol, until disease progression.  All patients in the 
control arm must be followed up until disease progression.  This also includes patients who discontinue to receive alternative therapy after 
the MTB. 
q Concomitant medications include any prescription medications or over-the-counter medications. 
– During the Treatment Period: changes to current medications or medications used since the last documentation of medications should be
recorded.
r After initiation of molecularly-guided therapy (including the control arm for Category 1 patients): all AEs, SAEs and AESIs, regardless of 
relationship to study drug, will be reported until 30 days after the final dose of study drug or initiation of new systemic anticancer therapy, 
whichever occurs first, for all drugs except for atezolizumab, where it will be 90 days.  After this period, the investigator  should report any 
SAEs or AESIs believed to be related to prior study drug treatment.  The investigator should follow each AE 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 patie nt withdraws consent.  
Every effort should be made to follow all SAEs considered to be related to study drug or study-related procedures until a final outcome can be 
reported. 
Note: For atezolizumab, the first Follow-Up Visit (90 days after the final dose of study drug) is regarded as the end of AE reporting period. 
s After treatment discontinuation, information on survival status and new anticancer therapies, including local assessment of overall tumor 
response and dates of progression to the following subsequent anticancer therapies, will be collected via telephone contact, patient medical 
records, and/or clinic visits approximately every 3 (± 1) months until death, loss to follow up, end of study, patient withdr awal or study 
termination by the Sponsor, whichever occurs first.  Patients who discontinue treatment for reason other than PD but who do not withdraw 
consent to follow up will be assessed for progression as described during the Treatment Period (including scans) until diseas e progression 
(refer to footnote v).  After disease progression, these patients will continue with survival follow up.


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
191/Protocol MX39795, Version 11 
A1–2
SCHEDULE OF ACTIVITIES BEFORE THE PRIMARY ANALYSIS CUT-OFF DATE (CCOD) 
Screening Period a 
Induction Period 
End of 
Induction Visit d 
Treatment 
Period 
Safety Follow-Up 
Visit e 
Follow-up Period 
Day –28 
to 
Day –1 
Day –14 
to 
Day –1 
Cycle 1 
Day 1 b 
First day of 
each 21-day 
cycle 
(± 3 days) 
for Cycles 2 
and 3 c 
Cycle 3 Day 14 
to 
Cycle 3 Day 21 
(+ 3 days) 
First day of each 
21-day or 28-day
cycle (± 3 days) 
Dosing schedule 
per RSI c 
30 (±7) days from 
last treatment or at 
initiation of other 
systemic anticancer 
therapy (whichever 
occurs first) 
Every 3 (± 1) 
months 
(Starting 3 
months post final 
dose of study 
treatment) 
Informed Consent–
General (Part 1) f 
X 
Informed Consent– 
IMP-specific (Part 2)  f 
X 
Eligibility criteria 
X 
X c 
General and IMP-
specific exclusion 
criteria re-evaluation 
X 
Medical history and 
demographics g 
X 
Weight 
X 
X 
X 
X 
X 
Height 
X 
Complete physical 
examination h 
X 
X 
X 
Limited physical 
examination i 
X  
X 
X 
Specific physical 
examination j 
X 
(vemurafenib 
patients only) 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
192/Protocol MX39795, Version 11 
Screening Period a 
Induction Period 
End of 
Induction Visit d 
Treatment 
Period 
Safety Follow-Up 
Visit e 
Follow-up Period 
Day –28 
to 
Day –1 
Day –14 
to 
Day –1 
Cycle 1 
Day 1 b 
First day of 
each 21-day 
cycle 
(± 3 days) 
for Cycles 2 
and 3 c 
Cycle 3 Day 14 
to 
Cycle 3 Day 21 
(+ 3 days) 
First day of each 
21-day or 28-day
cycle (± 3 days) 
Dosing schedule 
per RSI c 
30 (±7) days from 
last treatment or at 
initiation of other 
systemic anticancer 
therapy (whichever 
occurs first) 
Every 3 (± 1) 
months 
(Starting 3 
months post final 
dose of study 
treatment) 
ECOG performance 
status i
X 
X 
X 
X 
X 
X 
Vital signs k 
X 
X  
X 
X 
X 
X 
12-lead ECG l, i
X 
X 
As clinically 
indicated or as 
indicated for each 
individual IMP 
As indicated for each 
individual IMP 
Left ventricular 
ejection fraction 
(LVEF) 
X 
As clinically 
indicated or as 
indicated for each 
individual IMP 
As clinically indicated 
or as indicated for 
each individual IMP 
As indicated  
for each individual 
IMP 
Ophthalmologic 
exams m 
X 
(entrectinib, 
pemigatinib and 
vemurafenib only) 
X 
HIV, HBV, HCV 
serology n
X 
Hematology o, i 
X 
X 
X 
X 
X 
X 
Coagulation 
(aPTT, INR) i 
X 
X 
X 
X 
X 
X 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
193/Protocol MX39795, Version 11 
Screening Period a 
Induction Period 
End of 
Induction Visit d 
Treatment 
Period 
Safety Follow-Up 
Visit e 
Follow-up Period 
Day –28 
to 
Day –1 
Day –14 
to 
Day –1 
Cycle 1 
Day 1 b 
First day of 
each 21-day 
cycle 
(± 3 days) 
for Cycles 2 
and 3 c 
Cycle 3 Day 14 
to 
Cycle 3 Day 21 
(+ 3 days) 
First day of each 
21-day or 28-day
cycle (± 3 days) 
Dosing schedule 
per RSI c 
30 (±7) days from 
last treatment or at 
initiation of other 
systemic anticancer 
therapy (whichever 
occurs first) 
Every 3 (± 1) 
months 
(Starting 3 
months post final 
dose of study 
treatment) 
Thyroid function 
panel p, i 
X 
X 
Every 9 weeks 
(atezolizumab 
only) 
Chemistry panel q, i 
X 
X 
X 
X 
X 
X 
Chemistry panel 
(IMP-specific) r, i 
X 
As indicated  
for each individual 
IMP 
Urinalysis s, i 
X 
X 
X 
X 
X 
X 
Pregnancy test t 
X 
(serum 
within 7 
days) 
X 
X 
(serum) 
(within 7 days of 
first dose in the 
treatment Period) 
Refer to 
Footnote t 
(urine) 
X 
Refer to 
Footnote t 
(urine) 
Tumor assessment u 
X 
Days 7 – 21 post 
C3 D1 (+3 days) 
Every 9 weeks ± 3 
days until PD or 
treatment 
discontinuation 
(whichever is the 
later) 
X v 
(as per comment) 
Archival tumor 
tissue w 
X 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
194/Protocol MX39795, Version 11 
Screening Period a 
Induction Period 
End of 
Induction Visit d 
Treatment 
Period 
Safety Follow-Up 
Visit e 
Follow-up Period 
Day –28 
to 
Day –1 
Day –14 
to 
Day –1 
Cycle 1 
Day 1 b 
First day of 
each 21-day 
cycle 
(± 3 days) 
for Cycles 2 
and 3 c 
Cycle 3 Day 14 
to 
Cycle 3 Day 21 
(+ 3 days) 
First day of each 
21-day or 28-day
cycle (± 3 days)
Dosing schedule 
per RSI c 
30 (±7) days from 
last treatment or at 
initiation of other 
systemic anticancer 
therapy (whichever 
occurs first) 
Every 3 (± 1) 
months 
(Starting 3 
months post final 
dose of study 
treatment) 
Tumor tissue biopsy 
(if insufficient or not 
suitable archival 
tissue is available) w 
X 
Blood sample for 
FoundationOne® 
F1LCDx (Liquid) 
test profiling w 
After eligibility 
confirmation, 
at C1 D1 
Before starting 
the 
chemotherapy 
infusion 
X 
can be taken up 
to C1 D1 of 
Treatment Period 
(before starting 
the treatment) 
Whole blood sample 
for exploratory 
research (for optional 
germline analyses) 
X 
Single sample 
prior to 
infusion 
Serum blood sample 
for exploratory 
research 
X 
Single sample 
prior to 
infusion 
Plasma blood sample 
for exploratory 
research  
X 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
195/Protocol MX39795, Version 11 
Screening Period a 
Induction Period 
End of 
Induction Visit d 
Treatment 
Period 
Safety Follow-Up 
Visit e 
Follow-up Period 
Day –28 
to 
Day –1 
Day –14 
to 
Day –1 
Cycle 1 
Day 1 b 
First day of 
each 21-day 
cycle 
(± 3 days) 
for Cycles 2 
and 3 c 
Cycle 3 Day 14 
to 
Cycle 3 Day 21 
(+ 3 days) 
First day of each 
21-day or 28-day
cycle (± 3 days) 
Dosing schedule 
per RSI c 
30 (±7) days from 
last treatment or at 
initiation of other 
systemic anticancer 
therapy (whichever 
occurs first) 
Every 3 (± 1) 
months 
(Starting 3 
months post final 
dose of study 
treatment) 
FACT-G
HADS 
EQ-5D-5L x 
X 
X 
(Category 1 
patients only) 
X 
(Category 1 
patients only) 
X 
(Category 1 
patients only) 
X y 
Category 1 patients 
only (not applicable 
if visit is done by 
phone) 
Concomitant 
medications z 
X 
X 
X 
X 
X 
X 
Adverse events aa 
X 
X 
X 
X 
X 
X 
X 
Additional safety 
visits 
Ipatasertib + 
paclitaxel only 
Days 4, 8, 15 and  
22 of Cycle 1 
D8 and 15 of 
Cycle 2 
Then D15 of all 
cycles until 
paclitaxel is 
stopped  
Collection of 
information on 
survival and 
anticancer therapy bb 
X 
X 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
196/Protocol MX39795, Version 11 
Screening Period a 
Induction Period 
End of 
Induction Visit d 
Treatment 
Period 
Safety Follow-Up 
Visit e 
Follow-up Period 
Day –28 
to 
Day –1 
Day –14 
to 
Day –1 
Cycle 1 
Day 1 b 
First day of 
each 21-day 
cycle 
(± 3 days) 
for Cycles 2 
and 3 c 
Cycle 3 Day 14 
to 
Cycle 3 Day 21 
(+ 3 days) 
First day of each 
21-day or 28-day
cycle (± 3 days)
Dosing schedule 
per RSI c 
30 (±7) days from 
last treatment or at 
initiation of other 
systemic anticancer 
therapy (whichever 
occurs first) 
Every 3 (± 1) 
months 
(Starting 3 
months post final 
dose of study 
treatment) 
Molecular Tumor 
Board (MTB) and 
Randomization cc 
Within 10 days of 
End of Induction 
Visit 
Study treatment 
Platinum-based 
induction 
chemotherapy 
X 
(as per chosen 
treatment 
schedule) 
X 
(for 2 cycles, 
as per 
chosen 
treatment 
schedule) 
Molecularly-guided 
therapy in patients 
with a CR, PR or SD 
during induction 
X aa 
(until PD) 
Platinum-based 
chemotherapy in 
patients with a CR, 
PR or SD during 
induction 
X aa 
(at least 3 cycles) 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
197/Protocol MX39795, Version 11 
Screening Period a 
Induction Period 
End of 
Induction Visit d 
Treatment 
Period 
Safety Follow-Up 
Visit e 
Follow-up Period 
Day –28 
to 
Day –1 
Day –14 
to 
Day –1 
Cycle 1 
Day 1 b 
First day of 
each 21-day 
cycle 
(± 3 days) 
for Cycles 2 
and 3 c 
Cycle 3 Day 14 
to 
Cycle 3 Day 21 
(+ 3 days) 
First day of each 
21-day or 28-day
cycle (± 3 days)
Dosing schedule 
per RSI c 
30 (±7) days from 
last treatment or at 
initiation of other 
systemic anticancer 
therapy (whichever 
occurs first) 
Every 3 (± 1) 
months 
(Starting 3 
months post final 
dose of study 
treatment) 
Molecularly-guided 
therapy in patients 
with PD during 
induction (Category 2 
patients) 
X aa 
(until PD) 
Abbreviations: aPTT = activated partial thromboplastin time; C = cycle; chemo = chemotherapy; CR = complete response; CUP = cancer of 
unknown primary site; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FACT-G = Functional Assessment of 
Cancer Therapy–General; HADS = Hospital Anxiety and Depression Scale; EQ-5D-5L = EuroQoL 5 Dimensions 5 Levels; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; IMP = Investigational Medicinal Product; INR, international normalized ratio; MTB = 
Molecular Tumor Board; PD = progressive disease; PR = partial response; RSI= reference safety information; SD = stable disease. 
Note: Unless otherwise indicated, assessments scheduled on the study treatment days should be performed prior to initiation of study treatment. 
a The Screening Period may be extended in exceptional cases: 
– Up to 42 days (extension by 2 weeks) in case the first tissue submitted was not suitable or insufficient per central pathology assessment and a
fresh biopsy has to be taken (see above)
– Up to 35 days (extension by 1 week):
If there has been a delay in the shipment of the tissue sample 
If escalation of the eligibility review to the referent oncologist and further information is requested or further tests are needed to determine 
eligibility 
b Assessments on Day 1 must be performed prior to study treatment.  Day 1 is baseline for the study. 
c 21-day cycles for all treatment arms (including for cohorts with oral therapies), except for cobimetinib and vemurafenib, ipatasertib and paclitaxel, 
and ivosidenib, where the administration cycle will be 28 days: 


Appendix 1: Schedule of Activities 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
198/Protocol MX39795, Version 11 
– Assessments must be performed within 72 hours of first study treatment (Cycle 1 Day 1) and of first administration of treatment in the
Treatment Period.  If any of the assessments occurring within 72 hours of Cycle 1 Day 1 and of first administration of treatment in the
Treatment Period are abnormal, all assessments must be repeated on the first day of study treatment and of first administration of treatment in
the Treatment Period, respectively
– If any of the Cycle 1 Day 1 assessments do not meet eligibility criteria, study drug administration should be held and the tests repeated (timing
of repeat testing should be based on clinical judgment).  If eligibility criteria remain unsatisfied by the end of the initially defined Screening
Period, the patient should be discontinued from the study
– If any of the Day 1 of the Treatment Period assessments do not meet safety criteria for starting treatment in the Treatment Period, study drug
administration should be held and the tests repeated (timing of repeat testing should be based on clinical judgment).
d  For patients who reach Cycle 3, the End of Induction Visit will occur between Cycle 3 Day 14 and Cycle 3 Day 21 (+ 3 days).  For patients who 
progress (PD) before Cycle 3, it will occur within 10 days of disease progression assessment. 
e If the timing of the Safety Follow-Up Visit overlaps with a visit already completed, e.g., the End of Induction Visit, then the Safety Follow-Up Visit 
may not be performed. The Safety Follow-Up Visit is applicable for all patients, whether they discontinued permanently the treatment in the 
Induction or in the Treatment Period. 
f Written informed consent is required for performing any study-specific tests or procedures.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to Cycle 1 Day 1 (except where otherwise specified) may be used for 
screening assessments rather than repeating such tests, providing that these tests meet protocol requirements.  The only exception to this 
requirement is that the imaging assessments mandatory for RECIST v1.1 (including head images) may occur up to 42 days prior to Day 1. 
  In cases where the Screening Period has been extended (see Section 3.1.1.2), screening assessments conducted during the initial Screening 
Period (e.g., CT scans) that met protocol requirements will remain valid during the Screening Period extension, with the following exceptions: 
- Pregnancy tests and tests that should be repeated at baseline
- Imaging tests performed up to 49 days prior to first dose of study treatment are acceptable
g Medical history includes surgical and cancer histories.  Cancer history includes stage, date of diagnosis, and prior anticancer treatment. 
Reproductive status and smoking history should also be captured.  Demographic information includes age, sex, and self-reported race/ethnicity. 
h A complete physical examination should include 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.  At subsequent visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed (see next footnote).  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. 
i Limited physical examination, ECOG performance status, ECG, urinalysis, and local laboratory assessments (hematology, coagulation, 
chemistry and thyroid function panel [when mandated]) may be obtained ≤ 72 hours before Day 1 of each cycle.  It is not necessary to repeat 
these assessments again prior to Cycle 1 Day 1 of the Induction Period if they have been conducted for screening within this time period.  


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
199/Protocol MX39795, Version 11 
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. 
j In patients who are assigned vemurafenib treatment: head and neck examination, consisting of at least a visual inspection of oral mucosa and 
lymph node palpation, should occur prior to initiation of treatment and every 3 months during treatment.  Anal examinations (for all patients) and 
pelvic examinations (for women) should occur before and at the end of treatment or when considered clinically indicated.  Monitoring for non-
cuSCC should continue for up to 6 months after end of treatment or until initiation of another anti-neoplastic therapy.  Dermatologic evaluation 
should occur prior to initiation of therapy, and then examination for cuSCC should occur at each study visit until end of study treatment; 
thereafter, evaluation should occur monthly up to six months after treatment or until initiation of another anti-neoplastic therapy.  
k Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressures while the patient is in a seated position, and temperature.  
Vital sign assessments performed on the first day of a treatment cycle should be done prior to IV study treatment (if applicable).  
I ECG recordings will be obtained during screening and when clinically indicated.  Patients should be resting and in a supine position for at least 
10 minutes prior to each ECG collection.  
m Ophthalmologic exams should only occur in patients who are assigned to entrectinib, pemigatinib or vemurafenib treatment: 
– In patients assigned to entrectinib: Ophthalmologic exams, including at least visual acuity and slit-lamp tests (which may be performed by an 
optometrist), should be performed prior to starting the first administration, at Day 1 of the second cycle of treatment, at the end of treatment, 
and as clinically indicated 
– In patients assigned to pemigatinib: A comprehensive eye examination should be performed by a qualified ophthalmologist. The eye 
examination should include a visual acuity test, slit-lamp examination, and fundoscopy with digital imaging and optical coherence tomography, 
and is required prior to the first administration of pemigatinib, once every 3 cycles (± 7 days, starting at Cycle 3), at end of treatment (not 
needed if completed within 28 days before the end of treatment), and more often if participants report any visual adverse events or change in 
visual acuity.  An optometrist can perform the assessments if adequately trained and qualified; however, the optometrist should be supervised 
by an ophthalmologist, if possible, to provide the requisite clinical assessment.  Every effort should be made to ensure that all subsequent 
examinations are performed by the same ophthalmologist. 
– In patients assigned to vemurafenib: Routine monitoring of ophthalmologic reactions should occur at each cycle 
 
n HIV testing is mandatory for participation in the study.  HBV serology includes HBsAg and total HBcAb.  If the HBsAg test is negative and total 
HBcAb test is positive, HBV DNA must also be assessed (see Section 4.5.7).  HCV antibody serology includes HCV antibody testing.  If the HCV 
antibody test is positive, HCV RNA must also be assessed (see Section 4.5.7).  
o Hematology consists of CBC (including RBC count), hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, and other cells), and platelet count.  A manual differential may be done if clinically indicated. 
p Thyroid function panel includes: thyroid-stimulating hormone (TSH), free T3 (or total T3 for sites where free T3 is not performed), and free T4 


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
200/Protocol MX39795, Version 11 
q Chemistry panel (serum or plasma): sodium, potassium, chloride, bicarbonate or total carbon dioxide (both optional and if considered standard of 
care for the region), glucose, BUN or urea, creatinine + creatinine clearance (calculated through use of Cockcroft-Gault formula), total protein, 
albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, urate and LDH.   
At the End of Induction Visit, the panel will also include CPK, fasting lipid profile (total cholesterol, high-density lipoprotein cholesterol, low-
density lipoprotein cholesterol, and triglycerides; all performed following ≥ 4-hour fast prior to testing), amylase and lipase and glycated 
hemoglobin (HbA1c).  
During the Treatment Period, the panel may also include some IMP-specific exam at the timepoints indicated in the footnote r. 
r The following should be tested for specific IMPs only 
(Note: Assessments that do not coincide with planned study visits may be performed within ± 3 days of the timing described below for tests 
planned at intervals ≤ 3-weekly and within ± 7 days of the timing for tests planned at monthly or greater intervals): 
 
– Alectinib: CPK levels, and liver function tests (ALT, AST, total bilirubin, alkaline phosphatase) every two weeks for 12 weeks of treatment, then 
every 6 weeks between weeks 12 and 48 and every 12 weeks thereafter, until week 96 (during the Treatment Period only) 
 
– Atezolizumab: Thyroid function panel: thyroid-stimulating hormone (TSH), free T3 (or total T3 for sites where free T3 is not performed), and 
free T4 every 9 weeks; ECG as clinically indicated 
 
– Cobimetinib: LVEF after the first month of treatment and at least every 3 months or as clinically indicated until treatment discontinuation.  CPK 
levels every 4 weeks during treatment and as clinically indicated in patients reporting severe myalgias 
 
– Entrectinib: LVEF at Cycle 3 Day 1 (± 7 days), as clinically indicated, and at the Safety Follow-Up Visit (if patient experienced Grade 2 or 
higher ejection fraction decrease at Cycle 3 or at any time during treatment, or if clinically indicated).  Safety Follow-Up LVEF is not necessary 
if the last LVEF assessment was performed within 1 week prior to the Safety Follow-Up Visit and if the investigator deems it not clinically 
indicated.  Evaluation of LVEF must be performed by the same method (echocardiogram or MUGA) for each patient.  It is strongly 
recommended that the same laboratory and operator perform echocardiogram/MUGA scans for each individual patient. 
ECGs:  
- At Day 1 of Cycles 1 to 5 of treatment with entrectinib with a single 12-Lead ECG assessment performed pre-dose and 4 hours (± 
15 minutes) post-dose,  
- At end of treatment, and 
- As clinically indicated. 
In case of an event of QTc prolongation (Grade > 1), patient should be followed more closely.  In addition, the ECG should be read over 
for confirmation, and continuous ECG monitoring may be implemented as clinically indicated 
 
– Erlotinib + bevacizumab: No additional assessments 
 


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
201/Protocol MX39795, Version 11 
– Ipatasertib (only if administered without paclitaxel [see next bullet if ipatasertib is administered with paclitaxel]):  
Every 3 weeks, on Day 1 of each cycle and on Day 8 of Cycle 1: Fasting blood glucose and fasting lipid profile (total cholesterol, high-
density lipoprotein, low-density lipoprotein and triglycerides, all performed following ≥ 4-hour fast prior to testing); amylase and lipase; and 
glycosylated hemoglobin (HbA1c). In addition, on Days 4, 15 of Cycle 1 and Days 8 and 15 of Cycle 2: fasting blood glucose (patients 
should fast  4 hours prior to testing) 
 
– Ipatasertib and paclitaxel:  
On Day 1 and 15 of each 28-day cycle, on Days 4, 8 and 22 of Cycle 1 and on Day 8 of Cycle 2: fasting blood glucose and fasting lipid 
profile (total cholesterol, high-density lipoprotein, low-density lipoprotein and triglycerides; all performed following ≥ 4-hour fast prior to 
testing), amylase and lipase, and glycosylated hemoglobin (HbA1c) 
On Days 1, 8 and 15 of each 28-day cycle (until paclitaxel is stopped): hematology including WBC count, WBC differential count 
(including absolute neutrophil counts, lymphocytes), hemoglobin, hematocrit, and platelet count. 
On paclitaxel dosing days, vital signs should be recorded prior to dosing and at the end of the infusion 
Additional safety visits at Day 15 of each cycle should coincide with paclitaxel administration. These visits are necessary only until 
paclitaxel is stopped 
 
– Ivosidenib: 
ECGs: On Day 1 of each 28-day cycle, on Cycle 1 Day 15, and at the Safety Follow-Up Visit 
LVEF: As clinically indicated and at the Safety Follow-Up Visit (ECHO or other method per institutional practice) 
 
– Olaparib: No additional assessments 
 
– Pemigatinib:  
Parathyroid hormone at Cycle 1 Day 1, every 3 cycles on Day 1 starting with Cycle 3, and at the Safety Follow-Up Visit  
Serum phosphorus levels at: 
- Day 1, Day 8 and Day 15 of Cycle 1 
- Day 1 of Cycle 2 and the first day of every cycle thereafter until end of treatment 
- Safety Follow-Up Visit 
 
 Note: Any patient assigned to pemigatinib who does not reach a target serum phosphate level of > 5.5 mg/dL at any time during 
Cycle 1, is compliant with taking study drug, and does not experience an ongoing Grade 2 or higher treatment-related AE will 
increase the daily dose to 18 mg QD starting from Cycle 2 Day 1.  Hyperphosphatemia in Cycle 1 requires Day 8 testing of serum 
phosphate in Cycle 2+ until phosphate is < 7 mg/dL on Day 8 for at least 2 consecutive cycles on stable dose of binders.   
 


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
202/Protocol MX39795, Version 11 
ECGs on the first day of every cycle and at the Safety Follow-Up Visit 
Nail check, as part of the physical exam, on the first day of every cycle and at the Safety Follow-Up Visit 
 
– Trastuzumab + pertuzumab (± chemotherapy): LVEF at Cycle 3 Day 1, then every 3 cycles during treatment.  Patients who develop 
asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g., every 6–8 weeks).  LVEF every 6 months following 
discontinuation of treatment until 24 months from the last administration of trastuzumab 
 
– Vemurafenib: Amylase and lipase at each cycle; ECG and electrolytes (including magnesium) must be monitored in all patients before 
treatment, monthly for 3 months, then every third month while on study treatment and after dose modification.  Note: Patients who are 
assigned vemurafenib will also have additional assessments during their ongoing physical examinations, as described in Footnote j 
 
– Vismodegib: No additional chemistry laboratory assessments 
 
s Urinalysis including dipstick: specific gravity, pH, glucose, protein, ketones, and blood. 
t A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 7 days prior to Day 1 and prior to the first dose in the Treatment Period (see specific requirements for 
vismodegib).  Pregnancy tests (urine) should be conducted at each study visit (every 21 days ± 3 days or every 28 days ± 3 days depending on 
the IMP schedule of administration) during both Induction and Treatment Periods and no less than monthly if a study visit is delayed.  For all 
treatments, pregnancy tests should be conducted at the Safety Follow-Up Visit and at the end of each contraception period, which corresponds 
to the following time points after their final dose of study treatment: 2 weeks for erlotinib, 1 month for ipatasertib and olaparib, 5 weeks for 
entrectinib and pemigatinib; 3 months for alectinib and ivosidenib; 5 months for atezolizumab; 6 months for bevacizumab, cobimetinib, 
vemurafenib, carboplatin, cisplatin, paclitaxel and gemcitabine; 7 months for trastuzumab and pertuzumab.  
Note: For vismodegib, a blood pregnancy test should be performed within 7 days prior to initiating treatment and a supervised pregnancy test, 
conducted by a healthcare provider, should be performed at each study visit during treatment and 2 months and 24 months after their final dose 
of study treatment (the 2 and 24 months post treatment tests can be performed by a local health practitioner and reported to the investigator).  If 
study visits are delayed, the pregnancy tests must be performed independently of the visits and no less than monthly.  Pregnancy tests should 
have a minimum sensitivity of 25 mIU/mL, as per local availability.  Patients who present with amenorrhea during treatment with vismodegib 
should continue monthly pregnancy testing while on treatment. 
u The same radiographic procedure should be used throughout the study for each patient: 
– Screening Period: A CT (with contrast) or MRI scan of the head must be included in screening tumor assessments.  Imaging assessments 
mandatory for RECIST v1.1 (including head images) may occur up to 42 days prior to Day 1, unless the Screening Period is extended, in 
which case imaging tests performed up to 49 days prior to first dose of study treatment are acceptable.   
– Before start of the Treatment Period: A CT (with contrast) or MRI scan of the head must be included in the End of Induction tumor 
assessments (results must be available at the End of Induction Visit, similar to other scans for RECIST assessment) 


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
203/Protocol MX39795, Version 11 
– Treatment Period: During the Treatment Period, tumor assessments should occur every 9 weeks (± 3 days, with first assessment during the 
Treatment Period being made 9 weeks post C1D1) regardless of dose interruptions.  Results must be reviewed by the investigator before 
dosing at the next cycle 
– Treatment beyond progression: Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 should be 
monitored with a follow-up scan every 9 weeks until treatment discontinuation. Based on clinical judgment, the investigator can extend this 
period to every 12 weeks. 
 
v Patients who enter the Follow-up Period before PD should continue to be assessed, per protocol, until disease progression.  All patients in the 
control arm must be followed up until disease progression.  This also includes patients who discontinue to receive alternative therapy after the 
MTB. 
w Refer to the Laboratory Manual for specimen collection instructions and for specific requirements for a sample to be suitable for genomic profile 
generation.  Tumor FFPE blocks are preferred.  In exceptional cases, 25 slides (4 µm slide thickness each) may be accepted.  Archival tumor 
tissue samples and tumor biopsies should be sent to special laboratories no less than 14 days prior to planned study Day 1.  
– Archival tumor tissue must not be older than 4 months at start of the Screening Period.  If older, a new tissue biopsy must be obtained 
– If the tissue submitted to the central laboratory for testing does not fulfill acceptance criteria and a new tumor tissue biopsy is required, the 
Screening Period may be extended for up to 14 days 
– Blood sample for FoundationOne® F1LCDx (Liquid) test will be collected and sent after eligibility confirmation (collection at Cycle 1 Day 1 
before starting the chemotherapy infusion) 
– The local pathology reports confirming compatibility with CUP diagnosis and the associated slides used for the diagnosis must also be 
submitted.  If the slides used for the local test reports confirming local CUP diagnosis are not available, the FFPE block submitted for genomic 
profiling must be sufficient to allow for central confirmation of CUP diagnosis. 
x See Appendices 7 to 9 for the questionnaires.  The baseline exam at Cycle 1 Day 1 of the Induction Period must be done prior to chemotherapy 
start. 
y Only in patients who have not progressed at the Safety Follow-Up Visit.  In those patients who have not progressed, PRO assessments should 
occur at the same times as the tumor assessments during the Follow-Up Period. 
z Concomitant medications include any prescription medications or over-the-counter medications.   
– At Screening: Any medications used by the patient within 7 days prior to initiation of study drug should be documented.   
– During the Induction Period: Only the medications related to the captured adverse reactions during this period and changes to medications 
existing at baseline should be collected (see footnote aa for AE reporting guidelines). 
– At the End of Induction Visit: all ongoing medications should be collected (to allow for an appropriate assessment of the general inclusion 
criteria in the Treatment Period and to comply with the re-baselining activities at the start of the Treatment Period). 


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
204/Protocol MX39795, Version 11 
– At subsequent visits (during the Treatment Period): changes to current medications or medications used since the last documentation of 
medications should be recorded. 
aa After informed consent has been obtained, but prior to initiation of study drug: only SAEs caused by a protocol-mandated intervention (e.g., 
invasive procedures such as biopsies) should be reported.   
– During the Induction Period: only adverse events leading to dose modifications, interruption or discontinuation of the platinum-based 
chemotherapy and all SAEs will be captured.  
– At the End of Induction Visit: all ongoing adverse events will be collected (to allow for an appropriate assessment of the general inclusion 
criteria in the Treatment Period and to comply with the re-baselining activities at the start of the Treatment Period) 
– After initiation of molecularly-guided therapy (including the control arm for Category 1 patients): all AEs, SAEs and AESIs, regardless of 
relationship to study drug, will be reported until 30 days after the final dose of study drug or initiation of new systemic anticancer therapy, 
whichever occurs first, for all drugs except for atezolizumab, where it will be 90 days.  After this period, the investigator should report any 
SAEs or AESIs believed to be related to prior study drug treatment.  The investigator should follow each AE 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 SAEs considered to be related to study drug or study-related procedures until a final outcome can be 
reported. 
Note: For atezolizumab, the first Follow-Up Visit (90 days after the final dose of study drug) is regarded as the end of AE reporting period.  
bb After treatment discontinuation, information on survival status and new anticancer therapies, including local assessment of overall tumor 
response and dates of progression to the following subsequent anticancer therapies, will be collected via telephone contact, patient medical 
records, and/or clinic visits approximately every 3 (± 1) months until death, loss to follow up, end of study, patient withdrawal or study termination 
by the Sponsor, whichever occurs first.  Patients who discontinue treatment for reason other than PD but who do not withdraw consent to follow 
up will be assessed for progression as described during the Treatment Period (including scans) until disease progression (refer to footnote v).  
After disease progression, these patients will continue with survival follow up. 
cc  The MTB must be scheduled to take place no later than 10 days after the End of Induction Visit for all patients. The MTB will be cancelled for 
Category 1 patients randomized to continue chemotherapy: 
– Randomization (for Category 1 patients only) should occur between the End of Induction Visit and no less than 48 hours before the planned 
MTB meeting date. 
– The MTB (for all patients) and randomization (for Category 1 patients) must be delayed after the End of Induction Visit if general safety criteria 
for entrance into the Treatment Period are not met, however the Sponsor’s study team must be informed of the delay (Section 4.1.1.2). If the 
MTB is delayed, starting treatment in the Treatment Period of the study will be subject to verifying that the general safety criteria for entry into 
the study are met:  
– If the MTB is delayed up to Cycle 3 Day 42 (or until 42 days after Day 1 of the last induction treatment cycle for Category 2 patients 
who receive less than 3 cycles), only the general safety criteria previously not met will need verifying. 


Appendix 1: Schedule of Activities 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
205/Protocol MX39795, Version 11 
– If the MTB is delayed beyond Cycle 3 Day 42 (or until 42 days after Day 1 of the last induction treatment cycle for Category 2 
patients who receive less than 3 cycles), all general safety eligibility criteria must be checked, and if they are still not met, the 
patient will not be eligible to receive further treatment in the study.  Instead, the patient will move directly to the Safety Follow-Up 
Visit and, then, proceed into the Follow-up Period, where he or she will receive non-IMP treatment outside of the study (see below). 
– If the MTB is delayed to Day 15 or more after the End of Induction Visit, Investigator’s judgment will be exercised to determine which tests 
need repeating prior to the MTB. 
Treatment initiation must occur within 21 calendar days after the End of Induction Visit.  
If any of the mandatory Day1 Treatment Period assessments do not meet the criteria for starting treatment in the Treatment Period, study drug 
administration should be held.  If therapy is delayed beyond Cycle 3 Day 42 (or until 42 days after Day 1 of the last induction treatment cycle for 
Category 2 patients who receive less than 3 cycles), Medical Monitor should be informed. 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
206/Protocol MX39795, Version 11 
Appendix 2
Timeline of Key Study Events 
Study Period 
Timing 
Key Events 
Screening Period 
All patients: 
Day –28 to Day –1 

Complete Part 1 of the ICF

Assess patient eligibility

Collect and ship tissue sample for central laboratory:
–
Archival tumor tissue samples for FoundationOne® FMI F1CDx (tissue) test that
meets study requirements
Must not be older than 4 months at start of the Screening Period 
If an acceptable archival tumor FFPE block is not available or is not suitable (in 
quantity and quality) at screening, an FFPE block from a freshly obtained biopsy 
sample must be provided that meets the study’s requirements 
–
Local pathology reports confirming compatibility with CUP diagnosis and associated
slides used for the diagnosis.  If the slides used for confirming local CUP diagnosis
are not available, the FFPE block submitted for genomic profiling must be sufficient to
allow for central confirmation of CUP diagnosis
The Screening Period may be extended in exceptional cases: 

Up to 42 days (extension by 2 weeks) in case the first tissue submitted was not suitable or
insufficient per central pathology assessment and a fresh biopsy has to be taken (see
above)

Up to 35 days (extension by 1 week):
–
If there has been a delay in the shipment of the tissue sample
–
If escalation of the eligibility review to the referent oncologist and further information is
requested or further tests are needed to determine eligibility
Screening assessments conducted during the initial Screening Period (e.g., CT 
scans) that met protocol requirements will remain valid during the Screening 
Period extension, with the following exceptions: 
- Pregnancy tests and tests that should be repeated at baseline
- Imaging tests performed up to 49 days prior to first dose of study treatment are
acceptable 


Appendix 2: Timeline of Key Study Events 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
207/Protocol MX39795, Version 11 
Study Period 
Timing 
Key Events 
Induction Period 
All patients: 
Day 1 until 
randomization (Category 
1 patients)  
or assignment of 
molecularly-guided 
treatment 
(Category 2 patients) 
 
Collect and ship blood sample for central laboratory: 
– 
Blood sample for FoundationOne® F1LCDx (Liquid) test after eligibility confirmation 
(collection at Cycle 1 Day 1 before starting the chemotherapy infusion) 
 
 
Treatment will start after the CUP diagnosis and the availability of suitable tumor tissue 
have been reviewed and confirmed by the Eligibility Review Team 
– 
Treatment must start as soon as possible after eligibility confirmation and no later than 
42 days after the start of screening (depending on screening extension) 
 
 
Administer 3 cycles of platinum-based chemotherapy to all eligible patients 
 
Assess tumor response on Cycle 3 any time after Day 7 
– 
Tumor response results must be available for End of Induction Visit 
End of Induction 
Visit 
(Part of Induction 
Period) 
Cycle 3 Day 14 to 21 
(+3 days) if no 
progression before 
Cycle 3 or within 
10 days of disease 
progression assessment 
if progression before 
Cycle 3 a 
 
Categorize patients based on tumor assessments 
– 
Category 1: CR, PR or SD after 3 cycles of platinum induction chemotherapy 
– 
Category 2: documented PD after 3 cycles of platinum induction chemotherapy or at 
any time during the Induction Period 
 
Perform or collect results for all assessments planned at End of Induction Visit 
 
Evaluate all exclusion/inclusion criteria and safety criteria for entrance into the 
Treatment Period 
MTB scheduling 
 
 
A tentative date for MTB should be set at Day 1 of induction chemotherapy, and the target 
date should be within 10 days of the planned End of Induction Visit 
 
Once the End of Induction Visit has taken place, the MTB date should be finalized and 
should be within 10 days of the End of Induction Visit 
 
The MTB (for all patients) and randomization (for Category 1 patients) must be delayed 
after the End of Induction Visit if general safety criteria for entrance into the Treatment 
Period are not met, however the Sponsor’s study team must be informed of the delay. If 
the MTB is delayed, starting treatment in the Treatment Period of the study will be subject 
to verifying that the general safety criteria for entry into the study are met:  


Appendix 2: Timeline of Key Study Events 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
208/Protocol MX39795, Version 11 
Study Period 
Timing 
Key Events 
– If the MTB is delayed up to Cycle 3 Day 42 (or until 42 days after Day 1 of the 
last induction treatment cycle for Category 2 patients who receive less than 3 
cycles), only the general safety criteria previously not met will need verifying. 
– If the MTB is delayed beyond Cycle 3 Day 42 (or until 42 days after Day 1 of 
the last induction treatment cycle for Category 2 patients who receive less than 
3 cycles), all general safety eligibility criteria must be checked, and if they are 
still not met, the patient will not be eligible to receive further treatment in the 
study.  Instead, the patient will move directly to the Safety Follow-Up Visit and, 
then, proceed into the Follow-up Period, where he or she will receive non-IMP 
treatment outside of the study. 
 
MTB will be cancelled for Category 1 patients randomized to continue chemotherapy 
Randomization 
Category 1 patients: 
After End of Induction 
Visit and no less than 48 
hours before planned 
MTB 
 
Category 2 patients: 
Not applicable 
 
Patients will be assigned to molecularly-guided therapy or to the control arm with 
chemotherapy 
 
Note: If not meeting safety criteria for entrance into the Treatment Period, the MTB and 
randomization will be delayed accordingly  
Molecular Tumor 
Board 
Category 1 patients 
assigned to molecularly-
guided therapy b 
And 
Category 2 patients 
 
Assign molecularly-guided therapy to Category 1 patients who were randomized to 
investigational treatment and to all Category 2 patients 
Treatment Period 
Initiate treatment within 
21 days post End of 
Induction Visit 
 
 
Complete Part 2 of the ICF prior to enrollment to Treatment Period 
 
Ensure tumor assessments have been re-assessed for re-baseline in the Treatment 
Period and that Treatment Period Day 1 physical evaluation, performance status, weight, 
vital signs and laboratory assessments are performed prior to administration of first dose 
to serve as baseline for the Treatment Period 


Appendix 2: Timeline of Key Study Events 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
209/Protocol MX39795, Version 11 
Study Period 
Timing 
Key Events 
 
Start treatment  
– 
Treat until loss of clinical benefit, unacceptable toxicity, patient or investigator decision 
to discontinue, or death (whichever occurs first) 
– 
An assessment cycle will be 21 days for all treatment arms (including for cohorts with 
oral therapies) except for cobimetinib and vemurafenib, ipatasertib and paclitaxel, and 
ivosidenib, where the administration cycle will be 28 days 
 
Note: If any of the mandatory Day1 Treatment Period assessments do not meet the criteria for 
starting treatment in the Treatment Period, study drug administration should be held.  If therapy 
is delayed beyond Cycle 3 Day 42 (or until 42 days after Day 1 of the last induction treatment 
cycle for Category 2 patients who receive less than 3 cycles), Medical Monitor should be 
informed. 
Safety Follow-Up 
Visit 
All patients: 
30 (±7) days after last 
treatment or at initiation 
of other systemic 
anticancer therapy 
(whichever occurs first) 
 
Refer to Appendix 1 for assessments 
Survival Follow-Up 
Period 
All patients: 
Every 3 (± 1) months 
after the final dose of 
treatment until death, 
loss to follow up, 
withdrawal of consent or 
end of the study 
 
 
Follow up for survival and further anticancer treatment (name of therapies, start and end 
dates, best response and date of progression) 
 
Patients who enter the Follow-up Period before PD should continue to be assessed, per 
protocol, until disease progression.  All patients in the control arm must be followed up 
until disease progression.  This also includes patients who discontinue to receive 
alternative therapy after the MTB. 


Appendix 2: Timeline of Key Study Events 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
210/Protocol MX39795, Version 11 
a Assessments to be performed within 10 days of randomization and can start before the C3 tumor assessment to allow for planning and analysis 
of tests.  All results must be available before randomization (Category 1 patients) or the date of the Molecular Tumor Board (Category 2 
patients). 
b Not applicable for Category 1 patients assigned to platinum-based chemotherapy. 
 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
211/Protocol MX39795, Version 11 
Appendix 3
Schedule of Study Sample Collection 
Visit/Period 
Timing 
Sample Type 
Screening 
Day −28 to 
Day –1 

For central laboratory
–
Archival tumor tissue sample, if available (sent no
less than 14 days prior to planned Day 1)
–
Tumor tissue biopsy, if no archival tumor tissue is
available or is insufficient or unsuitable (see
Laboratory Manual for details) for study purposes
(sent no less than 14 days prior to planned Day 1)
–
Local pathology reports confirming compatibility
with CUP diagnosis and associated slides used
for the diagnosis.  If the slides used for confirming
local CUP diagnosis are not available, the FFPE
block submitted for genomic profiling must be
sufficient to allow for central confirmation of CUP
diagnosis

For local laboratory
–
Blood sample for HIV, HBV and HCV serology
Screening 
Day −14 to 
Day –1 

For local laboratory
–
Blood sample for hematology, coagulation, thyroid
function panel and chemistry
–
Urine sample for urinalysis
Day −7 to Day 
–1

For local laboratory
–
Blood sample for serum pregnancy test a
Day 1 
(Cycle 1 Day 1 
of the 
Induction 
Period) 
Prior to first 
infusion of 
platinum 
chemotherapy 

Pregnancy test
–
urine sample for pregnancy test

For central laboratory
–
Blood sample for FoundationOne® F1LCDx
(Liquid) test
–
Serum blood sample for exploratory research
–
Optional: whole blood sample for exploratory
germline mutation analyses

For local laboratory
–
Blood sample for hematology, coagulation and
chemistry
–
Urine sample for urinalysis
Cycle 2 Day 1 
(± 3 days) 
Cycle 3 Day 1 
(± 3 days) of 
the Induction 
Period 
Prior to  
infusion of 
platinum 
chemotherapy 

Pregnancy test
–
urine sample for pregnancy test

For local laboratory
–
Blood sample for hematology, coagulation and
chemistry
–
Urine sample for urinalysis and pregnancy test


Appendix 4: Preexisting Autoimmune Diseases and Immune Deficiencies  
Contraindicating Atezolizumab Use 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
212/Protocol MX39795, Version 11 
Visit/Period 
Timing 
Sample Type 
End of 
Induction Visit 
Cycle 3 Day 14 
to 21 (+ 3 
days) 
 
For central laboratory 
– 
Blood sample for FoundationOne® F1LCDx 
(Liquid) test 
 
 
For local laboratory 
– 
Blood sample for hematology, coagulation, thyroid 
function panel and chemistry (which will also 
include CPK, fasting lipid profile, amylase and 
lipase and glycated hemoglobin [HbA1c]) 
– 
Urine sample for urinalysis  
Treatment 
Period 
 
Prior to IMP 
administration  
on the first day 
(± 3 days) of  
each treatment 
cycle 
 
Pregnancy test  
– 
Within 7 days of first dose: blood sample for 
serum test 
– 
At all cycles for patients randomized to 
chemotherapy and from 2nd cycle of molecularly 
guided therapy: urine sample for pregnancy test a 
 
 
For local laboratory 
– 
Blood sample for hematology, coagulation,  
– 
Blood sample for chemistry and IMP-specific 
chemistry, as indicated for each individual IMP 
(see below) 
– 
Urine sample for urinalysis 
 
 
There are additional tests for some IMPs: 
– 
Alectinib: CPK levels and liver function tests (ALT, 
AST, total bilirubin, alkaline phosphatase) every 
two weeks for the first 12 weeks of treatment, then 
every 6 weeks between weeks 12 and 48 and 
every 12 weeks thereafter, until week 96 
– 
Atezolizumab: Thyroid function panel every 
9 weeks 
– 
Cobimetinib:  CPK levels every 4 weeks during 
treatment and as clinically indicated in patients 
reporting severe myalgias 
– 
Ipatasertib (only if administered without 
paclitaxel): 
Every 3 weeks, on Day 1 of each cycle and on 
Day 8 of Cycle 1: fasting blood glucose and 
fasting lipid profile (total cholesterol, high-
density lipoprotein, low-density lipoprotein and 
triglycerides, all performed following ≥ 4 hour 
fast); amylase and lipase; and glycosylated 
hemoglobin (HbA1c).  
On Days 4, 8, 15 of Cycle 1 and Day 8 of 
Cycle 2: fasting glycemia blood glucose 
(patients should fast ≥ 4 hours prior to testing 


Appendix 4: Preexisting Autoimmune Diseases and Immune Deficiencies  
Contraindicating Atezolizumab Use 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
213/Protocol MX39795, Version 11 
Visit/Period 
Timing 
Sample Type 
Every 3 weeks, on Day 1 of each cycle and on 
Day 8 of Cycle 1: Fasting blood glucose and 
fasting lipid profile (total cholesterol, high-
density lipoprotein, low-density lipoprotein and 
triglycerides, all performed following ≥ 4-hour 
fast prior to testing); amylase and lipase; and 
glycosylated hemoglobin (HbA1c). In addition, 
on Days 4, 15 of Cycle 1 and Days 8 and 15 
of Cycle 2: fasting blood glucose (patients 
should fast  4 hours prior to testing) 
– 
Ipatasertib and paclitaxel:  
On Day 1 and 15 of each 28-day cycle, on 
Days 4, 8 and 22 of Cycle 1 and on Day 8 of 
Cycle 2: fasting blood glucose and fasting lipid 
profile (total cholesterol, high-density 
lipoprotein, low-density lipoprotein and 
triglycerides; all performed following ≥ 4-hour 
fast prior to testing), amylase and lipase, and 
glycosylated hemoglobin (HbA1c) 
On Days 1, 8 and 15 of each 28-day cycle 
(until paclitaxel is stopped): hematology 
including WBC count, WBC differential count 
(including absolute neutrophil counts, 
lymphocytes), hemoglobin, hematocrit, and 
platelet count 
Additional safety visits at Day 15 of each cycle 
should coincide with paclitaxel administration. 
These visits are necessary only until paclitaxel is 
stopped. 
– 
Pemigatinib: 
Parathyroid hormone at Cycle 1 Day 1, every 
3 cycles on Day 1 starting with Cycle 3, and at 
the Safety Follow-Up Visit 
Serum phosphorus levels at: Day 1, Day 8 
and Day 15 of Cycle 1; Day 1 of Cycle 2 and 
the first day of every cycle thereafter until end 
of treatment; Safety Follow-Up Visit 
 
Note: Any patient assigned to pemigatinib who 
does not reach a target serum phosphate 
level of > 5.5 mg/dL at any time during 
Cycle 1, is compliant with taking study drug, 
and does not experience an ongoing Grade 2 
or higher treatment-related AE will increase 
the daily dose to 18 mg QD starting from 
Cycle 2 Day 1.  In patients who up-titrate to 
pemigatinib 18 mg QD, two additional 
measurements of serum phosphate level must 
occur at Cycle 2 Day 8 and Cycle 2 Day 15 .   


Appendix 4: Preexisting Autoimmune Diseases and Immune Deficiencies  
Contraindicating Atezolizumab Use 
  
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Visit/Period 
Timing 
Sample Type 
– 
Vemurafenib: amylase and lipase at each cycle 
Safety Follow-Up Visit 
30 (±7) days 
from last 
treatment or at 
initiation of 
other systemic 
anticancer 
therapy 
(whichever 
occurs first) 
 
For central laboratory 
– 
Plasma blood sample for 
exploratory research 
 
 
For local laboratory 
– 
Blood sample for hematology, 
coagulation and chemistry 
– 
Urine sample for urinalysis and 
pregnancy test 
Follow-up Period 
As indicated 
for each 
individual IMP 
 
Pregnancy tests (urine; note special 
requirements for patients on 
vismodegib, including blood test 
prior to starting treatment and 
supervised pregnancy tests 
thereafter b), occurring at the end of 
each contraception period after the 
final dose of study treatment:  
– 
2 weeks for erlotinib 
– 
1 month for ipatasertib and 
olaparib 
– 
5 weeks for entrectinib and 
pemigatinib 
– 
3 months for alectinib and 
ivosidenib 
– 
5 months for atezolizumab 
 – 6 months for bevacizumab, 
cobimetinib, vemurafenib, 
carboplatin, cisplatin, paclitaxel 
and gemcitabine 
 – 7 months for trastuzumab and 
pertuzumab 
– 
2 months and 24 months for 
vismodegib 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IMP = 
Investigational Medicinal Product; MTB = Molecular Tumor Board. 
a. Women of childbearing potential must have a negative serum pregnancy test result within 7 
days prior to first dose.  If the serum pregnancy test is uninterpretable (e.g., beta-HCG is 
elevated in the absence of other signs of pregnancy), the reason for non-interpretability should 
be adequately documented, and intra- or extra-uterine pregnancy should be ruled out by 
ultrasound within 7 days prior to the first administration of study treatment 


Appendix 4: Preexisting Autoimmune Diseases and Immune Deficiencies  
Contraindicating Atezolizumab Use 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
215/Protocol MX39795, Version 11 
b. For vismodegib, a blood pregnancy test should be performed within 7 days prior to initiating 
treatment and a supervised pregnancy test, conducted by a healthcare provider, should be 
performed at each study visit during treatment and 2 months and 24 months after their final 
dose of study treatment (the 2 and 24 months post treatment tests can be performed by a local 
health practitioner and reported to the investigator).  If study visits are delayed, the pregnancy 
tests must be performed independently of the visits and no less than monthly.  Pregnancy tests 
should have a minimum sensitivity of 25 mIU/mL, as per local availability.  Patients who 
present with amenorrhea during treatment with vismodegib should continue monthly 
pregnancy testing while on treatment. 


Appendix 4: Preexisting Autoimmune Diseases and Immune Deficiencies  
Contraindicating Atezolizumab Use 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
216/Protocol MX39795, Version 11 
Appendix 4  
Pre-existing Autoimmune Diseases and 
Immune Deficiencies Contraindicating Atezolizumab Use 
Patients who are assigned atezolizumab (as monotherapy or in combination) 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 anticancer agent.  The Medical 
Monitor is available to advise on any uncertainty over autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Anti-phospholipid 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 
 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 
 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 


Appendix 4: Preexisting Autoimmune Diseases and Immune Deficiencies  
Contraindicating Atezolizumab Use 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
217/Protocol MX39795, Version 11 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease  
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 
 Wegener granulomatosis 
 
 


Appendix 5
Response Evaluation Criteria in Solid Tumors, Version 1.1: 
Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
Measurable Tumor 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 
of:  

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan
(CT/MRI scan slice thickness/interval no greater than 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 no greater than 5 mm).  At baseline and in follow up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-target Lesions” for information on lymph node 
measurement. 
Non-measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly non-
measurable 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 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. 
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
218/Protocol MX39795, Version 11 


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masses/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: 
 
Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure 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 noncystic 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.  Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS  
Measurement of Lesions 
All measurements should be recorded in metric notation, with use of 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. 


Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 (Excerpt) 
  
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Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  Imaging-
based evaluation should always be the preferred option. 
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, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 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 on a different modality 
and interpretation of non-target disease or new lesions since the same lesion may 
appear to have a different size with use of a new modality. 
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised. 


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TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NONTARGET 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 in instances where 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 
recorded as non-measurable lesions (even if the size is  10 mm by CT scan).   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, 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.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, 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 x 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 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 


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nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
 
Complete response (CR):  disappearance of all target lesions 
 
Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
 
Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters 
 
Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline 
 
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
 
The appearance of one or more new lesions is also considered progression. 
 
Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study 
 
Special Notes on the Assessment of Target Lesions 
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 nodes regress to < 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
< 10 mm. 


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Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) 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 the CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being too small to measure.  When this 
occurs, it is important that a value be recorded on the eCRF 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 below measurable limit (BML) 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 BML should also be ticked.)  
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  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 maximal 
longest diameter for the coalesced lesion. 
Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Whereas some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the time points specified in the protocol. 
 
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 lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits 
 
PD:  unequivocal progression of existing non-target lesions 
 
The appearance of one or more new lesions is also considered progression. 


Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 (Excerpt) 
  
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Special Notes on Assessment of Progression of Non-target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, 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 disease in the face of SD or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable disease 
is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from “trace” 
to “large” or an increase in lymphangitic disease from localized to widespread or may 
be described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  Whereas it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial. 
When the patient has bone lesions at baseline.  When a bone scan is the sole 
indicator of progression, progression in bone will be defined as when at least two or 
more new lesions are seen on bone scan compared with screening.  In situations where 
the scan findings are suggestive of a flare reaction, or apparent new lesion(s) which may 
represent trauma, these results must be confirmed with other imaging modalities such as 
MRI or fine-cut CT to constitute progression.  Only a single new bone lesion on bone 
scan is required for progression if the lesion can be correlated on CT, MRI or plain film. 
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 


Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 (Excerpt) 
  
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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 pre-existing 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  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, then progression should be declared using the date of 
the initial scan. 
New osteoblastic bone lesions identified on plain films, CT, or MRI will not be considered 
progression in an otherwise stable or responding subject, if, in the opinion of the 
physician, the osteoblastic lesion appears to be healing or a response to therapy. 
EVALUATION OF RESPONSE 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table A5-1 provides a summary of the overall response status calculation at each time 
point for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table A5-2 is 
to be used. 
Table A5-1 Timepoint Response:  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 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 


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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
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. 
 
Table A5-2 Timepoint Response: Patients with Non-target Lesions Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point 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.  
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that time point. 


Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 (Excerpt) 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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Table A5-3 Best Overall Response When Confirmation Is Required 
Overall Response at 
First Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a If a CR is truly met at the first time point, any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first time point.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
NOTE: In this study, stable disease must persist for at least 6 weeks (minimum duration) to be 
considered a bona fide SD.  
 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of 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 


Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 (Excerpt) 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
228/Protocol MX39795, Version 11 
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 disease as shown in Table A5-1 , Table A5-2 , and Table A5-3 . 
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. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion. 
 
 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
229/Protocol MX39795, Version 11 
Appendix 6
Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale Study 
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 self-care; totally confined to 
bed or chair 
5 
Dead 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
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Appendix 7
Functional Assessment of Cancer Therapy – General (FACT-G) 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
231/Protocol MX39795, Version 11 
Appendix 8
Hospital Anxiety and Depression Scale (HADS) 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
232/Protocol MX39795, Version 11 
Appendix 9
EQ-5D-5L Scale 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
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Appendix 10
IMP-Specific Safety and Administration Information 
NOTE:  For each Investigational Medicinal Product, it is the responsibility of the 
investigator to check for potential interactions in the investigator’s brochure and 
local product information (if a marketed product). 
This Appendix does not detail contraindications and warning and precautions that are 
covered by inclusion and exclusion criteria of the study protocol. 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
234/Protocol MX39795, Version 11 
A10–1 
ALECTINIB  
BACKGROUND 
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in 
cancer due to gene alterations, such as chromosomal rearrangement. 
Alectinib is a highly-selective CNS-active ALK inhibitor with a benzo[b]carbazole 
scaffold.  In enzyme inhibition assays performed in vitro, this compound has been shown 
to selectively inhibit ALK.  The compound also shows high antitumor activity both in vitro 
and in vivo against tumor cell lines with some types of ALK gene alterations, including 
NSCLC and anaplastic large cell lymphoma lines harboring an ALK translocation and a 
neuroblastoma line harboring an amplified ALK gene. 
Alectinib has demonstrated antitumor activity in ALK-positive NSCLC, including in 
crizotinib-resistant disease and in patients with CNS metastases (Gadgeel et al. 2014; 
Barlesi et al. 2016; Gadgeel et al. 2016; Shaw et al. 2016; Hida et al. 2017; Peters et al. 
2017; Tamura et al. 2017). 
SAFETY 
SAFETY PROFILE 
A comprehensive description of the safety profile of alectinib is provided in the Alectinib 
Investigator’s Brochure. 
The summary information provided in the following section must always be checked 
against any update of the Alectinib Investigator’s Brochure that may have occurred after 
the protocol has been issued. 
Adverse reactions associated with Warning and Precautions: 
 
Interstitial lung disease (ILD)/pneumonitis 
 
Hepatotoxicity 
 
Severe myalgia and creatine phosphokinase (CPK) elevation 
 
Bradycardia 
 
Photosensitivity 
 
Hemolytic anemia 
 
Other selected adverse reaction: 
 
Rash 
 
Anemia  
 
Gastrointestinal disorders (nausea, vomiting, constipation, diarrhea, stomatitis) 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
235/Protocol MX39795, Version 11 
 
Dysgeusia 
 
Blood alkaline phosphatase increase 
 
Edema 
 
Vision disorders 
 
Renal impairment (Increased blood creatinine, acute kidney injury) 
 
Weight increase 
 
Management guidelines for alectinib that are applicable to this study are provided in 
A10–1. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For alectinib, there are no AESIs to be reported. 
ADMINISTRATION 
POSOLOGY 
Alectinib will be administered as a 600-mg oral dose (four 150-mg capsules) taken twice 
daily with food (total daily dose of 1200 mg). 
METHOD OF ADMINISTRATION 
The hard capsules should be swallowed whole and must not be opened or dissolved.  
They must be taken with food 
DURATION OF TREATMENT 
Treatment with alectinib should continue until loss of clinical benefit or the development 
of unacceptable toxicity.  
DELAYED OR MISSED DOSES 
If a planned dose of alectinib is missed, patients can make up that dose unless the next 
dose is due within 6 hours.  Patients should not take two doses at the same time to 
make up for a missed dose.  If vomiting occurs after taking a dose of alectinib, patients 
should take the next dose at the scheduled time. 
PROHIBITED THERAPY 
Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents (other than 
study drug treatment), ergot derivatives, probenecid, and bile acid-binding resins while 
on study treatment 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
236/Protocol MX39795, Version 11 
DOSE ADJUSTMENTS AND DISCONTINUATION 
Management of adverse events may require dose reduction, temporary interruption, or 
discontinuation of treatment with alectinib.  The dose of alectinib should be reduced in 
steps of 150 mg twice daily based on tolerability.   
Alectinib treatment should be permanently discontinued if patients are unable to tolerate 
the 300 mg twice daily dose. 
Alectinib should be permanently discontinued if the following is occurring: 
 
Patients are unable to tolerate the 300 mg twice-daily dose after two dose reductions 
due to adverse events as specified in the last section of Table A10-2 
 
Grade 3 or 4 events related to alectinib not improving within 21 days, as specified in 
the last section of Table A10-2 
 
Interstitial lung disease of any grade, regardless of relatedness to alectinib  
 
Hepatotoxicity events according to the specific criteria detailed in Table A10-2 
 
Abnormal kidney function AEs  of Grade 4 related to alectinib  
 
Hemolytic anemia according to the criteria specified in Table A10-2 
 
Bradycardia Grade 4 if no contributing concomitant medicinal product is identified, or in 
case of reoccurrence of bradycardia Grade 4. 
The dose reduction schedule is provided in Table A10-1 
Table A10-1 
 
Dose Reduction Schedule 
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 
 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
237/Protocol MX39795, Version 11 
Table A10-2 
 
Dose Modification and Discontinuation Advice for 
Specified Adverse Drug Reactions 
Event 
Action to Be Taken 
Interstitial lung disease 
/pneumonitis 
 
Patients should be monitored for pulmonary symptoms 
indicative of pneumonitis 
 
Regardless of relatedness to alectinib, study drug should be 
permanently discontinued in patients diagnosed with interstitial 
lung disease of any grade. 
Hepatotoxicity 
 
At any time during the study treatment, if symptoms compatible 
with liver injury are observed, liver enzymes should be 
measured as soon as possible. 
 
Regardless of relatedness to alectinib, the grade-dependent 
rules for dose interruptions and dose modification outlined in 
the last 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 x ULN 
– 
ALT or AST  5 x ULN for more than 2 weeks 
– 
First observation of ALT or AST  3 x ULN and total 
bilirubin  2 x ULN  
– 
First observation of ALT or AST  3 x 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 pre-treatment 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) 
The events are expected to be minimized by taking the study drug 
with meal.  In case 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 last section of 
this table. 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
238/Protocol MX39795, Version 11 
Event 
Action to Be Taken 
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 sun screen and lip balm of at least SPF 50 to help protect 
against potential sunburn. 
In case of AEs related to alectinib, follow the grade-dependent rules 
for dose interruption and modification outlined in the last section of 
this table. 
Vision disorders 
Investigators should consider referring the patients for an 
ophthalmological 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 last section of 
this table. 
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 last section of 
this table. 
Abnormal kidney 
function AEs 
 If, at any time during the study treatment, eGFR decreases by > 
50% of the baseline visit value, the patient has to be carefully 
monitored.  All of the 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 eGFR decrease by > 50% of 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 
outlined in the last 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. 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
239/Protocol MX39795, Version 11 
Event 
Action to Be Taken 
Severe myalgia and 
CPK elevations 
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 assessed 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 last section of 
this table. 
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 antihypertensive 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 (see Table A10-1 – 
dose reduction schedule) upon recovery to  Grade 1 
(asymptomatic) bradycardia or to a heart rate of  60 bpm. 
Bradycardia b 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 
(see Table A10-1 – dose reduction schedule) 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. 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
240/Protocol MX39795, Version 11 
Event 
Action to Be Taken 
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 Table A10-1 -Dose reduction 
schedule) 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 last section of this 
table. 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
241/Protocol MX39795, Version 11 
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 within 21 days, 
decrease the current dose of alectinib by 150 mg (1 capsule) BID. 
 
Second episode: If improvement to Grade  1 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 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 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 
Sodium content 
The recommended daily dose (1200 mg) of alectinib contains 2.1 
mmol (or 48 mg) sodium. To be taken into consideration by patients 
on a controlled sodium diet. 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
242/Protocol MX39795, Version 11 
Event 
Action to Be Taken 
AE  adverse event; BID  twice a day; eGFR  estimated glomerular filtration rate; 
GI  gastrointestinal; ULN  upper limit of normal. 
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Pre-existing 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. 
 
DRUG INTERACTIONS 
No pharmacokinetic interactions with alectinib requiring dosage adjustment have been 
identified. 
Refer to the Alectinib Investigator’s Brochure for a description of drug-drug interactions 
other than concomitant anticancer treatment. 
EFFECTS OF ALECTINIB ON OTHER DRUGS 
CYP Substrates 
In vitro studies indicate that neither alectinib nor its major active metabolite (M4) inhibits 
CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP2D6 at clinically relevant concentrations.  
Alectinib and M4 showed weak time-dependent inhibition of CYP3A4.  In vitro, alectinib 
exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations. 
Results from a clinical drug-drug interaction study in ALK-positive NSCLC patients 
demonstrated that multiple doses of alectinib had no influence on the exposure of MDZ, 
a sensitive CYP3A substrate.  Therefore, no dose adjustment is required for co-
administered CYP3A substrates. 
Although in vitro studies indicate that alectinib is an inhibitor of CYP2C8, physiologically-
based pharmacokinetics (PBPK) modeling supports that alectinib does not have the 
potential to increase plasma concentrations of co-administered substrates of CYP2C8 at 
clinically relevant concentrations. 
P-gp and BCRP Substrates 
In vitro, alectinib and M4 are inhibitors of the efflux transporters P-gp and breast cancer 
resistance protein (BCRP).  Therefore, alectinib may have the potential to increase 
plasma concentrations of co-administered substrates of P-gp or BCRP transporters (the 
increase in exposure is not expected to be more than 2-fold).  When alectinib is co-
administered with P-gp or BCRP substrates with narrow therapeutic index (e.g., digoxin, 
dabigatran, methotrexate), appropriate monitoring is recommended. 


Appendix 10-1:  Alectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
243/Protocol MX39795, Version 11 
Effects of Other Drugs on Alectinib 
Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both 
alectinib and its major active metabolite M4, and CYP3A contributes to 40% to 50% of 
total hepatic metabolism.  M4 has shown similar in vitro potency and activity to alectinib 
against ALK. 
CYP3A Inducers 
Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong 
CYP3A inducer, with a single oral dose of 600 mg alectinib exhibited a minor effect on 
combined exposure of alectinib and M4 (geometric mean ratio [GMR] with/without 
rifampicin [90% CI]: Cmax: 0.96 [0.88–1.05], AUCinf: 0.82 [0.74–0.90]).  Therefore, no 
dose adjustments are required when alectinib is co-administered with CYP3A inducers. 
CYP3A Inhibitors 
Co-administration of multiple oral doses of 400 mg posaconazole BID, a strong CYP3A 
inhibitor, with a single oral dose of 300 mg alectinib had a minor effect on combined 
exposure of alectinib and M4 (GMR with/without posaconazole [90% CI]: Cmax: 0.93 
[0.81–1.08], AUCinf: 1.36 [1.24–1.49]).  Therefore, no dose adjustments are required 
when alectinib is co-administered with CYP3A inhibitors. 
Medicinal Products that Increase Gastric pH 
Although the aqueous solubility of alectinib in vitro is pH-dependent, a dedicated clinical 
drug-drug interaction study with 40 mg esomeprazole once daily, a proton pump inhibitor 
(PPI), demonstrated no clinically relevant effect on the combined exposure of alectinib 
and M4.  Therefore, no dose adjustments are required when alectinib is co-administered 
with PPIs or other drugs which raise gastric pH (e.g., H2 receptor antagonists or 
antacids). 
Effect of Transporters on Alectinib Disposition 
Based on in vitro data, alectinib is not a substrate of P-gp.  Alectinib and M4 are not 
substrates of BCRP or organic anion transporting polypeptide (OATP) 1B1/B3.  In 
contrast, M4 is a substrate of P-gp.  Alectinib inhibits P-gp, and it is therefore not 
expected that co-medication with P-gp inhibitors will have a relevant effect on M4 
exposure. 
 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
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A10–2 
ATEZOLIZUMAB 
BACKGROUND 
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 antitumor 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. 
Atezolizumab shows antitumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved in various countries for the treatment of urothelial carcinoma, 
non-small cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, and 
melanoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
SAFETY 
SAFETY PROFILE 
A comprehensive description of the safety profile of atezolizumab is provided in the 
Atezolizumab Investigator’s Brochure and this summary only lists specific risks, and 
warnings and precautions. 
The summary information provided in the following section must always be checked 
against any update of the Atezolizumab Investigator’s Brochure that may have occurred 
after the protocol has been issued. 
Adverse reactions associated with Warnings and Precautions: 

Immune-mediated hepatitis

Immune-mediated pneumonitis

Immune-mediated colitis

Immune-mediated pancreatitis

Immune-mediated endocrinopathies (i.e., diabetes mellitus,
hypothyroidism/hyperthyroidism, adrenal insufficiency, hypophysitis)


Appendix 10-2:  Atezolizumab 
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
245/Protocol MX39795, Version 11 

Immune-mediated meningoencephalitis

Immune-mediated neuropathies (i.e., myasthenic syndrome/myasthenia gravis,
Guillain-Barré syndrome)

Infusion-mediated reactions

Immune mediated myocarditis

Immune-mediated nephritis

Immune-mediated myositis
Other selected adverse reactions: 

Immune-mediated uveitis

Immune-mediated myopathies, including rhabdomyolysis
Management guidelines for atezolizumab that are applicable to this study are provided in 
Tables A10-3 to A10-18 .
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For atezolizumab, AESIs include: 

Systemic lupus erythematosus

Events suggestive of hypersensitivity, infusion-mediated reactions, cytokine-
release syndrome,  hemophagocytic lymphohistiocytosis (HLH), and macrophage
activation syndrome (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


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
246/Protocol MX39795, Version 11 
ADMINISTRATION 
POSOLOGY AND ROUTE 
The dose of atezolizumab will be 1,200 mg administered intravenously every three 
weeks. 
Administration in combination with chemotherapy 
For the doses of chemotherapy to be administered in combination with atezolizumab, 
refer to Section 4.3.4.7 in the Protocol. 
METHOD OF ADMINISTRATION 
The infusions must not be administered as an intravenous push or bolus. 
The initial dose of atezolizumab must be administered over 60 minutes.  If the first 
infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. 
For instructions on dilution and handling of the medicinal product before administration, 
refer to the Atezolizumab Investigator’s Brochure. 
Administration in combination with chemotherapy 
Atezolizumab and chemotherapy must be administered sequentially and not mixed in the 
same infusion bag.  Chemotherapy should be administered after atezolizumab. 
DURATION OF TREATMENT 
Treatment with atezolizumab should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  
 
PROPHYLAXIS FOR ATEZOLIZUMAB (WHEN NOT ADMINISTERED WITH 
PACLITAXEL) 
No premedication is indicated for the administration of Cycle 1 of atezolizumab. 
Patients who experience an infusion-related reaction with Cycle 1 of atezolizumab may 
receive premedication with antihistamines or antipyretics/analgesics (e.g., 
acetaminophen) for subsequent infusions. 
PREMEDICATION FOR ATEZOLIZUMAB + PACLITAXEL 
All patients should be premedicated prior to paclitaxel administration to prevent severe 
hypersensitivity reactions.  This premedication should consist of the institution’s standard 
of care or one of the following premedications: 
 
Dexamethasone 20 mg orally approximately 12 hours prior and 6 hours prior to the 
paclitaxel infusion  


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
247/Protocol MX39795, Version 11 
– 
Patients may be treated with dexamethasone 10−20 mg IV within 1 hour prior to 
paclitaxel infusion if the patient did not take the oral dexamethasone 
 
 
Diphenhydramine 50 mg IV (or equivalent) 30−60 minutes prior to paclitaxel infusion 
 
Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30−60 minutes prior to 
paclitaxel infusion 
 
DELAYED OR MISSED DOSES 
If a planned dose of atezolizumab is missed, it should be administered as soon as 
possible; it is recommended not to wait until the next planned dose. The schedule of 
administration must be adjusted to maintain a 3-week interval between doses. 
PROHIBITED THERAPY 
 
Systemic immunostimulatory agents (including, but not limited 
to, interferons and IL2) 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 
 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS ASSOCIATED 
WITH ATEZOLIZUMAB 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice, unless special management is 
indicated, in which case management should be per protocol according to instructions 
provided in this appendix.  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 atezolizumab 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 


Appendix 10-2:  Atezolizumab 
  
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treatment and survival follow-up.  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. 
 
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. 
DOSE MODIFICATIONS  
There will be no dose reductions of atezolizumab. 
Administration in combination with chemotherapy 
Patients may continue therapy with atezolizumab during periods of reversible 
chemotherapy-induced myelosuppression, but they should be monitored carefully for 
complications of neutropenia and other toxicities during this time.  
For platinum-based chemotherapy dose modifications, see the relevant EMA Summary 
of Product Characteristics. 
DOSE INTERRUPTION OR DISCONTINUATION 
Dose interruption and discontinuation advice are summarized in the “Management 
Guidelines below (including Tables A10-3 to A10-18). 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
249/Protocol MX39795, Version 11 
Discontinuation 
Administration in combination with chemotherapy 
 
After platinum-based chemotherapy is discontinued (per protocol or due to toxicity), 
treatment with atezolizumab will continue per protocol 
 
If atezolizumab treatment is discontinued prior to the planned end of concomitant 
chemotherapy, treatment with chemotherapy may continue in the Treatment Period 
per the guidance provided in Section 4.3.4.7. 
 
Interruptions 
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 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. 
Summary of Reasons for Dose Discontinuation:  
 
Myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome and 
meningoencephalitis of any grade 
 
For Grade 4 toxicities except for endocrinopathies that are controlled with 
replacement hormones 
 
For Grades 3–4 pneumonitis, hepatitis, type 1 diabetes mellitus, infusion-related 
reactions 
 
AND for the specific adverse reactions described in Tables A10-3 to A10-18, 
atezolizumab should be permanently discontinued: 
 
For any recurrent event at Grade ≥ 3 severity 
 
If a treatment-related toxicity does not resolve to Grade 0 or Grade 1 within 12 
weeks after adverse reaction onset date  
 
If a corticosteroid dose of > 10 mg prednisone or equivalent per day is required for 
treatment-related toxicity beyond 12 weeks after adverse reaction onset date 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
250/Protocol MX39795, Version 11 
 
MANAGEMENT GUIDELINES 
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 administration in a clinical setting: 
 
Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for intramuscular (preferred route), subcutaneous, intravenous, 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 
administration, the following procedures should be performed: 
– 
Stop the study treatment administration, if possible 
– 
Call for additional medical assistance 
– 
Maintain an adequate airway 
– 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible 
– 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge 
– 
Continue to observe the patient and document observations 
 
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 and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment.   


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
251/Protocol MX39795, Version 11 
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 A10-3. 
Table A10-3 
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 1−2 mg/kg/day oral prednisone or equivalent 
 
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, d 
 
For recurrent events or events with no improvement after 48–
72 hours of corticosteroids, treat as a Grade 3 or 4 event 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
252/Protocol MX39795, Version 11 
Event 
Management 
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 with or without transbronchial biopsy or BAL is 
recommended 
 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 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. 
 
HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table A10-4. 
Patients 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. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
253/Protocol MX39795, Version 11 
Table A10-4 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 
Continue atezolizumab. 
 
Monitor LFTs until values resolve to within normal limits or to 
baseline values. 
Hepatic event, 
Grade 2 
All events: 
 
Monitor LFTs more frequently until return to baseline values 
 
Events of > 5 days’ duration: 
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
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 
Hepatic event, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 
Consider patient referral to gastrointestinal specialist for evaluation 
and liver biopsy to establish etiology of hepatic injury. 
 
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. 
LFT = liver function test. 
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. 
 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
254/Protocol MX39795, Version 11 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table A10-5. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
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.  
Table A10-5 
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 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
255/Protocol MX39795, Version 11 
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. 
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 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. 
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table A10-6. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
256/Protocol MX39795, Version 11 
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. 
Table A10-6 
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. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
257/Protocol MX39795, Version 11 
Event 
Management 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
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. 
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). 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
258/Protocol MX39795, Version 11 
Event 
Management 
 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 
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. 
 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table A10-7. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
259/Protocol MX39795, Version 11 
Table A10-7 
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 the 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 an 
of 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. 
 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table A10-8. 
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 pre-existing 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 A10-8. 
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 A10-8.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
261/Protocol MX39795, Version 11 
 
Table A10-8 
Management Guidelines for Immune-Mediated Cardiac 
Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2-
4 
Immune-mediated 
pericardial disorders, 
Grades 2-4 
 
Permanently discontinue 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. 
 
 
INFUSION-RELATED REACTIONS AND CYTOKINE RELEASE SYNDROME 
There may be significant overlap in signs and symptoms of IRRs and cytokine-release 
syndrome (CRS).  While IRRs occur during or within 24 hours after treatment 
administration, time to onset of CRS may vary.  Differential diagnosis should be applied, 
particularly for late-onset CRS (occurring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 
sepsis or infections, HLH, tumor lysis syndrome, early disease progression, or other 
manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured on the 
Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" or "cytokine-
release syndrome").  Avoid ambiguous terms such as "systemic reaction."  Cases of 
late-onset CRS should be reported as "cytokine-release syndrome" on the Adverse 
Event eCRF.  Associated signs and symptoms of an IRR should be recorded on the 
dedicated Infusion-Related Reaction eCRF. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
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If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms of an IRR also recorded separately on the 
dedicated Infusion-Related Reaction eCRF. 
Management 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines, 
antipyretics, 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 
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 A10-9. 
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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Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
263/Protocol MX39795, Version 11 
Table A10-9 
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, antipyretics, 
and/or analgesics, and monitor closely for IRRs and/or 
CRS 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
264/Protocol MX39795, Version 11 
Event 
Management 
Grade 2 a 
Fever b with hypotension not 
requiring vasopressors  
and/or  
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 atezolizumab, and contact the Medical 
Monitor e 
 
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, antipyretics, 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 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
265/Protocol MX39795, Version 11 
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, non-rebreather 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 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
266/Protocol MX39795, Version 11 
Event 
Management 
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 
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: These management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019). 
a  Grading system for these management guidelines is based on ASTCT consensus grading for 
CRS. NCI CTCAE (version as specified in the protocol) 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 event.  The decision to re-challenge patients with atezolizumab should 
be based on the investigator’s benefitrisk assessment and documented by the investigator .  


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
267/Protocol MX39795, Version 11 
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). 
 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up 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 A10-10. 
Table A10-10 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 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
268/Protocol MX39795, Version 11 
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. 
 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
269/Protocol MX39795, Version 11 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab 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 A10-11. 
Table A10-11 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 
Dermatologic 
event, Grade 4 
 
Permanently discontinue atezolizumab and contact the Medical 
Monitor c 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
270/Protocol MX39795, Version 11 
Event 
Management 
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, 
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 of 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. 
 
 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic work-up is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table A10-12, with specific guidelines for myelitis provided in Table A10-13. 
Table A10-12 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. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
271/Protocol MX39795, Version 11 
Event 
Management 
Immune-mediated 
neuropathy including 
facial paresis, Grade 2  
 
Withhold 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 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 1−2 mg/kg/day oral or IV prednisone or 
equivalent 
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 of 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 or equivalent 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. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
272/Protocol MX39795, Version 11 
Table A10-13 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. 
 
 
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 A10-
14. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
273/Protocol MX39795, Version 11 
Table A10-14 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 
 
 
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 A10-15. 
Table A10-15 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 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
274/Protocol MX39795, Version 11 
Event 
Management 
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 of 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. 
 
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 A10-16. 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
275/Protocol MX39795, Version 11 
Table A10-16 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 
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 
the Medical Monitor c 
 
For recurrent events, treat as a Grade 4 event. Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
276/Protocol MX39795, Version 11 
Event 
Management 
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 of 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. 
 
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 (McClain and Eckstein).  A patient should be classified as having 
HLH if five of the following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
277/Protocol MX39795, Version 11 
 
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. (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 A10-17. 
Table A10-17 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 Rosee 2015; Schram and Berliner 2015; La Rosee et al. 
2019) 


Appendix 10-2:  Atezolizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
278/Protocol MX39795, Version 11 
Event 
Management 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
DRUG INTERACTIONS  
No formal pharmacokinetic drug interaction studies have been conducted with 
atezolizumab.  The drug interaction potential of atezolizumab is unknown. 
 
 


A10–3 
BEVACIZUMAB 
Bevacizumab will be administered in combination with erlotinib—Refer to 
Appendix 10-6 for details on erlotinib. 
BACKGROUND 
Bevacizumab is a recombinant humanized anti-vascular endothelial growth factor (anti-
VEGF) monoclonal immunoglobulin G1 (IgG1) antibody, produced by DNA technology in 
Chinese Hamster Ovary cells. 
VEGF, a diffusible glycoprotein produced by normal and neoplastic cells, is an important 
regulator of physiologic and pathologic angiogenesis. Increased levels of VEGF 
expression have been found in most human malignancies examined to date [1-3]. 
Increased VEGF serum levels have been correlated with poor survival. Nonclinical 
studies have shown that the murine anti-human VEGF monoclonal antibody A4.6.1 
inhibits the growth of human tumor xenografts, and a humanized variant of this antibody 
(bevacizumab) has therefore been developed as a treatment of various cancers. 
Bevacizumab has been approved in various countries for the treatment of patients with 
metastatic carcinoma of the colon or rectum, unresectable, locally advanced, recurrent 
or metastatic non-squamous non-small-cell lung cancer; locally recurrent or metastatic 
breast cancer, advanced and/or metastatic renal cell cancer; epithelial ovarian, fallopian 
tube or primary peritoneal cancer; malignant glioma (WHO Grade IV -glioblastoma); and 
cervical cancer. 
Bevacizumab, in combination with erlotinib, has been approved for first-line treatment of 
adult patients with unresectable advanced, metastatic or recurrent non-squamous non-
small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating 
mutations. 
SAFETY 
SAFETY PROFILE 
Comprehensive descriptions of the safety profiles of bevacizumab and erlotinib are 
provided in their respective EMA Summary of Product Characteristics. 
The summary information provided in the following section must always be checked 
against any update of the Bevacizumab EMA Summary of Product Characteristics that 
may have occurred after the protocol has been issued. 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
279/Protocol MX39795, Version 11 


Appendix 10-3:  Bevacizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
280/Protocol MX39795, Version 11 
Treatment-Emergent Adverse Events 
The most serious adverse reactions were: 
 
Gastrointestinal perforations  
 
Hemorrhage, including pulmonary hemorrhage/hemoptysis, which is more 
common in non-small cell lung cancer patients  
 
Arterial thromboembolism 
 
Adverse reactions associated with Warnings and Precautions: 
 
Gastrointestinal perforations and fistulae 
 
Non-GI fistulae  
 
Hemorrhage 
 
Pulmonary hemorrhage/hemoptysis 
 
Hypertension 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
 
Arterial Thromboembolism 
 
Venous thromboembolism events, including pulmonary embolism 
 
Congestive heart failure 
 
Wound-healing complications 
 
Neutropenia and infections 
 
Proteinuria 
 
Hypersensitivity reactions, infusion reactions 
 
Osteonecrosis of the jaw 
 
Ovarian failure/fertility 
 
Management guidelines for bevacizumab that are applicable to this study are provided in 
Table A10-18. 
Adverse Events of Special Interest 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For bevacizumab, AESIs with grades include: 
 
Grade ≥ 3 hypertension 
 
Grade ≥ 3 proteinuria  
 
Any grade GI perforation, abscesses, or fistulae 


Appendix 10-3:  Bevacizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
281/Protocol MX39795, Version 11 
 
Grade ≥ 3 wound-healing complication 
 
Hemorrhage  
 
Any grade CNS bleeding 
 
Grade ≥ 2 hemoptysis) 
 
Other Grade ≥ 3 bleeding 
 
Any grade arterial thromboembolic event 
 
Grade ≥ 3 venous thromboembolic event 
 
Any grade posterior reversible encephalopathy syndrome (PRES) 
 
Grade ≥ 3 CHF  
 
Grade ≥ 2 non-GI fistula or abscess 
 
For erlotinib, AESIs include: 
 
Interstitial lung disease 
 
ADMINISTRATION 
POSOLOGY  
When used in addition to erlotinib, bevacizumab will be administered at the dose of 15 
mg/kg of body weight given once every 3 weeks as an intravenous infusion. 
The initial dose should be delivered over 90 minutes as an intravenous infusion. If the 
first infusion is well tolerated, the second infusion may be administered over 60 minutes. 
If the 60-minute infusion is well tolerated, all subsequent infusions may be administered 
over 30 minutes.  
It should not be administered as an intravenous push or bolus. 
DURATION OF TREATMENT 
Treatment with bevacizumab in addition to erlotinib should continue until loss of clinical 
benefit or the development of unacceptable toxicity.  
DOSE MODIFICATIONS DURING TREATMENT 
Dose Adjustments 
Dose reduction for adverse reactions is not recommended. If indicated, therapy should 
either be permanently discontinued or temporarily suspended, as described in 
Table A10-18. 


Appendix 10-3:  Bevacizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
282/Protocol MX39795, Version 11 
Interaction With Erlotinib 
No pharmacokinetic interactions with erlotinib have been identified. 
MANAGEMENT AND DISCONTINUATION ADVICE FOR SPECIFIED 
ADVERSE DRUG REACTIONS 
 
Table A10-18 Guidelines for Management and Discontinuation of Patients 
Who Experience Specific Adverse Events 
Event 
Action to Be Taken 
Gastrointestinal (GI) 
perforations and fistulae 
Permanently discontinue bevacizumab 
Non-GI fistulae 
 
Permanently discontinue bevacizumab if tracheoesophageal (TE) 
fistula or any Grade 4 fistula.  Limited information is available on 
the continued use of bevacizumab in patients with other fistulae. 
In cases of internal fistula not arising in the GI tract, 
discontinuation of bevacizumab should be considered 
Hemorrhage – especially 
tumor-associated 
hemorrhage 
Permanently discontinue bevacizumab if Grade 3 or 4 bleeding 
during bevacizumab therapy 
Monitor for signs and symptoms of CNS bleeding, and 
discontinue treatment in cases of intracranial bleeding 
Exercise caution before initiating bevacizumab therapy in patients 
with congenital bleeding diathesis, acquired coagulopathy or in 
patients receiving full dose of anticoagulants for the treatment of 
thromboembolism at time of initiating bevacizumab 
Hypertension 
Permanently discontinue bevacizumab if medically significant 
hypertension cannot be adequately controlled with 
antihypertensive therapy, or if, the patient develops hypertensive 
crisis or hypertensive encephalopathy 
Posterior Reversible 
Encephalopathy 
Syndrome (PRES) 
PRES can present with the following signs and symptoms 
(among others): seizures, headache, altered mental status, visual 
disturbance, or cortical blindness, with or without associated 
hypertension 
A diagnosis of PRES requires confirmation by brain imaging, 
preferably MRI 
If developing PRES, treatment of specific symptoms including 
control of hypertension is recommended along with 
discontinuation of bevacizumab 
The safety of reinitiating bevacizumab therapy in patients 
previously experiencing PRES is not known 
Arterial thromboembolism 
Permanently discontinue bevacizumab if arterial 
thromboembolism 
Patients with a history of arterial thromboembolism, diabetes or 
age > 65 years have an increased risk of developing arterial 
thromboembolic events during bevacizumab therapy.  Caution 
should be taken when treating such patients with bevacizumab 


Appendix 10-3:  Bevacizumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
283/Protocol MX39795, Version 11 
Event 
Action to Be Taken 
Venous thromboembolism 
events, including 
pulmonary embolism 
Permanently discontinue bevacizumab in patients with life-
threatening (Grade 4) venous thromboembolic events, including 
pulmonary embolism 
Patients with thromboembolic events ≤Grade 3 need to be 
closely monitored 
Congestive heart failure 
Caution should be exercised when treating patients with clinically 
significant cardiovascular disease such as pre-existing coronary 
artery disease, or congestive heart failure 
Wound Healing 
In patients who experience wound healing complications during 
bevacizumab treatment, bevacizumab should be withheld until 
the wound is fully healed 
Bevacizumab therapy should be withheld for elective surgery 
Bevacizumab therapy should be discontinued in patients who 
develop necrotizing fasciitis, and appropriate treatment should 
be promptly initiated 
Proteinuria 
Permanently discontinue bevacizumab in the event of nephrotic 
syndrome 
Testing for proteinuria is recommended prior to administration of 
bevacizumab therapy. If urine protein levels of ≥ 2g /24 hrs held 
bevacizumab until recovery to < 2g /24hrs 
Hypersensitivity 
Reactions, Infusion 
Reactions 
Close observation of the patient during and following the 
administration of bevacizumab is recommended 
If a reaction occurs, the infusion should be discontinued and 
appropriate medical therapies should be administered 
Osteonecrosis of the jaw 
Caution should be exercised when bevacizumab and intravenous 
bisphosphonates are administered simultaneously or sequentially 
A dental examination and appropriate preventive dentistry should 
be considered prior to starting the treatment with bevacizumab. In 
patients who have previously received or are receiving 
intravenous bisphosphonates invasive dental procedures should 
be avoided 
 
Please also refer to the Erlotinib EMA Summary of Product Characteristics and 
Appendix 10-6 for warnings and precautions when using bevacizumab in combination 
with erlotinib. 
DRUG INTERACTIONS 
No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics 
of co-administered erlotinib (and its active metabolite OSI-420). 
No formal pharmacokinetic drug interaction studies have been conducted with 
bevacizumab, other than interactions with anti-neoplastic agents. 


 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
/Protocol MX39795, Version 11 
A10–4 
COBIMETINIB  
 
Cobimetinib will be administered in combination with vemurafenib—Refer to 
Appendix 10-13 for details on vemurafenib. 
 
BACKGROUND ON COBIMETINIB 
Cobimetinib is a potent and highly selective small molecule inhibitor of MEK1 and MEK2, 
central components of the RAS/RAF pathway.  
Inhibition of MEK is a promising strategy to control the growth of tumors that are 
dependent on aberrant signaling in the RAS/RAF pathway.  
Cobimetinib is being developed for use in the treatment of cancers. Cobimetinib, in 
combination with vemurafenib, has been approved in various countries for the treatment 
of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. 
SAFETY 
SAFETY PROFILE 
A comprehensive description of the safety profile of cobimetinib as monotherapy and in 
combination with vemurafenib is provided in the Cobimetinib Investigator’s Brochure and 
this summary only lists specific risks, and warnings and precautions. 
Identified risks with Cobimetinib are: 
 
Hemorrhage 
 
Serous retinopathy 
 
Left ventricular dysfunction 
 
Rhabdomyolysis and CPK elevations 
 
Pneumonitis  
 
Photosensitivity (when administered in combination with vemurafenib) 
 
Diarrhea 
 
Potential risks with Cobimetinib are: 
 
Liver laboratory abnormalities 
 
 
Management guidelines for cobimetinib adverse reactions that are applicable to this 
study are provided in Table A10-19. 


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
285/Protocol MX39795, Version 11 
The summary information provided in the following sections must always be checked 
against any update of the Cobimetinib Investigator’s Brochure that may have occurred 
after the protocol has been issued. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For cobimetinib, AESIs include: 
 
Grade ≥ 1 retinal vein occlusion  
 
Any retinal detachment, retinal pigment epithelium detachment, neurosensory 
retinal detachment or central serous chorioretinopathy 
 
Rhabdomyolysis or Grade ≥ 3 CPK elevation 
 
Grade ≥ 3 hemorrhage or any grade cerebral hemorrhage 
 
Grade ≥ 3 rash 
 
Grade ≥ 3 diarrhea 
 
Symptomatic heart failure or Grade ≥ 2 left ventricular ejection fraction reduction 
 
Photosensitivity 
 
Grade ≥ 3 hepatotoxicity  
 
ADMINISTRATION OF COBIMETINIB 
POSOLOGY AND ROUTE 
The dose of cobimetinib will be 60 mg (3 tablets of 20 mg) once daily. 
Cobimetinib is taken on a 28-day cycle.  Each dose consists of three 20 mg tablets 
(60 mg) and should be taken once daily for 21 consecutive days (Day 1 to 21 of 
treatment cycle), followed by a 7-day break (Day 22 to 28 of treatment cycle).  Each 
subsequent cobimetinib treatment cycle should start after the 7-day treatment break has 
elapsed. 
For instructions on handling of the medicinal product, refer to the Cobimetinib 
Investigator’s Brochure. 
DURATION OF TREATMENT 
Treatment with cobimetinib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
286/Protocol MX39795, Version 11 
DELAYED OR MISSED DOSES 
If a planned dose of cobimetinib is missed, it can be taken up to 12 hours prior to the 
next dose to maintain the once -daily regimen.  If vomiting occurs after taking a dose of 
cobimetinib the patient should not take an additional dose on that day and treatment 
should be continued as prescribed the following day.  
DOSE MODIFICATIONS AND DISCONTINUATION DURING TREATMENT 
Dose modification of cobimetinib is independent of vemurafenib dose modification. If 
doses are omitted for toxicity, these doses should not be replaced.  Once the dose has 
been reduced, it should not be increased at a later time.  
Table A10-19 below gives general cobimetinib dose modification guidance. 
Table A10-19 Recommended Cobimetinib Dose Modifications 
Grade (CTCAE) a 
Recommended Cobimetinib Dose 
Grade 1 or Grade 2 (tolerable)  
No dose reduction.  Maintain cobimetinib at a dose of 
60 mg once daily (3 tablets) 
Grade 2 (intolerable) or Grade 3/4  
 
 
1st Appearance 
Interrupt treatment until Grade ≤ 1, restart treatment 
at 40 mg once daily (2 tablets) 
 
2nd Appearance 
Interrupt treatment until Grade ≤ 1, restart treatment 
at 20 mg once daily (1 tablet) 
 
3rd Appearance 
Consider permanent discontinuation 
a The intensity of clinical adverse events graded by the Common Terminology Criteria for 
Adverse Events v4.0 (CTCAE) 
 
Summary of Dose Discontinuation Advice (see Below for Details): 
Cobimetinib should be permanently discontinued for: 
 
Grade 4 hemorrhage events attributed to cobimetinib 
 
Symptomatic or asymptomatic decrease of LVEF < 40% or ≥ 10% absolute 
decrease from baseline after treatment break or recurrent symptomatic absolute 
decrease of LVEF < 10% (see Table A10-19 for details) 
 
Rhabdomyolysis or symptomatic CPK elevations not improving within 4 weeks of 
dose interruption 
 
Liver laboratory abnormalities not resolving to Grade ≤ 1 within 4 weeks of dose 
interruption or if Grade 4 liver laboratory abnormalities recur after initial 
improvement 


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
287/Protocol MX39795, Version 11 
 
QTc increase meets values of both > 500 ms and > 60 ms change from pre-
treatment values or 3rd occurrence of QTc > 500 ms during treatment and change 
from pre-treatment value remains ≤ 60ms 
 
Dose modification and discontinuation advice for hemorrhage  
Grade 4 events or cerebral hemorrhage:  
 
Cobimetinib treatment should be interrupted 
 
Cobimetinib treatment should be permanently discontinued for hemorrhage events 
attributed to cobimetinib 
 
Grade 3 events:  
 
Cobimetinib treatment should be interrupted during evaluation of the event  
 
There are no data on the effectiveness of cobimetinib dose modification for 
hemorrhage events 
 
Clinical judgment should be applied when considering restarting cobimetinib 
treatment.  Vemurafenib dosing can be continued when cobimetinib treatment is 
interrupted, if clinically indicated 
 
Dose modification and discontinuation advice for left ventricular dysfunction  
 
Permanent discontinuation of cobimetinib treatment should be considered if cardiac 
symptoms are attributed to cobimetinib and do not improve after temporary 
interruption 
 
Table A10-20 Recommended Dose Modifications and Discontinuation for 
Cobimetinib in Patients With Left Ventricular Ejection Fraction 
(LVEF) Decrease From Baseline  
Patient 
LVEF Value 
Recommended 
Cobimetinib 
Dose 
Modification 
LVEF Value 
Following 
Treatment Break 
Recommended 
Cobimetinib Daily 
Dose 
Asymptomatic 
≥ 50%  
(or 40-49% 
and < 10% 
absolute 
decrease 
from 
baseline) 
Continue at 
current dose 
N/A 
N/A 
< 40% 
1st occurrence: 40 mg 
2nd occurrence: 20 mg 


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
288/Protocol MX39795, Version 11 
Patient 
LVEF Value 
Recommended 
Cobimetinib 
Dose 
Modification 
LVEF Value 
Following 
Treatment Break 
Recommended 
Cobimetinib Daily 
Dose 
(or 40-49% 
and ≥ 10% 
absolute 
decrease 
from 
baseline) 
Interrupt 
treatment for 2 
weeks 
< 10% absolute 
decrease from 
baseline 
3rd occurrence:  
permanent 
discontinuation 
< 40%  
(or ≥ 10% absolute 
decrease from 
baseline) 
Permanent 
discontinuation 
Symptomatic 
N/A 
Interrupt 
treatment for 4 
weeks 
Asymptomatic and 
< 10% absolute 
decrease from 
baseline 
1st occurrence: 40 mg 
2nd occurrence: 20 mg 
3rd occurrence:  
permanent 
discontinuation 
Asymptomatic and 
< 40%  
(or ≥ 10% absolute 
decrease from 
baseline) 
Permanent 
discontinuation 
Symptomatic 
regardless of LVEF 
Permanent 
discontinuation 
N/A = Not Applicable 
Vemurafenib treatment can be continued when cobimetinib treatment is modified, if clinically 
indicated. 
 
Dose modification and discontinuation advice for rhabdomyolysis and CPK elevations  
Rhabdomyolysis or symptomatic CPK elevations  
 
Cobimetinib treatment should be interrupted 
 
If rhabdomyolysis or symptomatic CPK elevations do not improve within 4 weeks, 
discontinue permanently cobimetinib 
 
If severity is improved by at least one grade within 4 weeks, cobimetinib could be 
restarted at a dose reduced by 20 mg, if clinically indicated. Vemurafenib dosing can 
be continued when cobimetinib treatment is modified, if clinically indicated. 
 


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
289/Protocol MX39795, Version 11 
Asymptomatic CPK elevations  
Grade 4: 
 
Cobimetinib treatment should be interrupted. If CPK elevations do not improve to 
Grade ≤3 within 4 weeks following dose interruption, discontinue permanently 
cobimetinib 
 
If CPK improves to Grade ≤3 within 4 weeks, cobimetinib could be restarted, if 
clinically indicated, at a dose reduced by 20 mg and the cobimetinib patient should 
be closely monitored. Vemurafenib dosing can be continued when treatment is 
modified, if clinically indicated. 
 
Grade ≤3: 
 
After rhabdomyolysis has been ruled out, cobimetinib dosing does not need to be 
modified 
 
Dose modification advice for cobimetinib when used with vemurafenib  
Liver laboratory abnormalities  
 
Grade 3: 
– 
Cobimetinib dose should not be modified. The dose of vemurafenib may be reduced 
as clinically appropriate - Refer to the vemurafenib dose modification 
recommendation 
 
 
Grade 4: 
– 
Cobimetinib treatment and vemurafenib treatment should be interrupted.  
If liver laboratory abnormalities improve to Grade ≤1 within 4 weeks, cobimetinib 
should be restarted at a dose reduced by 20 mg and vemurafenib at a clinically 
appropriate dose, per dose modification recommendation 
– 
Cobimetinib treatment and vemurafenib treatment should be discontinued if liver 
laboratory abnormalities do not resolve to Grade ≤1 within 4 weeks or if Grade 4 
liver laboratory abnormalities recur after initial improvement 
 
Photosensitivity  
Grade ≤2 (tolerable) photosensitivity should be managed with supportive care.  
If patients experience Grade 2 (intolerable) or Grade ≥3 photosensitivity, cobimetinib 
and vemurafenib should be interrupted until resolution to Grade ≤1.  Treatment can be 
restarted with no change in cobimetinib dose.  Vemurafenib dosing should be reduced 
as clinically appropriate (refer to the vemurafenib dose modification recommendations).  


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
290/Protocol MX39795, Version 11 
Rash 
The dose of cobimetinib and/or vemurafenib may be either temporarily interrupted and/or 
reduced as clinically indicated.  
Additionally: 
 
Grade ≤2 (tolerable) rash should be managed with supportive care.  Cobimetinib 
dosing can be continued without modification 
 
Grade 2 (intolerable) or Grade ≥3 acneiform rash: General dose modification 
recommendations in Table A10-19 for cobimetinib should be followed.  Vemurafenib 
dosing can be continued when cobimetinib treatment is modified (if clinically 
indicated) 
 
Grade 2 (intolerable) or Grade ≥3 non-acneiform or maculopapular rash: 
cobimetinib dosing can be continued without modification if clinically indicated.  
Vemurafenib dosing may be either temporarily interrupted and/or reduced (refer to 
the vemurafenib dose modification recommendations) 
 
QT prolongation  
If during treatment the QTc exceeds 500 msec, please refer to dose modifications for 
vemurafenib.  No dose modification of cobimetinib is required when taken in combination 
with vemurafenib. 
Please also refer to the Vemurafenib Investigator’s Brochure and to its warnings and 
precautions when using cobimetinib in combination with vemurafenib. 
INTERACTION WITH VEMURAFENIB 
There is no evidence of any clinically significant drug interaction between cobimetinib 
and vemurafenib. 
MANAGEMENT ADVICE FOR SPECIFIED ADVERSE DRUG REACTIONS 
 


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
291/Protocol MX39795, Version 11 
Table A10-21 Guidelines for Management and Discontinuation of Patients 
Who Experience Specific Adverse Events on Cobimetinib Plus 
Vemurafenib 
Event 
Action to Be Taken  
Hemorrhage, including major 
hemorrhages, defined as 
symptomatic bleeding in a critical 
area or organ 
Caution should be used in patients with additional risk 
factors for bleeding, and in patients that use concomitant 
medications that increase the risk of bleeding (including 
antiplatelet or anticoagulant therapy) 
Serous Retinopathy 
(mostly chorioretinopathy or retinal 
detachment) 
If reporting new or worsening visual disturbances, an 
ophthalmologic examination is strongly recommended.  
If serous retinopathy is diagnosed, vemurafenib 
treatment should be withheld until visual symptoms 
improve to Grade ≤ 1.  
Serious retinopathy can be managed with treatment 
interruption, dose reduction or with treatment 
discontinuation. 
Patients should be advised to use caution when driving 
or using machines if their vision is impaired. 
Left Ventricular Dysfunction 
Decrease in LVEF from baseline can be managed using 
treatment interruption, dose reduction or with treatment 
discontinuation 
All patients restarting treatment with a dose reduction of 
vemurafenib should have LVEF measurements taken at 
approximately 2 weeks, 4 weeks, 10 weeks, and 16 
weeks, and then as clinically indicated until treatment 
discontinuation 
Rhabdomyolysis and CPK 
Elevations 
Monitor CPK at baseline and during treatment (per 
protocol) or more frequently as clinically indicated. 
Liver Laboratory Abnormalities 
(increases in ALT, AST, and ALP) 
 
Monitor liver laboratory tests at baseline and during 
treatment (per protocol) or more frequently as clinically 
indicated. 
Manage Grade 3 and 4 liver laboratory abnormalities 
with dose interruption, reduction, or discontinuation of 
both cobimetinib and vemurafenib 


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
292/Protocol MX39795, Version 11 
Event 
Action to Be Taken  
Hypersensitivity 
In reported cases occurring in patients exposed to 
vemurafenib, signs and symptoms of hypersensitivity or 
anaphylaxis improved or resolved after treatment with 
steroids and/or other medications as clinically indicated. 
QT prolongation 
● 
QTc increase meets 
values of both > 500 
ms and >60 ms 
change from pre-
treatment values  
● 
1st occurrence of 
QTc>500 ms during 
treatment and change 
from pre-treatment 
value remains ≤60 ms 
● 
2nd occurrence of 
QTc>500 ms during 
treatment and change 
from pre-treatment 
value remains ≤60ms 
● 
3rd occurrence of 
QTc>500 ms during 
treatment and change 
from pre-treatment 
value remains ≤60ms 
 
● 
Discontinue permanently 
 
 
 
● 
Temporarily interrupt treatment until QTc decreases below 
500 ms 
Reduce dose by 240 mg twice daily 
● 
Temporarily interrupt treatment until QTc decreases below 
500 ms 
Reduce dose by 240 mg twice daily 
● 
Discontinue permanently 
 
DRUG INTERACTIONS 
Effects of Concomitant Medications on Cobimetinib 
CYP3A inhibitors/inducers 
Cobimetinib is metabolized by CYP3A and exposures increased approximately 7-fold in 
the presence of a potent CYP3A inhibitor (itraconazole) in healthy subjects.  Because 
cobimetinib is a sensitive substrate of CYP3A, it is likely that cobimetinib exposures will 
be significantly lower in the presence of CYP3A inducers.  Therefore, concomitant 
administration of potent CYP3A inducers and inhibitors is not recommended.  Caution 
should be exercised when cobimetinib is co-administered with moderate CYP3A 
inducers and inhibitors). 
Acid reducing agents 
Cobimetinib PK are not altered by the co-administration of a proton pump inhibitor.  
Thus, gastric pH elevations do not affect cobimetinib absorption.  


Appendix 10-4:  Cobimetinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
293/Protocol MX39795, Version 11 
Effects of Cobimetinib on Concomitant Medications 
CYP Substrates 
Co-administration of cobimetinib 60 mg once daily for 15 days with a single 30 mg dose 
of dextromethorphan (sensitive CYP2D6 substrate) or a 2 mg dose of midazolam 
(sensitive CYP3A substrate) to 20 patients with solid tumors did not change 
dextromethorphan or midazolam systemic exposure.  In vitro data indicate that 
cobimetinib may inhibit CYP3A and CYP2D6.  Cobimetinib is not an inhibitor of CYP1A2, 
2B6, 2C8, 2C9 and 2C19 or an inducer of CYP1A2, 2B6 and 3A4 at clinically relevant 
concentrations. 


A10–5 
ENTRECTINIB 
BACKGROUND 
Entrectinib (also known as RXDX-101) is a potent inhibitor of the receptor tyrosine 
kinases TrkA (encoded by the gene neurotrophic tyrosine receptor kinase NTRK1), TrkB 
(encoded by the gene NTRK2), TrkC (encoded by the gene NTRK3), ROS1 (encoded by 
the gene ROS1) and anaplastic lymphoma kinase (ALK; encoded by the gene ALK), with 
median inhibitory concentrations (IC50) for kinase inhibition in the low nanomolar range 
(1.7, 0.1, 0.1, 0.2, and 1.6 nM, respectively).  While these enzymes play various roles in 
normal cellular function, gene rearrangements (fusions) in these target kinases have the 
potential to be oncogenic drivers, tend to be mutually exclusive, and are present in small 
percentages (< 10%; (Vaishnavi et al. 2015)) in a variety of tumor types, including non-
small cell lung cancer (NSCLC), colorectal cancer (CRC), salivary gland cancer, 
papillary thyroid cancer, melanoma, and sarcoma.  A pan-TRK, ROS1, and ALK inhibitor 
such as entrectinib may have broad potential therapeutic utility. 
SAFETY 
SAFETY PROFILE 
A comprehensive description of the safety profile of entrectinib is provided in the 
Entrectinib Investigator’s Brochure  
Identified Risks 
Cognitive Disorders 
Cognitive disorders, including confusion, mental status changes, memory impairment, 
and hallucinations, were reported in patients treated with entrectinib in clinical trials.  
Patients should be monitored for signs of cognitive changes. 
Based on the severity of the cognitive disorder, entrectinib treatment should be modified 
as described below in Table A10-23 of this Appendix. 
Patients who experience symptoms of cognitive disorders should be instructed not to 
drive or use machines until symptoms resolve. 
Congestive Heart Failure 
Congestive heart failure (CHF) has been reported in patients treated with entrectinib in 
clinical trials.  These reactions were observed in patients with or without a history of 
cardiac disease and resolved upon treatment with diuretics and/or dose reduction or 
interruption. 
Patients receiving entrectinib should be carefully monitored and those with clinical signs 
and symptoms of CHF, including shortness of breath or edema, should be evaluated as 
clinically appropriate. 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
294/Protocol MX39795, Version 11 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
295/Protocol MX39795, Version 11 
Based on the severity of CHF, entrectinib treatment should be modified as described 
below in  Table A10-23 of this Appendix. 
QT Interval Prolongation 
QT interval prolongation has been observed in patients treated with entrectinib in clinical 
trials.  Use of entrectinib should be avoided in patients with congenital long QT 
syndrome and in patients taking medications that are known to prolong QT interval. 
Potential Risks (Refer to the Entrectinib Investigator’s Brochure for Details) 
Entrectinib-related adverse events generally occur within the first 2 cycles of treatment. 
In general, the events listed below are reversible and can be managed with dose hold 
and/or dose reduction, as needed. 
Neurologic Effects  
TRK receptors are involved with neuronal development and maintenance; as such, 
central and peripheral neurologic events are expected.  In the clinic, the following 
neurologic events have been reported: dysgeusia, paresthesia, and cognitive 
disturbance (manifested as confusion, gain disturbance, dizziness, slurred speech, 
muscle weakness, memory impairment and vision changes). 
Weight Gain 
A trend for weight gain has been observed.  This is likely an on-target effect of 
entrectinib as TRKB is associated with appetite control; ALK and ROS1 genes may also 
play a role as they are part of the insulin gene family and could therefore have effects on 
glucose metabolism and control. 
Peripheral Edema 
Peripheral edema, fluid retention, and pulmonary edema have been reported.  All have 
resolved with dose interruption and/or dose reduction, as needed. 
Hypotension 
Hypotension and orthostatic hypotension have been observed.  
Anemia 
In the clinic, Grade 1 and 2 anemia, neutropenia, and lymphocyte count decreased have 
been observed.  Most of these adverse events do not require intervention and/or can be 
easily managed with dose modifications, such as short drug holidays. 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
296/Protocol MX39795, Version 11 
Increased Creatinine 
Clinically, moderate serum creatinine elevations have been observed in patients, 
independent of dose level that recover following entrectinib discontinuation.  
Visual Effects  
To date, among the eye disorders that have been reported across the ongoing studies 
(vision blurred, diplopia, photophobia, dry eye, abnormal sensation in eye, conjunctivitis, 
corneal opacity, eye irritation, eye pain, eyelid edema, halo vision, lacrimation increased, 
scotoma, visual acuity reduced, and vitreous floaters), vision blurred is the most likely 
consequence of potential corneal-related visual disturbances. 
Adverse Events of Special Interest 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For entrectinib, the following AESIs are to be reported 
 
Grade ≥ 2 Congestive Heart Failure 
 
Grade ≥ 2 QT prolongation 
 
Any grade syncope 
 
Grade ≥ 2 cognitive disturbances 
 
Bone fracture (all grades) 
 
ADMINISTRATION 
POSOLOGY AND ROUTE 
The recommended dose is 600 mg per day (three 200-mg capsules per day).  
Entrectinib will be self-administered orally at home, on a continuous daily dosing 
regimen. 
The capsules of entrectinib must be swallowed intact without chewing, crushing, or 
opening them. 
Entrectinib should be administered approximately at the same time each day.  For 
patients experiencing fatigue, nausea, or other mild tolerability issues, an evening time 
administration is recommended. 
For instructions on handling of the medicinal product, refer to the Entrectinib 
Investigator’s Brochure. 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
297/Protocol MX39795, Version 11 
DURATION OF TREATMENT 
Treatment with entrectinib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  
DELAYED OR MISSED DOSES 
If a patient misses a dose, it should be replaced only if the patient remembers within a 
12-hour window.  After that, patients should just take the next dose the following day, 
without compensating for the missed dose (including vomited doses). 
DOSE MODIFICATIONS 
Adverse events associated with entrectinib can often be managed with concomitant 
medications, supportive care and/or dose modifications, as per Table A10-23 . 
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 AE resolves to Grade ≤ 1.  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 
2 dose reductions will be allowed. 
Table A10-22 Dose Reduction Schedule 
Dose Reduction Schedule 
Dose Level 
Starting dose 
600 mg daily 
1st reduction 
400 mg daily 
2nd reduction 
200 mg daily 
 
Doses reduced for drug-related toxicity should generally not be re-escalated.  However, 
intra-patient re-escalation back to the previous dose level may be permitted at the 
discretion of the investigator after discussion with the Sponsor.  
Entrectinib treatment may be interrupted for a maximum of 28 days to allow sufficient 
recovery from any toxicity, if the patient is still deriving clinical benefit in the judgment of 
the investigator. 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
298/Protocol MX39795, Version 11 
MANAGEMENT OF SELECTED IDENTIFIED AND POTENTIAL RISKS 
Management of Entrectinib-Related Adverse Events 
 
Table A10-23 Dose Modifications for Entrectinib-Related Adverse Events 
Toxicity 
(treatment-
related) a 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-
hematologic 
 Continue at 
same dose 
level 
 Continue at 
same dose 
level 
 Withhold dose 
until toxicity is 
Grade 1 or has 
returned to 
baseline, then 
reduce by one 
dose level and 
resume 
treatment 
 Withhold dose 
until toxicity is 
Grade 1 or has 
returned to 
baseline, then 
reduce by one 
dose level and 
resume 
treatment; or 
discontinue 
treatment as 
per the 
investigator’s 
discretion 
Cognitive 
disorders or 
intolerable 
CNS toxicity 
 Continue at 
same dose 
level 
 For Grade 2 or higher, withhold until recovery to 
Grade 1 or to baseline, then resume treatment at 
reduced dose by one level.  If event recurs, further 
reduce dose by one level 
 For prolonged, severe, or intolerable events, 
discontinue as clinically appropriate 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
299/Protocol MX39795, Version 11 
Toxicity 
(treatment-
related) a 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematologic 
 Continue at 
same dose 
level 
 Continue at 
same dose 
level 
 Withhold dose 
until toxicity is 
≤ Grade 2 or 
has returned to 
baseline, then 
resume 
treatment at the 
same dose 
level or reduce 
by one dose 
level as per 
investigator’s 
discretion 
 Grade 3 
lymphopenia 
without other 
dose limiting 
events (e.g., 
opportunistic 
infection) may 
continue study 
treatment 
without 
interruption 
 Withhold dose 
until toxicity is 
≤ Grade 2 or 
has returned 
to baseline, 
then reduce by 
one dose level 
and resume 
treatment 
 Grade 4 
lymphopenia 
without other 
dose limiting 
events (e.g., 
opportunistic 
infection) may 
continue study 
treatment 
without 
interruption 
Diarrhea 
 Continue at 
same dose 
level 
 Continue at 
same dose 
level unless 
patient is 
intolerant or 
symptom is 
recurrent 
 Interrupt 
entrectinib until 
recovery to 
Grade 1 or 
better 
 Interrupt 
entrectinib 
until recovery 
to Grade 1 or 
better 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
300/Protocol MX39795, Version 11 
Toxicity 
(treatment-
related) a 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Prolonged 
QTc interval 
 Continue at 
same dose 
level 
 Interrupt 
entrectinib until 
recovery to 
baseline 
 Continue at 
same dose 
level 
 Interrupt 
entrectinib until 
recovery to 
baseline 
 Reduce dose 
by one dose 
level and 
resume 
treatment.  If an 
alternative 
cause for QTc 
prolongation is 
found and 
corrected, 
resume at 
same dose 
level 
 The decision to 
resume 
entrectinib 
treatment, 
without dose 
reduction, 
should be 
subject to a 
specialist 
opinion 
(cardiologist) 
 Discontinue 
treatment 
permanently 
Syncope 
 For any grade syncope event, withhold entrectinib until recovered and then 
resume treatment at reduced dose by one level 
 If event recurs, further reduce dose by one level or consider discontinuation 
of entrectinib as clinically appropriate 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
301/Protocol MX39795, Version 11 
Toxicity 
(treatment-
related) a 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Congestive 
heart failure 
 Continue at 
same dose 
level 
 Continue at 
same dose 
level; may 
reduce by one 
dose level at 
the 
investigator’s 
discretion 
 Withhold dose 
until recovery 
to Grade 1 or 
has returned to 
baseline, then 
reduce by 
one dose level 
and resume 
treatment 
 Managing heart 
failure should 
be subject to a 
specialist 
opinion 
(cardiologist) 
 Withhold dose 
until recovery 
to Grade 1 or 
return to 
baseline, or 
discontinue 
treatment as 
per the 
investigator’s 
discretion.  
Managing 
heart failure 
and the 
decision to 
resume 
treatment 
should be 
subject to a 
specialist 
opinion 
(cardiologist).  
Reintroduction 
of entrectinib 
at a dose 
reduced by 
one level can 
be considered 
only for 
patients 
deriving 
clinical benefit  
Pneumonitis 
(in absence of 
disease 
progression, 
pulmonary 
embolism, 
positive 
cultures or 
radiation 
effect) 
 Withhold dose 
until toxicity is 
Grade 0, then 
resume 
treatment at 
same dose 
 Discontinue 
treatment 
permanently if 
pneumonitis 
recurs 
 Withhold dose 
until toxicity is 
Grade 0, then 
resume 
treatment at 
same dose 
 Discontinue 
treatment 
permanently if 
pneumonitis 
recurs 
 Discontinue 
treatment 
permanently 
 Discontinue 
treatment 
permanently 
QTc, corrected QT interval. 
a. Dose modifications are to be based on worst toxicity grade as per NCI CTCAE v5.0. 
 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
302/Protocol MX39795, Version 11 
Additional Guidance on Specific Adverse Events 
Congestive Heart Failure (CHF) 
For Grade 3 or 4 heart failure, management of heart failure should be subject to the 
opinion of a cardiologist.  Dose modification guidelines set forth in Table A10-23 of this 
Appendix should also be followed. 
QTc 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 A10-23 of this 
Appendix.  In cases of Grade 4 QT interval prolongation, entrectinib should be 
permanently discontinued. 
For Grade 3 or 4 QTc prolongation, patient must remain hospitalized with continuous 
cardiac monitoring until an opinion is obtained from a cardiologist.  Dose modification 
guidelines set forth in Table A10-23 of this Appendix should also be followed. 
Cognitive Disorders 
Cognitive disorders, including confusion, mental status changes, memory impairment, 
and hallucinations, were reported in patients treated with entrectinib in clinical trials.  
Patients should be monitored for signs of cognitive changes. 
Based on the severity of the cognitive disorder, entrectinib treatment should be modified 
as described in Table A10-23. 
Patients who experience symptoms of cognitive disorders should be instructed not to 
drive or use machines until symptoms resolve. 
Syncope 
Syncope events were reported in patients treated with entrectinib in clinical trials.  In 
some patients, syncope was reported with concurrent hypotension, dehydration, or QT 
prolongation and in other patients no other concurrent related conditions were reported. 
Patients experiencing syncope should be evaluated and entrectinib treatment should be 
modified as described in Table A10-23. 
Bone fractures 
Entrectinib use has been associated with an increased risk of fractures.  Patients with 
signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures should be 
evaluated promptly.  In adult patients, some fractures occurred in the setting of a fall or 
other trauma to the affected area.  There are no data on the effects of entrectinib on 
healing of known fractures and the risk of future fractures. 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
303/Protocol MX39795, Version 11 
Pneumonitis/Pneumonia 
Investigators must thoroughly evaluate patients who demonstrate potential 
signs/symptoms of pneumonitis/pneumonia.  If a patient has a potential diagnosis of 
pneumonitis or drug-related lung injury, the following evaluations/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)  
 
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 thoracoscopic 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 β-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/exclude the diagnosis. 
For any case of suspected pneumonitis, please contact the Sponsor.  See Table A10-22 
for appropriate dose modifications. 
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 A10-24, Table A10-25, and Table A10-26 for concomitant 
medications that should be administered with caution. 
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 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
304/Protocol MX39795, Version 11 
 
For Grade ≥ 3 (despite use of loperamide), treatment should be withheld until 
recovery to Grade ≤ 1 
 
Concomitant Radiotherapy 
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 radiation therapy will generally be 
considered indicative of progressive disease. 
It is recommended to avoid radiotherapy for at least 5 days after the final 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 pre-irradiation levels after 2 weeks of rest, 
entrectinib should be discontinued. 
Lifestyle Guidelines 
Use of herbal medications (e.g., St. John’s Wort) and consumption of grapefruit and/or 
grapefruit juice should be avoided during the Treatment Period. 
 
MEDICATIONS TO BE GIVEN WITH PRECAUTION 
Use of concomitant medications that increase or possibly increase the risk of QTc 
prolongation and/or induce torsades de pointes ventricular arrhythmia (See Table A10-
24) must be used with caution or avoided if possible during treatment with entrectinib. 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
305/Protocol MX39795, Version 11 
Table A10-24 Concomitant Medications to be Used with Caution 
Antiarrhythmics 
Amiodarone (Cordarone)  
Procainamide (Pronestyl) 
Disopyramide (Norpace) 
Quinidine (Quinaglute) 
Dofetilide (Tikosyn)  
Sotalol (Betapace) 
Ibutilide (Corvert) 
Antipsychotics 
Chlorpromazine (Thorazine)  
Clozapine (Clozaril)  
Haloperidol (Haldol) 
Risperidone (Risperdal)  
Quetiapine (Seroquel) 
Thioridazine (Mellaril) 
Antibiotics 
Azithromycin (Zithromax) 
Ciprofloxacin (Cipro)  
Clarithromycin (Biaxin) 
Erythromycin (Erythrocin)  
Fluconazole (Diflucan)  
Gatifloxacin (Tequin)  
Itraconazole (Sporanox)  
Ketoconazole (Nizoral) 
Levofloxacin (Levaquin) 
Moxifloxacin (Avelox) 
Ofloxacin (Floxin) 
Sparfloxacin (Zagam)  
Telithromycin (Ketek) 
Trimethoprim-Sulfa (Bactrim) 
Antidepressants 
Amitriptyline (Elavil)  
Citalopram (Celexa)  
Desipramine (Pertofrane)  
Doxepin (Sinequan)  
Fluoxetine (Prozac)  
Imipramine (Norfranil) 
Nortriptyline (Pametor) 
Paroxetine (Paxil) 
Sertraline (Zoloft) 
Venlaxafine (Effexor) 
Antiemetics 
Ondansetron (Zofran)  
Prochlorperazine (Compazine) 
 
DRUG INTERACTIONS 
Antacids 
Absorption of entrectinib may be pH sensitive.  Patients requiring H2-receptor 
antagonists, proton pump inhibitors (PPIs), and/or antacids should preferentially take 
only H2 receptor antagonists or antacids as the duration of action of these drugs is 
relatively transient in contrast to PPIs, which have longer half-lives.  These medications 
should be taken at a time point that is not proximal to entrectinib administration (at least 
3–4 hours before or after administration during the day, or the night before) to minimize 
any potential effect on entrectinib absorption. 
Cytochrome P450 Substrates 
A study with recombinant human cytochrome P450 isoforms (CYP450) suggests that 
entrectinib is metabolized by multiple CYP450 isoforms.  Entrectinib inhibited the 
activities of CYP2C9, CYP2D6, and CYP3A4 isoforms with IC50 values of 5.5, 5.6, and 
2.8-6.3 μM, respectively.  Entrectinib also exhibited the potential to induce CYP3A4, 
suggesting a potential for interactions with other drugs primarily metabolized by 
CYP3A4.  Due to this potential, concomitant use of moderate to strong CYP3A inhibitor 
and inducer medications, including those listed in Table A10-25, should be avoided.  
Entrectinib should be administered with caution with the drugs listed in Table A10-26 
below. 


Appendix 10-5:  Entrectinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
306/Protocol MX39795, Version 11 
The following enzyme-inducing anti-epileptic drugs (EIAEDs) are prohibited: 
 
Carbamazepine  
 
Oxcarbazepine  
 
Phenytoin  
 
Fosphenytoin  
 
Phenobarbital  
 
Primidone 
 
Table A10-25 Cytochrome P450 CYP3A Inhibitors and Inducers 
Strong Inhibitors 
Strong Inducers 
Boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole 
Alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus 
 
Table A10-26 Cytochrome P450 Enzyme-Specific Substrates 
CYP450 
Enzyme 
Sensitive Substrates 
Substrates with Narrow Therapeutic 
Range 
CYP2C9 
Celecoxib 
Warfarin 
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 
 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
307/Protocol MX39795, Version 11 
A10–6 
ERLOTINIB 
Erlotinib will be administered in combination with bevacizumab—Refer to 
Appendix 10-3 for details on bevacizumab. 
BACKGROUND ON ERLOTINIB 
Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor 
type 1 (EGFR also known as HER1) tyrosine kinase inhibitor.  Erlotinib potently inhibits 
the intracellular phosphorylation of EGFR. EGFR is expressed on the cell surface of 
normal cells and cancer cells.  In nonclinical models, inhibition of EGFR phosphotyrosine 
results in cell stasis and/or death. 
EGFR alterations may lead to constitutive activation of anti-apoptotic and proliferation 
signaling pathways.  The potent effectiveness of erlotinib in blocking EGFR-mediated 
signaling in these EGFR alteration-positive tumors is attributed to the tight binding of 
erlotinib to the ATP-binding site in the mutated kinase domain of the EGFR.  Due to the 
blocking of downstream-signaling, the proliferation of cells is stopped, and cell death is 
induced through the intrinsic apoptotic pathway.  Tumor regression is observed in mouse 
models of enforced expression of these EGFR activating mutations.  
Erlotinib is being developed for use in the treatment of cancers.  Erlotinib, has been 
approved in various countries for the treatment of patients with non-small cell lung and 
pancreatic cancers. 
Bevacizumab, in combination with erlotinib, has been approved for first-line treatment of 
adult patients with unresectable advanced, metastatic or recurrent non-squamous non-
small cell lung cancer with epidermal growth factor receptor (EGFR) activating 
mutations. 
Rationale for the use of erlotinib in combination with bevacizumab is described in 
Appendix 10-3 (Bevacizumab). 
SAFETY 
SAFETY PROFILE 
The safety profile of erlotinib as monotherapy or in combination with chemotherapy is 
presented in the Erlotinib EMA Summary of Product Characteristics. 
Adverse reactions associated with Warnings and Precautions: 

Smokers

Interstitial lung disease

Diarrhea, dehydration, electrolyte imbalance and renal failure


Appendix 10-6:  Erlotinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
308/Protocol MX39795, Version 11 
 
Hepatitis, hepatic failure 
 
Gastrointestinal perforation  
 
Bullous and exfoliative skin disorders 
 
Ocular disorders 
 
Interactions with other medicinal products 
 
Management guidelines for erlotinib that are applicable to this study are provided in 
Table A10-27. 
A comprehensive description of the safety profile of erlotinib in combination with 
bevacizumab is provided in the Bevacizumab and Erlotinib EMA Summary of Product 
Characteristics. 
Appendix 10-3 presents a brief overview of the safety profile of bevacizumab in 
combination with erlotinib. 
The summary information provided in the following sections must always be checked 
against any update of the Erlotinib EMA Summary of Product Characteristics that may 
have occurred after the protocol has been issued. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For erlotinib, AESIs include: 
 
interstitial lung disease 
ADMINISTRATION OF ERLOTINIB 
POSOLOGY AND ROUTE 
The dose of erlotinib will be 150 mg taken at least one hour before or two hours after the 
ingestion of food. 
For instructions on handling of the medicinal product, refer to the EMA Summary of 
Product Characteristics. 
DURATION OF TREATMENT 
Treatment with erlotinib should continue until loss of clinical benefit or the development 
of unacceptable toxicity.  


Appendix 10-6:  Erlotinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
309/Protocol MX39795, Version 11 
DOSE MODIFICATIONS AND DISCONTINUATION DURING TREATMENT 
When dose adjustment is necessary, the dose should be reduced in 50 mg steps (see 
Table A10-27).  
Concomitant use of CYP3A4 substrates and modulators may require dose adjustment 
(see Table A10-27). 
Table A10-27 below gives general erlotinib dose modification guidance 
Summary of Advice for Dose Discontinuation (See Table A10-27 for 
Details): 
Erlotinib must be discontinued if: 
 
Interstitial lung disease 
 
Gastrointestinal perforation 
 
Discontinuation: may be considered if: 
 
Bullous and exfoliative skin disorders 
 
Ocular disorders (mostly keratitis) 
 
Please also refer to the Bevacizumab EMA Summary of Product Characteristics and to 
its warnings and precautions when using erlotinib in combination with bevacizumab. 
MANAGEMENT ADVICE FOR SPECIFIED ADVERSE DRUG REACTIONS 
 
Table A10-27 Guidelines for Management of Patients Who Experience 
Specific Adverse Events 
Event 
Action to Be Taken  
Smokers 
Current smokers should be advised to stop smoking, as plasma 
concentrations of erlotinib in smokers as compared to non-smokers 
are reduced.  The degree of reduction is likely to be clinically 
significant 
Interstitial Lung Disease 
In patients who develop acute onset of new and/or progressive 
unexplained pulmonary symptoms such as dyspnea, cough and 
fever, interrupt erlotinib pending diagnostic evaluation.  
If ILD is diagnosed, discontinue erlotinib and initiate appropriate 
treatment as necessary 
Diarrhea, dehydration, 
electrolyte imbalance 
and renal failure 
● 
Moderate or severe diarrhea  
Treat with e.g. loperamide.  Dose reduction may be 
necessary.  If so, reduce dose by 50 mg steps 
 
● 
Severe or persistent diarrhea, nausea, anorexia, or vomiting 
associated with dehydration,  


Appendix 10-6:  Erlotinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
310/Protocol MX39795, Version 11 
Event 
Action to Be Taken  
Interrupt erlotinib and treat the dehydration 
● 
If more severe or persistent cases of diarrhea, or cases leading 
to dehydration, particularly in groups of patients with 
aggravating risk factors (other medications, symptoms or 
diseases or other predisposing conditions including advanced 
age) 
 
Interrupt erlotinib and take appropriate measures to intensively 
rehydrate the patient intravenously.  
Renal function and serum electrolytes including potassium should 
be monitored in patients at risk of dehydration. 
Hepatitis, hepatic failure 
Confounding factors have included pre-existing liver disease or 
concomitant hepatotoxic medications. 
Interrupted erlotinib if changes in liver function are severe. 
Gastrointestinal 
perforation 
Discontinue erlotinib permanently. 
Patients receiving concomitant anti-angiogenic agents, 
corticosteroids, NSAIDs, or who have prior history of peptic 
ulceration or diverticular disease are at increased risk. 
Bullous and exfoliative 
skin disorders 
Interrupt or discontinue permanently erlotinib. 
If bullous or exfoliative skin disorders, test patients for skin infection 
and treat according to local management guidelines. 
Ocular disorders 
(mostly keratitis) 
Promptly refer to an ophthalmology specialist.  
If a diagnosis of ulcerative keratitis is confirmed, treatment with 
erlotinib should be interrupted or discontinued. 
If keratitis is diagnosed, the benefits and risks of continuing 
treatment should be carefully considered.  
Exert caution in patients with a history of keratitis, ulcerative keratitis 
or severe dry eye.  Contact lens use is also a risk factor for keratitis 
and ulceration. 
Cutaneous Toxicity 
For patients who are exposed to sun, protective clothing and/or use 
of sun screen (e.g., mineral containing) may be advisable. 
Interactions with other 
medicinal products 
● 
Potent inducers of CYP3A4 may reduce the efficacy of erlotinib 
whereas potent inhibitors of CYP3A4 may lead to increased 
toxicity.  
Concomitant treatment with these types of agents should be 
avoided 
 
REFER TO THE EU SmPC FOR OTHER FORMS OF 
INTERACTIONS e.g.  
● 
Medicinal products that alter the pH of the upper gastrointestinal 
(GI) tract, like proton pump inhibitors, H2 antagonists and 
antacids 
● 
Other CYP substrates - Erlotinib is a potent inhibitor of CYP1A1, 
and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a 
strong inhibitor of glucuronidation by UGT1A1 in vitro 
● 
Coumarin-derived anticoagulants 


Appendix 10-6:  Erlotinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
311/Protocol MX39795, Version 11 
Event 
Action to Be Taken  
● 
Statins 
● 
P-glycoprotein inhibitors 
● 
Medicinal products altering pH 
 
DRUG INTERACTIONS 
There is no evidence of clinically significant drug interactions between erlotinib and 
bevacizumab. 
Erlotinib and Other CYP Substrates  
Erlotinib is metabolized in the liver by the hepatic CYPs in humans, primarily CYP3A4 
and to a lesser extent by CYP1A2, and the pulmonary isoform CYP1A1.  Potential 
interactions may occur with drugs that are metabolized by or are inhibitors or inducers of 
these enzymes. 
Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib 
plasma concentrations.  Inhibition of CYP3A4 metabolism by ketoconazole (200 mg po 
BID for 5 days) resulted in increased exposure to erlotinib (86% in median erlotinib 
exposure [AUC] and a 69% increase in Cmax) when compared to erlotinib alone.  When 
erlotinib was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and 
CYP1A2, the erlotinib exposure (AUC) and maximum concentration (Cmax) increased by 
39% and 17%, respectively.  Therefore, caution should be used when administering 
erlotinib with potent CYP3A4 or combined CYP3A4/CYP1A2 inhibitors.  In these 
situations, the dose of erlotinib should be reduced if toxicity is observed. 
Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly 
decrease erlotinib plasma concentrations.  Induction of CYP3A4 metabolism by 
rifampicin (600 mg po QD for 7 days) resulted in a 69% decrease in the median erlotinib 
AUC, following a 150 mg dose of erlotinib as compared to erlotinib alone.  Pre-treatment 
and co-administration of rifampicin with a single 450 mg dose of erlotinib resulted in a 
mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg erlotinib dose in 
the absence of rifampicin treatment.  Alternative treatments lacking potent CYP3A4-
inducing activity should be considered when possible.  For patients who require 
concomitant treatment with erlotinib and a potent CYP3A4 inducer such as rifampicin, an 
increase in dose to 300 mg should be considered while their safety is closely monitored, 
and if well tolerated for more than 2 weeks, further increase to 450 mg could be 
considered with close safety monitoring.  Higher doses have not been studied in this 
setting. 
Pre-treatment or co-administration of erlotinib did not alter the clearance of the 
prototypical CYP3A4 substrates midazolam and erythromycin.  Significant interactions 


Appendix 10-6:  Erlotinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
312/Protocol MX39795, Version 11 
with the clearance of other CYP3A4 substrates are therefore unlikely.  Oral availability of 
midazolam did appear to decrease by up to 24%, which was however not attributed to 
effects on CYP3A4 activity.  
Erlotinib and Medicinal Products Altering pH  
The solubility of erlotinib is pH dependent.  Erlotinib solubility decreases as pH 
increases.  Drugs that alter the pH of the upper gastrointestinal tract may alter the 
solubility of erlotinib and hence its bioavailability.  Co-administration of erlotinib with 
omeprazole, a proton pump inhibitor, decreased the erlotinib exposure (AUC) and Cmax 
by 46% and 61%, respectively.  There was no change to tmax or half-life.  Concomitant 
administration of erlotinib with 300 mg ranitidine, an H2-receptor antagonist, decreased 
erlotinib exposure (AUC) and Cmax by 33% and 54%, respectively.  Therefore, co-
administration of drugs reducing gastric acid production with erlotinib should be avoided 
where possible.  Increasing the dose of erlotinib when co-administered with such agents 
is not likely to compensate for this loss of exposure.  However, when erlotinib was dosed 
in a staggered manner 2 hour before or 10 hours after ranitidine 150 mg twice a day, 
erlotinib exposure (AUC) and Cmax decreased only by 15% and 17%, respectively.  If 
patients need to be treated with such drugs, then an H2-receptor antagonist such as 
ranitidine should be considered and used in a staggered manner.  Erlotinib must be 
taken at least 2 hours before or 10 hours after the H2-receptor antagonist dosing. 
Erlotinib and Coumarin-derived Anticoagulants  
Interaction with coumarin-derived anticoagulants, including warfarin, leading to 
increased INR and bleeding events, which in some cases were fatal, have been reported 
in patients receiving erlotinib.  Patients taking coumarin-derived anticoagulants should 
be monitored regularly for any changes in prothrombin time or INR.  
Erlotinib and Statins  
The combination of erlotinib and a statin may increase the potential for statin-induced 
myopathy, including rhabdomyolysis, which was observed rarely. 
Erlotinib and Smokers  
Cigarette smoking (a moderate CY1A2 inducer) has been shown to reduce erlotinib 
exposure by 50% to 60%.  Smokers should be advised to stop smoking. Concomitant 
use of erlotinib with moderate CYP1A2 inducers should be avoided. 
 
 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
313/Protocol MX39795, Version 11 
A10–7 
IPATASERTIB 
BACKGROUND ON IPATASERTIB 
Ipatasertib is a potent, highly selective small-molecule inhibitor of all three isoforms of 
the serine/threonine kinase Akt (protein kinase B).  Ipatasertib is being developed as a 
single agent and in combination with other therapies for the treatment of cancers in 
which activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of 
rapamycin (mTOR) pathway may be relevant for tumor growth or therapeutic resistance. 
Akt is a central node in cell signaling downstream of growth factors, cytokines, and other 
cellular stimuli.  It plays an important role in cancer development, progression, and 
therapeutic resistance and is activated in most, if not all, human cancers (Altomare and 
Testa 2005).  The ubiquity and importance of Akt activation in human cancers provide a 
strong rationale for developing therapeutics targeting Akt. 
Ipatasertib selectively binds to the active conformation of Akt and inhibits its kinase 
activity (Altomare and Testa 2005).  Consistent with its mechanism of action, in 
nonclinical studies, ipatasertib has proven to be especially effective on cells with 
activated Akt, including phosphatase and tensin homolog (PTEN)-null and PIK3CA- 
altered tumor models, resulting in G1 arrest and/or apoptosis in human cancer cells.  In 
vivo efficacy studies support the use of ipatasertib as a single agent or in combination 
with chemotherapeutic, hormonal, or targeted agents for the treatment of patients with 
advanced or metastatic solid tumors. 
SAFETY 
SAFETY PROFILE 
The safety profile of ipatasertib is presented in the Ipatasertib Investigator’s Brochure. 
The identified risks associated with ipatasertib treatment include: 

Gastrointestinal toxicities (diarrhea, nausea, vomiting and oral mucositis)

Fatigue/asthenia

Rash

Erythema multiforme

Fasting Hyperglycemia

AST/ALT increased

Dehydration

Decreased appetite


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
314/Protocol MX39795, Version 11 
 
Potential risks:  
The following list presents adverse events that are Adverse Drug Reactions (ADRs) of 
other inhibitors of the PI3K-AKT-mTOR pathway or that nonclinical data suggest could 
be observed in patients receiving ipatasertib.  These risks are not considered ADRs: 
 
Hematological or Immunosuppressants effects 
 
Hyperlipidemia 
 
Hepatotoxicity 
 
Pneumonitis 
 
Colitis 
 
Developmental toxicity 
 
Drug-drug Interactions 
 
Management guidelines for ipatasertib that are applicable to this study are provided in  
Table A10-28 to Table A10-36. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For ipatasertib, AESIs include: 
 
Grade ≥  3 diarrhea 
 
Grade ≥ 3 fasting hyperglycemia 
 
Grade ≥ 3 rash 
 
Grade ≥  2 pneumonitis 
 
Grade ≥  2 colitis/enterocolitis 
 
Grade ≥ 3 hepatotoxicity including ALT/AST elevations 
 
ADMINISTRATION OF IPATASERTIB 
POSOLOGY AND ROUTE 
The dose of ipatasertib will be 400 mg daily. 
Each dose of ipatasertib should be taken with a minimum of 90 mL (3 ounces) of fluid. 
Ipatasertib may be taken with or without food. 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
315/Protocol MX39795, Version 11 
For instructions on handling of the medicinal product, refer to the Ipatasertib 
Investigator’s Brochure. 
DURATION OF TREATMENT 
Treatment with ipatasertib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  
PROPHYLAXIS 
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.  Refer to 
Table A10-29 for further details on treatment of gastrointestinal toxicities during 
ipatasertib treatment. 
DELAYED OR MISSED DOSES 
If a dose is missed (not taken within 8 hours after the scheduled dosing time), the patient 
should resume dosing with the next scheduled dose.  If vomiting occurs after taking a 
dose of ipatasertib, the patient should not take an additional dose on that day and 
treatment should be continued as prescribed the following day. 
DOSE MODIFICATIONS 
Management of adverse events may require dose reduction, temporary interruption, or 
discontinuation of treatment with ipatasertib.  The dose of ipatasertib should be reduced 
according to the dose reduction schedule provided in Table A10-28.  
Table A10-28 Dose Reduction Schedule 
Dose Reduction Schedule a 
Dose Level 
Starting dose 
400 mg daily 
1st reduction 
300 mg daily 
2nd reduction 
200 mg daily 
3rd reduction 
Discontinue 
a. If the patient continues to experience specified drug-related adverse events after the second 
reduction, the treatment should be discontinued. 
 
Patients may hold 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 patient does not tolerate the once-daily dosing of ipatasertib, dosing with food may 
be used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
316/Protocol MX39795, Version 11 
diarrhea.  No more than two dose reductions of ipatasertib per patient.  Dose re-
escalation is not permitted for ipatasertib. 
TREATMENT INTERRUPTION 
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 treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures)  
SUMMARY OF ADVICE FOR DOSE DISCONTINUATION AND DOSE 
INTERRUPTION (see Table A10-28 to Table A10-36 for details): 
Ipatasertib must be discontinued if: 
 
Grade 4 diarrhea 
 
Recurrent Grade 4 hyperglycemia 
 
Febrile and Grade 4 neutropenia if recovery to Grade 2 or better does not occur 
after up to 4 weeks of treatment hold 
 
Grade 4 and recurrent Grade 3 hepatotoxicity 
 
Grade 4 rash, recurrent Grade 3 rash, or Grade 3 rash that remains clinically 
significant for 4 weeks after treatment hold 
 
Grade 4 non-infectious pneumonitis, recurrent Grade 3 non-infectious pneumonitis, 
Grade 2 non-infectious pneumonitis if recovery to Grade 1 or better is not observed 
within 28 days of treatment hold 
 
Grade ≥ 3 mucositis, if recovery to Grade 2 or better does not occur within 4 weeks 
of treatment hold 
 
Ipatasertib must be interrupted if:  
 
Systemic corticosteroids are recommended, at the discretion of the investigator, for 
the treatment of specific adverse events.  Ipatasertib treatment should be 
temporarily held during systemic corticosteroids treatment (except when 
corticosteroids are given as pre-medication to paclitaxel). 
 
MANAGEMENT OF SELECTED IDENTIFIED AND POTENTIAL RISKS  
DIARRHEA MANAGEMENT GUIDELINES 
Specific guidelines for managing diarrhea to improve safety and tolerability are provided 
in Table A10-29.  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 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
317/Protocol MX39795, Version 11 
the prophylaxis dose may be adjusted as necessary, using their discretion based on 
clinical judgment and per local guidance.  If diarrhea occurs, it should be managed per 
guidelines; upon resolution or when study treatment is restarted, loperamide prophylaxis 
should be considered to resume and continue based on clinical judgments (if allowed by 
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 
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.  


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
318/Protocol MX39795, Version 11 
Table A10-29 Diarrhea Management Guidelines 
Severity of Diarrhea a 
Management Guideline 
Prevention 
 
All patients are should receive loperamide (2 mg BID 
or 4 mg QD) as prophylaxis for diarrhea in the first 
cycle, if allowed by local guidance or unless there is a 
clinical concern precluding their use.  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. 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
319/Protocol MX39795, Version 11 
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 one (or one additional) dose 
level 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 until diarrhea improves to Grade 1 
or better.  Ipatasertib should be reduced by one dose 
level when treatment is restarted.   
 
For recurrent Grade 3 diarrhea, reduce ipatasertib 
dose by one additional dose level.   
 
When study treatment is resumed, loperamide 
prophylaxis should also be resumed and continues as 
clinically indicated, if allowed by local guidance. 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
320/Protocol MX39795, Version 11 
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. 
ADL  activities of daily living; BID  twice a day; NCI CTCAE v4.0  National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; QD  once a day. 
a  Diarrhea, as defined by NCI CTCAE v4.0, a disorder characterized by frequent and watery 
bowel movements. 
 
FASTING HYPERGLYCEMIA 
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours.  The treatment goals for glycemic control should be:  1) fasting glucose 
under 160 mg/dL and 2) HbA1c  8%. 
Dose modification guidelines for fasting hyperglycemia attributable to study treatment 
are outlined below (see Table A10-30) 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. 
In the event of ipatasertib interruption, anti-diabetic medications may need to be held or 
reduced (per investigator judgment) and glucose should be monitored closely to 
minimize the risk of hypoglycemia. 
Because the hyperglycemia observed with ipatasertib treatment is consistently 
associated with endogenous elevations in insulin, insulin-based therapy to manage any 
hyperglycemia should be used with caution because severe hypoglycemic episodes 
could potentially occur.  Therefore, initial treatment should be considered with 
biguanides (preferred), sulfonylureas, and other hypoglycemic treatments. 
Table A10-30 Fasting Hyperglycemia Management Guidelines 
Hyperglycemia  
 
Management Guideline 
General Guidance 
 
Thoroughly evaluate all events of hyperglycemia for more common 
etiologies other than drug-induced effects.  
 
Investigate for diabetes. If patient has Type 1 diabetes, treat as an 
event of fasting glucose value 250500 mg/dL.  
 
Workup could include confirmation of fasting blood glucose, 
urinary glucose and ketones, arterial blood gas, serum 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
321/Protocol MX39795, Version 11 
Hyperglycemia  
 
Management Guideline 
bicarbonate, hemoglobin A1C, C-peptide levels, anti-islet 
antibodies, and anti-GAD65 antibody.  
 
Treat hyperglycemia per institutional guidelines with fluid 
replacement, insulin, and correction of electrolyte abnormalities. 
Fasting glucose 
value  ULN to 
160 mg/dL 
(8.9 mmol/L) * 
 
Continue ipatasertib.  
 
Provide patient with education on a diabetic diet and consider home 
glucose monitoring.  
 
Consider oral anti-diabetic medications (e.g., metformin) or insulin 
replacement, guided by etiology of hyperglycemia. 
Fasting glucose value 
160 to 250 mg/dL 
( 8.913.9 mmol/L) * 
 
Withhold ipatasertib dosing until fasting glucose value resolves to 
160 mg/dL. (Investigate for diabetes. If patient has Type 1 
diabetes, treat as a fasting glucose value 250500 mg/dL event. If 
patient does not have Type 1 diabetes, treat as per institutional 
guidelines.)  
 
Encourage a diabetic diet and initiate home glucose monitoring.  
 
Start oral anti-diabetic medications (e.g., metformin) or insulin 
replacement, guided by etiology of hyperglycemia.  
 
If patient is already on an oral anti-diabetic medication, the dose of 
ipatasertib should be reduced by one dose level (refer to 
Table A10-29).  
 
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) * 
 
Withhold ipatasertib dosing until fasting glucose value resolves to 
160 mg/dL and contact the Medical Monitor.  
 
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).  
 
Encourage a diabetic diet and initiate home glucose monitoring.  
 
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 hyperglycemia 250500 mg/dL recurs, the dose of ipatasertib 
should be reduced by one dose level (see Table A10-29) when 
treatment is restarted.  
Fasting glucose 
value  500 mg/dL 
( 27.8 mmol/L); 
life-threatening 
consequences * 
 
Withhold ipatasertib dosing until fasting glucose value 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).  


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
322/Protocol MX39795, Version 11 
Hyperglycemia  
 
Management Guideline 
 
Assess for volume depletion and appropriate intravenous or oral 
hydration.  
 
Encourage a diabetic diet and initiate home glucose monitoring.  
 
Upon recovery of fasting glucose to 160 mg/dL, reduce ipatasertib 
by one dose level (see Table A10-29) when treatment is restarted.  
 
If glucose value  500 mg/dL recurs, permanently discontinue 
ipatasertib and contact the Medical Monitor.  Reduce ipatasertib by 
one dose level if and when treatment is restarted. 
 
If Grade 4 hyperglycemia recurs, permanently discontinue 
ipatasertib. 
ULNupper limit of normal. 
* For all grades, the patient should receive education on a diabetic diet. 
 
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 
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 are outlined in Table A10-31. 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
323/Protocol MX39795, Version 11 
Table A10-31 Neutropenia Management Guidelines 
Severity of Neutropenia 
and/or Thrombocytopenia 
Management Guideline 
Grade 2 
 
Ipatasertib may be continued at the original dose.  
Grade 3 
 
Ipatasertib 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 should be reduced by one 
dose level when treatment is restarted.   
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. 
ANC  absolute neutrophil count; G-CSF Granulocyte-colony stimulating factor. 
 
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 antiemetics (i.e., prochlorperazine or 
metoclopramide per institutional guidelines; see Table A10-32).  For persistent nausea 
and/or vomiting attributable to ipatasertib, dosage modification guidelines are outlined in 
Table A10-29 . 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
324/Protocol MX39795, Version 11 
Table A10-32 Nausea and Vomiting 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 when treatment is restarted.   
 
HEPATOTOXICITY 
Permanently discontinue ipatasertib for any patients who develop a concurrent elevation 
of ALT and/or AST greater than 3  ULN 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 A10-33). 
Table A10-33 Hepatotoxicity Management Guidelines 
Severity of LFT Elevation 
Management Guideline 
Grade 1  
AST or ALT  baseline  
3  ULN or  
T bilirubin  baseline 1.5  ULN 
Continue study drugs. 
Grade 2  
AST or ALT  3–5  ULN or 
T bilirubin  1.5–3.0  ULN 
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   5–20  ULN or 
T bilirubin  3–10  ULN 
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 A10-28)  
Following treatment resumption, monitor serum 
transaminases and bilirubin at a minimum every 2 weeks for 
3 months and monthly thereafter. 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
325/Protocol MX39795, Version 11 
Severity of LFT Elevation 
Management Guideline 
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  ULN or 
T bilirubin  10  ULN 
Permanently discontinue ipatasertib. 
LFT  liver function test; QD  once daily; ULN  upper limit of normal. 
 
RASH 
Treatment-related rash, has occurred in patients receiving ipatasertib treatment 
particularly when ipatasertib has been used certain combinations (e.g. ipatasertib in 
combination with paclitaxel and atezolizumab or with abiraterone). The following 
prophylaxis measures can be considered, in particular for combinations with overlapping 
skin toxicity. 
 
Unless contraindicated, daily PO antihistamine prophylaxis can be considered 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).  
 
Ipatasertib should be permanently discontinued for rash associated with 
Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS (Drug Reaction with 
Eosinophilia and Systemic Symptoms), or other suspected severe hypersensitivity or 
allergic reaction.  Dosage modification and symptom management guidelines for skin 
toxicity, including erythema multiforme, attributable to ipatasertib are shown below in 
Table A10-34. 
Table A10-34 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.  


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
326/Protocol MX39795, Version 11 
Severity of Rash 
Management Guideline 
 
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. 
 
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. 
 
PNEUMONITIS 
Pneumonitis is not known to be causally related to ipatasertib; 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 A10-35). 
Table A10-35 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 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.   
 
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. 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
327/Protocol MX39795, Version 11 
Severity of 
Pneumonitis 
Management Guideline 
 
Interrupt ipatasertib treatment until improvement to Grade 1 or better.  
Resume ipatasertib at one dose level below previous dose 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. 
 
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 A10-36. 
Table A10-36 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.   
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.   
 
If recovery of mucositis to Grade 2 or better does not occur within a 
maximum of 4 weeks, the patient will permanently discontinue 
ipatasertib. 
 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
328/Protocol MX39795, Version 11 
OTHER NON-HEMATOLOGIC TOXICITIES 
If other Grade  3 non hematologic toxicities not described above develop in patients, 
treatment with ipatasertib may be held, depending on the attribution of the toxicity, at the 
discretion of the investigator.  Ipatasertib should be discontinued for any non-
hematologic grade 4 adverse event considered related to ipatasertib. 
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. 
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 based on clinical judgment. 
SURGERY AND PALLIATIVE RADIOTHERAPY 
Patients who require radiotherapy or surgery as part of medical treatment in the absence 
of radiographic disease progression must exercise caution: ipatasertib should be 
temporarily withheld 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 of ipatasertib may be shorter, upon clinical judgment.  After the temporary treatment 
hold is complete, study treatment may be re-initiated when the patient has sufficiently 
recovered. 
DRUG INTERACTIONS 
A clinical study in patients showed that ipatasertib at a dose of 600 mg QD is a moderate 
inhibitor of CYP3A, which resulted in a 2.22-fold increase in midazolam (sensitive 
CYP3A substrate) exposures.  Ipatasertib is primarily metabolized by CYP3A and, 
hence, strong inhibitors and inducers of CYP3A may result in increased or decreased 
ipatasertib exposures, respectively.  Therefore, the following drugs should be avoided, or 
used with caution when administering ipatasertib.  If using of one of these drugs is 
necessary, the risks and benefits should be evaluated prior to its concomitant use with 
ipatasertib per protocol guidelines: 
 
Strong CYP3A inhibitors, such as but not limited to atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandamycin, voriconazole, and/or grapefruit juice or grapefruit 
supplements 
 
Strong CYP3A inducers, such as but not limited to rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin 


Appendix 10-7:  Ipatasertib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
329/Protocol MX39795, Version 11 
 
CYP3A4 substrates with a narrow therapeutic index, such as but not limited to 
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, ergot alkaloids ergotamine, and/or 
dihydroergotamine 
 


A10–8 
IPATASERTIB IN COMBINATION WITH PACLITAXEL 
BACKGROUND ON IPATASERTIB 
Ipatasertib is a potent, highly selective small-molecule inhibitor of all three isoforms of 
the serine/threonine kinase Akt (protein kinase B).  Ipatasertib is being developed as a 
single agent and in combination with other therapies for the treatment of cancers in 
which activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of 
rapamycin (mTOR) pathway may be relevant for tumor growth or therapeutic resistance. 
Akt is a central node in cell signaling downstream of growth factors, cytokines, and other 
cellular stimuli.  It plays an important role in cancer development, progression, and 
therapeutic resistance and is activated in most, if not all, human cancers (Altomare and 
Testa 2005).  The ubiquity and importance of Akt activation in human cancers provide a 
strong rationale for developing therapeutics targeting Akt. 
Ipatasertib selectively binds to the active conformation of Akt and inhibits its kinase 
activity (Altomare and Testa 2005).  Consistent with its mechanism of action, in 
nonclinical studies, ipatasertib has proven to be especially effective on cells with 
activated Akt, including phosphatase and tensin homolog (PTEN)-null and PIK3CA- 
altered tumor models, resulting in G1 arrest and/or apoptosis in human cancer cells.  In 
vivo efficacy studies support the use of ipatasertib as a single agent or in combination 
with chemotherapeutic, hormonal, or targeted agents for the treatment of patients with 
advanced or metastatic solid tumors. 
Recent research has demonstrated that considerable cross talk occurs in the PI3K/AKT 
signaling pathway, which may limit the action of PI3K/AKT pathway inhibitors like 
ipatasertib, particularly when used as single agents.  Combination of ipatasertib with 
several cytotoxic agents, however, has shown synergistic effects.  For instance, 
ipatasertib enhanced the in vitro efficacy of the taxane paclitaxel in a human breast 
cancer model system (Morgillo et al. 2017).  This may be of significant clinical import in 
the case of CUP, as a meta-analysis of 32 trials found that taxane-based regimens 
prolonged median survival time and improved 1-year survival rates among CUP patients 
(Lee et al. 2013).  Based on these considerations, patients in the current study with 
AKT1, PTEN or PIK3CA alterations who are assigned to molecularly-guided treatment 
will receive a combination of ipatasertib and paclitaxel (any patient who started 
ipatasertib monotherapy under Versions 2–5 of the protocol can be switched to 
ipatasertib combined with paclitaxel if judged clinically appropriate by the investigator 
and accepted by the patient). 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
330/Protocol MX39795, Version 11 


Appendix 10-8:  Ipatasertib in Combination With Paclitaxel 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
331/Protocol MX39795, Version 11 
SAFETY  
SAFETY PROFILE 
The safety profile of ipatasertib as monotherapy and in combination with paclitaxel is 
presented in the Ipatasertib Investigator’s Brochure.   
The identified risks associated with ipatasertib treatment include: 
 
Gastrointestinal toxicity (diarrhea, nausea, vomiting and oral mucositis) 
 
Fatigue/asthenia 
 
Rash 
 
Erythema multiforme 
 
Fasting Hyperglycemia 
 
AST/ALT increased 
 
Dehydration 
 
Decreased appetite 
 
 
Potential risks:  
The following list presents adverse events that are Adverse Drug Reactions (ADRs) of 
other inhibitors of the PI3K-AKT-mTOR pathway or that nonclinical data suggest could 
be observed in patients receiving ipatasertib.  These risks are not considered ADRs: 
 
Hematological or Immunosuppressants effects 
 
Hyperlipidemia 
 
Hepatotoxicity 
 
Pneumonitis 
 
Colitis 
 
Developmental toxicity  
 
Drug-drug interactions 
RISKS ASSOCIATED WITH IPATASERTIB IN COMBINATION WITH 
PACLITAXEL 
Data for ipatasertib in combination with paclitaxel come primarily from 61 cancer patients 
in Study GO29227, where patients were randomized to ipatasertib + placebo or 
ipatasertib + paclitaxel. 
 
Adverse events related to ipatasertib which incidences were higher by > 10% in 
patients receiving ipatasertib + paclitaxel versus placebo +paclitaxel were diarrhea 
(88.5% vs. 16.1%) and nausea (41.0% vs. 19.4%) 


Appendix 10-8:  Ipatasertib in Combination With Paclitaxel 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
332/Protocol MX39795, Version 11 
 
The Grade ≥ 3 adverse events reported more frequently in the ipatasertib + 
paclitaxel arm versus the placebo + paclitaxel arm were diarrhea (23.0%, all Grade 
3, vs. 0), neutropenia (9.8% vs. 1.6%], and decreased neutrophil count (8.2% vs. 
6.5%) 
 
The incidence of overall neutropenia was similar in both arms (34% in the 
ipatasertib + paclitaxel arm vs. 39% in the placebo + paclitaxel arm), but Grade ≥3 
neutropenia was higher in the ipatasertib + paclitaxel arm (18% vs. 8%) 
 
Management guidelines for ipatasertib that are applicable to this study are provided in 
Table A10-37 to Table A10-46. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For ipatasertib, AESIs include: 
 
Grade ≥ 3 diarrhea 
 
Grade ≥ 3 fasting hyperglycemia 
 
Grade ≥ 3 rash 
 
Grade ≥ 2 pneumonitis 
 
Grade ≥ 2 colitis/enterocolitis 
 
Grade  3 hepatotoxicity including ALT/AST elevations 
 
ADMINISTRATION OF IPATASERTIB IN COMBINATION WITH PACLITAXEL 
POSOLOGY AND ROUTE 
The dose of ipatasertib will be 400 mg daily on Day 1 to 21 of a 28-day cycle.  There is 
no administration of ipatasertib on Day 22 to 28.  Ipatasertib will continue to be dosed as 
a monotherapy after the final administration of paclitaxel (see below) until loss of clinical 
benefit. 
Each dose of ipatasertib should be taken with a minimum of 90 mL (3 ounces) of fluid. 
Ipatasertib may be taken with or without food. 
Paclitaxel will be administered at a dose of 80 mg/m2 IV over 1 hour on Days 1, 8, and 
15 of a 28-day cycle.  If the dose on Day 1, 8, or 15 is missed, it can be given on Day 22.  
Paclitaxel will be given for 3 cycles.  If relevant and tolerated, it may be continued 
beyond 3 cycles (refer to Section 4.3.4.7). 


Appendix 10-8:  Ipatasertib in Combination With Paclitaxel 
  
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Note: On days when patients are to receive both medications, ipatasertib should be 
administered before paclitaxel infusions. 
For instructions on handling of ipatasertib, refer to the Ipatasertib Investigator’s 
Brochure.  For instructions on handling of paclitaxel, refer to the local reference 
information. 
DURATION OF TREATMENT 
Treatment with ipatasertib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  
Paclitaxel in combination with ipatasertib will be administered for 3 cycles.  If relevant 
and tolerated, it may be continued beyond 3 cycles. 
PROPHYLAXIS 
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.  Refer to 
Table A10-39 for further details on treatment of gastrointestinal toxicities during 
ipatasertib treatment. 
 
PREMEDICATION FOR IPATASERTIB+PACLITAXEL 
All patients should be premedicated prior to paclitaxel administration to prevent severe 
hypersensitivity reactions.  This premedication should consist of the institution’s standard 
of care or one of the following premedications: 
 
Dexamethasone 20 mg orally approximately 12 hours prior and 6 hours prior to the 
paclitaxel infusion  
– 
Patients may be treated with dexamethasone 10−20 mg IV within 1 hour prior to 
paclitaxel infusion if the patient did not take the oral dexamethasone 
 
 
Diphenhydramine 50 mg IV (or equivalent) 30−60 minutes prior to paclitaxel infusion 
 
Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30−60 minutes prior to 
paclitaxel infusion 
 
DELAYED OR MISSED DOSES 
If a dose is missed (not taken within 8 hours after the scheduled dosing time), the patient 
should resume dosing with the next scheduled dose. If vomiting occurs after taking a 
dose of ipatasertib, the patient should not take an additional dose on that day, and 
treatment should be continued as prescribed the following day. 
If a dose of paclitaxel is missed on Day 1, 8, or 15, it can be given on Day 22. 


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DOSE MODIFICATIONS 
Management of adverse events may require dose reduction, temporary interruption, or 
discontinuation of treatment with ipatasertib. 
The doses of ipatasertib and paclitaxel should be reduced according to the dose 
reduction schedules provided in Table A10-37 and Table A10-38 .  
Table A10-37 Dose Reduction Schedule for Ipatasertib 
Dose Reduction Schedule a 
Dose Level 
Starting dose 
400 mg daily 
1st reduction 
300 mg daily 
2nd reduction 
200 mg daily 
3rd reduction 
Discontinue 
a. If the patient continues to experience specified drug-related adverse events after the second 
reduction, the treatment should be discontinued. 
 
Patients may hold 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 patient does not tolerate the once-daily 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.  Dose re-
escalation is not permitted for ipatasertib. 
Table A10-38 Dose Reduction Schedule for Paclitaxel 
Dose Reduction Schedule 
Dose Level 
Starting dose 
80 mg/m2 
1st reduction 
65 mg/m2 
Further reduction 
Not permitted 
 
TREATMENT INTERRUPTION 
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 treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures) 


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SUMMARY OF ADVICE FOR DOSE DISCONTINUATION AND DOSE 
INTERRUPTION (see Table A10-39 to Table A10-46 for details): 
Ipatasertib must be discontinued if: 
 
Grade 4 diarrhea 
 
Recurrent Grade 4 hyperglycemia 
 
Febrile and Grade 4 neutropenia if recovery to Grade 2 or better does not occur 
after up to 4 weeks of treatment hold 
 
Grade 4 and recurrent Grade 3 hepatotoxicity 
 
Grade 4 rash, recurrent Grade 3 rash, or Grade 3 rash that remains clinically 
significant for 4 weeks after treatment hold 
 
Grade 4 non-infectious pneumonitis, recurrent Grade 3 non-infectious pneumonitis, 
Grade 2 non-infectious pneumonitis if recovery to Grade 1 or better is not observed 
within 28 days of treatment hold 
 
Grade ≥ 3 mucositis, if recovery to Grade 2 or better does not occur within 4 weeks 
of treatment hold 
 
Ipatasertib must be interrupted if:  
 
Systemic corticosteroids are recommended, at the discretion of the investigator, for 
the treatment of specific adverse events.  Ipatasertib treatment should be 
temporarily held during systemic corticosteroids treatment (except when 
corticosteroids are given as pre-medication to paclitaxel) 
 
MANAGEMENT OF SELECTED IDENTIFIED AND POTENTIAL RISKS OF 
IPATASERTIB AND PACLITAXEL 
 
DIARRHEA MANAGEMENT GUIDELINES 
Specific guidelines for managing diarrhea to improve safety and tolerability are provided 
in Table A10-39.  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.  If diarrhea occurs, it should be managed per 
guidelines; upon resolution or when study treatment is restarted, loperamide prophylaxis 
should be considered to resume and continue based on clinical judgments (if allowed by 
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 


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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 
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.  
Table A10-39 Diarrhea Management Guidelines 
Severity of Diarrhea a 
Management Guideline 
Prevention 
 
All patients are should receive loperamide (2 mg BID 
or 4 mg QD) as prophylaxis for diarrhea in the first 
cycle, if allowed by local guidance or unless there is a 
clinical concern precluding their use.  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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337/Protocol MX39795, Version 11 
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 one (or one additional) dose 
level 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 until diarrhea improves to Grade 1 
or better.  Ipatasertib should be reduced by one dose 
level when treatment is restarted.   
 
For recurrent Grade 3 diarrhea, reduce ipatasertib 
dose by one additional dose level.   
 
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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Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
338/Protocol MX39795, Version 11 
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. 
ADL  activities of daily living; BID  twice a day; NCI CTCAE v4.0  National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0; QD  once a day. 
a  Diarrhea, as defined by NCI CTCAE v4.0, a disorder characterized by frequent and watery 
bowel movements. 
 
FASTING HYPERGLYCEMIA 
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours.  The treatment goals for glycemic control should be:  1) fasting glucose 
under 160 mg/dL and 2) HbA1c  8%. 
Dose modification guidelines for fasting hyperglycemia attributable to study treatment 
are outlined below (see Table A10-40) 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. 
In the event of ipatasertib interruption, anti-diabetic medications may need to be held or 
reduced (per investigator judgment) and glucose should be monitored closely to 
minimize the risk of hypoglycemia. 
Because the hyperglycemia observed with ipatasertib treatment is consistently 
associated with endogenous elevations in insulin, insulin-based therapy to manage any 
hyperglycemia should be used with caution because severe hypoglycemic episodes 
could potentially occur.  Therefore, initial treatment should be considered with 
biguanides (preferred), sulfonylureas, and other hypoglycemic treatments. 
Table A10-40 Fasting Hyperglycemia Management Guidelines 
Hyperglycemia  
 
Management Guideline 
General Guidance 
 
Thoroughly evaluate all events of hyperglycemia for more common 
etiologies other than drug-induced effects.  
 
Investigate for diabetes. If patient has Type 1 diabetes, treat as an 
event of fasting glucose value 250500 mg/dL.  
 
Workup could include confirmation of fasting blood glucose, 
urinary glucose and ketones, arterial blood gas, serum 


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Hyperglycemia  
 
Management Guideline 
bicarbonate, hemoglobin A1C, C-peptide levels, anti-islet 
antibodies, and anti-GAD65 antibody.  
 
Treat hyperglycemia per institutional guidelines with fluid 
replacement, insulin, and correction of electrolyte abnormalities. 
Fasting glucose 
value  ULN to 
160 mg/dL 
(8.9 mmol/L) * 
 
Continue ipatasertib.  
 
Provide patient with education on a diabetic diet and consider home 
glucose monitoring.  
 
Consider oral anti-diabetic medications (e.g., metformin) or insulin 
replacement, guided by etiology of hyperglycemia. 
Fasting glucose value 
160 to 250 mg/dL 
( 8.913.9 mmol/L) * 
 
Withhold ipatasertib dosing until fasting glucose value resolves to 
160 mg/dL. (Investigate for diabetes. If patient has Type 1 
diabetes, treat as a fasting glucose value 250500 mg/dL event. If 
patient does not have Type 1 diabetes, treat as per institutional 
guidelines.)  
 
Encourage a diabetic diet and initiate home glucose monitoring.  
 
Start oral anti-diabetic medications (e.g., metformin) or insulin 
replacement, guided by etiology of hyperglycemia.  
 
If patient is already on an oral anti-diabetic medication, the dose of 
ipatasertib should be reduced by one dose level (refer to 
Table A10-37).  
 
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) * 
 
Withhold ipatasertib dosing until fasting glucose value resolves to 
160 mg/dL and contact the Medical Monitor.  
 
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).  
 
Encourage a diabetic diet and initiate home glucose monitoring.  
 
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 hyperglycemia 250500 mg/dL recurs, the dose of ipatasertib 
should be reduced by one dose level (see Table A10-37) when 
treatment is restarted.  
Fasting glucose 
value  500 mg/dL 
( 27.8 mmol/L); 
life-threatening 
consequences * 
 
Withhold ipatasertib dosing until fasting glucose value 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).  


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Hyperglycemia  
 
Management Guideline 
 
Assess for volume depletion and appropriate intravenous or oral 
hydration.  
 
Encourage a diabetic diet and initiate home glucose monitoring.  
 
Upon recovery of fasting glucose to 160 mg/dL, reduce ipatasertib 
by one dose level (see Table A10-37) when treatment is restarted.  
 
If glucose value  500 mg/dL recurs, permanently discontinue 
ipatasertib and contact the Medical Monitor.  Reduce ipatasertib by 
one dose level if and when treatment is restarted. 
 
If Grade 4 hyperglycemia recurs, permanently discontinue 
ipatasertib. 
ULNupper limit of normal. 
* For all grades, the patient should receive education on a diabetic diet. 
 
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 
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 are outlined in Table A10-41. 
Table A10-41 Neutropenia Management Guidelines 
Severity of Neutropenia 
and/or Thrombocytopenia 
Management Guideline 
Grade 2 
 
Ipatasertib may be continued at the original dose.  
Grade 3 
 
Ipatasertib 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 should be reduced by one 
dose level when treatment is restarted.   


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Severity of Neutropenia 
and/or Thrombocytopenia 
Management Guideline 
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. 
ANC  absolute neutrophil count; G-CSF Granulocyte-colony stimulating factor. 
 
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 antiemetics (i.e., prochlorperazine or 
metoclopramide per institutional guidelines; see Table A10-42 ).  For persistent nausea 
and/or vomiting attributable to ipatasertib, dosage modification guidelines are outlined in 
Table A10-37. 
Table A10-42 Nausea and Vomiting 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 antiemetics, 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 antiemetics, including ondansetron. 
 
If Grade  3 nausea or vomiting recurs, ipatasertib should be 
reduced by one dose level when treatment is restarted.   
 
HEPATOTOXICITY 
Permanently discontinue ipatasertib for any patients who develop a concurrent elevation 
of ALT and/or AST greater than 3  ULN and total bilirubin greater than 2  ULN and/or 
clinical jaundice in the absence of biliary obstruction or other causes responsible for the 


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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 A10-43) 
Table A10-43 Hepatotoxicity Management Guidelines 
Severity of LFT Elevation 
Management Guideline 
Grade 1  
AST or ALT  baseline  
3  ULN or  
T bilirubin  baseline 1.5  ULN 
Continue study drugs. 
Grade 2  
AST or ALT  3–5  ULN or 
T bilirubin  1.5–3.0  ULN 
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   5–20  ULN or 
T bilirubin  3–10  ULN 
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 A10-37)  
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  ULN or 
T bilirubin  10  ULN 
Permanently discontinue ipatasertib. 
LFT  liver function test; QD  once daily; ULN  upper limit of normal. 
 
RASH 
Treatment-related rash, has occurred in patients receiving ipatasertib treatment 
particularly when ipatasertib has been used certain combinations (e.g. ipatasertib in 
combination with paclitaxel and atezolizumab or with abiraterone). The following 
prophylaxis measures can be considered, in particular for combinations with overlapping 
skin toxicity. 
 
Unless contraindicated, daily PO antihistamine prophylaxis can be considered for at 
least the first cycle. It is suggested that a non-sedating longer-acting oral 


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antihistamine be used (such as 10 mg of cetirizine PO QD or comparable dose of 
other antihistamines, e.g., loratadine, fexofenadine).  
 
Ipatasertib should be permanently discontinued for rash associated with 
Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS (Drug Reaction with 
Eosinophilia and Systemic Symptoms), or other suspected severe hypersensitivity or 
allergic reaction.  Dosage modification and symptom management guidelines for skin 
toxicity, including erythema multiforme, attributable to ipatasertib are shown below in 
Table A10-44. 
Table A10-44 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. 
 
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. 
 
PNEUMONITIS 
Pneumonitis is not known to be causally related to ipatasertib; 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 A10-45). 


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Table A10-45 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 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.   
 
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 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. 
 


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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 A10-46. 
Table A10-46 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.   
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.   
 
If recovery of mucositis to Grade 2 or better does not occur within a 
maximum of 4 weeks, the patient will permanently discontinue 
ipatasertib. 
 
OTHER NON-HEMATOLOGIC TOXICITIES 
If other Grade  3 non hematologic toxicities not described above develop in patients, 
treatment with ipatasertib may be held, depending on the attribution of the toxicity, at the 
discretion of the investigator.  Ipatasertib should be discontinued for any non-
hematologic grade 4 adverse event considered related to ipatasertib. 
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. 
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 based on clinical judgment. 


Appendix 10-8:  Ipatasertib in Combination With Paclitaxel 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
346/Protocol MX39795, Version 11 
SURGERY AND PALLIATIVE RADIOTHERAPY  
Patients who require radiotherapy or surgery as part of medical treatment in the absence 
of radiographic disease progression must exercise caution, and paclitaxel and 
ipatasertib should be temporarily withheld 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 of paclitaxel and ipatasertib may be shorter, upon 
clinical judgment.  After the temporary treatment hold is complete, study treatment may 
be re-initiated when the patient has sufficiently recovered. 
DRUG INTERACTIONS 
A clinical study in patients showed that ipatasertib at a dose of 600 mg QD is a moderate 
inhibitor of CYP3A, which resulted in a 2.22-fold increase in midazolam (sensitive 
CYP3A substrate with a narrow therapeutic window) exposures.  Ipatasertib is primarily 
metabolized by CYP3A and, hence, strong inhibitors and inducers of CYP3A may result 
in increased or decreased ipatasertib exposures, respectively.  Therefore, the following 
drugs should be avoided, or used with caution when administering ipatasertib.  If using 
of one of these drugs is necessary, the risks and benefits should be evaluated prior to its 
concomitant use with ipatasertib per protocol guidelines: 
 
Strong CYP3A inhibitors, such as but not limited to atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandamycin, voriconazole, and/or grapefruit juice or grapefruit 
supplements 
 
Strong CYP3A inducers, such as but not limited to rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin 
 
CYP3A4 substrates with a narrow therapeutic index, such as but not limited to 
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, ergot alkaloids ergotamine, and/or 
dihydroergotamine 
 


A10–9 
IVOSIDENIB 
BACKGROUND ON IVOSIDENIB 
Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 
α-ketoglutarate and CO2.  Three isoforms of IDH exist in human cells: IDH1, IDH2 and 
IDH3.  Although alike in enzymatic activity, the three isoforms can be distinguished, in 
part, on the basis of cellular localization.  Specifically, IDH1 is found in peroxisomes and 
the cytosol, while IDH2 and IDH3 are found within mitochondria. 
A mutation in IDH1 that replaces arginine at position 132 with histidine (R132H) has 
been shown to be associated with various types of cancer, including acute myeloid 
leukemia, cholangiocarcinoma, chondrosarcoma, glioma, myelodysplastic syndromes, 
and others.  The R132H mutation results in an enzyme that has lost the wild-type ability 
to convert isocitrate to α-ketoglutarate (Yan et al. 2009; Zhao et al. 2009), while gaining 
a new ability to catalyze the reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate 
(2-HG) (Dang et al. 2009).  2-HG is an onco-metabolite that has been shown to be 
associated with elevated risks of brain tumors and other types of cancer (Kolker et al. 
2002; Wajner et al. 2004; Aghili et al. 2009).  High levels of 2-HG inhibits enzymes 
involved in DNA and histone methylation (Yan et al. 2009; Gross et al. 2010; Ward et al. 
2010; Borger et al. 2012; Fan et al. 2017), which in turn blocks cellular differentiation and 
promotes tumorigenesis in both hematologic and non-hematologic malignancies 
(Chowdhury et al. 2011; Xu et al. 2011; Koivunen et al. 2012). 
Ivosidenib is a potent and selective inhibitor of the IDH1 mutant protein; no significant 
off-target activity has been identified to date (see Ivosidenib Investigator’s Brochure).  
The compound has been demonstrated to reduce 2-HG levels by > 95%, to reverse 
growth factor-independent growth in vitro, and to induce differentiation in cancer cell 
models.  The US Food and Drug Administration has approved ivosidenib for the 
treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as 
detected by an FDA-approved test in: adult patients with newly diagnosed AML who are 
≥75 years old or who have comorbidities that preclude use of intensive induction 
chemotherapy; and adult patients with relapsed or refractory AML. 
SAFETY 
The safety profile of ivosidenib is detailed in the Ivosidenib Investigator’s Brochure. 
Identified or potential risks associated with ivosidenib treatment are described 
immediately below.  Management guidelines for these and other adverse reactions are 
provided in a later section of this Appendix (see Table A10-47). 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
347/Protocol MX39795, Version 11 


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
348/Protocol MX39795, Version 11 
QT PROLONGATION 
Prolongation of heart-rate corrected QT (QTc) interval has been observed in monkeys at 
relatively high doses of ivosidenib, as well as in patients while receiving ivosidenib.  
Please refer to the current Ivosidenib Investigator’s Brochure for detailed information. 
Subjects may be at increased risk for the development of QT prolongation when treated 
with ivosidenib in combination with fluoroquinolones, azole antifungal agents, or 
serotonin (5-HT3) antagonists.  Investigators need to be vigilant regarding concomitant 
medications associated with QT prolongation, and if no other therapeutic options are 
available, monitor subjects receiving ivosidenib with the combination of these drugs, and 
evaluate ECG and electrolytes (including potassium, magnesium, and calcium) 
particularly in subjects presenting with nausea, vomiting, or diarrhea. 
LEUKOENCEPHALOPATHY 
Leukoencephalopathy is a potential risk associated with ivosidenib treatment based on 
clinical safety findings observed across the ivosidenib clinical development program.  
Progressive multifocal leukoencephalopathy (PML) and posterior reversible 
encephalopathy syndrome (PRES), both Grade 3 SAEs, have each been reported in 
1 subject.  
The signs and/or symptoms of PML may begin gradually, usually worsen rapidly, and 
vary depending on which part of the brain is infected.  Signs and symptoms may include 
difficulty with walking and other movements, progressive weakness, decline in mental 
function, visual field deficits, and speech and language disturbances.  Rarely, 
headaches and seizures occur.  Subjects should be monitored for onset of signs or 
symptoms suggestive of PML.  Diagnostic evaluations may include consultation with a 
neurologist, MRI of the brain, lumbar puncture, and/or brain biopsy as clinically 
warranted.  Treatment with ivosidenib should be suspended in the setting of suspected 
PML and permanently discontinued in subjects with confirmed PML. 
PRES is a rare clinico-radiological neurological syndrome (Linda and von Heijne 2015).  
Clinical characteristics may include sub-acute onset of headache, hypertension, 
seizures, altered mental status, visual disturbances, and occasionally other focal 
neurological signs.  Radiologically, signs of vasogenic edema are usually seen bilaterally 
in the white mater of the parieto-occipital lobes, but changes can also be seen in frontal 
and temporal lobes, brainstem, cerebellum, and in cortical as well as deep gray matter.  
Subjects should be monitored for onset of neurological signs and/or symptoms that are 
clinically associated with PRES.  Diagnostic evaluations may include consultation with a 
neurologist, MRI of the brain, and other recognized standard of care measures as 
clinically warranted.  


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
349/Protocol MX39795, Version 11 
Refer to Section 6.6.2.1 (PML) and Section 6.6.2.2 (PRES) in the Ivosidenib 
Investigator’s Brochure for further details on these events.  
SENSORIMOTOR NEUROPATHY/POLYNEUROPATHY 
Sensorimotor neuropathy/polyneuropathy is a potential risk associated with ivosidenib 
treatment based on safety findings observed across the ivosidenib clinical development 
program.  Guillain-Barre syndrome (Grade 2 SAE in one subject; Grade 3 SAE in one 
subject) and lumbosacral plexopathy (Grade 2 SAE in one subject) are rare, serious 
syndromes that affect the central and peripheral nervous systems.  
Subjects should be monitored for onset of new signs or symptoms or motor and/or 
sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or 
paresthesia.  If a subject experiences signs or symptoms suggestive of sensorimotor 
neuropathy, Guillain-Barre syndrome, or lumbosacral plexopathy, diagnostic evaluation 
may include a consultation with a neurologist, lumbar puncture, and electromyography.  
Ivosidenib should be permanently discontinued in subjects with a confirmed diagnosis of 
Guillain-Barre syndrome.  
Refer to Section 6.6 (Potential Risks) in the Ivosidenib Investigator’s Brochure for further 
details on these events. 
IDH INHIBITOR-INDUCED DIFFERENTIATION SYNDROME 
Subjects with hematologic malignancies receiving treatment ivosidenib have developed 
signs and symptoms of IDH differentiation syndrome as early as 1 day and as late as 
3 months while on treatment.  The median time to onset was approximately 30 days 
after treatment initiation.  
Clinical features may include some or all of the following: respiratory compromise, 
interstitial pulmonary infiltrates, pleural and/or pericardial effusion, hypoxia, unexplained 
fever, rash, weight gain, and clinical deterioration.  Laboratory features may include an 
increase in absolute neutrophil count (ANC) and/or platelets.  An increase in mature 
leukocytes may be observed in the bone marrow aspirate differential if a bone marrow 
biopsy is conducted during this time.  However, no single sign or symptom may be 
considered per se as diagnostic of the syndrome, and other causes should be sought 
and excluded.  In addition, clinical and/or laboratory features may require further medical 
intervention and could be life-threatening or fatal if left untreated.   
LEUKOCYTOSIS 
Ivosidenib may be associated with leukocytosis that can occur without progression of 
AML.  


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
350/Protocol MX39795, Version 11 
It is recommended that the prophylactic and therapeutic measures indicated below are 
undertaken at the earliest manifestations of leukocytosis: 
Temporary hold of study treatment only if symptoms cannot be medically managed with 
the following: 
 
Prompt initiation of hydroxyurea at up to a dose of 2,000 or 3,000 mg PO BID 
 
Prompt initiation of leukapheresis, if required 
Treatment with hydroxyurea is allowed during treatment with ivosidenib for control of 
peripheral leukemic blasts in subjects with leukocytosis (WBC >30,000/μL). Once the 
signs and symptoms resolve and the subject’s clinical condition improves, ivosidenib 
may be re-initiated if study treatment was held.  
Refer to Section 6.6 (Potential Risks) in the Ivosidenib Investigator’s Brochure for further 
details on these events.  
 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For ivosidenib, AESIs include: 
 
Grade ≥ 3 QT / QTc prolongation 
 Any Grade Leukoencephalopathy 
 Grade ≥ 2 Sensorimotor Neuropathy/Polyneuropathy 
 Any Grade Leucocytosis  
 Any Grade Differentiation syndrome 
 
ADMINISTRATION OF IVOSIDENIB 
POSOLOGY AND ROUTE 
Ivosidenib will be administered continuously at an oral dosage of 500 mg once daily 
across a 28-day treatment cycle. 
Patients should refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices for 7 days 
before the start of study treatment until 30 days after the final dose, as this can affect the 
metabolism of the study drug. 
Ivosidenib should be administered at about the same time each day.  Ivosidenib may be 
administered with or without food, although it should NOT be administered with a high-


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
351/Protocol MX39795, Version 11 
fat meal because of an increase in ivosidenib concentration.  Ivosidenib tablets should 
not be split or crushed. 
DURATION OF TREATMENT 
Treatment with ivosidenib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  Patients without disease progression or 
unacceptable toxicity should be treated for a minimum of 6 months to allow time for 
clinical response. 
DELAYED OR MISSED DOSES 
If a dose of ivosidenib is vomited, a replacement dose should not be administered.  
Instead, wait until the next scheduled dose is due.  
If a dose of ivosidenib is missed or not taken at the usual time, the dose should be 
administered as soon as possible and at least 12 hours prior to the next scheduled dose.  
Return to the normal schedule on the following day.  Two doses of ivosidenib should not 
be administered within 12 hours of each other. 


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
352/Protocol MX39795, Version 11 
DOSE MODIFICATIONS OR DISCONTINUATION DURING TREATMENT 
 
Table A10-47 Guidelines for Management (Including Discontinuation) of 
Patients Who Experience Specific Adverse Events 
IDH Differentiation Syndrome 
 
Initiate dexamethasone 10 mg IV every 12 
hours (or an equivalent dose of an 
alternative oral or IV corticosteroid) and 
hemodynamic monitoring until symptoms 
resolution and for a minimum of 3 days 
 
If concomitant non-infectious leukocytosis 
is observed, initiate treatment with 2–
3 g/day hydroxyurea or leukapheresis, as 
clinically indicated 
 
Taper corticosteroids and hydroxyurea 
after resolution of symptoms and 
administer corticosteroids for a minimum 
of 3 days.  Symptoms of differentiation 
syndrome may recur with premature 
discontinuation of corticosteroid and/or 
hydroxyurea treatment 
 
If severe signs and/or symptoms persist 
for more than 48 hours after initiation of 
corticosteroids, interrupt ivosidenib until 
signs and symptoms are no longer severe 
 
Resume ivosidenib when signs and 
symptoms improve to Grade 2 or lower 
 
QTc Prolongation 
QTc interval > 480 msec to ≤ 500 msec 
 
Monitor and supplement electrolyte levels 
as clinically indicated.  Review and adjust 
concomitant medications with known QTc 
interval-prolonging effects 
 
The dose of ivosidenib may be reduced 
without interruption of dosing. The 
ivosidenib dose may be re-escalated to 
the prior dose in ≥14 days after QT 
prolongation has decreased to Grade ≤1 
 
Restart at 500 mg once daily after the 
QTc interval returns to less than or equal 
to 480 msec 
 
Monitor ECGs at least weekly for 2 weeks 
following resolution of QTc prolongation 
 
QTc interval > 500 msec 
 
Monitor and supplement electrolyte levels 
as clinically indicated. 
 
Hospitalization for continuous cardiac 
monitoring and evaluation by a 
cardiologist should both be considered. 


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
353/Protocol MX39795, Version 11 
 
Review and adjust concomitant 
medications with known QTc interval-
prolonging effects [see Appendix). 
 
Dosing with ivosidenib will be interrupted. 
If QTcF returns to within 30 msec of 
baseline or <450 msec within 14 days, 
treatment may be resumed at a reduced 
dose.  Monitor ECGs at least weekly for 2 
weeks following resolution of QTc 
prolongation. 
 
The ivosidenib dose cannot be re-
escalated following dose reduction for 
Grade 3 QTcF prolongation unless the 
prolongation was associated with an 
electrolyte abnormality or concomitant 
medication. 
 
QTc interval prolongation with signs/ 
symptoms of life-threatening arrhythmia 
 
Discontinue ivosidenib permanently 
 
Non-infectious Leukocytosis 
 
(White blood cell [WBC] > 25 ×109/L or an 
absolute increase in total WBC 
of > 15 × 109/L from baseline) 
 
Initiate treatment with hydroxyurea, as per 
standard institutional practices, and 
leukapheresis if clinically indicated 
 
Taper hydroxyurea only after leukocytosis 
improves or resolves 
 
Interrupt ivosidenib if leukocytosis is not 
improved with hydroxyurea, and then 
resume ivosidenib at 500 mg daily when 
leukocytosis has resolved 
 
Guillain-Barré Syndrome 
 
Discontinue ivosidenib permanently 
Other Grade 3 or higher toxicities considered 
related to ivosidenib treatment 
 
Interrupt ivosidenib until toxicity resolves 
to Grade 2 or lower 
 
Resume ivosidenib at 250 mg once daily; 
may increase to 500 mg once daily if 
toxicities resolve to Grade 1 or lower 
 
If Grade 3 or higher toxicity recurs, 
discontinue ivosidenib 
 
 
DRUG INTERACTIONS 
 
Table A10-48 Effects of Other Drugs on Ivosidenib 
Strong or Moderate CYP3A4 Inhibitors 
Clinical Impact 
 Co-administration of ivosidenib with strong or moderate 
CYP3A4 inhibitors increased ivosidenib plasma 
concentrations 
 Increased ivosidenib plasma concentrations may increase 
the risk of QTc interval prolongation 


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
354/Protocol MX39795, Version 11 
Strong or Moderate CYP3A4 Inhibitors 
Prevention or Management 
 Consider alternative therapies that are not strong or 
moderate CYP3A4 inhibitors during treatment with 
ivosidenib 
 If co-administration of a strong CYP3A4 inhibitor 
is unavoidable, reduce ivosidenib to 250 mg once daily 
 Monitor patients for increased risk of QTc interval 
prolongation 
Strong CYP3A4 Inducers 
Clinical Impact 
 Co-administration of ivosidenib with strong CYP3A4 
inducers decreased ivosidenib plasma concentrations 
Prevention or Management 
 Avoid co-administration of strong CYP3A4 inducers with 
ivosidenib 
QTc Prolonging Drugs 
Clinical Impact 
 
 Co-administration of ivosidenib with QTc prolonging drugs 
may increase the risk of QTc interval prolongation 
Prevention or Management 
 Avoid co-administration of QTc prolonging drugs with 
ivosidenib or replace with alternative therapies 
 If co-administration of a QTc prolonging drug is 
unavoidable, monitor patients for increased risk of QTc 
interval prolongation 
 
Effect of Ivosidenib on Other Drugs 
Cytochrome P450 (CYP)-phenotyping of ivosidenib metabolism performed in human 
liver microsomes and recombinant CYP enzymes suggest that CYP3A4 played a major 
role in the oxidative metabolism of ivosidenib, while other CYP enzymes such as 
CYP2B6 and CYP2C8 play a minor role. 
Ivosidenib induced CYP2B6, CYP2C8, CYP2C9, and CYP3A4 but not CYP1A2 in 
cultured human hepatocytes, and therefore, there is the possibility of drug-drug 
interactions upon co-administration with sensitive substrates of CYP2B6, CYP2C8, 
CYP2C9 and CYP3A4/5. 
Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 
substrates and may decrease concentrations of drugs that are sensitive CYP2C9.  Use 
alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during 
ivosidenib treatment.  Do not administer ivosidenib with itraconazole or ketoconazole 
(CYP3A4 substrates) due to expected loss of antifungal efficacy.  Co-administration of 
ivosidenib may decrease the concentrations of hormonal contraceptives; consider 
alternative methods of contraception in patients receiving ivosidenib.  If co-administration 


Appendix 10-9:  Ivosidenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
355/Protocol MX39795, Version 11 
of ivosidenib with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, 
monitor patients for loss of therapeutic effect of these drugs. 
Caution should be used in case of co-administration of ivosidenib with sensitive 
substrates of CYP2B6, CYP2C8. 
 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
356/Protocol MX39795, Version 11 
A10–10 
OLAPARIB 
BACKGROUND ON OLAPARIB 
Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-
1, PARP-2, and PARP-3). 
PARP are required for the efficient repair of DNA single strand breaks.  An important 
aspect of PARP-induced repair requires that after chromatin modification, PARP auto-
modifies itself and dissociates from the DNA to facilitate access for base excision repair 
(BER) enzymes.  When OLAPARIB is bound to the active site of DNA-associated PARP, 
it prevents the dissociation of PARP and traps it on the DNA, thus blocking repair.  In 
replicating cells, this leads to DNA double strand breaks (DSBs) when replication forks 
meet the PARP-DNA adduct.  In normal cells, homologous recombination repair (HRR), 
which requires functional BRCA1 and 2 genes, is effective at repairing these DNA 
double-strand breaks.  In the absence of functional BRCA1 or 2, DNA DSBs cannot be 
repaired via HRR.  Instead, alternative and error-prone pathways are activated, such as 
the non-homologous end joining (NHEJ) pathway, leading to increased genomic 
instability.  After a number of rounds of replication genomic instability can reach 
insupportable levels and result in cancer cell death, as cancer cells have a high DNA 
damage load relative to normal cells.  
Olaparib is being developed for use in the treatment of cancers.  Olaparib has been 
approved in various countries as monotherapy for the maintenance treatment of adult 
patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic), high 
grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in 
response (complete response or partial response) to platinum-based chemotherapy. 
SAFETY 
The safety profile of olaparib is presented in the Olaparib EMA Summary of Product 
Characteristics. 
Adverse reactions associated with Warnings and Precautions: 

Hematological toxicity

Myelodysplastic syndrome/acute myeloid leukemia

Pneumonitis

Interactions with other drugs
Management guidelines for olaparib adverse reactions that are applicable to this study 
are provided in Table A10-49. 


Appendix 10-10:  Olaparib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
357/Protocol MX39795, Version 11 
The summary information provided in the following sections must always be checked 
against any update of the olaparib local prescription guidelines/EMA Summary of 
Product Characteristics that may have occurred after the protocol has been issued. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For olaparib, no AESI needs reporting. 
 
ADMINISTRATION OF OLAPARIB 
POSOLOGY AND ROUTE 
The dose of olaparib will be either: 
 
400 mg (eight 50 mg capsules) taken twice daily, equivalent to a total daily dose 
of 800 mg. 
 
or 300 mg (two 150 mg film-coated tablets) taken twice daily, equivalent to a total 
daily dose of 600 mg. 
– 
Note: After the film-coated tablets are available for use in the study,   
▪ 
patients newly randomized should start olaparib treatment with 300 mg BID 
using film-coated tablets.  
▪ 
patients who already started treatment with 400 mg BID using capsules 
should only switch to 300 mg BID using film-coated tablets, after capsules 
are not any more available (when the last batch of capsules expires). 
Due to the effect of food on olaparib absorption, patients should take olaparib at least 
one hour after food, and refrain from eating preferably for up to 2 hours afterwards. 
For more details and instructions on handling of the medicinal product, refer to the 
Olaparib Summary of Product Characteristics from the EMA. 
DURATION OF TREATMENT 
Treatment with olaparib should continue until loss of clinical benefit or the development 
of unacceptable toxicity.  
DELAYED OR MISSED DOSES 
If a dose is missed, the next normal dose should be taken at its scheduled time. 
DOSE MODIFICATIONS OR DISCONTINUATION DURING TREATMENT 
Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, 
diarrhea, and anemia and dose reduction can be considered. 


Appendix 10-10:  Olaparib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
358/Protocol MX39795, Version 11 
For Treatment with capsules: 
The recommended dose reduction is to 200 mg twice daily (equivalent to a total daily 
dose of 400 mg). 
If a further final dose reduction is required, then reduction to 100 mg twice daily 
(equivalent to a total daily dose of 200 mg) could be considered. 
For Treatment with film-coated tablets: 
The recommended dose reduction is to 250 mg (one 150 mg tablet and one 100 mg 
tablet) twice daily (equivalent to a total daily dose of 500 mg). 
If a further dose reduction is required, then reduction to 200 mg (two 100 mg tablets) 
twice daily 
(equivalent to a total daily dose of 400 mg) is recommended. 
 
Renal Impairment  
For Treatment with capsules: 
For patients with moderate renal impairment (creatinine clearance 31 to 50 mL/min), the 
recommended dose of olaparib is 300 mg twice daily (equivalent to a total daily dose of 
600 mg).  
For Treatment with film-coated tablets: 
For patients with moderate renal impairment (creatinine clearance 31 to 50 mL/min) the 
recommended dose is 200 mg (two 100 mg tablets) twice daily (equivalent to a total 
daily dose of 400 mg). 
 
Dose Adjustments for Co-administration With CYP3A Inhibitors 
Concomitant use of strong and moderate CYP3A inhibitors is not recommended and 
alternative agents should be considered.   
For Treatment with capsules: 
If a strong or moderate CYP3A inhibitor must be co-administered, the recommended 
olaparib dose reduction is to 150 mg taken twice daily (equivalent to a total daily dose of 
300 mg) with a strong CYP3A inhibitor or 200 mg taken twice daily (equivalent to a total 
daily dose of 400 mg) with a moderate CYP3A inhibitor. It is also not recommended to 
consume grapefruit juice while on olaparib therapy as it is a CYP3A inhibitor. 
For Treatment with film-coated tablets: 
If a strong or moderate CYP3A inhibitor must be co-administered, the recommended 
Lynparza dose reduction is to 100 mg taken twice daily (equivalent to a total daily dose 
of 200 mg) with a strong CYP3A inhibitor or 150 mg taken twice daily (equivalent to a 
total daily dose of 300 mg) with a moderate CYP3A inhibitor. It is also not recommended 
to consume grapefruit juice while on olaparib therapy as it is a CYP3A inhibitor. 
 


Appendix 10-10:  Olaparib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
359/Protocol MX39795, Version 11 
Summary of Advice for Dose Discontinuation (see Table A10-49 for Details): 
Olaparib must be discontinued if: 
 
Myelodysplastic syndrome/acute myeloid leukemia 
 
Pneumonitis 
 
Table A10-49 Guidelines for Management (Including Discontinuation) of 
Patients Who Experience Specific Adverse Events 
Event 
Action to Be Taken  
Hematological toxicity 
Follow up of hematological parameters per protocol  
If severe hematological toxicity or blood transfusion 
dependence, treatment with olaparib should be 
interrupted and appropriate hematological testing should 
be initiated.  If the blood parameters remain clinically 
abnormal after 4 weeks of olaparib dose interruption, 
bone marrow analysis and/or blood cytogenetic analysis 
are recommended 
Myelodysplastic syndrome/acute 
myeloid leukemia 
If MDS and/or AML are confirmed while on treatment 
with olaparib, it is recommended that the patient be 
treated appropriately.  Treatment with olaparib will be 
discontinued 
Pneumonitis 
If patients present with new or worsening respiratory 
symptoms such as dyspnea, cough and fever, or a 
radiological abnormality occurs, olaparib treatment 
should be interrupted and prompt investigation initiated.  
If pneumonitis is confirmed, olaparib treatment should be 
discontinued and the patient treated appropriately 
Interactions 
Olaparib co-administration with strong or moderate 
CYP3A inhibitors is not recommended (see SPC).  If a 
strong or moderate CYP3A inhibitor must be co-
administered, the dose of olaparib should be reduced 
(see SPC and section Dose adjustments for co-
administration with CYP3A inhibitors above) 
Olaparib co-administration with strong or moderate 
CYP3A inducers is not recommended (see section SPC).  
In the event that a patient already receiving olaparib 
requires treatment with a strong or moderate CYP3A 
inducer, the efficacy of olaparib may be substantially 
reduced (see section SPC) 
In the event that a patient already receiving olaparib 
requires treatment with a P-gp inhibitor, careful 
monitoring of olaparib associated adverse events and 
management of those events via the dose reduction 
strategy is recommended (see SPC section Dose 
Adjustments for co-administration with CYP3A inhibitors 
above) 
SEE SPC FOR FULL DETAILS ON INTERACTIONS 


Appendix 10-10:  Olaparib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
360/Protocol MX39795, Version 11 
SPC = EMA Summary of Product Characteristics 
 
DRUG INTERACTIONS 
Pharmacodynamic Interactions  
Combination of olaparib with vaccines or immunosuppressant agents has not been 
studied.  Therefore, caution should be taken if these drugs are co-administered with 
olaparib and patients should be closely monitored. 
Pharmacokinetic Interactions  
Effect of other drugs on olaparib 
CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of 
olaparib.  A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer 
has shown that co-administration with olaparib decreased olaparib mean Cmax by 71% 
(treatment ratio: 0.29; 90% CI: 0.24–0.33) and mean AUC by 87% (treatment ratio: 0.13; 
90% CI: 0.11–0.16).  Therefore, known strong inducers of this isozyme (e.g., phenytoin, 
rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital and St John's Wort) 
are not recommended with olaparib, as it is possible that the efficacy of olaparib could 
be substantially reduced.  The magnitude of the effect of moderate to strong inducers 
(e.g., efavirenz, rifabutin) on olaparib exposure is not established, therefore the co-
administration of olaparib with these drugs is also not recommended. 
A clinical study to evaluate the impact of itraconazole, a known CYP3A inhibitor has 
shown that co-administration with olaparib increased mean olaparib mean Cmax 1.42-fold 
(90% CI: 1.33-1.52) and mean AUC 2.70-fold (90% CI: 2.44-2.97).  Therefore, known 
strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with 
ritonavir or cobicistat, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, 
erythromycin, diltiazem, fluconazole, verapamil) inhibitors of this isozyme are not 
recommended with olaparib If the strong or moderate CYP3A inhibitors must be co-
administered, the dose of olaparib should be reduced.  The recommended olaparib dose 
reductions are described above. 
In vitro olaparib is a substrate for the efflux transporter P-gp and therefore P-gp inhibitors 
may increase exposure to olaparib.  
Effect of olaparib on other drugs  
Olaparib inhibits CYP3A4 in vitro and is predicted to be a mild CYP3A inhibitor in vivo.  
Therefore, caution should be exercised when sensitive CYP3A substrates or substrates 
with a narrow therapeutic margin (e.g., simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine) are combined with 


Appendix 10-10:  Olaparib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
361/Protocol MX39795, Version 11 
olaparib.  Appropriate clinical monitoring is recommended for patients receiving CYP3A 
substrates with a narrow therapeutic margin concomitantly with olaparib. 
Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro with CYP2B6 being most 
likely to be induced to a clinically relevant extent.  The potential for olaparib to induce 
CYP2C9, CYP2C19 and P-gp can also not be excluded.  Therefore, olaparib upon co-
administration may reduce the exposure to substrates of these metabolic enzymes and 
transport protein.  The efficacy of hormonal contraceptives may be reduced if co-
administered with olaparib. 
In vitro, olaparib inhibits the efflux transporter P-gp (IC50 = 76μM), therefore it cannot be 
excluded that olaparib may cause clinically relevant drug interactions with substrates of 
P-gp (e.g., simvastatin, pravastatin, dabigatran, digoxin and colchicine).  Appropriate 
clinical monitoring is recommended for patients receiving this type of medication 
concomitantly. 
In vitro, olaparib has been shown to be an inhibitor of OATP1B1, OCT1, OCT2, OAT3, 
MATE1 and MATE2K.  It cannot be excluded that olaparib may increase the exposure to 
substrates of OATP1B1 (e.g., bosentan, glibenclamide, repaglinide, statins and 
valsartan), OCT1 (e.g., metformin), OCT2 (e.g., serum creatinine), OAT3 (e.g., 
furosemide and methotrexate), MATE1 (e.g., metformin) and MATE2K (e.g., metformin).  
In particular, caution should be exercised if olaparib is administered in combination with 
any statin. 
 
 


A10–11 
PEMIGATINIB 
BACKGROUND ON PEMIGATINIB 
Pemigatinib is a potent inhibitor of the fibroblast growth factor receptor (FGFR) family of 
receptor tyrosine kinases and is being developed for use in the treatment of solid tumor 
malignancies with activating FGFR gene mutations or chromosomal translocations. 
The mammalian FGFR family is composed of four highly conserved receptors (FGFR1, 
FGFR2, FGFR3, and FGFR4) that have an extracellular ligand-binding domain, a single 
transmembrane domain and an intracellular tyrosine kinase domain.  Eighteen FGFR 
ligands, divided into canonical and hormonal FGFRs, bind to FGFRs, leading to receptor 
dimerization, activation of the kinase domain and transphosphorylation of the receptors 
(Eswarakumar et al. 2005).  Subsequent signal transduction occurs through 
phosphorylation of substrate proteins, such as FGFR substrate 2, which leads to 
activation of the RAS–mitogen-activated protein kinase, the phosphoinositide 3–kinase-
protein kinase B pathway and phospholipase Cγ, which activates the protein kinase C 
pathway. 
There is strong genetic and functional evidence that dysregulation of FGFR can lead 
to the establishment and progression of cancer (Knights and Cook 2010; Turner and 
Grose 2010).  Moreover, a substantial body of evidence indicates that genetically 
activated FGFR pathways sensitize FGFR-altered cancer cells to knockdown or 
inhibition of these receptors (Kunii et al. 2008; Qing et al. 2009; Weiss et al. 2010; 
Lamont et al. 2011).  Consistent with these molecular studies, pemigatinib has been 
shown to produce significant anticancer response in patients with previously treated, 
locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions 
(Abou-Alfa et al. 2020), leading the US FDA to grant accelerated approval to pemigatinib 
as a treatment in this setting (https://bit.ly/3eQVuzc). 
SAFETY 
The safety profile of pemigatinib is presented in the Pemigatinib Investigator’s Brochure. 
Management guidelines for pemigatinib adverse reactions that are applicable to this 
study are provided in Table A10-50 to Table A10-53 (see below). 
The most frequently serious adverse events occurring in greater than 2% of patients 
included urinary tract infection, acute kidney injury, abdominal pain, pneumonia, pyrexia, 
back pain, hyponatremia, and general physical health deterioration.  Rare but significant 
AEs associated with pemigatinib use include serous retinal detachment and soft tissue 
mineralization including calcinosis and calciphylaxis. 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
362/Protocol MX39795, Version 11 


Appendix 10-11:  Pemigatinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
363/Protocol MX39795, Version 11 
WARNINGS AND PRECAUTIONS 
Hyperphosphatemia  
Data from clinical studies of selective FGFR inhibitors, including the ongoing studies of 
pemigatinib, have indicated that hyperphosphatemia is an on-target pharmacologic 
effect of FGFR inhibition.  Therefore, participants must be monitored closely for 
hyperphosphatemia.  Hyperphosphatemia (defined as > 5.5 mg/dL) can be managed 
appropriately with low-phosphate diet, phosphate-lowering medication, dose 
interruptions and dose reductions (see Table A10-51, below).  
Serous Retinal Detachment  
Treatment-emergent AEs, which may represent serous retinal detachment (including 
PTs chorioretinal folds, chorioretinal scar, chorioretinopathy, detachment of macular 
retinal pigment epithelium, detachment of retinal pigment epithelium, macular 
detachment, macular edema, maculopathy, retinal detachment, retinal disorder, retinal 
exudates, retinal edema, retinal pigmentation, retinal thickening, serous retinal 
detachment and subretinal fluid) have been reported in 9.1% of patients with advanced 
malignancies who received pemigatinib as monotherapy (N = 592).   
Serous retinal detachment is due to subretinal fluid accumulation and is caused by some 
tyrosine kinase inhibitors.  Most cases are self-limiting, frequently without treatment 
discontinuation (Arkenau et al. 2014; Duncan et al. 2015; Urner-Bloch et al. 2016; Saka 
et al. 2017).  Nevertheless, participants should be monitored for signs and symptoms of 
serous retinal detachment, and the retina should be assessed with optical coherence 
tomography.  Mild and moderate intensity events should be monitored with 
ophthalmology examination and, in case of worsening of vision and in severe (Grade 3) 
cases of serous retinal detachment, pemigatinib treatment should be interrupted.  
Effects on Embryo/Fetal Development  
Pemigatinib has been shown to affect embryo/fetal development in rats. 
Pemigatinib must not be used by female participants who are or may become pregnant.  
There is an extremely high risk that severe birth defects will result if pregnancy occurs 
while taking pemigatinib in any amount, even for short periods of time.  Potentially any 
fetus exposed during pregnancy can be affected. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 


Appendix 10-11:  Pemigatinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
364/Protocol MX39795, Version 11 
For pemigatinib, no AESI needs reporting. 
 
ADMINISTRATION OF PEMIGATINIB 
POSOLOGY AND ROUTE 
Pemigatinib will be administered at a continuous oral dosage of 13.5 mg QD (given in 
the morning with water) across a 21-day treatment cycle. 
Pemigatinib may be administrated with or without food.  Patients should refrain from 
consumption of red wine, Seville oranges, grapefruit or grapefruit juice, pomelos, exotic 
citrus fruits, grapefruit hybrids, or fruit juices for 7 days before the start of study 
treatment until 30 days after the final dose, as this can affect the metabolism of the study 
drug. 
Any patient who does not reach a target serum phosphate level of > 5.5 mg/dL at any 
time during Cycle 1, is compliant with taking study drug and does not experience an 
ongoing Grade 2 or higher treatment-related AE will increase the daily dose to 18 mg 
starting from Cycle 2 Day 1.  
Patients who are titrated up to 18 mg QD will begin the next cycle at the new dose level.  
Up-titration may occur no earlier than on Day 1 of Cycle 2, so that participants are 
observed for phosphate level and AEs for at least for 1 cycle. 
For instructions on handling of the medicinal product, refer to the Pemigatinib Pharmacy 
Manual. 
DURATION OF TREATMENT 
Treatment with pemigatinib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.   
DELAYED OR MISSED DOSES 
Treatment with pemigatinib may be delayed up to 2 weeks (14 days) to allow for 
resolution of toxicity.  Participants may resume treatment if no medical condition or other 
circumstance exists that, in the opinion of the investigator, would make the participant 
unsuitable for further participation in the study.  The treating investigator should contact 
the Sponsor to discuss the case of any participant whose treatment has been delayed 
for more than 14 days before restarting treatment with pemigatinib. 
If a dose of pemigatinib is missed by 4 or more hours or vomiting occurs after taking a 
dose, an additional dose should not be administered and dosing should be resumed with 
the next scheduled dose. 


Appendix 10-11:  Pemigatinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
365/Protocol MX39795, Version 11 
DOSE MODIFICATIONS OR DISCONTINUATION DURING TREATMENT 
A maximum of two reductions in dose level are allowed with pemigatinib for patients 
dosed at 13.5 mg.  Thus, for these patients, pemigatinib can be decreased to 9 mg and, 
if additional dose reduction is required, further to 4.5 mg.  Dose reductions below 4.5 mg 
are not allowed.  
The frequency and schedule of pemigatinib administration (continuous once-daily 
dosing) should remain the same following dose reduction. 
A maximum of three reductions in dose level are allowed with pemigatinib for patients 
who are up-titrated from 13.5 mg to 18 mg (see above). Thus, for these patients, 
pemigatinib can be decreased to 13.5 mg, and if additional dose reductions are required, 
to 9 mg and then to 4.5 mg. 
 
AST and/or ALT Elevations 
 
Table A10-50 Guidelines for Management (Including Discontinuation) of 
Patients With AST and/or ALT Elevations 
Event 
Action to Be Taken 
 AST and/or ALT > 5.0 × ULN 
 
Note: In patients with liver 
metastases-related elevations at 
baseline, contact the Sponsor to 
discuss clinical management and 
possible dose reductions 
Step 1: Interrupt pemigatinib up to 2 weeks (14 days) 
until the toxicity has resolved to ≤ Grade 1 
Step 2: Restart pemigatinib at same dose.  If 
assessed as related to pemigatinib, restart 
pemigatinib at next lower dose; monitor as clinically 
indicated 
 
AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal. 
 
Hyperphosphatemia  
Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition.  
Hyperphosphatemia should be managed with diet modifications, phosphate binders and 
diuretics, or a dose reduction per the recommendations in Table A10-51.  For grading of 
hyperphosphatemia, please note that CTCAE v5.0 now has a category for 
hyperphosphatemia.  
The use of diet modifications alone include food exchanges from high-phosphate foods 
to low-phosphate foods and can be implemented once serum phosphate levels are 
above the ULN but do not exceed 7.0 mg/dL.  Diet modification should continue with the 
inclusion of phosphate binders once serum phosphate levels exceed 7.0 mg/dL.  
Examples of phosphate binders are sevelamer HCl (examples of brand names: 
Renegel® or Renvela®) or lanthanum HCl. 


Appendix 10-11:  Pemigatinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
366/Protocol MX39795, Version 11 
Administration of phosphate binders should be 3 times per day (e.g., with each meal) to 
reduce absorption of phosphate.  Doses and frequency of doses should be based on the 
participant's tolerance for the binder and the control of serum phosphate.  If binders are 
used to manage hyperphosphatemia during treatment, it is recommended to stop 
binders at the same time pemigatinib is stopped to reduce the risk of hypophosphatemia. 
Table A10-51 Guidelines for Management (Including Discontinuation) of 
Patients With Hyperphosphatemia 
Serum 
Phosphate Level 
Supportive Care 
Guidance for 
Interruption/ 
Discontinuation of 
Pemigatinib 
Guidance for 
Restarting 
Pemigatinib 
> 5.5 mg/dL and 
≤ 7 mg/dL 
Initiate a low-
phosphate diet 
No action 
Not applicable 
> 7 mg/dL and 
≤ 10 mg/dL 
Initiate/continue a low-
phosphate diet and 
initiate phosphate-
binding therapy.  
Monitor serum 
phosphate 
approximately twice a 
week and adjust the 
dose of binders as 
needed; continue to 
monitor serum 
phosphate at least 
twice a week until level 
returns to ≤ 7 mg/dL 
If serum phosphate 
level continues to 
be > 7 mg/dL and 
≤ 10 mg/dL with 
concomitant 
phosphate-binding 
therapy for 2 weeks, or 
if there is recurrence of 
serum phosphate level 
in this range, interrupt 
pemigatinib for up to 
2 weeks 
Restart at the same 
dose when serum 
phosphate is 
< 7 mg/dL.  If serum 
phosphate level 
recurs at > 7 mg/dL, 
restart pemigatinib 
with dose reduction 
> 10 mg/dL 
Continue to maintain a 
low-phosphate diet, 
adjust phosphate-
binding therapy, and 
start/continue 
phosphaturic agent.  
Continue to monitor 
serum phosphate 
approximately twice a 
week until level returns 
to ≤ 7 mg/dL 
If serum phosphate 
level is > 10 mg/dL for 
1 week following 
phosphate-binding 
therapy and low-
phosphate diet, 
interrupt pemigatinib.  
If there is recurrence of 
serum phosphate level 
in this range following 
two dose reductions, 
permanently 
discontinue 
pemigatinib 
Restart pemigatinib 
at reduced dose with 
phosphate binders 
when serum 
phosphate is 
< 7 mg/dL 
 


Appendix 10-11:  Pemigatinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
367/Protocol MX39795, Version 11 
QT Interval Prolongation 
 
Table A10-52 Guidelines for Management (Including Discontinuation) of 
Patients With QT Interval Prolongation 
Event 
Action to Be Taken 
 QT/QTc to > 500 msec or to 
> 60 msec over baseline 
Discontinue pemigatinib administration 
 
Other Toxicities 
 
Table A10-53 Guidelines for Management (Including Discontinuation) of 
Patients With Other Toxicities 
Event 
Action to Be Taken 
 Any Grade 1 or 2 toxicity 
Continue pemigatinib treatment and treat toxicity; 
monitor as clinically indicated 
 Any Grade 3 toxicity, if clinically 
significant and not manageable 
by supportive care 
Step 1: Interrupt pemigatinib up to 2 weeks (14 days) 
until toxicity resolves to ≤ Grade 1 
Step 2: Restart pemigatinib at same dose.  If assessed 
as related to pemigatinib, restart pemigatinib at next 
lower dose; monitor as clinically indicated 
 Any recurrent Grade 3 toxicity 
after two dose reductions 
Discontinue pemigatinib administration  
 Any Grade 4 toxicity 
Discontinue pemigatinib administration 
 
DRUG INTERACTIONS 
Pemigatinib is predominantly metabolized by CYP3A4.   
 
Potent CYP3A4 inhibitors and inducers and moderate CYP3A4 inducers are 
prohibited with pemigatinib. Concomitant use of pemigatinib with St John's wort 
(CYP3A4 inducer) is contraindicated 
– 
Based on the low overall bioavailability of topical ketoconazole, there are no 
restrictions on topical ketoconazole 
The use of moderate CYP3A4 inhibitors is not prohibited but should involve careful 
monitoring, especially in relation to safety.  
Careful monitoring is required when pemigatinib is concomitantly administered with 
OCT2 substrates, such as dofetilide and metformin.  
The gastric pH-modifying agents esomeprazole and ranitidine have a modest effect on 
the overall exposure of pemigatinib when co-administered. 


Appendix 10-11:  Pemigatinib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
368/Protocol MX39795, Version 11 
Proton pump inhibitors (PPIs) should be avoided with pemigatinib. 
Close clinical surveillance is recommended when pemigatinib is administered with 
CYP2B6 substrates (e.g. methadone, efavirenz). 
Co-administration of pemigatinib with P-gp substrates (e.g. digoxin, dabigatran, 
colchicine) may increase their exposure and thus their toxicity. Pemigatinib 
administration should be separated by at least 6 hours before or after administration of 
P-gp substrates with a narrow therapeutic index. 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
369/Protocol MX39795, Version 11 
A10–12 
PERTUZUMAB IN COMBINATION WITH TRASTUZUMAB 
BACKGROUND 
Pertuzumab and trastuzumab bind to distinct epitopes on the HER2 receptor without 
competing with each other, and have complementary mechanisms for disrupting HER2 
signaling.  This results in augmented anti-proliferative activity in vitro and in vivo when 
pertuzumab and trastuzumab are given in combination.  
In various countries, trastuzumab is indicated for the treatment of metastatic or operable 
early breast cancers that overexpress the HER2 protein, as monotherapy or in 
combination with aromatase inhibitors or chemotherapy.  It is also indicated for the 
treatment of metastatic gastric cancers that overexpress the HER2 protein. 
In various countries pertuzumab is indicated for use in combination with trastuzumab 
and docetaxel in adult patients with HER2-positive metastatic or locally recurrent 
unresectable breast cancer, who have not received previous anti-HER2 therapy or 
chemotherapy for their metastatic disease and in combination with trastuzumab and 
chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally 
advanced, inflammatory, or early stage breast cancer as part of a complete treatment 
regimen for early breast cancer. 
In this study pertuzumab will be administered as an intravenous infusion and 
trastuzumab will be administered as a subcutaneous injection in combination with a 
platinum-based chemotherapy (see Section 4.3.4.5 of the protocol). 
SAFETY 
SAFETY PROFILE 
A comprehensive description of the safety profile of pertuzumab in combination with 
trastuzumab and cytotoxic agents in metastatic breast cancer and for the neoadjuvant 
treatment of breast cancer is provided in the Pertuzumab Investigator’s Brochure.  This 
summary only lists specific risks, warnings and precautions. 
The summary information provided in the following section must always be checked 
against any update of the Pertuzumab Investigator’s Brochures that may have occurred 
after the protocol has been issued.  Please also refer to the Trastuzumab Investigator’s 
Brochure and to its warnings and precautions when using pertuzumab in combination 
with trastuzumab. 
Adverse reactions associated with Warnings and Precautions (common to pertuzumab, 
trastuzumab and their combination): 

Cardiac dysfunction


Appendix 10-12:  Pertuzumab in Combination With Trastuzumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
370/Protocol MX39795, Version 11 
 
Infusion-related reactions (IRRs)/administration-related reactions (ARRs) and 
hypersensitivity/anaphylaxis 
 
Pulmonary events 
 
Other selected adverse reactions:  
 
Hematotoxicity 
 
Management guidelines for pertuzumab in combination with trastuzumab that are 
applicable to this study are provided in Table A10-54. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For pertuzumab, AESIs include: 
 
Asymptomatic decline in LVEF requiring treatment or leading to discontinuation 
of monoclonal antibodies 
 
For trastuzumab, AESIs include: 
 
Congestive heart failure 
 
ADMINISTRATION 
POSOLOGY 
Pertuzumab will be administered as initial loading dose of 840 mg administered as a 60 
(± 10) minute IV infusion, followed every 3 weeks thereafter by a maintenance dose of 
420 mg administered over a period of 30 to 60 (± 10) minutes.  If a dose is delayed (i.e. 
the time between two sequential infusions is less than 6 weeks), the 420 mg dose of 
pertuzumab should be administered.  If a dose is missed (i.e. the time between two 
sequential infusions is 6 weeks or more), a re-loading dose of pertuzumab (840 mg) 
should be given as described for loading dose. 
Trastuzumab will be administered at a dose of 600 mg fixed dose SC injection over 2 to 
5 minutes every 3 weeks 
For the doses of chemotherapy to be administered in combination with pertuzumab and 
trastuzumab, see Section 4.3.4.7 of the protocol.  


Appendix 10-12:  Pertuzumab in Combination With Trastuzumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
371/Protocol MX39795, Version 11 
METHOD OF ADMINISTRATION  
Pertuzumab and trastuzumab must be administered by a healthcare professional 
prepared to manage anaphylaxis and in an environment where full resuscitation facilities 
are immediately available. 
Trastuzumab, pertuzumab, and chemotherapy must be administered sequentially and 
not mixed in the same infusion bag. Trastuzumab and pertuzumab can be given in any 
order.  Chemotherapy should be administered after trastuzumab and pertuzumab.  An 
observation period of 30 to 60 minutes is recommended after each trastuzumab infusion 
and before commencement of any subsequent infusion of pertuzumab or chemotherapy. 
Pertuzumab is administered intravenously by infusion.  It should not be administered as 
an intravenous push or bolus.  For the initial dose, the recommended infusion period is 
60 (± 10) minutes.  If the first infusion with the initial loading dose was well tolerated, 
subsequent infusions may be administered over a period of 30 minutes to 60 (± 10) 
minutes.  
Patients should be observed for at least one hour after the end of the first administration 
of pertuzumab (intravenously) and trastuzumab (subcutaneously) and for 30 minutes 
after the end of the subsequent administrations for symptoms like fever and chills or 
other infusion-related symptoms.  Interruption or slowing the rate of the infusion of 
pertuzumab may help control such symptoms.  The infusion of pertuzumab may be 
resumed when symptoms abate. The observation period should be completed prior to 
any subsequent infusion of trastuzumab or chemotherapy. 
DURATION OF TREATMENT 
Treatment with pertuzumab in combination with trastuzumab and a platinum-based 
chemotherapy should continue until loss of clinical benefit or the development of 
unacceptable toxicity.  The administration of the chemotherapy must be limited to the 
number of chemotherapy cycles described in Section 4.3.4.7 of the protocol. 
DOSE MODIFICATIONS DURING TREATMENT 
Dose reductions of pertuzumab or trastuzumab are not recommended. 
Patients may continue therapy with pertuzumab and trastuzumab during periods of 
reversible chemotherapy-induced myelosuppression but they should be monitored 
carefully for complications of neutropenia and other toxicities during this time.  For 
platinum-based chemotherapy dose modifications, see the relevant EMA Summary of 
Product Characteristics. 


Appendix 10-12:  Pertuzumab in Combination With Trastuzumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
372/Protocol MX39795, Version 11 
DOSE DELAY OR DISCONTINUATION  
If pertuzumab treatment is discontinued, treatment with trastuzumab should be 
discontinued.  If trastuzumab treatment is discontinued, treatment with pertuzumab 
should be discontinued. 
After platinum-based chemotherapy is discontinued (per protocol or due to toxicity), 
treatment with pertuzumab and trastuzumab will continue per protocol. 
If pertuzumab and trastuzumab treatment is discontinued prior to the planned end of 
concomitant chemotherapy, treatment with chemotherapy may continue in the Treatment 
Period per the guidance provided in Section 4.3.4.7. 
Dose delay and discontinuation advice are summarized in Table A10-54.  See also 
Table A10-55 for management of specific toxicities, according to special warnings and 
precautions.  
Summary of Advice for Dose Discontinuation (See Table A10-54 for 
Details): 
Pertuzumab and trastuzumab must be discontinued if: 
 
Hypersensitivity reactions/anaphylaxis 
 
LVEF decrease with symptomatic heart failure 
 
LVEF< 50% or LVEF of 40%–45% associated with a fall of ≥ 10% points below pre-
treatment values not improving after a 3 week dose interruption 
 
Table A10-54 Dose Delay and Discontinuation Advice 
Adverse Reaction 
Severity 
Treatment Modification 
Hypersensitivity 
reactions/anaphylaxis 
Grade 4 
(anaphylaxis), 
bronchospasm or 
acute respiratory 
distress syndrome  
Discontinue immediately and 
permanently 
Infusion reactions 
(pertuzumab) 
 
Slow or the infusion rate or interrupt 
infusion of pertuzumab 
The infusion may be resumed when 
symptoms abate. Treatment including 
oxygen, beta agonists, 
antihistamines, rapid IV fluids and 
antipyretics may also help alleviate 
symptoms 


Appendix 10-12:  Pertuzumab in Combination With Trastuzumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
373/Protocol MX39795, Version 11 
Adverse Reaction 
Severity 
Treatment Modification 
Left ventricular dysfunction 
including any of the following: 
signs and symptoms 
suggestive of congestive heart 
failure 
drop in left ventricular ejection 
fraction (LVEF) to less than 
50% 
LVEF of 40%–45% associated 
with a fall of ≥ 10% points 
below pre-treatment values 
 
Withheld pertuzumab and 
trastuzumab for at least 3 weeks 
Discontinue pertuzumab and 
trastuzumab if symptomatic heart 
failure is confirmed 
Resume pertuzumab and 
trastuzumab if the LVEF has 
recovered to > 50% or 40-45% 
associated with < 10% points below 
pre-treatment value. 
If after a repeat assessment within 
approximately 3 weeks, the LVEF 
has not improved, or has declined 
further, discontinue pertuzumab and 
trastuzumab, unless the benefits for 
the individual patient are deemed to 
outweigh the risks (Medical Monitor 
advice should be sought) 
Patients who develop asymptomatic 
cardiac dysfunction may benefit from 
more frequent monitoring (e.g., every 
6–8 weeks). 
If patients have a continued decrease 
in left ventricular function, but remain 
asymptomatic, the physician should 
consider discontinuing therapy if no 
clinical benefit of trastuzumab 
therapy has been seen. 
 
 
MANAGEMENT ADVICE FOR SPECIFIED ADVERSE DRUG REACTIONS 
 
Table A10-55 Management Advice for Specified Adverse Drug Reactions 
Adverse Reaction 
Severity 
Treatment Modification 
Exacerbation of chemotherapy 
associated neutropenia 
 
Hematological monitoring for 
neutropenia per protocol. 
Diarrhea 
 
To prevent dehydration, early 
treatment of diarrhea with anti-
diarrheal medication should be 
considered and patients treated with 
fluids and electrolyte replacement, as 
clinically indicated. 


Appendix 10-12:  Pertuzumab in Combination With Trastuzumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
374/Protocol MX39795, Version 11 
Adverse Reaction 
Severity 
Treatment Modification 
Rash 
 
Treatment recommendations include 
topical or oral antibiotics, topical 
pimecrolimus, topical or (for severe 
reactions) systemic steroids  
Mucositis 
 
 
Mucositis is generally not considered 
preventable although for some 
cytotoxic agents, mucositis may be 
reduced by cooling the mouth using 
ice chips before and during the 
infusion. 
 
DRUG INTERACTIONS  
Pertuzumab 
A sub-study in 37 patients in the pivotal trial CLEOPATRA showed no evidence of drug-
drug interaction between pertuzumab and trastuzumab and between pertuzumab and 
docetaxel.  In addition, no clinical relevant pharmacokinetic interaction of co-
administered docetaxel or trastuzumab on pertuzumab was evident, based on the 
population pharmacokinetics analysis.  The lack of drug-drug interaction between 
pertuzumab and trastuzumab and between pertuzumab and docetaxel was further 
confirmed by pharmacokinetic data from the WO209697 (NEOSPHERE) trial. 
Four studies have evaluated the effects of pertuzumab on the pharmacokinetics of co-
administered cytotoxic agents, docetaxel, gemcitabine, erlotinib and capecitabine, 
respectively.  There was no evidence of any pharmacokinetics interaction between 
pertuzumab and any of these agents.  The pharmacokinetics of pertuzumab in these 
studies was comparable to those observed in single agent studies. 
Trastuzumab 
There have been no formal drug interaction studies performed with trastuzumab in 
humans.  Clinically significant interactions between trastuzumab and the concomitant 
medications used in clinical trials have not been observed. 
 
Effect of trastuzumab on the pharmacokinetics of other anti-neoplastic agents  
 
Study BO15935 found no observable drug-drug interaction between trastuzumab 
and paclitaxel 
 
Study M77004 was a study of trastuzumab and doxorubicin plus paclitaxel followed 
by qW paclitaxel and trastuzumab in women with HER2-positive MBC.  There was 
no observable drug-drug interaction between trastuzumab and paclitaxel and 
doxorubicin (and their major metabolites) in this study 


Appendix 10-12:  Pertuzumab in Combination With Trastuzumab 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
375/Protocol MX39795, Version 11 
 
Study JP19959 was a randomized study in male and female Japanese patients with 
AGC to investigate potential changes to capecitabine or cisplatin pharmacokinetics 
when administered either together or in the presence of trastuzumab.  Comparisons 
of plasma concentrations and PK parameters of capecitabine and its metabolites 
(5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, 5-FU and α-fluoro-β-alanine) 
and plasma concentration of cisplatin (total platinum in plasma and unbound 
platinum in ultrafiltered plasma) suggest that the pharmacokinetics of these two 
chemotherapy agents are not altered by concomitant trastuzumab treatment 
 
Study H4613g (Her-Q-Les), a Phase Ib, single-arm, open-label clinical trial 
evaluated corrected QT interval and drug-drug interaction of trastuzumab with 
carboplatin in the presence of docetaxel in patients with HER2-positive metastatic or 
locally advanced inoperable cancer.  Trastuzumab administration had no impact on 
the pharmacokinetics of carboplatin, and carboplatin had no impact on the 
pharmacokinetics of trastuzumab.  No new safety signals were identified 
 
In a published study in patients with NSCLC where trastuzumab was administered 
in combination with gemcitabine and cisplatin, trastuzumab did not appear to alter 
the kinetics of either gemcitabine or cisplatin, and trastuzumab serum levels did not 
appear to be altered by these agents  
 
 


Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
376/Protocol MX39795, Version 11 
A10–13 
VEMURAFENIB 
Vemurafenib will be administered in combination with cobimetinib—Refer to 
Appendix 10-4 for details on cobimetinib. 
BACKGROUND 
Vemurafenib is a selective inhibitor of oncogenic BRAF kinase. Oncogenic mutations in 
BRAF kinase, predominantly V600E, have been observed in approximately 8% of all 
solid tumors.  Such mutations result in constitutive activation of BRAF kinase, which 
causes dysregulated downstream signaling via MEK and ERK, leading to excessive cell 
proliferation and survival.  
Inhibition of MEK1/2 (MAPK/ERK kinase) is a potential strategy to control the growth of 
tumors that are dependent on aberrant MAPK pathway signaling.  Clinical and preclinical 
data have demonstrated that the addition of a MEK inhibitor can delay or overcome 
BRAF inhibitor (BRAFi) resistance, which supports the clinical evaluation of combination 
therapeutic strategies incorporating MEK inhibition with BRAF inhibition.  
Vemurafenib is being developed for use in the treatment of cancers.  Cobimetinib, in 
combination with vemurafenib, has been approved in various countries for the treatment 
of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. 
SAFETY 
SAFETY PROFILE 
A comprehensive description of the safety profile of vemurafenib as monotherapy is 
provided in the Vemurafenib Investigator’s Brochure and a comprehensive description of 
the safety profile of vemurafenib in combination with cobimetinib is provided in the 
Cobimetinib Investigator’s Brochure. 
Adverse reactions associated with Warnings and Precautions: 

Cutaneous squamous cell carcinoma (cuSCC)

Non-cutaneous squamous cell carcinoma (non-cuSCC)

New primary melanoma

Other malignancies

Potentiation of radiation toxicity

Hypersensitivity reactions

Dermatologic reactions

Risk of Ventricular Arrhythmia

Liver injury


Appendix 10-13:  Vemurafenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
377/Protocol MX39795, Version 11 
 
Photosensitivity 
 
Ophthalmologic reactions 
 
Other selected adverse reactions:  
 
Pancreatitis 
 
Colorectal polyps 
 
Acute kidney injury 
 
Management guidelines for vemurafenib adverse reactions that are applicable to this 
study are provided in Table A10-56.  For management of adverse events of cobimetinib 
in combination with vemurafenib. 
The summary information provided in the following sections must always be checked 
against any update of the Vemurafenib and Cobimetinib Investigator’s Brochures that 
may have occurred after the protocol has been issued. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For vemurafenib, AESIs include: 
 
Acute kidney injury 
 
Bone marrow toxicity  
 
Cutaneous squamous cell carcinoma 
 
Hypersensitivity 
 
Severe cutaneous reactions (cutaneous reactions reported as severe or Grade 3 
or Grade 4) 
 
New/second primary melanoma 
 
Non cutaneous squamous cell carcinoma 
 
Pancreatitis 
 
Photosensitivity 
 
Potentiation of radiation toxicity 
 
Progression of RAS mutant malignancy 
 
QT Prolongation 
 
Retinal vein inclusion 
 
VII nerve paralysis 


Appendix 10-13:  Vemurafenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
378/Protocol MX39795, Version 11 
 
Liver injury 
 
Uveitis 
 
GI polyps 
 
ADMINISTRATION 
POSOLOGY AND ROUTE 
The recommended dose of vemurafenib is 960 mg (4 tablets of 240 mg) twice daily 
(equivalent to a total daily dose of 1,920 mg).  Vemurafenib may be taken with or without 
food, but consistent intake of both daily doses on an empty stomach should be avoided. 
For instructions on handling of the medicinal product, refer to the Vemurafenib 
Investigator’s Brochure. 
DURATION OF TREATMENT 
Treatment with vemurafenib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  
DELAYED OR MISSED DOSES 
If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the 
twice daily regimen.  Both doses should not be taken at the same time.  
In case of vomiting after vemurafenib administration, the patient should not take an 
additional dose of the medicinal product.  Instead, the treatment should be continued as 
usual. 
DOSE MODIFICATION OR DISCONTINUATION 
Dose modification of vemurafenib is independent of cobimetinib dose modification.  If 
doses are omitted for toxicity, these doses should not be replaced.  Once the dose has 
been reduced, it should not be increased at a later time.  
Table A10-56 below gives general vemurafenib dose modification guidance. 
Management of Adverse Drug Reactions or QTc prolongation may require dose 
reduction, temporary interruption and/or treatment discontinuation (see  Table A10-56 
and Table A10-57).  Posology adjustments resulting in a dose below 480 mg twice daily 
are not recommended. 
In the event the patient develops cutaneous squamous cell carcinoma (cuSCC), it is 
recommended to continue treatment without modifying the dose of vemurafenib. 


Appendix 10-13:  Vemurafenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
379/Protocol MX39795, Version 11 
Summary of Advice for Dose Discontinuation (see Table A10-56 for Details): 
Vemurafenib must be discontinued if: 
 
Second (2nd) occurrence of Grade 4 adverse event or 3rd occurrence of Grade 2–3 
adverse event 
 
QTc increase meets values of both > 500 ms and > 60 ms change from pre-
treatment values or 3rd occurrence of QTc > 500 ms during treatment and change 
from pre-treatment value remains ≤ 60ms 
 
Hypersensitivity reaction (including Stevens-Johnson syndrome, generalized rash, 
erythema or hypotension) 
 
Dermatologic reactions (including rare cases of Stevens-Johnson syndrome and 
toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic 
symptoms) 
 
Discontinuation of vemurafenib may be considered for 
 
First (1st) occurrence of Grade 4 adverse event 
 
Table A10-56 Dose Modification or Discontinuation Schedule Based on 
the Grade of any Adverse Events  
Grade (CTCAE) a 
Recommended Dose Modification  
Grade 1 or Grade 2 (tolerable)  
Maintain vemurafenib at a dose of 960 mg twice 
daily. 
Grade 2 (intolerable) or Grade 3  
 
1st occurrence of any Grade 2 or 3 AE 
Interrupt treatment until Grade 0 – 1.  Resume 
dosing at 720 mg twice daily (or 480 mg twice 
daily if the dose has already been lowered). 
2nd occurrence of any Grade 2 or 3 AE 
or persistence after treatment 
interruption 
Interrupt treatment until Grade 0 – 1.  Resume 
dosing at 480 mg twice daily (or discontinue 
permanently if the dose has already been lowered 
to 480 mg twice daily). 
3rd occurrence of any Grade 2 or 3 AE 
or persistence after 2nd dose reduction 
Discontinue permanently. 
Grade 4  
 
1st occurrence of any Grade 4 AE 
Discontinue permanently or interrupt vemurafenib 
treatment until Grade 0 – 1. 
Resume dosing at 480 mg twice daily (or 
discontinue permanently if the dose has already 
been lowered to 480 mg twice daily). 


Appendix 10-13:  Vemurafenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
380/Protocol MX39795, Version 11 
Grade (CTCAE) a 
Recommended Dose Modification  
2nd occurrence of any Grade 4 AE or 
persistence of any Grade 4 AE after 1st 
dose reduction 
Discontinue permanently. 
a. The intensity of clinical adverse events graded by the Common Terminology Criteria for 
Adverse Events v4.0 (CTCAE). 
 
Exposure-dependent QT prolongation was observed in an uncontrolled, open-label 
phase II study in previously treated patients with metastatic melanoma.  Management of 
QTc prolongation may require specific monitoring measures. 
Table A10-57 Dose Modification Schedule Based on Prolongation of the 
QT Interval  
QTc Value  
Recommended Dose Modification  
QTc>500 ms at baseline 
Treatment not recommended. 
QTc increase meets values of both >500 ms and >60 
ms change from pre-treatment values 
Discontinue permanently. 
1st occurrence of QTc>500 ms during treatment 
and change from pre-treatment value remains 
<60 ms 
Temporarily interrupt treatment until 
QTc decreases below 500 ms. 
See monitoring measures in section 
4.4. 
Resume dosing at 720 mg twice daily 
(or 480 mg twice daily if the dose has 
already been lowered). 
2nd occurrence of QTc>500 ms during treatment 
and change from pre-treatment value remains 
<60 ms 
Temporarily interrupt treatment until 
QTc decreases below 500 ms. 
See monitoring measures in section 
4.4. 
Resume dosing at 480 mg twice daily 
(or discontinue permanently if the 
dose has already been lowered to 480 
mg twice daily). 
3rd occurrence of QTc>500 ms during treatment 
and change from pre-treatment value remains 
<60 ms 
Discontinue permanently. 
 


Appendix 10-13:  Vemurafenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
381/Protocol MX39795, Version 11 
Table A10-58 Guidelines for Management of Patients Who Experience 
Specific Adverse Events 
Event 
Action to Be Taken  
Cutaneous squamous cell 
carcinoma (cuSCC) 
(which includes keratoacanthoma 
or mixed keratoacanthoma 
subtype) 
Dermatologic evaluation prior to initiation of therapy 
During treatment, examination for cuSCC at each study 
visit until end of study treatment - Thereafter evaluation 
monthly up to six months after treatment or until initiation 
of another anti-neoplastic therapy.  
Any suspicious skin lesions should be excised, sent for 
dermatopathologic evaluation and treated as per local 
standard of care.  
In patients, who develop cuSCC, continue treatment 
without dose adjustment.  
Patients should be instructed to inform their physicians 
upon the occurrence of any skin changes. 
Non-cutaneous squamous cell 
carcinoma (non-cuSCC) 
 
Perform head and neck examination, consisting of at 
least a visual inspection of oral mucosa and lymph node 
palpation prior to initiation of treatment and every 12 
weeks during treatment. Anal examinations (for all 
patients) and pelvic examinations (for women) are before 
and at the end of treatment or when considered clinically 
indicated. 
Monitoring for non-cuSCC should continue for up to 6 
months after end of treatment or until initiation of another 
anti-neoplastic therapy.  
Abnormal findings should be managed according to 
clinical practices. 
New primary melanoma 
Monitor for skin lesions should occur as outlined above 
for cutaneous squamous cell carcinoma. 
Other malignancies 
Carefully consider benefits and risks before 
administering vemurafenib to patients with a prior or 
concurrent cancer associated with RAS mutation 
Potentiation of radiation toxicity 
Vemurafenib should be used with caution when given 
concomitantly or sequentially with radiation treatment 
Hypersensitivity reaction  
(including Stevens-Johnson 
syndrome, generalized rash, 
erythema or hypotension) 
Permanently discontinue vemurafenib 
Dermatologic reactions  
(including rare cases of Stevens-
Johnson syndrome and toxic 
epidermal necrolysis, and Drug 
reaction with eosinophilia and 
systemic symptoms) 
Permanently discontinue vemurafenib 


Appendix 10-13:  Vemurafenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
382/Protocol MX39795, Version 11 
Event 
Action to Be Taken  
QT prolongation 
(may lead to an increased risk of 
ventricular arrhythmias including 
Torsade de Pointes) 
Monitor of ECG and electrolytes (including magnesium) 
per protocol. 
If during treatment the QTc exceeds 500 ms, 
vemurafenib treatment should be temporarily interrupted, 
electrolyte abnormalities (including magnesium) should 
be corrected, and cardiac risk factors for QT prolongation 
(e.g. congestive heart failure, bradyarrhythmias) should 
be controlled.  
Re-initiation of treatment should occur once the QTc 
decreases below 500 ms and at a lower dose as 
described in Table A10-57.  
Permanent discontinuation of vemurafenib treatment is 
recommended if the QTc increase meets values of 
both >500 ms and >60 ms change from pre-treatment 
values 
Liver injury 
Monitoring of liver enzymes and bilirubin per protocol 
and management if laboratory abnormalities per  
Table A10-56  
Photosensitivity 
Advise patients to minimize sun exposure and use sun 
block and lip balm with broad-spectrum, UVA and UVB 
protection (minimum of SPF 30, re-applied every 2 to 3 
hours) during vemurafenib treatment and for at least 5 to 
10 days after study drug discontinuation.  
For photosensitivity, Grade 2 (intolerable) or greater 
AEs, dose modifications are recommended (see 
Table A10-56)  
Ophthalmologic reactions 
(including uveitis) 
Monitor routinely for ophthalmologic reactions 
Pancreatitis 
Investigate unexplained abdominal pain (including 
measurement of serum amylase and lipase).  
Close monitored when restarting vemurafenib after an 
episode of pancreatitis. 
 
Please also refer to the Cobimetinib Investigator’s Brochure and to its warnings and 
precautions when using vemurafenib in combination with cobimetinib. 
DRUG INTERACTIONS 
Concomitant Use with Other Medications 
Effects of vemurafenib on drug metabolizing enzymes 
Results from an in vivo drug-drug interaction study in metastatic melanoma patients 
demonstrated that vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer.  
Concomitant use of vemurafenib with agents with narrow therapeutic windows that are 
metabolized by CYP1A2 and CYP3A4 is not recommended as vemurafenib may alter 


Appendix 10-13:  Vemurafenib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
383/Protocol MX39795, Version 11 
their concentrations.  If co-administration cannot be avoided, exercise caution and 
consider a dose reduction of the concomitant CYP1A2 substrate drug.  Co-
administration of vemurafenib increased the AUC of caffeine (CYP1A2 substrate) 2.6-
fold, while it decreased the AUC of midazolam (CYP3A4 substrate) by 39%.  In another 
clinical trial, vemurafenib increased AUClast and AUCinf of a single 2-mg dose of 
tizanidine (CYP1A2 substrate) approximately 4.2 and 4.7 fold, respectively.  The AUC of 
dextromethorphan (CYP2D6 substrate) and its metabolite dextrorphan were increased 
by approximately 47%, indicating an effect on dextromethorphan kinetics that may not 
be mediated by inhibition of CYP2D6. 
Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin 
(CYP2C9 substrate).  Exercise caution and consider additional INR monitoring when 
vemurafenib is used concomitantly with warfarin. 
Vemurafenib moderately inhibited CYP2C8 in vitro.  The in vivo relevance of this finding 
is unknown, but a risk for a clinically relevant effect on concomitantly administered 
CYP2C8 substrates cannot be excluded.  Concomitant administration of CYP2C8 
substrates with a narrow therapeutic window should be made with caution since 
vemurafenib may increase their concentrations. 
Drugs that inhibit or induce CYP3A4 
Based on in vitro data, vemurafenib is a substrate of CYP3A4, and concomitant 
administration of strong CYP3A4 inhibitors or inducers may therefore alter vemurafenib 
concentrations.  Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, 
nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital) should be used with caution when co-administered 
with vemurafenib.  
Interaction of vemurafenib with drug transport systems 
In vitro studies have demonstrated that vemurafenib is both a substrate and an inhibitor 
of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP).  In vitro studies have also demonstrated that vemurafenib is a weak inhibitor of 
the bile salt export pump (BSEP).  A clinical study (Study GO28394) demonstrated that 
multiple oral doses of vemurafenib (960 mg BID) increased the AUC of a single 0.25 mg 
oral dose of digoxin approximately 1.8-fold. 
INTERACTION WITH COBIMETINIB 
There is no evidence of any clinically significant drug interaction between vemurafenib 
and cobimetinib in unresectable or metastatic melanoma patients. 


 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
/Protocol MX39795, Version 11 
A10–14 
VISMODEGIB  
 
BACKGROUND 
The Hedgehog signaling pathway presents a novel and potentially beneficial target for 
cancer therapy.  The secreted Hedgehog ligands (Desert Hedgehog, Indian Hedgehog 
and Sonic Hedgehog) bind to PTCH1, a 12-pass transmembrane receptor on the 
surface of cells.  Binding of Hedgehog to PTCH1 relieves the catalytic inhibitory effect of 
PTCH1 on SMO, a 7-pass transmembrane domain protein with homology to the G-
protein coupled receptor superfamily.   
Hedgehog signaling regulates epithelial and mesenchymal interactions in a variety of 
tissues during mammalian embryogenesis (Ingham and McMahon 2001).  The outcome 
of Hedgehog signaling varies according to the receiving cell type, but it can include 
upregulation of D-type cyclins (resulting in cell proliferation); upregulation of anti-
apoptotic proteins such as B-cell lymphoma 2 (mediating cell survival); production of 
vascular endothelial growth factor and angiopoietins (regulating angiogenesis); and 
transcription of SNAIL (initiating the epithelial-mesenchyme transition in metastasis) 
(Scales and de Sauvage 2009). 
Vismodegib (vismodegib is a small-molecule inhibitor of the Hedgehog signal pathway 
that binds to and inhibits SMO (Zhang et al. 2001).  Vismodegib is currently indicated for 
the treatment of symptomatic metastatic basal cell carcinoma and locally-advanced 
basal cell carcinoma that is inappropriate for surgery or radiotherapy. 
SAFETY 
SAFETY PROFILE 
A comprehensive description of the safety profile of vismodegib is provided in the 
Vismodegib Investigator’s Brochure. 
Adverse reactions associated with Warnings and Precautions: 
 
Embryofetal death or severe birth defects 
 
Refer to the Vismodegib Investigator’s Brochure for guidance on the use of vismodegib 
in women of childbearing potential and in men.  There are specific recommendations for 
contraception for both women and men. 
The summary information provided in the following sections must always be checked 
against any update of the vismodegib local prescription guidelines and the EMA 
Summary of Product Characteristics that may have occurred after the protocol has been 
issued. 


Appendix 10-14:  Vismodegib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
385/Protocol MX39795, Version 11 
ADVERSE EVENTS OF SPECIAL INTEREST 
Non-serious AESIs follow the same process flow as SAEs and require immediate 
reporting in a clinical trial. 
For vismodegib, there are no AESIs to report  
ADMINISTRATION 
POSOLOGY AND ROUTE 
The recommended dose is one 150 mg capsule taken once daily.  
Vismodegib may be taken with or without food.  Capsules should be swallowed whole; 
capsules should not be crushed. 
For instructions on handling of the medicinal product, refer to the Vismodegib 
Investigator’s Brochure. 
DURATION OF TREATMENT 
Treatment with vismodegib should continue until loss of clinical benefit or the 
development of unacceptable toxicity.  
DELAYED OR MISSED DOSES 
If a dose is missed, patients should be instructed not to take the missed dose but to 
resume with the next scheduled dose. 
Treatment interruptions of up to 4 weeks are allowed based on individual tolerability. 
DOSE MODIFICATION 
Dose modification of vismodegib is not recommended. 
CONTRAINDICATIONS 
Vismodegib is contraindicated in nursing mothers during the course of treatment and for 
9 months after the final dose because of the potential to cause serious development 
defects in breastfed infants and children. 
DRUG INTERACTIONS 
In vitro, vismodegib is an inhibitor of OATP1B1.  It cannot be excluded that vismodegib 
may increase the exposure to substrates of OATP1B1, e.g., bosentan, ezetimibe, 
glibenclamide, repaglinide, valsartan and statins.  In particular, caution should be 
exercised if vismodegib is administered in combination with any statin.  


Appendix 10-14:  Vismodegib 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
386/Protocol MX39795, Version 11 
In vitro studies indicate that vismodegib also has the potential to act as an inhibitor of 
breast cancer resistance protein. 
No other clinically relevant pharmacokinetic reactions between vismodegib and other 
drugs have been identified. 


Appendix 11:  IMP/NIMP designation 
Cancer of Unknown Primary —F. Hoffmann-La Roche Ltd 
387/Protocol MX39795, Version 11 
Appendix 11  
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European Economic 
Area and United Kingdom) 
!Investigational and Non-Investigational Medicinal Product
Designations for European Economic Area / United Kingdom} 
Product Name 
IMP/NIMP 
Designation 
Marketing 
Authorization Status 
in EEA/UK  
Used within 
Marketing 
Authorization 
Alectinib 
(RO5424802) 
IMP (test 
product) 
Authorized 
Noa 
Atezolizumab 
(RO5541267) 
IMP (test 
product)
Authorized 
Noa 
Bevacizumab 
(RO4876646) 
IMP (test 
product)
Authorized 
Noa 
Cobimetinib 
(RO5514041) 
IMP (test 
product)
Authorized 
Noa 
Entrectinib 
(RO7102122) 
IMP (test 
product)
Authorized 
Noa 
Erlotinib 
(RO508231) 
IMP (test 
product)
Authorized 
Noa 
Ipatasertib 
(RO5532961) 
IMP (test 
product)
Unauthorized 
Not applicable 
Ivosidenib 
(RO7499824) 
IMP (test 
product)
Unauthorized 
Not applicable 
Olaparib 
(RO5508245) 
IMP (test 
product)
Authorized 
Noa 
Pemigatinib 
(RO7496200) 
IMP (test 
product)
Authorized 
Noa 
Pertuzumab 
(RO4368451) 
IMP (test 
product)
Authorized 
Noa 
Trastuzumab 
(RO0452317) 
IMP (test 
product)
Authorized 
Noa 


Appendix 11:  IMP/NIMP Designation 
  
Cancer of Unknown Primary—F. Hoffmann-La Roche Ltd 
388/Protocol MX39795, Version 11 
Product Name 
IMP/NIMP 
Designation 
Marketing 
Authorization Status 
in EEA/UK  
Used within 
Marketing 
Authorization 
Vemurafenib 
(RO5185426) 
IMP (test 
product)  
Authorized 
Noa 
Vismodegib 
(RO5450815) 
IMP (test 
product)  
Authorized 
Noa 
Carboplatin 
(RO4843791) 
IMP (test 
product)  
Authorized 
Noa 
Cisplatin 
(RO0232538) 
IMP (test 
product)  
Authorized 
Noa 
Gemcitabine 
(RO0249587) 
IMP (test 
product)  
Authorized 
Noa 
Paclitaxel 
(RO0247506) 
IMP (test 
product) 
Authorized 
Noa 
Loperamide 
NIMP (Pre-
medication) 
Not applicable 
Not applicable 
Dexamethasone 
NIMP (Pre-
medication) 
Not applicable 
Not applicable 
Diphenhydramine 
NIMP (Pre-
medication) 
Not applicable 
Not applicable 
Cimetidine 
NIMP (Pre-
medication) 
Not applicable 
Not applicable 
Acetaminophen 
NIMP (Pre-
medication)b 
Not applicable 
Not applicable 
EEA = European Economic Area; IMP  = investigational medicinal product; NIMP  = non-
investigational medicinal product;  
aNo molecules are approved for the treatment of Cancer of Unknown Primary (CUP) 
b 
bIf needed 
 


Signature Page for Protocol - MX39795 - TECENTRIQ - v11 - Global/Core - Publishe
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