Clinical trial NCT04298918
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2020-09-23; Completion date: 2021-02-04
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-escalation phase and an expansion phase; and a Phase II, randomized, placebo-controlled, double-blind, multicenter stage. The Phase Ib stage will assess the safety and tolerability, determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D), and evaluate the preliminary efficacy of trastuzumab emtansine in combination with venetoclax in participants with previously treated human epidermal growth factor receptor 2 (HER2) positive unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). Additional patients may be enrolled in an expansion phase to evaluate the safety, tolerability, and efficacy of trastuzumab emtansine in combination with venetoclax at RP2D in patients with previously treated HER2-positive LABC or MBC who have previously received either trastuzumab emtansine or trastuzumab deruxtecan (DS-8201a). The Phase II randomized stage will evaluate the safety, efficacy, tolerability, and pharmacokinetics of trastuzumab emtansine in combination with venetoclax at RP2D compared with trastuzumab emtansine plus placebo in participants with previously treated HER2-positive LABC or MBC who have not received prior trastuzumab emtansine therapy, either alone or in combination with other anti-cancer therapies.

Detailed description:

Arms: arm 1: Participants received venetoclax in combination with a fixed dose of trastuzumab emtansine. arm 2: Participants were to receive venetoclax at the Phase II Recommended Dose (RP2D) in combination with trastuzumab emtansine. arm 3: Participants were to receive trastuzumab emtansine + placebo. arm 4: Participants were to receive trastuzumab emtansine + venetoclax.
Interventions: intervention 1: Placebo intervention 2: Venetoclax intervention 3: Trastuzumab emtansine
Intervention descriptions: intervention 1: Participants will receive oral placebo in combination with trastuzumab emtansine. intervention 2: Participants will receive oral venetoclax. intervention 3: Participants will receive intravenous (IV) trastuzumab emtansine.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase Ib/II, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Venetoclax in Combination With 
Trastuzumab Emtansine in Patients With Previously Treated Her2-
Positive Locally Advanced or Metastatic Breast Cancer 
NCT Number: NCT04298918 
Document Dates: Protocol Version 1: 19-December-2019 
Protocol Version 2: 06-April-2020 
 
 


FINAL PROTOCOL APPROVAL
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.
Venetoclax F. Hoffmann-La Roche Ltd
Protocol CO41863, Version 1
PROTOCOL
TITLE:
A PHASE Ib/II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
EVALUATING THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF VENETOCLAX 
IN COMBINATION WITH TRASTUZUMAB EMTANSINE IN 
PATIENTS WITH PREVIOUSLY TREATED HER2-POSITIVE 
LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER
PROTOCOL NUMBER:
CO41863
VERSION NUMBER:
1
EUDRACT NUMBER:
2019-004200-35
IND NUMBER:
137088
NCT NUMBER:
To be determined
TEST PRODUCT:
Venetoclax (RO5537382)
Trastuzumab emtansine (RO5304020)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
19-Dec-2019 22:32:51
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Venetoclax—F. Hoffmann-La Roche Ltd
2/Protocol CO41863, Version 1
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 30
1.1
Background on HER2-Positive Breast Cancer ...................... 30
1.2
BCL-2 Signaling Pathway and HER2-Positive 
Breast Cancer........................................................................ 31
1.3
Background on Trastuzumab Emtansine............................... 32
1.3.1
Study TDM4370g/BO21977 (EMILIA) ................................... 32
1.3.2
Study WO30085 (KATE2)...................................................... 33
1.3.3
Study TDM4997g/BO25734 (TH3RESA)............................... 34
1.3.4
Study BO27938 (KATHERINE) ............................................. 35
1.4
Background On Venetoclax................................................... 35
1.5
Study Rationale and Benefit-Risk Assessment...................... 37
2.
OBJECTIVES AND ENDPOINTS ............................................................... 39
2.1
Objectives and Endpoints for Dose-Escalation 
Phase .................................................................................... 40
2.1.1
Primary Safety Objective ....................................................... 40
2.1.2
Exploratory Efficacy Objective............................................... 40
2.1.3
Pharmacokinetic Objective .................................................... 40
2.1.4
Biomarker Objective .............................................................. 41
2.2
Objectives and Endpoints for Expansion Phase.................... 41
2.2.1
Primary Efficacy Objective..................................................... 41
2.2.2
Secondary Efficacy Objective................................................ 41
2.2.3
Safety Objective .................................................................... 41
2.2.4
Pharmacokinetic Objective .................................................... 42
2.2.5
Biomarker Objective .............................................................. 42
2.3
Objectives and Endpoints for Randomized Phase 
II Stage .................................................................................. 42
2.3.1
Primary Efficacy Objective..................................................... 42
2.3.2
Secondary Efficacy Objective................................................ 42
2.3.3
Exploratory Efficacy Objective............................................... 43


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2.3.4
Safety Objective .................................................................... 43
2.3.5
Pharmacokinetic Objective .................................................... 43
2.3.6
Immunogenicity Objectives.................................................... 43
2.3.7
Biomarker Objective .............................................................. 44
2.3.8
Health Status Utility Objective ............................................... 44
3.
STUDY DESIGN......................................................................................... 44
3.1
Description of the Study......................................................... 44
3.1.1
Dose-Escalation Phase ......................................................... 46
3.1.1.1
Definition of Dose-Limiting Toxicity........................................ 48
3.1.1.2
Dose-Escalation Rules, Determination of 
Dose-Limiting Toxicities, and Recommended 
Phase II Dose........................................................................ 49
3.1.2
Expansion Phase................................................................... 50
3.1.3
Randomized Phase II Stage.................................................. 51
3.1.4
Internal Monitoring Committee for the 
Randomized Phase II Stage.................................................. 54
3.2
End of Study and Length of Study......................................... 54
3.3
Rationale for Study Design.................................................... 54
3.3.1
Rationale for Venetoclax Dose Selection in the 
Phase Ib Dose-Escalation Phase of the Study ...................... 54
3.3.2
Rationale for Venetoclax Dose Selection in the 
Phase II Randomized Portion of the Study............................ 55
3.3.3
Rationale for Trastuzumab Emtansine Dose and 
Schedule................................................................................ 56
3.3.4
Rationale for Dose-Finding Rules.......................................... 56
3.3.5
Rationale for Dosing Schedule .............................................. 56
3.3.6
Rationale for Patient Population ............................................ 56
3.3.7
Rationale for Control Group................................................... 56
3.3.8
Rationale for Randomization and Blinding............................. 57
3.3.9
Rationale for Objective Response Rate and 
Progression-Free Survival as Co-Primary 
Endpoints for the Randomized Phase II Stage...................... 57
3.3.10
Rationale for Pharmacokinetic Assessments......................... 58
3.3.11
Rationale for Assessments of DrugDrug 
Interactions between Study Treatments ................................ 58


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3.3.12
Rationale for Biomarker Assessments................................... 58
3.3.13
Rationale for Stratification and Enrichment by B-
Cell Lymphoma-2 (Bcl-2) Status............................................ 59
3.3.14
Rationale for Stratification by Visceral 
Metastases ............................................................................ 60
3.3.15
Rationale for Stratification by HER2 Expression 
Status .................................................................................... 60
3.3.16
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 61
4.
MATERIALS AND METHODS .................................................................... 61
4.1
Patients.................................................................................. 61
4.1.1
Inclusion Criteria (All Study Phases) ..................................... 61
4.1.1.1
Inclusion Criteria for Expansion Phase Only.......................... 65
4.1.1.2
Inclusion Criteria for Randomized Phase II Stage ................. 65
4.1.2
Exclusion Criteria................................................................... 66
4.1.2.1
Exclusion Criteria for Randomized Phase II 
Stage ..................................................................................... 69
4.2
Method of Treatment Assignment and Blinding 
(Applicable to Randomized Phase II Stage ONLY)
.............................................................................................. 69
4.2.1
Treatment Assignment........................................................... 69
4.2.2
Blinding.................................................................................. 70
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 71
4.3.1.1
Venetoclax and Placebo........................................................ 71
4.3.1.2
Trastuzumab Emtansine........................................................ 71
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 72
4.3.2.1
Venetoclax and Placebo........................................................ 72
4.3.2.2
Trastuzumab Emtansine........................................................ 73
4.3.2.3
Sequence of Study Drug Administration................................ 74
4.3.3
Investigational Medicinal Product Accountability ................... 74
4.3.3.1
Continued Access to Venetoclax and 
Trastuzumab Emtansine........................................................ 74
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 75


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4.4.1
Permitted Therapy................................................................. 75
4.4.2
Prohibited Food ..................................................................... 76
4.4.3
Prohibited and Cautionary Therapy....................................... 77
4.4.3.1
Herbal Therapies................................................................... 79
4.5
Study Assessments ............................................................... 79
4.5.1
Informed Consent Forms and Screening Log........................ 80
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 80
4.5.3
Physical Examinations........................................................... 80
4.5.4
Vital Signs.............................................................................. 81
4.5.5
Tumor and Response Evaluations......................................... 81
4.5.6
Left Ventricular Ejection Fraction Assessment ...................... 83
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 83
4.5.8
Electrocardiograms................................................................ 86
4.5.9
Patient-Reported Outcome Assessments.............................. 87
4.5.9.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 87
4.5.9.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 88
4.5.10
Optional Tumor Biopsies ....................................................... 89
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 89
4.5.11.1
Overview of the Research Biosample Repository.................. 89
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 90
4.5.11.3
Sample Collection.................................................................. 90
4.5.11.4
Confidentiality........................................................................ 91
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 91
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 91
4.5.11.7
Monitoring and Oversight....................................................... 92
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 92
4.6.1
Study Treatment Discontinuation........................................... 92


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4.6.2
Patient Discontinuation from the Study.................................. 93
4.6.3
Study Discontinuation............................................................ 94
4.6.4
Site Discontinuation............................................................... 94
5.
ASSESSMENT OF SAFETY....................................................................... 94
5.1
Safety Plan ............................................................................ 94
5.1.1
Risks Associated with Venetoclax ......................................... 95
5.1.1.1
Tumor Lysis Syndrome.......................................................... 95
5.1.1.2
Neutropenia........................................................................... 96
5.1.1.3
Serious Infections.................................................................. 96
5.1.1.4
Other Hematological Effects.................................................. 96
5.1.1.5
Effects on Reproductive System and Pregnancy................... 97
5.1.1.6
Treatment-Emergent Malignancies (Second 
Primary Malignancies) ........................................................... 97
5.1.1.7
Food Effect ............................................................................ 97
5.1.1.8
Concomitant Use with Other Medications.............................. 98
5.1.2
Risks Associated with Trastuzumab Emtansine .................... 98
5.1.2.1
Pulmonary Toxicity ................................................................ 98
5.1.2.2
Hepatotoxicity........................................................................ 98
5.1.2.3
Left Ventricular Dysfunction................................................... 99
5.1.2.4
Infusion-Related Reactions and Hypersensitivity 
Reactions............................................................................. 100
5.1.2.5
Hematologic Toxicity ........................................................... 100
5.1.2.6
Hemorrhage......................................................................... 101
5.1.2.7
Neurotoxicity........................................................................ 101
5.1.2.8
Extravasation....................................................................... 101
5.1.3
Management of Patients Who Experience 
Adverse Events ................................................................... 102
5.1.3.1
Dose Modifications .............................................................. 102
5.1.3.2
Treatment Interruption ......................................................... 104
5.1.3.3
Management Guidelines...................................................... 104
5.2
Safety Parameters and Definitions ...................................... 109
5.2.1
Adverse Events ................................................................... 109
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 109


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5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 110
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 111
5.3.1
Adverse Event Reporting Period ......................................... 111
5.3.2
Eliciting Adverse Event Information..................................... 111
5.3.3
Assessment of Severity of Adverse Events ......................... 112
5.3.4
Assessment of Causality of Adverse Events ....................... 112
5.3.5
Procedures for Recording Adverse Events.......................... 113
5.3.5.1
Infusion-Related Reactions.................................................. 113
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 113
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 113
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 114
5.3.5.5
Abnormal Laboratory Values ............................................... 114
5.3.5.6
Abnormal Vital Sign Values ................................................. 115
5.3.5.7
Abnormal Liver Function Tests............................................ 116
5.3.5.8
Deaths ................................................................................. 116
5.3.5.9
Preexisting Medical Conditions............................................ 116
5.3.5.10
Lack of Efficacy or Worsening of Metastatic 
Breast Cancer...................................................................... 117
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 117
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse ........................................................ 118
5.3.5.13
Safety Biomarker Data......................................................... 120
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 120
5.4.1
Emergency Medical Contacts.............................................. 120
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 121
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 121
5.4.2.2
Events That Occur after Study Drug Initiation...................... 121
5.4.3
Reporting Requirements for Pregnancies............................ 121
5.4.3.1
Pregnancies in Female Patients.......................................... 121
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 122


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5.4.3.3
Abortions ............................................................................. 122
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 123
5.5
Follow-Up of Patients after Adverse Events ........................ 123
5.5.1
Investigator Follow-Up......................................................... 123
5.5.2
Sponsor Follow-Up .............................................................. 123
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 123
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 124
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 124
6.1
Determination of Sample Size ............................................. 125
6.1.1
Dose-Escalation Phase ....................................................... 125
6.1.2
Expansion Phase................................................................. 125
6.1.3
Randomized Phase II Stage................................................ 126
6.2
Summaries of Conduct of Study.......................................... 128
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 128
6.4
Efficacy Analyses (Randomized Phase II Stage 
Only).................................................................................... 129
6.4.1
Co-Primary Efficacy Endpoints............................................ 129
6.4.1.1
Objective Response Rate.................................................... 129
6.4.1.2
Progression-Free Survival ................................................... 129
6.4.2
Secondary Efficacy Endpoints............................................. 129
6.4.2.1
Duration of Objective Response.......................................... 129
6.4.2.2
Overall Survival ................................................................... 130
6.4.3
Exploratory Efficacy Endpoints............................................ 130
6.4.3.1
Clinical Benefit Rate ............................................................ 130
6.4.3.2
Patient-Reported Outcomes Data........................................ 130
6.5
Safety Analyses................................................................... 130
6.5.1
Analyses of Exposure, Adverse Event, 
Laboratory, and Vital Sign Data........................................... 131
6.6
Pharmacokinetic Analyses................................................... 131
6.7
Immunogenicity Analyses.................................................... 132


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6.8
Biomarker Analyses............................................................. 132
6.9
Interim Analyses .................................................................. 132
6.9.1
Planned Interim Analyses (Randomized Phase II 
Stage Only).......................................................................... 132
7.
DATA COLLECTION AND MANAGEMENT ............................................. 133
7.1
Data Quality Assurance....................................................... 133
7.2
Electronic Case Report Forms............................................. 133
7.3
Electronic Patient Reported Outcome Data......................... 133
7.4
Source Data Documentation................................................ 134
7.5
Use of Computerized Systems ............................................ 134
7.6
Retention of Records........................................................... 135
8.
ETHICAL CONSIDERATIONS.................................................................. 135
8.1
Compliance with Laws and Regulations .............................. 135
8.2
Informed Consent................................................................ 135
8.3
Institutional Review Board or Ethics Committee.................. 136
8.4
Confidentiality...................................................................... 137
8.5
Financial Disclosure ............................................................ 138
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 138
9.1
Study Documentation .......................................................... 138
9.2
Protocol Deviations.............................................................. 138
9.3
Management of Study Quality ............................................. 138
9.4
Site Inspections ................................................................... 139
9.5
Administrative Structure....................................................... 139
9.6
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 139
9.7
Protocol Amendments ......................................................... 140
10. REFERENCES ......................................................................................... 141


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LIST OF TABLES
Table 1
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine ............................................................. 74
Table 2
Therapies Prohibited for Specific Study Phases, or Allowed 
with Caution, Restrictions, and/or Dose Adjustments ................. 78
Table 3
Venetoclax Dose Reductions for Strong and Moderate 
CYP3A Inhibitors......................................................................... 79
Table 4
Dose Modification Scheme for Venetoclax/Placebo.................. 103
Table 5
Dose Modification Scheme for Trastuzumab Emtansine .......... 104
Table 6
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Venetoclax and Trastuzumab 
Emtansine................................................................................. 106
Table 7
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 112
Table 8
Potential 90% Confidence Interval Estimated for the True 
ORR.......................................................................................... 125
Table 9
Potential 90% Confidence Interval Estimates for Adverse 
Event Rates .............................................................................. 126
Table 10
Operating Characteristics for Proposed Study Design for 
Possible True Underlying ORR Values.................................. 127
Table 11
Operating Characteristics for Proposed Study Design for 
Possible True Underlying PFS Hazard Ratio Values ................ 128
Table 12
Operating Characteristics in the Bcl-2 High Group for 
Proposed Study Design for Possible True Underlying PFS 
Hazard Ratio Values................................................................. 128
LIST OF FIGURES
Figure 1
Overall Study Schema ................................................................ 45
Figure 2
Phase Ib Dose-Escalation Study Schema .................................. 47
Figure 3
Phase Ib Expansion Cohorts Study Schema .............................. 51
Figure 4
Phase II Randomized Study Schema ......................................... 53
LIST OF APPENDICES
Appendix 1
Schedule of Activities: Dose Escalation.................................... 145
Appendix 2
Schedule of Activities: Expansion Cohorts/Randomized 
Phase II..................................................................................... 150
Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Samples.... 155
Appendix 4
Biomarker Assessments ........................................................... 159
Appendix 5
Anaphylaxis Precautions........................................................... 161
Appendix 6
Patient-Reported Outcomes Questionnaires............................. 162


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Appendix 7
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome............. 165
Appendix 8
Guidelines for Defining Tumor Lysis Syndrome........................ 166
Appendix 9
Management of Venetoclax-Specific Adverse Events............... 168
Appendix 10
Management of Trastuzumab Emtansine-Specific Adverse 
Events....................................................................................... 169
Appendix 11
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 171
Appendix 12
National Cancer Institute Common Terminology Criteria .......... 180
Appendix 13
Guidelines for Liver Biopsy ....................................................... 181
Appendix 14
Sample List of Excluded and Cautionary Medications .............. 182


Venetoclax—F. Hoffmann-La Roche Ltd
12/Protocol CO41863, Version 1
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE Ib/II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
EVALUATING THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF 
VENETOCLAX IN COMBINATION WITH 
TRASTUZUMAB EMTANSINE IN PATIENTS WITH 
PREVIOUSLY TREATED HER2-POSITIVE 
LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER
PROTOCOL NUMBER:
CO41863
VERSION NUMBER:
1
EUDRACT NUMBER:
2019-004200-35
IND NUMBER:
137088
NCT NUMBER:
To be determined 
TEST PRODUCT:
Venetoclax (RO5537382)
Trastuzumab emtansine (RO5304020)
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)
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.


Venetoclax—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY EVALUATING THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF 
VENETOCLAX IN COMBINATION WITH TRASTUZUMAB 
EMTANSINE IN PATIENTS WITH PREVIOUSLY TREATED HER2-
POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER
PROTOCOL NUMBER:
CO41863
VERSION NUMBER:
1
EUDRACT NUMBER:
2019-004200-35
IND NUMBER:
137088
NCT NUMBER:
To be determined 
TEST PRODUCT:
Venetoclax (RO5537382)
Trastuzumab emtansine (RO5304020)
PHASE:
Ib/II
INDICATION:
Locally advanced or metastatic breast cancer 
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-controlled, 
double-blind, multicenter stage (hereafter referred to as the “randomized Phase II stage”).  
The dose-escalation phase will assess safety and tolerability, determine the maximum tolerated 
dose (MTD) and the recommended Phase II dose (RP2D), and evaluate preliminary efficacy of 
trastuzumab emtansine in combination with venetoclax in patients with previously treated 
HER2-positive unresectable locally advanced breast cancer (LABC) or metastatic breast cancer 
(MBC), irrespective of patients' prior trastuzumab emtansine exposure in the metastatic setting.  
After the RP2D is established, additional patients may be enrolled in the expansion phase to 
evaluate the safety, tolerability, and efficacy of trastuzumab emtansine in combination with 
venetoclax at the RP2D in patients with previously treated HER2-positive LABC or MBC who 
have previously received either trastuzumab emtansine or trastuzumab deruxtecan (DS-8201a).  
The decision to open these cohorts will be data-driven and dependent on the observations 
made in the dose-escalation phase, as well as emerging data about trastuzumab deruxtecan 
and other HER 2-targeted therapies.  Importantly, the expansion phase may run concurrent to 
and in parallel with the randomized Phase II stage of the study. 
The randomized Phase II stage will aim to evaluate the safety, tolerability, pharmacokinetics, 
and efficacy of trastuzumab emtansine in combination with venetoclax at the RP2D compared 
with trastuzumab emtansine plus placebo in patients with previously treated HER2-positive 
LABC or MBC who have not received prior trastuzumab emtansine therapy, either alone or in 
combination with other anticancer therapies.  Specific objectives and corresponding endpoints 
for the study are outlined below.


Venetoclax—F. Hoffmann-La Roche Ltd
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Objectives and Endpoints for Dose-Escalation Phase
Primary Safety Objective
The safety objective for the dose-escalation phase is to evaluate the safety and tolerability of 
trastuzumab emtansine in combination with venetoclaxincluding estimation of the MTD, 
determination of the RP2D, and characterization of dose-limiting toxicities (DLTs)on the basis 
of the following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0) 

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Exploratory Efficacy Objective
The exploratory efficacy objective for the dose-escalation phase is to make a preliminary 
assessment of the anti-tumor activity of trastuzumab emtansine and venetoclax on the basis of 
the following endpoints:

Objective response rate (ORR), defined as the proportion of patients with complete 
response (CR) or partial response (PR) on two consecutive assessments, at least 28 days 
apart, as determined by investigator assessment using Response Evaluation Criteria in 
Solid Tumors, Version 1.1 (RECIST v1.1)

Duration of response (DOR), defined as the time from the first occurrence of a documented 
objective response to disease progression as determined by the investigator using 
RECIST v1.1, or death from any cause, whichever occurs first
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for the dose-escalation phase of this study is to 
characterize the pharmacokinetics of venetoclax when given in combination with trastuzumab 
emtansine on the basis of the following endpoint:

Plasma concentrations of venetoclax at specified timepoints
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or evaluate 
biomarkers that are predictive of response to venetoclax in combination with trastuzumab 
emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to trastuzumab emtansine and venetoclax, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of venetoclax and/or trastuzumab 
emtansine activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the knowledge and 
understanding of disease biology and drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
Objectives and Endpoints for Expansion Phase
Primary Efficacy Objective
The primary efficacy objective for the expansion phase is to evaluate the efficacy of venetoclax 
at the RP2D in combination with trastuzumab emtansine on the basis of the following endpoint:

ORR
Secondary Efficacy Objective
The secondary efficacy objective for the expansion phase is to evaluate the efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoint:

DOR


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Safety Objective
The safety objective for the expansion phase is to evaluate the safety and tolerability of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to NCI CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Pharmacokinetic Objective
The PK objective for the expansion phase of the study is to characterize the pharmacokinetics 
of venetoclax when given in combination with trastuzumab emtansine on the basis of the 
following endpoint:

Plasma concentrations of venetoclax at specified timepoints
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or evaluate 
biomarkers that are predictive of response to venetoclax in combination with trastuzumab 
emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to trastuzumab emtansine and venetoclax, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of venetoclax and/or trastuzumab 
emtansine activity (i.e., PD biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
Objectives and Endpoints for Randomized Phase II Stage
Primary Efficacy Objective
The primary efficacy objective for the randomized Phase II stage is to evaluate the efficacy of 
trastuzumab emtansine in combination with venetoclax compared with trastuzumab emtansine 
plus placebo on the basis of the following co-primary endpoints:

ORR

Progression-free survival (PFS) after randomization, 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
Secondary Efficacy Objective
The secondary efficacy objective for the randomized Phase II stage is to evaluate the efficacy of 
trastuzumab emtansine in combination with venetoclax compared with trastuzumab emtansine 
plus placebo on the basis of the following endpoints:

DOR

Overall survival (OS) after randomization, defined as the time from randomization to death 
from any cause
Exploratory Efficacy Objective
The exploratory efficacy objective for the randomized Phase II stage is to evaluate the efficacy 
of trastuzumab emtansine in combination with venetoclax compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoints:

Clinical benefit rate (CBR), defined as the proportion of patients with CR, PR, or stable 
disease (SD) at 6 months after randomization, as determined by the investigator according 
to RECIST v1.1


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Safety Objective
The safety objective for the randomized Phase II stage is to evaluate safety of trastuzumab 
emtansine in combination with venetoclax compared with trastuzumab emtansine plus placebo 
on the basis of the following endpoints:

Incidence and severity of adverse events with severity determined according to 
NCI CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Pharmacokinetic Objective
The PK objective for the randomized Phase II stage of this study is to characterize the 
pharmacokinetics of trastuzumab emtansine and venetoclax when given in combination on the 
basis of the following endpoints:

Serum concentrations of trastuzumab emtansine at specified timepoints

Plasma concentrations of venetoclax at specified timepoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to trastuzumab 
emtansine when given with placebo or in combination with venetoclax on the basis of the 
following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or evaluate 
biomarkers that are predictive of response to venetoclax in combination with trastuzumab 
emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to trastuzumab emtansine and venetoclax, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of venetoclax and/or trastuzumab 
emtansine activity (i.e., PD biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
Health Status Utility Objective
The exploratory health status utility objective for the randomized Phase II stage is to evaluate 
health status utility scores of patients treated with trastuzumab emtansine in combination with 
venetoclax compared with trastuzumab emtansine plus placebo on the basis of the following 
endpoint:

Change from baseline in patient-reported symptoms and their impact on functioning and 
health-related quality of life as measured by the European Organisation for Research and 
Treatment of Cancer Quality of Life Core 30 Questionnaire (EORTC QLQ-C30) and EORTC 
Item List 46 (EORTC IL46)


 
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Study Design 
Description of Study 
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-controlled, 
double-blind, multicenter stage (hereafter referred to as the “randomized Phase II stage”). The 
expansion phase may run concurrent to and parallel with the randomized Phase II stage. 
Dose-Escalation Phase 
The dose-escalation phase will determine the RP2D and MTD for venetoclax when given in 
combination with a fixed dose of trastuzumab emtansine (3.6 mg/kg) in patients with previously 
treated, HER2-positive LABC or MBC, irrespective of prior trastuzumab emtansine exposure in 
the metastatic setting.  
The dose-escalation phase will enroll 6−24 patients and will include 2−4 cohorts: 
• 
Cohort 1A, 400 mg QD Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (every 3 weeks [Q3W]) and venetoclax 400 mg 
orally (PO) once a day (QD) continuous on Days 1−21 of each cycle.  
• 
Cohort 1B, 400 mg NC Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 400 mg PO QD non-
continuous (NC) on either Days 1−7 or 1−14 of each cycle. 
• 
Cohort 2A, 800 mg QD Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 800 mg PO QD 
continuous on Days 1−21 of each cycle. 
• 
Cohort 2B, 800 mg NC Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 800 mg PO QD non-
continuous on either Days 1−7 or 1−14 of each cycle. 
The 400-mg and 800-mg cohorts for dose escalation will be run sequentially (i.e., the 400-mg 
cohort followed by the 800-mg cohort).  Dose escalation will be performed based on a standard 
3 + 3 design.  Each cohort will consist of at least 3 patients, unless 1 of the 3 patients 
experiences DLTs (refer to the protocol for DLT criteria), in which case 3 additional patients will 
be treated at the same dose level.  The dose escalation will continue until 2 patients among a 
cohort of 6 patients experience a DLT (i.e., ≥33% of patients with a DLT at that dose level; refer 
to dose-escalation rules in the protocol).  Patients who experience a DLT will continue at the 
same dose level. 
Dose de-escalation may be explored by incorporating non-continuous (NC) dosing of 
venetoclax (e.g., less than 21 days of dosing, such as 7 days out of 21 days or 14 days out of 
21 days) dependent on the severity and timing of DLTs as well as the specific adverse events 
encountered.  For example, if DLTs such as a Grade 3 rash occurred between Day 8 and 
Day 14, an NC schedule of Days 1−7 would be tested.  Alternatively, if DLTs are thought to be 
possibly mitigated by a 7-day break such as Grade 3 fatigue occurring near the end of the DLT 
window (e.g., Day 20), then an NC schedule of Days 1−14 could be chosen to be tested.  
Patients may be treated in up to two NC sub-cohorts (i.e., either 400 mg NC and/or 800 mg 
NC).  At each dose de-escalation level, either a Days 1−7 or Days 1−14 NC treatment schedule 
will be assessed. 
Refer to the protocol for definition of DLT, dose-escalation rules, and determination of DLTs and 
RP2D.  
Expansion Phase 
An expansion phase may be initiated to evaluate the safety, tolerability, and efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine in previously treated HER2-
positive locally advanced or MBC patients who have received prior trastuzumab emtansine or 
trastuzumab deruxtecan (DS-8201a).  
The decision to open cohorts as part of an expansion phase will be data-driven and dependent 
on the observations made in the dose-escalation phase, emerging data with trastuzumab 
deruxtecan, as well as other HER2-targeted therapies.  The expansion phase may run 
concurrent to and in parallel with the randomized Phase II stage of the study. 


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Randomized Phase II Stage
The randomized Phase II stage will be initiated once the RP2D has been identified based on the 
cumulative data collected from the dose-escalation phase.  It will consist of two interventional 
arms of trastuzumab emtansine plus placebo or trastuzumab emtansine plus venetoclax in 
patients with previously treated HER2-positive LABC or MBC, who have not received prior 
trastuzumab emtansine therapy.
Approximately 220 patients will be randomized 1:1 to one of the following treatment arms:  

Control Arm:  Patients will receive trastuzumab emtansine 3.6 mg/kg by IV infusion Q3W 
plus placebo at the RP2D and schedule of venetoclax. 

Experimental Arm:  Patients will receive trastuzumab emtansine 3.6 mg/kg by IV infusion 
Q3W plus venetoclax at the RP2D and schedule. 
Each arm will include at least 50% Bcl-2 high patients. Randomization will be stratified 
according to the following criteria:

Bcl-2 status (Bcl-2 high vs. Bcl-2 low)

Visceral disease (Yes vs. No)

HER2 status IHC 3+ (Yes vs. No)
Number of Patients
Approximately 226284 patients will be enrolled in this study across approximately 145 sites 
globally.  The study will enroll 624 patients in Part 1 of the study and approximately 
220 patients in Part 2. An additional approximately 2040 patients may be enrolled in the 
expansion cohorts.
Target Population
Inclusion Criteria (All Study Phases)
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form 

Ability to comply with the study protocol, in the investigator's judgment

Histologically or cytologically confirmed invasive MBC or LABC that is incurable, 
unresectable, and previously treated with multimodality therapy:

Prior treatment for BC in the adjuvant, unresectable locally advanced, or 
metastatic settings, which must include both a taxane and trastuzumab (alone or in 
combination with another agent) 

Progression must have occurred during or after most recent treatment for 
LABC/MBC or within 6 months after completing adjuvant therapy

Measurable disease that is evaluable per RECIST v1.1

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Willing to provide tumor biopsy sample at the time of screening
A tumor biopsy sample (either archival or fresh) must be collected from all patients 
from either the primary tumor or a metastatic site (preferred and within 6 months of 
enrollment, if clinically feasible) for determination of HER2 status by central laboratory 
testing for patient eligibility purposes, for Bcl-2 expression, and for research on 
biomarkers. 
The tumor specimen must contain adequate evaluable tumor cells (20% tumor cells) 
to enable Bcl-2, HER2, and other relevant biomarker analysis. Samples can be a 
tissue block (preferred) or at least 20 unstained freshly cut serial slides, and should be 
accompanied by an associated pathology report.  If fewer than 20 slides are available, 
the Sponsor should be consulted. If a tumor sample is not available, a fresh biopsy 
must be collected. 
The specimen must be a formalin-fixed, paraffin-embedded (FFPE) tumor specimen, or 
another appropriate fixative must be used (notation of the type of fixative should be 
included).  Cytological or fine-needle aspiration samples are not acceptable.


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
Local histological or cytological confirmation of estrogen receptor (ER) and/or progesterone 
receptor status as defined by using IHC per American Society of Clinical Oncology/College 
of American Pathologists criteria

Percentage of ER and/or progesterone receptor positivity, if available

Willing to provide blood samples at the time of screening, on-study, and at progression for 
exploratory research on biomarkers

HER2-positive breast cancer (BC) as defined by an IHC score of 3+ or gene amplified by in 
situ hybridization (ISH) as defined by a ratio of 2.0 for the number of HER2 gene copies to 
the number of chromosome 17 copies
For the expansion phase and randomized Phase II stage:  Centrally confirmed HER2-
positive status prospectively tested by a Sponsor-designated central laboratory prior to 
enrollment.
For the dose-escalation phase:  Enrollment can be based upon prospective central 
testing or local IHC or ISH results; however, for local IHC or ISH results, the same 
tissue sample must be sent for central HER2 confirmation and the testing platform 
documented in the eCRF.
Both IHC and ISH assays can be performed; however, unless reflex testing is 
necessary, only one positive result is required for eligibility.
If multiple tumor specimens are submitted, the HER2 IHC score and or ISH 
amplification ratio will first be assessed on the most recently obtained specimen for the 
purpose of determining eligibility.  For patients with bilateral BC, HER2 positivity must 
be demonstrated in both locations for archival tissue or in a metastatic biopsy.
Centrally confirmed HER2 results (either IHC or ISH) from a current or previous 
Sponsor study can be used to determine eligibility for this study.  Approval must be 
obtained from the Medical Monitor prior to randomization.

Adequate hematologic and end-organ function, as evidenced by the following local 
laboratory results obtained within 7 days prior to the first study treatment (Cycle 1, Day 1):

Absolute neutrophil count 1500 cells/L (without granulocyte-colony 
stimulating factor support within 7 days prior to Cycle 1, Day 1)

Platelet count 100,000/L (without transfusion within 7 days prior to Cycle 1, 
Day 1)

Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet 
this criterion.

Albumin 2.5 g/dL

Total bilirubin 1.5 ULN with the following exceptions:
Patients with previously documented Gilbert syndrome who may have
bilirubin 5 ULN
Patients with documented liver metastases may have bilirubin 
2.5 ULN

AST, ALT, and ALP 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases may have ALP 
5 ULN

Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min on the basis 
of either 24-hour urine collection or the Cockroft-Gault glomerular filtration 
rate estimation:
(140 age) (weight in kg) (0.85 if female)
72 (serum creatinine in mg/dL)


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
INR or aPTT 1.5 ULN
For patients requiring anticoagulation therapy with warfarin or other 
coumarins, a stable INR between 2 and 3 is required.  If anti-coagulation 
is required for a prosthetic heart valve, then INR should be between 2.5 
and 3.5.

Screening left ventricular ejection fraction (LVEF) 50% on echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan
LVEF assessment may be repeated once up to 3 weeks following the initial screening 
assessment to assess eligibility.

Negative HIV test at screening

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening
The HBV DNA test will be performed only for patients who have a negative HBsAg test 
and a positive total HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive HCV 
antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 
1% per year during the treatment period and for at least 30 days after the last dose of 
venetoclax or 7 months after the last dose of trastuzumab emtansine, whichever is later.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or regulations.
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 methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for at least 30 days after the last dose of venetoclax or 7 months 
after the last dose of trastuzumab emtansine, whichever is later. 
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 30 days after the last dose of venetoclax or 7 
months after the last dose of trastuzumab emtansine, whichever is later to avoid 
exposing the embryo.


 
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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 acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
Inclusion Criteria for Expansion Phase Only 
In addition to the general inclusion criteria, patients in the expansion phase of the study must 
also meet the following criteria for study entry: 
• 
Trastuzumab emtansine experienced cohort:  
− 
Disease progression during or after trastuzumab emtansine in the 
advanced/metastatic setting or disease recurrence in the neoadjuvant/adjuvant 
setting   
− 
At least 50% patients in the expansion cohort (e.g., 10 out of 20) must have 
tumor that is Bcl-2 high.  
Bcl-2 high is defined as  ≥ 50% of tumor cells stained with an intensity of 
IHC 2+ or 3+, and Bcl-2 low is defined as IHC 0 or 1+ or < 50% of tumor 
cells stained with an intensity of IHC 2+ or 3+. 
 
• 
Trastuzumab deruxtecan (DS-8201a) experienced cohort:  
− 
Disease progression during or after trastuzumab deruxtecan in the 
advanced/metastatic setting 
− 
Prior trastuzumab emtansine in any setting is allowed 
− 
At least 50% patients in the expansion cohort (e.g., 10 out of 20) must have 
tumor that is Bcl-2 high.  
Inclusion Criteria for Randomized Phase II Stage 
In addition to the general inclusion criteria, patients in the randomized Phase II stage of the 
study must also meet the following criteria for study entry: 
• 
Bcl-2 expression status by IHC either from fresh tissue or the most recent archival tissue 
(see criteria for all study phases) by a central laboratory using the Ventana Bcl-2 IHC assay 
prior to randomization.   
At least 50% of patients in the randomized Phase II (e.g., 110 out of 220 patients) must 
be Bcl-2 high. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to Cycle 1, 
Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1 
• 
Radiation therapy within 2 weeks prior to Cycle 1, Day 1 
• 
The patient must have recovered from any resulting acute toxicity (to Grade < 1) prior to 
randomization.  
• 
History of exposure to the following cumulative doses of anthracyclines as specified below: 
− 
Doxorubicin > 500 mg/m2 
− 
Liposomal doxorubicin > 500 mg/m2  
− 
Epirubucin > 720 mg/m2  
− 
Mitoxantrone > 120 mg/m2 
− 
Idarubicin > 90 mg/m2 
If another anthracycline or more than one anthracycline has been used, then the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin. 


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
History of other malignancy within the previous 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
patients who have undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to be at low risk for recurrence

Cardiopulmonary dysfunction as defined by:

Uncontrolled hypertension (systolic 150 mm Hg and/or diastolic 
100 mm Hg with or without medication)

Inadequate LVEF at baseline, 50% by either ECHO or MUGA

History of symptomatic congestive heart failure (CHF)-Grade 3 per NCI
CTCAE version 5.0 or Class II New York Heart Association 

History of a decrease in LVEF to 40% or symptomatic CHF with prior 
trastuzumab treatment

Myocardial infarction or unstable angina within 6 months of randomization

Concurrent dyspnea at rest due to complications of advanced malignancy, or 
other disease requiring continuous oxygen therapy

Evidence of transmural infarction on ECG

Significant symptoms (Grade 2) relating to LVEF, cardiac arrhythmia, or 
cardiac ischemia

High-risk uncontrolled arrhythmias (i.e., supraventricular tachycardia with a 
heart rate 100/min at rest, significant ventricular arrhythmia [ventricular 
tachycardia], or higher-grade atrioventricular [AV]-block [second-degree AV-
block Type 2 (Mobitz 2) or third-degree AV-block])

Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures)

Major surgical procedure or significant traumatic injury within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the completion of the 
course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, sclerosis cholangitis, or active infection with HBV or HCV)

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

Known HIV infection or human T-cell leukemia virus 1 infection

Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for 2 weeks prior to randomization

Known central nervous system (CNS) disease, except for patients treated and currently with 
asymptomatic CNS metastases, provided that all of the following criteria are met:

Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord)

No ongoing requirement for corticosteroids as therapy for CNS disease 

No stereotactic radiation within 14 days prior to randomization

No evidence of interim progression between the completion of CNS-directed
therapy and the screening radiographic study
Note: Patients with new asymptomatic CNS metastases detected at the 
screening scan must receive radiation therapy and/or surgery for CNS 
metastases.  Following treatment, these patients may be eligible without 
the need for an additional brain scan prior to enrollment, if all other 
criteria are met.


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
Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once a month or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed regardless of drainage 
frequency.

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL or 
corrected serum calcium greater than the ULN) or symptomatic hypercalcemia requiring 
continued use of bisphosphonate therapy
Patients who are receiving denosumab must discontinue use of denosumab and 
replace it with a bisphosphonate instead while on study.
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are eligible.

Current Grade 3 peripheral neuropathy (according to the NCI CTCAE v 5.0)

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins

Prior allogeneic stem cell or solid organ transplantation

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
30 days after the last dose of venetoclax or 7 months after the last dose of trastuzumab 
emtansine after the final dose of study treatment, whichever is later
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

Administration of the following agents within 7 days prior to the first dose of study drug:

Strong or moderate CYP3A inhibitors

Strong or moderate CYP3A inducers
Additional restrictions for on-study use of CYP3A inhibitors/inducers are outlined in the 
protocol.

Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade-
containing Seville oranges), or starfruit (carambola) within 3 days before anticipated first 
dose of study drug until the last dose of study drug

Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the study

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
judgment

Malabsorption syndrome or other condition that would interfere with enteral absorption

History of active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) 
requiring specific medication in the 12 months prior to randomization, or active and 
uncontrolled bowel inflammation (e.g., diverticulitis) at time of randomization

Inability or unwillingness to swallow a large number of tablets

Known hypersensitivity to venetoclax or trastuzumab emtansine or to any of their excipients

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study

Other medical or psychiatric conditions that, in the opinion of the investigator, may interfere 
with the patient’s participation in the study

Blood transfusions if performed within 2 weeks prior to screening


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Exclusion Criteria for Randomized Phase II Stage
In addition to the general exclusion criteria, patients in the randomized Phase II stage of this 
study who meet the following criteria will be excluded:

Prior treatment with trastuzumab emtansine in any setting (neoadjuvant/adjuvant or 
advanced/metastatic setting)

Prior treatment with venetoclax in any setting

Prior treatment with anti-HER2 antibody drug conjugates (e.g. trastuzumab deruxtecan [DS-
8201a]), margetuximab, pyrotinib, or tucatinib. 
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later.  The end of study is planned to occur approximately 
24 months after last patient in (LPI).  In addition, the Sponsor may decide to terminate the study 
at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 48 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, Inc. and will be supplied by the 
Sponsor as oral film-coated tablets of 100-mg strength. Each dose of venetoclax will be taken 
orally once daily.  The venetoclax treatment regimens for the dose-escalation phase, dose-
expansion phase, and randomized Phase II stage are summarized in the Description of Study
above.
Comparator
The formulation of placebo is equivalent to venetoclax but without the active agent.  Each dose 
of placebo will be taken orally once daily.  The placebo treatment regimen for the randomized 
Phase II stage is summarized in the Description of Study above.
Trastuzumab emtansine will serve as the comparator/active control and will not be blinded.
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion Q3W.
The oral dose of venetoclax should be administered first, followed by infusion of trastuzumab 
emtansine.
Statistical Methods
Primary Analysis for Dose-Escalation Phase
The primary objective for the dose-escalation phase is to evaluate the safety and tolerability of 
trastuzumab emtansine in combination with venetoclax, including estimation of the MTD, 
determination of the RP2D, and characterization of DLTs.  The safety analysis population will 
consist of all randomized patients who received at least one dose of study drug, with patients 
grouped according to treatment received.  Safety will be assessed separately for each study 
phase through summaries of exposure to study treatment, adverse events, changes in 
laboratory test results, and changes in vital signs and ECGs.  Study treatment exposure (such 
as treatment duration, total dose received, and number of cycles and dose modifications) will be 
summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms, and adverse event severity will be graded according to NCI 
CTCAE v5.0.  All adverse events, serious adverse events, adverse events leading to death, 
adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur on or after the first dose of study treatment (i.e., treatment emergent 
adverse events) will be summarized by mapped term, appropriate thesaurus level, and severity 
grade.  For events of varying severity, the highest grade will be used in the summaries.  Deaths 
and cause of death will be summarized.


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Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse oximetry, and 
temperature), and ECG data will be displayed by time, with grades identified where appropriate.  
Additionally, a shift table of selected laboratory tests will be used to summarize the baseline and 
maximum postbaseline severity grade.  Changes in vital signs and ECGs will be summarized.
Primary Analysis for Randomized Phase II Stage
The co-primary endpoints for the randomized Phase II stage are ORR and PFS.  The primary 
efficacy analysis population will consist of all randomized patients, with patients grouped 
according to their assigned treatment (the intent-to-treat [ITT] population).  The primary efficacy 
analysis will occur when 161 patients have experienced a PFS event.  It is anticipated that this 
will occur six months after the last patient enters treatment.  Patients with no disease 
assessments for any reason will be classified as non-responders.  An estimate of ORR with 95% 
CI will be calculated for each treatment arm using the normal approximation to the binomial 
distribution.  An estimate and 95% CI for the difference in ORR between the two treatment 
groups will be presented based on the normal approximation to the binomial distribution.
PFS is defined as the time from randomization to the first occurrence of disease progression (as 
defined by the investigator according to RECIST v1.1) or death from any cause, whichever 
comes first.  Data for patients without the occurrence of disease progression or death as of the 
clinical data cut-off date will be censored at the time of last tumor assessment (or the time of 
randomization plus 1 day if no tumor assessment was performed after the baseline visit).
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm. 
Kaplan-Meier curves of time to PFS for each treatment group will be provided.  The Cox 
proportional hazards model stratified by the randomization stratification factors (Bcl-2 status 
[high, low], visceral disease [yes, no], and HER2 status IHC 3+ [yes, no] will be used to provide 
an estimate of the hazard ratio of venetoclax plus trastuzumab emtansine to placebo plus 
trastuzumab emtansine with associated 95% CI and p-value.  The unstratified hazard ratio 
estimate and 95% CI will also be presented.
Determination of Sample Size  
The sample size for the dose-escalation phase is based on the dose-escalation rules described 
in the protocol.  The planned enrollment for the dose-escalation phase is approximately 
624 patients enrolled across 24 dose-escalation treatment groups.  
Approximately 20 patients each may be enrolled in the expansion phase (trastuzumab 
emtansine-experienced cohort and trastuzumab deruxtecan-experienced cohort).
With 20 patients per cohort and an observed ORR of 60%, the exact 90% Clopper-Pearson 
confidence interval for the ORR would be 39%78%, which would rule out an ORR of 35% or 
less.  The protocol provides exact 90% confidence intervals for a range of observed proportions 
of ORR based on a sample size of 20 patients.  For a given adverse event with a true rate of 
10%, 5%, or 1%, the probability of observing at least one such event in a cohort of 20 patients is 
87.8%, 64.2%, and 18.2%, respectively.  The protocol describes exact 90% confidence intervals 
for a range of observed proportions of adverse events based on a sample size of 20 patients.
After the RP2D has been determined for venetoclax when given in combination with a fixed 
dose of trastuzumab emtansine, a total of 220 patients will be enrolled in the randomized 
Phase II stage of the study.  The purpose of the randomized Phase II stage is estimation and 
hypothesis generation regarding the effect of venetoclax in combination with trastuzumab 
emtansine on ORR and duration of PFS relative to trastuzumab emtansine plus placebo.  The 
point and interval estimates of the true underlying HR will be obtained.  
For the co-primary endpoints of ORR and PFS in the primary efficacy analysis population, the 
trial will have:

85% power (0.05) to detect a 20% improvement in ORR (i.e., ORR ) (assuming a 44% 
ORR in the trastuzumab emtansine plus placebo arm).  In the meantime, a 20% 
improvement in ORR will have a 95% CI of (7%, 33%).


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
90% power (0.05) to detect a PFS HR of 0.6 venetoclax plus trastuzumab emtansine 
arm relative to the trastuzumab emtansine plus placebo arm, when approximately 161 total 
PFS events have occurred. In the meantime, a PFS HR of 0.6 will have a 95% CI of (0.44, 
0.82).  The assumptions of the sample size calculation are that the median PFS in the 
control arm is 6.8 months and that enrollment would occur non-uniformly over 24 months.  
Enrollment is anticipated to be lower during the second half of the enrolment period 
because it will be restricted to the Bcl-2 high population.
Within the Bcl-2 high population the study will have:

85% power (0.05) to detect a PFS HR of 0.5 venetoclax plus trastuzumab emtansine 
arm relative to the trastuzumab emtansine plus placebo arm, when approximately 75 total 
PFS events have occurred.  In the meantime, a PFS HR of 0.5 will have a 95% CI of (0.32, 
0.79).
The study will not, however, have adequate power to detect all potentially clinically meaningful 
differences in ORR and PFS.  For example, within the entire ITT population:

With 110 patients in each arm, there is only 60% power (0.05) to detect a 15% 
improvement in ORR (assuming a 44% ORR in the trastuzumab emtansine plus placebo 
arm), and 

With approximately 161 total PFS events, only 62% power (0.05) to detect an HR of 0.70, 
in venetoclax plus trastuzumab emtansine arm relative to the trastuzumab emtansine plus 
placebo arm.  
Thus, a statistically negative outcome in any of the co-primary endpoints does not necessarily 
rule out a clinically meaningful outcome.  The protocol describes the power and CIs for several 
possible true underlying improvements in ORR and PFS in favor of the venetoclax plus 
trastuzumab emtansine arm. 
Due to the smaller sample size of the Bcl-2 high population the power to detect a HR of 0.60 in 
the Bcl-2 population is 60% compared to 90% for the entire ITT population. The study has 
adequate power (85%) to detect a HR of 0.5 in the Bcl-2 high population.
Interim Analyses (Randomized Phase II Stage Only)
Periodic analyses of cumulative safety data and one interim analysis is planned for this study.  
Given the hypothesis-generating nature of this study, the Sponsor considers the interim efficacy 
analysis as exploratory.
The planned interim efficacy analysis of cumulative safety, ORR, and PFS will occur when 
approximately 56 PFS events have occurred.  This is expected to occur after the enrollment of 
the first 110 patients who have been followed up for at least 6 months.
If the interim analysis coincides within approximately 1 month of a planned safety review, the 
safety review may be combined with the efficacy interim analyses.  Outcomes from these 
reviews that may affect study conduct will be communicated in a timely manner to the 
investigators, and IRBs/ECs will be notified.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
AML
acute myeloid leukemia
AV
atrioventricular
BC
breast cancer
Bcl-2
B-cell lymphoma 2
CBR
clinical benefit rate
CHF
congestive heart failure
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
CLL
chronic lymphocytic leukemia
CNS
central nervous system
CR
complete response
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
DDI
drugdrug interaction
DLT
dose-limiting toxicity
DOR
duration of response
EBC
early breast cancer
EC
Ethics Committee
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of Cancer
EORTC IL46
EORTC Item List 46
EORTC QLQ-C30
EORTC Quality of LifeCore 30 Questionnaire
ER
estrogen receptor
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio


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ICH
International Council for Harmonisation
IHC
immunohistochemistry
IL46
Item List 46
ILD
interstitial lung disease
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
infusion-related reaction
ISH
in situ hybridization
ITT
intent-to-treat (population)
IxRS
interactive voice or web-based response system
LABC
locally advanced breast cancer
LDAC
low-dose cytarabine
LVEF
left ventricular ejection fraction
MBC
metastatic breast cancer
MM
multiple myeloma
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition (scan)
NC
non-continuous (dose)
NCI
National Cancer Institute
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0
NGS
next-generation sequencing
NHL
non-Hodgkin lymphoma
NIMP
non-investigational medicinal product
NRH
nodular regenerative hyperplasia
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic
PDX
patient-derived xenograft
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
PO
by mouth; orally
PR
partial response


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PRO
patient-reported outcome
Q3W
every 3 weeks
QD
once a day
QLQ-C30
Quality of LifeCore 30 Questionnaire
QTcF
QT interval corrected through use of Fridericia's formula
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase II dose
SD
stable disease
SLL
small lymphocytic lymphoma
SmPC
Summary of Product Characteristics
TGI
tumor growth inhibition
TIL
tumor-infiltrating lymphocyte
TLS
tumor lysis syndrome
TPC
treatment of physician’s choice
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON HER2-POSITIVE BREAST CANCER
Breast cancer (BC) is the most common cancer among women in the world, with an 
estimated 2.09 million cases diagnosed globally per year and a mortality rate of 
approximately 627,000 deaths (Bray et al. 2018).  While advances in early diagnosis and 
adjuvant therapy have led to a decrease in mortality rates from BC in developed 
countries, the prevalence of metastatic breast cancer (MBC) is still high and it is not 
curable, with the main goals of treatment being to prolong survival while maintaining or
improving patients’ quality of life (Cardoso et al. 2018).
BC risk assessment, prognosis, and treatment strategy rely on the status of key 
biomarkers: hormonal receptors (estrogen receptor [ER] and progesterone receptor) and 
HER2, also known as erbB2, neu, and p185HER2. Approximately 15%20% of patients 
with primary invasive BC overexpress the HER2 receptor (Reese and Slamon 1997; 
Owens et al. 2004; Wolff et al. 2013; Zhang et al. 2015).  Before HER2-targeted therapy
became available, primary BCs that overexpressed HER2 were associated with a poorer 
prognosis, including a greater risk of relapse and shortened survival compared with that 
of HER2-negative tumors (Slamon et al. 1987; Toikkanen et al. 1992; Andrulis et al. 
1998; Pauletti et al. 2000; Rubin and Yarden 2001). That changed with the introduction 
of trastuzumab, the first anti-HER2 therapy approved for HER2-positive BC, with HER2 
positivity being designated as an immunohistochemistry (IHC) score of 3+ or HER2 gene 
amplification ratio of 2.0 by in situ hybridization (ISH).
Until recently, for patients with HER2-positive MBC, the combination of trastuzumab and 
a taxane was widely accepted as the first-line treatment option of choice on the basis of 
the survival advantage demonstrated in two large pivotal trials (Studies H0648g [Slamon 
et al. 2001] and M77001 [Marty et al. 2005]).  More recently, the regimen of pertuzumab 
in combination with trastuzumab and docetaxel has shown clear superiority in terms of 
both progression-free survival (PFS) and overall survival (OS) with a generally similar 
safety profile (Study WO20698/TOC4129g [Baselga et al. 2012]), and became the new 
standard of care for first-line HER2-positive MBC.
In patients with HER2-positive advanced BC previously treated with trastuzumab and a 
taxane, trastuzumab emtansine has significantly prolonged PFS (up to 3 months
improvement) and OS (up to 7 months increase) with a more favorable safety profile 
than lapatinib plus capecitabine (Study BO21977/TDM4370g, EMILIA [Verma et al.
2012]) or compared with a treatment of physicians’ choice (TPC) in patients who 
previously received trastuzumab, taxane, and lapatinib (Wildiers et al. 2015). 
Trastuzumab emtansine is considered the standard of care in the aforementioned 
patient population (Cardoso et al. 2018; National Comprehensive Cancer Network 
[NCCN] 2019).


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Based on the clinical data mentioned above, for patients with HER2-positive BC, the 
continuous blockage of HER2 through the initial lines of therapy in the metastatic setting 
is recommended (NCCN 2019). Even though the survival time of patients with HER2-
positive BC has been prolonged in recent years, there remains a significant need for 
further outcome improvement. This could be achieved with the addition of new agents 
with novel mechanisms of action and acceptable toxicity, such as the pro-apoptotic 
molecule venetoclax, that can be combined with established HER2-targeted therapies.
1.2
BCL-2 SIGNALING PATHWAY AND HER2-POSITIVE BREAST 
CANCER
Cancer cells are characterized by their capacity for relentless growth, survival, and 
evasion of cell death (Adams and Cory 2007; Strasser et al. 2011). Apoptosis is the 
dominant mode of programmed cell death with two distinct pathways: the intrinsic 
mitochondrial pathway and the extrinsic death receptor pathway (Strasser et al. 2011). 
Intrinsic apoptosis is regulated by the B-cell lymphoma 2 (Bcl-2) family of anti-apoptotic 
proteins of which key members are Bcl-2, Bcl-XL, Bcl-w, A1, and MCL-1 (Cory et al.
2003). Bcl-2 family proteins have been described to be overexpressed in numerous 
cancer types. BCL-2 overexpression has been described in approximately 54%75% of 
BC cases.
Bcl-2 is a relevant therapeutic target in hematologic malignancies, including chronic 
lymphocytic leukemia (CLL])/small lymphocytic lymphoma (SLL), non-Hodgkin 
lymphoma (NHL), multiple myeloma (MM), myelodysplastic syndrome, and acute 
myeloid leukemia (AML) (Perini et al. 2018), and may have an important role in the 
survival of solid tumors such as BC and lung cancer. For example, patient-derived 
xenograft (PDX) tumor models of luminal B BC have demonstrated significant 
improvement in tumor responses and OS when treated with the dual BCL-2/BCL-XL
inhibitor ABT-737 in combination with tamoxifen, compared with tamoxifen alone (Oakes 
et al. 2012; Vaillant et al. 2013). Similar efficacy was observed using the Bcl-2specific 
inhibitor venetoclax (GDC-0199/ABT-199), suggesting that Bcl-2 may be a critical target 
(Vaillant et al. 2013; Lok et al. 2019) in patients with ER-positive, Bcl-2positive MBC. 
The combination appears to show preliminary efficacy as well as a favorable toxicity 
profile when compared with other adjunctive therapies used with endocrine therapy, 
such as the mTOR, PIK3CA, and CDK4/6 inhibitors (Lok et al. 2019). 
Bcl-2 is believed to be an important target in HER2-positive BC. Internal Genentech and 
Roche biomarker data in HER2-positive BC suggest that higher levels of Bcl-2
expression may be a poor prognostic factor in early breast cancer (EBC).  Analysis of 
EBC tumor samples demonstrated that 24% of HER2-positive tumors were Bcl-2 high by 
IHC analysis (Genentech internal, unpublished).  These data are consistent with 
previously reported data indicating that 21%26% of HER2-positive samples are Bcl-
2positive (Honma et al. 2015; Eom et al. 2016).


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1.3
BACKGROUND ON TRASTUZUMAB EMTANSINE
Trastuzumab emtansine (Kadcyla®) is a regulatory authorityapproved antibody-drug 
conjugate.  Linkage of a cytotoxic agent to highly specific monoclonal antibodies 
targeting unique and/or overexpressed cell-surface tumor antigens focuses the delivery 
of such agents to tumor cells, creating a more favorable therapeutic window than can be 
achieved by their administration as free drugs.  Trastuzumab emtansine is specifically 
designed for the treatment of HER2-positive cancer.  It is composed of the cytotoxic 
agent DM1 (a thiol-containing maytansinoid anti-microtubule agent; N2'deacetyl-N2'-[3-
mercapto-1-oxopropyl]-maytansine) conjugated to trastuzumab via lysine side chains, 
with an average drug-to-antibody ratio of approximately 3.5:1.
Trastuzumab emtansine binds to HER2 with an affinity similar to that of trastuzumab; 
such binding is required for its anti-tumor activity.  After binding to HER2, trastuzumab 
emtansine undergoes receptor-mediated internalization, followed by intracellular release 
of DM1 and subsequent cytotoxicity.
Based on Phase I, II, and III studies in which trastuzumab emtansine demonstrated 
clinical activity, it is currently approved as a single agent for the treatment of patients 
with HER2-positive MBC who previously received trastuzumab and a taxane, separately 
or in combination (Kadcyla U.S. Package Insert; E.U. Summary of Product 
Characteristics [SmPC]). Trastuzumab emtansine is also approved for the adjuvant 
treatment of patients with HER2-positive EBC who have residual invasive disease after 
neoadjuvant taxane and trastuzumab-based treatment. Data from clinical trials of 
trastuzumab emtansine that are relevant to the design of the current trial are 
summarized in the following sections.  Refer to the most recent version of the 
Trastuzumab Emtansine Investigator’s Brochure for further information on all of the 
completed and ongoing trastuzumab emtansine studies.
1.3.1
Study TDM4370g/BO21977 (EMILIA)
Study TDM4370g/BO21977 was a randomized Phase III study of trastuzumab 
emtansine versus lapatinib plus capecitabine in patients with HER2-positive, 
unresectable locally advanced BC (LABC) or MBC previously treated with trastuzumab 
and a taxane (n991).  Patients received trastuzumab emtansine (3.6 mg/kg IV every
3 weeks [Q3W]) or capecitabine (1000 mg/m2 orally [PO] twice a day, Days 114 Q3W) 
plus lapatinib (1250 mg PO once a day [QD]) until progressive disease or unmanageable 
toxicity.
Primary endpoints were PFS by independent review, OS, and safety. A total of 
991 patients were enrolled, and 978 patients received treatment.  Baseline patient 
demographics, prior therapy, and disease characteristics were balanced.  There was a 
significant improvement in PFS favoring trastuzumab emtansine (hazard ratio 
[HR]0.650; 95% CI:0.549 to 0.771; p0.0001; median PFS: 9.6 vs. 6.4 months).  
Objective response rate (ORR) was 43.6% for the trastuzumab emtansine arm versus 


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30.8% for the lapatinibpluscapecitabine arm, with a median duration of response (DOR) 
of 12.6 months versus 6.5 months, respectively. Final OS analysis showed a consistent 
survival benefit for trastuzumab emtansine compared with lapatinibpluscapecitabine 
(median OS 29.9 vs. 25.9 months; stratified HR0.75), despite 27% of patients 
crossing over from the control arm to trastuzumab emtansine (Diéras et al. 2017).
Trastuzumab emtansine was well tolerated, with no unexpected safety signals.  The 
most common Grade 3 adverse events in the trastuzumab emtansine arm were 
thrombocytopenia (12.9% vs. 0.2%, respectively), increased AST (4.3% vs. 0.8%), and 
increased ALT (2.9% vs. 1.4%); the most common Grade 3 adverse events in the 
lapatinibpluscapecitabine arm were diarrhea (20.7% vs. 1.6%), palmar plantar 
erythrodysesthesia (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).  The incidence of 
Grade 3 adverse events in the trastuzumab emtansine arm was 40.8% versus 57.0% in 
the lapatinibpluscapecitabine arm (Verma et al. 2012). Based on the results of the 
EMILIA study, trastuzumab emtansine was granted regulatory approval in the U.S. and 
E.U. for treatment-refractory HER2-positive LABC or MBC.
1.3.2
Study WO30085 (KATE2)
Study WO30085 (KATE2) is an ongoing, randomized, multicenter, double-blind, 
placebo-controlled Phase II study of the efficacy and safety of trastuzumab emtansine 
(3.6 mg/kg IV Q3W) in combination with atezolizumab (1200 mg IV Q3W) or 
trastuzumab emtansine plus placebo in patients with HER2-positive LABC or MBC who 
have received prior trastuzumab and taxane-based therapy. A total of 202 patients have 
been randomized to study treatment in a 2:1 ratio. Based on the primary efficacy 
endpoint of PFS, as determined by investigator-assessed Response Evaluation Criteria 
in Solid Tumors, Version 1.1 (RECIST v1.1), the study did not demonstrate a statistically 
significant benefit from the addition of atezolizumab to trastuzumab emtansine in the 
intent-to-treat (ITT) population. The stratified PFS HR was 0.82 (95% CI: 0.55 to 1.23), 
and p-value was 0.3332, with a median PFS of 8.2 months (95% CI: 5.8 to 10.7 months) 
for the treatment arm versus 6.8 months (95% CI: 4.011.1 months) for the control arm.
However, in the exploratory analysis of the PD-L1 immune cell-positive subgroup, the 
stratified HR was 0.60 (95% CI: 0.32–1.11) with a median PFS of 8.5 months (95% CI: 
5.7 months to non-evaluable) for the treatment arm versus 4.1 months (95% CI: 2.7 to 
11.1 months) for the control arm, suggesting a potential benefit for this patient subgroup
(Emens et al. 2019b). 
The ORR as assessed by investigator using RECIST v1.1 was similar between the 
treatment arms (43.5% vs. 45.5%). Of the 69 patients with measurable disease at 
baseline in the trastuzumab emtansine plus placebo arm, 36.2% had a partial response 
(PR) and 7.2% had a complete response (CR). Of the 132 patients with measurable 
disease at baseline in the trastuzumab emtansine plus atezolizumab arm, 39.4% had a 
PR and 6.1% had a CR. The DOR data based on investigator assessment in both arms 
were immature at the primary cancer-related causes of death with low event rates in 


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each arm (26.7% in the trastuzumab emtansine plus placebo arm vs. 28.3% in the 
trastuzumab emtansine plus atezolizumab arm). The median DOR was not reached.
At a second planned analysis (Emens et al. 2019a) with at least 18 months of follow-up 
in the ITT population, the median OS was not reached in either arm, but numerically 
favored the trastuzumab emtansine plus atezolizumab arm. One-year survival was 89.1% 
versus 89.0% (stratified HR0.74; 95% CI: 0.42 to 1.30) in the trastuzumab emtansine 
plus atezolizumab and trastuzumab emtansine plus placebo arms, respectively. In PD-
L1selected patients, 1-year survival rates were higher with trastuzumab emtansine plus 
atezolizumab as compared with trastuzumab emtansine plus placebo (94.3% vs. 87.9%;
stratified HR0.55; 95% CI: 0.22 to 1.38). All biomarkers of T-cell activation and 
quantity were enriched in the PD-L1selected subgroup. This included higher 
expression of PD-L1, Teff signature, and CD8 RNA, as well as greater numbers of 
tumor-infiltrating lymphocytes (TILs) observed in PD-L1positive tumors. Overall, the 
safety profile of the combination was consistent with the known safety profile of each 
drug.  Rate of high-grade adverse events (Grade 3) was 53% versus 45% in the 
trastuzumab emtansine plus atezolizumab as compared with trastuzumab emtansine 
plus placebo. Fatal Grade 5 events were similar in the two arms at 1.5% versus 1.5%. 
Adverse events leading to discontinuation of any study treatment was higher in the in the 
trastuzumab emtansine plus atezolizumab arm as compared with trastuzumab 
emtansine plus placebo arm (29% vs. 15%, respectively).
1.3.3
Study TDM4997g/BO25734 (TH3RESA)
Study TDM4997g/BO25734 was a Phase III, randomized, open-label trial to evaluate 
trastuzumab emtansine compared with TPC (these were approved or standard-of-care 
therapies based on frequently used regimens) in patients with HER2-positive MBC.  
Patients had received prior treatments with trastuzumab, lapatinib, and a taxane in any 
setting, and disease progression occurred after at least two regimens of HER2-directed 
therapy in the metastatic or unresectable locally advanced/recurrent setting.
The study demonstrated a statistically significant and clinically meaningful improvement 
in PFS for trastuzumab emtansine compared with TPC.  The median PFS was 
6.2 months for the trastuzumab emtansine arm and 3.3 months for the TPC arm, with a 
stratified HR of 0.528 (95% CI: 0.422, 0.661); p0.0001.  The ORR was 31% for the 
trastuzumab emtansine arm versus 9% for the TPC arm, resulting in an ORR difference 
of 22.7% (95% CI: 16.2 to 29.2; p0·0001).  
At the final OS analysis with a median 30.5 months of follow-up, trastuzumab emtansine 
demonstrated a clinically meaningful and statistically significant improvement in OS 
compared with TPC. The median OS improved from 15.8 months (95% CI: 13.5 to 
18.7 months) with TPC to 22.7 months (95% CI: 19.4 to 27.5 months) with trastuzumab 
emtansine. The stratified HR was 0.68 (95% CI: 0.54 to 0.85; p0.0007).  Despite the 
longer treatment duration relative to control (4.1 months; [0.0331.2]), trastuzumab 


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emtansine (7.9 months [0.0338]) had a favorable safety profile, which was consistent 
with prior studies (Krop et al. 2017).
In the updated safety analysis, fewer patients receiving trastuzumab emtansine than 
those receiving TPC had Grade 3 adverse events (40% vs. 47%). The most common 
Grade 3 adverse events (affecting 2% of patients in either group) that were more 
frequent with trastuzumab emtansine included thrombocytopenia (6% vs. 3%) and 
hemorrhage of any type (4% vs. 1%). Serious adverse events were reported in 25% of 
patients in the trastuzumab emtansine group and 22% in the TPC group. Deaths from 
adverse events were reported in 3 patients (2%) in the TPC group (of which 1 death was 
judged to be treatment related) and 9 patients (2%) in the trastuzumab emtansine group
(of which 3 deaths were judged to be treatment related) (Krop et al. 2017).
1.3.4
Study BO27938 (KATHERINE)
Study BO27938 is a multicenter, Phase III, randomized, open-label trial to evaluate 
patients with HER2-positive EBC who had residual invasive disease after completion of 
neoadjuvant therapy. At the interim analysis, among 1486 randomly assigned patients 
(743 in the trastuzumab emtansine group and 743 in the trastuzumab group), invasive 
disease or death had occurred in 91 patients in the trastuzumab emtansine group 
(12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage 
of patients who were free of invasive disease at 3 years was 88.3% in the trastuzumab 
emtansine group and 77.0% in the trastuzumab group. Invasive disease-free survival 
was significantly higher in the trastuzumab emtansine group than in the trastuzumab 
group (HR for invasive disease or death was 0.50; 95% CI: 0.390.64; p0.001). Distant 
recurrence as the first invasive-disease event occurred in 10.5% of patients in the 
trastuzumab emtansine group and 15.9% of those in the trastuzumab group. The safety 
data were consistent with the known safety profile of trastuzumab emtansine, with more 
adverse events associated with trastuzumab emtansine than with trastuzumab alone.
As of December 2019, based on the results of the KATHERINE study, trastuzumab 
emtansine (Kadcyla) was approved in the U.S. and has received recommendation for 
approval in the E.U. from the Committee for Medicinal Products for Human Use for the 
adjuvant treatment of patients with HER2-positive EBC who have residual invasive 
disease after neoadjuvant taxane and trastuzumab-based treatment.
1.4
BACKGROUND ON VENETOCLAX
Venetoclax (also referred to as GDC-0199, RO5537382, ABT-199, A-1195425.0, 
Venclexta, and Venclyxto) is an orally bioavailable, selective small-molecule inhibitor 
of Bcl-2 in the biaryl acylsulfonamide chemical class. Venetoclax binds with high affinity 
(Ki0.01 nM) to the anti-apoptotic protein Bcl-2 and with lower affinity to other anti-
apoptotic Bcl-2 family proteins such as Bcl-XL and Bcl-w (4,000-fold and 2,000- to 
20,000-fold lower affinity than to Bcl-2, respectively; Souers et al. 2013). Survival of 
platelets depends on Bcl-XL, and thrombocytopenia is therefore a major dose-limiting 
toxicity (DLT) caused by inhibition of BCL-XL in the clinic. Venetoclax has an improved 


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therapeutic index by maintaining efficacy against tumor cells while avoiding dose-limiting 
thrombocytopenia.
Venetoclax has been extensively studied in oncology, particularly in hematologic
malignancies but also in some solid tumors. Efficacy data indicate that venetoclax, both 
as a monotherapy and in combination with other therapeutic agents, shows promising 
safety, tolerability, pharmacokinetics, and efficacy. This includes combinations with 
rituximab; obinutuzumab; bendamustine plus rituximab; O6-benzylguanine; rituxan plus 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); obinutuzumab 
plus CHOP (G-CHOP); bortezomib plus dexamethasone, azacitidine, or decitabine; and 
cytarabine in patients with hematologic malignancies, including CLL/SLL, NHL, MM, 
myelodysplastic syndrome, and AML. 
In the United States, venetoclax (Venclexta) is indicated for the treatment of adult 
patients with CLL or SLL. In addition, it is approved in combination with azacitidine or 
decitabine or low-dose cytarabine (LDAC) for the treatment of adults with newly
diagnosed AML who are age 75 years or older or who have comorbidities that preclude 
use of intensive induction chemotherapy. The AML indication is approved under 
accelerated approval based on response rates. Continued approval for this indication 
may be contingent upon verification and description of clinical benefit in confirmatory 
trials.
In the European Union, venetoclax (Venclyxto) in combination with rituximab is 
indicated for the treatment of adult patients with CLL who have received at least one
prior therapy. Monotherapy is indicated for the treatment of CLL in the presence of 17p 
deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell 
receptor pathway inhibitor, or in the absence of 17p deletion or TP53 mutation in adult 
patients who have failed both chemoimmunotherapy and a B-cell receptor pathway 
inhibitor.
In solid tumors, such as ER-positive, Bcl-2 positive MBC, venetoclax has shown 
promising activity (Lok et al. 2019). In a Phase Ib dose-escalation study, venetoclax 
administered at 200, 400, 600, or 800 mg QD in combination with tamoxifen at 20 mg
QD was shown to be well tolerated.  No DLTs, including Grade 3 toxicity, were
observed in any of the cohorts and the maximum tolerated dose (MTD) was not reached. 
The 800 mg QD dose was selected as the recommended Phase II dose (RP2D).
Efficacy was promising with 54% ORR and a clinical benefit rate (CBR) of 75% for the 
800 mg QD cohort, comparing favorably with historical studies of patients treated with 
tamoxifen in the first-line relapse setting (e.g., ORR 17%33% and CBR 38%56%).
The combination of venetoclax plus hormonal therapy (fulvestrant) in ER-positive MBC is 
being further evaluated in the ongoing randomized Phase II Study WO40181 
(VERONICA). Study results will be reported in the Venetoclax Investigator’s Brochure(s) 
when available.


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Refer to the Venetoclax Investigator's Brochure(s) for details on nonclinical and clinical 
studies.
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Trastuzumab emtansine is an active regimen and the standard of care in second-line
HER2-positive MBC (Verma et al. 2012). The safety of trastuzumab emtansine is well 
established, having been evaluated in over 2000 patients with BC in clinical studies.  
Trastuzumab emtansine is generally well tolerated, with the most common adverse 
events being nausea, fatigue, and headache.  Adverse events of particular relevance 
include thrombocytopenia, hemorrhage, hepatotoxicity (increases in serum 
transaminases and nodular regenerative hyperplasia [NRH] of the liver), infusion
related-reactions/hypersensitivity, cardiac dysfunction (left ventricular dysfunction), 
peripheral neuropathy, and pulmonary toxicity (interstitial lung disease [ILD].  
Venetoclax has been evaluated in a variety of oncological indications, particularly in 
hematological malignancies, and has been generally well tolerated as a single agent as 
well as in combination with targeted therapies and chemotherapy (refer to the 
Venetoclax Investigator’s Brochure for more details). Adverse events commonly 
observed with venetoclax include nausea, vomiting, diarrhea, and myelotoxicity 
(including anemia, thrombocytopenia, and leukopenia). To date, the majority of these 
adverse events have been manageable without requiring treatment discontinuation. 
Important identified risks for venetoclax include tumor lysis syndrome (TLS), particularly 
in CLL and mantle cell lymphoma, and neutropenia. Serious infection is also an 
identified risk. Of note, cytopenias and TLS are commonly observed in hematologic 
malignances and in some cases independently of treatment, and their prevalence in 
solid tumors remains to be elucidated.
Nonclinical data indicate a potential synergistic mechanism of action between venetoclax 
and trastuzumab emtansine. Microtubule inhibitors, such as taxanes and vinca alkaloids, 
have been described to promote degradation of the anti-apoptotic protein MCL-1 (Wertz 
et al. 2011), which can be a resistance factor for venetoclax monotherapy (Bose et al. 
2017). The mechanism of DM1 inhibition of microtubules is similar to that of vinca
alkaloids and, as such, DM1 also induces degradation of MCL-1 (Genentech 
unpublished data). Direct inhibition of MCL-1 in combination with venetoclax has been 
shown to be synergistic nonclinically across various hematologic and solid tumor
malignancies (Phillips et al. 2015; Li et al. 2019; Moujalled et al. 2019). These
nonclinical data support the investigation of venetoclax with combination partners that 
inhibit MCL-1, either directly or indirectly, and provide scientific rationale to test the 
combination of trastuzumab emtansine (via MCL-1 degradation) and venetoclax. 
Further, Bcl-2 upregulation has been associated with resistance to trastuzumab 
emtansine in various BC cell lines (unpublished data; Saatci et al. 2018).  Combining
venetoclax with trastuzumab emtansine was shown to enhance apoptosis in vitro
compared to single agent treatments in these trastuzumab emtansineresistant cell lines 


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(Genentech unpublished data). The combination of trastuzumab emtansine and 
venetoclax has been tested in vivo in trastuzumab emtansine naive and resistant models,
and the results of the data are summarized as follows (Genentech unpublished data):

In the MDA-MB-361 HER2-positive trastuzumab emtansine naiveBC xenografts 
grown orthotopically in NOD-SCID mice, trastuzumab emtansine administered 
intravenously once in combination with venetoclax administered PO QD for 21 days 
demonstrated enhanced tumor growth inhibition (TGI) compared to trastuzumab 
emtansine or venetoclax monotherapy. TGI on Day 21 of the dosing period was 38% 
for trastuzumab emtansine, 34% for venetoclax, and 70% for the combination of 
trastuzumab emtansine and venetoclax.  

KPL-4 trastuzumab emtansineresistant cell line clones were generated to be 
trastuzumab emtansine resistant in vitro through long-term drug treatment. KPL-4 
clones 8 and 17 demonstrated upregulation of Bcl-2 protein at resistance. The 
combination of trastuzumab emtansine and venetoclax showed enhanced 
anti-tumor efficacy for both clones when grown orthotopically as xenografts in NOD-
SCID mice. Trastuzumab emtansine was administered once intravenously and 
venetoclax was administered PO QD for 21 days. For KPL-4 clone 17, TGI on 
Day 21 of the dosing period was 27% for trastuzumab emtansine, 3% for venetoclax,
and 74% for the combination of trastuzumab emtansine and venetoclax. For KPL-4 
clone 8, TGI 2 days after end of treatment (Study Day 23) was 93% for trastuzumab 
emtansine, 8% for venetoclax, and 143% for the combination of trastuzumab 
emtansine and venetoclax.
Importantly, in vivo assessment of altering venetoclax schedules dosed for either 10 or 
21 consecutive days has demonstrated equivalent anti-tumor efficacy when 
administered in combination with trastuzumab emtansine (Genentech unpublished data). 
Furthermore, a shorter schedule of venetoclax dosing (5 continuous days) was also 
shown to improve responses in combination with trastuzumab emtansine in 
HER2-positive BC PDX models that are sensitive as well as resistant to trastuzumab 
emtansine (unpublished data). In separate studies using additional HER2-positive PDX 
models, inhibition of Bcl-2 and Bcl-XL with navitoclax (ABT-263) significantly enhanced 
cytotoxicity of trastuzumab emtansine (Zoeller et al. 2019). The nonclinical data cited 
herein provide rationale for testing continuous and non-continuous schedules of 
venetoclax in combination with trastuzumab emtansine. Therefore, this study will offer 
an opportunity to evaluate the safety and activity of a promising novel approach 
combining venetoclax and trastuzumab emtansine for the treatment of HER2-positive 
MBC in the clinical setting.
The safety and tolerability of the combination of trastuzumab emtansine and venetoclax 
is currently unknown and will be evaluated in the Phase Ib portion of this study. 
Although the combination is expected to have limited overlapping toxicities, there 
remains the potential for unknown toxicities. Key overlapping toxicities for the 
combination include hematologic toxicities, such as neutropenia, febrile neutropenia, 
thrombocytopenia, and gastrointestinal toxicities (e.g., nausea, vomiting, diarrhea).


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To minimize this risk, stringent inclusion and exclusion criteria (Sections 4.1.1 and 4.2.2) 
and close safety monitoring (Section 5.1), together with rules for dose modifications and 
safety management guidelines for known risks of single-agent trastuzumab emtansine 
and venetoclax, have been implemented in the current study.  Furthermore, guidance on 
management of potential overlapping toxicities is described in Section 5.1.3.3.  
Specifically, during the Phase Ib portion of this study, safety review will be led by the 
Medical Monitor in consultation with the study investigators and a committee composed 
at a minimum of the following Sponsor representatives: statistician, safety scientist, PK 
scientist, and clinical scientist. During the randomized Phase II stage of the study, an 
Internal Monitoring Committee (IMC; Section 3.1.4) has also been incorporated into the 
trial design to periodically review aggregate efficacy and safety data (refer to the IMC 
charter for a detailed monitoring plan). 
HER2-positive MBC remains an incurable disease despite advances in patient care.  
Nearly all patients with HER2-positive MBC will eventually suffer disease progression 
and succumb to their disease. There continues to be a need for more efficacious 
therapies with acceptable safety profiles in patients with HER2-positive disease. 
Therefore, the addition of venetoclax based on its pro-apoptotic mechanism of action 
and potential to overcome resistance to trastuzumab emtansine, as well as a
manageable safety profile, can represent a potential valuable treatment option and offers
a favorable benefitrisk balance for patients in this study.
2.
OBJECTIVES AND ENDPOINTS
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-
controlled, double-blind, multicenter stage (hereafter referred to as the “randomized 
Phase II stage”). 
The dose-escalation phase will assess safety and tolerability, determine the MTD and 
the RP2D, and evaluate preliminary efficacy of trastuzumab emtansine in combination 
with venetoclax in patients with previously treated HER2-positive LABC or MBC, 
irrespective of patients' prior trastuzumab emtansine exposure in the metastatic setting.  
After the RP2D is established, additional patients may be enrolled in the expansion 
phase to evaluate the safety, tolerability, and efficacy of trastuzumab emtansine in 
combination with venetoclax at the RP2D in patients with previously treated HER2-
positive LABC or MBC who have previously received either trastuzumab emtansine or 
trastuzumab deruxtecan (DS-8201a). The decision to open these cohorts will be data-
driven and dependent on the observations made in the dose-escalation phase, as well 
as emerging data about trastuzumab deruxtecan and other HER2-targeted therapies.
Importantly, the expansion phase may run concurrent to and in parallel with the 
randomized Phase II stage of the study. 


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The randomized Phase II stage will aim to evaluate the safety, tolerability, 
pharmacokinetics, and efficacy of trastuzumab emtansine in combination with 
venetoclax at the RP2D compared with trastuzumab emtansine plus placebo in patients 
with previously treated HER2-positive LABC or MBC who have not received prior 
trastuzumab emtansine therapy, either alone or in combination with other anticancer 
therapies.
Specific objectives and corresponding endpoints for the study are outlined below.
2.1
OBJECTIVES AND ENDPOINTS FOR DOSE-ESCALATION 
PHASE
2.1.1
Primary Safety Objective
The safety objective for the dose-escalation phase is to evaluate the safety and 
tolerability of trastuzumab emtansine in combination with venetoclaxincluding 
estimation of the MTD, determination of the RP2D, and characterization of DLTs (see 
Section 3.1.1.1)on the basis of the following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
2.1.2
Exploratory Efficacy Objective
The exploratory efficacy objective for the dose-escalation phase is to make a preliminary 
assessment of the anti-tumor activity of trastuzumab emtansine and venetoclax on the 
basis of the following endpoints:

ORR, defined as the proportion of patients with CR or PR on two consecutive 
assessments, at least 28 days apart, as determined by investigator assessment 
using RECIST v1.1 (see Appendix 11)

DOR, defined as the time from the first occurrence of a documented objective 
response to disease progression as determined by the investigator using RECIST 
v1.1, or death from any cause, whichever occurs first
2.1.3
Pharmacokinetic Objective
The PK objective for the dose-escalation phase of this study is to characterize the 
pharmacokinetics of venetoclax when given in combination with trastuzumab emtansine 
on the basis of the following endpoint:

Plasma concentrations of venetoclax at specified timepoints


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2.1.4
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or 
evaluate biomarkers that are predictive of response to venetoclax in combination with 
trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to trastuzumab emtansine and venetoclax, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of venetoclax and/or trastuzumab emtansine activity (i.e., pharmacodynamic [PD] 
biomarkers), or can increase the knowledge and understanding of disease biology and 
drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab 
emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue (see 
Section 4.5.7) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
2.2
OBJECTIVES AND ENDPOINTS FOR EXPANSION PHASE
2.2.1
Primary Efficacy Objective
The primary efficacy objective for the expansion phase is to evaluate the efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoint:

ORR
2.2.2
Secondary Efficacy Objective
The secondary efficacy objective for the expansion phase is to evaluate the efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoint:

DOR
2.2.3
Safety Objective
The safety objective for the expansion phase is to evaluate the safety and tolerability of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to NCI CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results


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2.2.4
Pharmacokinetic Objective
The PK objective for the expansion phase of the study is to characterize the 
pharmacokinetics of venetoclax when given in combination with trastuzumab emtansine 
on the basis of the following endpoint:

Plasma concentrations of venetoclax at specified timepoints
2.2.5
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or 
evaluate biomarkers that are predictive of response to venetoclax in combination with 
trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to trastuzumab emtansine and venetoclax, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of venetoclax and/or trastuzumab emtansine activity (i.e., PD biomarkers), or can 
increase the knowledge and understanding of disease biology and drug safety, on the 
basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab 
emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue (see 
Section 4.5.7) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
2.3
OBJECTIVES AND ENDPOINTS FOR RANDOMIZED PHASE II 
STAGE
2.3.1
Primary Efficacy Objective
The primary efficacy objective for the randomized Phase II stage is to evaluate the 
efficacy of trastuzumab emtansine in combination with venetoclax compared with 
trastuzumab emtansine plus placebo on the basis of the following co-primary endpoints:

ORR

PFS after randomization, 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
2.3.2
Secondary Efficacy Objective
The secondary efficacy objective for the randomized Phase II stage is to evaluate the 
efficacy of trastuzumab emtansine in combination with venetoclax compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoints:

DOR


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
OS after randomization, defined as the time from randomization to death from any 
cause
2.3.3
Exploratory Efficacy Objective 
The exploratory efficacy objective for the randomized Phase II stage is to evaluate the 
efficacy of trastuzumab emtansine in combination with venetoclax compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoints:

CBR, defined as the proportion of patients with CR, PR, or stable disease (SD) at 
6 months after randomization, as determined by the investigator according to
RECIST v1.1
2.3.4
Safety Objective
The safety objective for the randomized Phase II stage is to evaluate safety of 
trastuzumab emtansine in combination with venetoclax compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoints:

Incidence and severity of adverse events with severity determined according to NCI 
CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
2.3.5
Pharmacokinetic Objective
The PK objective for the randomized Phase II stage of this study is to characterize the 
pharmacokinetics of trastuzumab emtansine and venetoclax when given in combination 
on the basis of the following endpoints:

Serum concentrations of trastuzumab emtansine at specified timepoints

Plasma concentrations of venetoclax at specified timepoints
2.3.6
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to
trastuzumab emtansine when given with placebo or in combination with venetoclax on 
the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during 
the study
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints


 
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2.3.7 
Biomarker Objective 
The exploratory biomarker objective for all phases in this study is to identify and/or 
evaluate biomarkers that are predictive of response to venetoclax in combination with 
trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to trastuzumab emtansine and venetoclax, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of venetoclax and/or trastuzumab emtansine activity (i.e., PD biomarkers), or can 
increase the knowledge and understanding of disease biology and drug safety, on the 
basis of the following endpoints: 
• 
Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab 
emtansine 
• 
The relationship between biomarkers in blood, plasma, and tumor tissue (see 
Section 4.5.7) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints 
 
2.3.8 
Health Status Utility Objective 
The exploratory health status utility objective for the randomized Phase II stage is to 
evaluate health status utility scores of patients treated with trastuzumab emtansine in 
combination with venetoclax compared with trastuzumab emtansine plus placebo on the 
basis of the following endpoint: 
• 
Change from baseline in patient-reported symptoms and their impact on functioning 
and health-related quality of life as measured by the European Organisation for 
Research and Treatment of Cancer Quality of Life Core 30 Questionnaire (EORTC 
QLQ-C30) and EORTC Item List 46 (EORTC IL46) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-
controlled, double-blind, multicenter stage (hereafter referred to as the “randomized 
Phase II stage”).  The expansion phase may run concurrent to and parallel with the 
randomized Phase II stage. 
Approximately 226−284 patients will be enrolled in this study across approximately 
145 sites globally.  The study will enroll 6−24 patients in the Phase Ib dose-escalation 
phase and approximately 220 patients in the Phase II stage.  An additional 
approximately 20−40 patients may be enrolled in the Phase Ib expansion cohorts. 


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Figure 1
Overall Study Schema
2Lsecond line; 3Lthird line; MBCmetastatic breast cancer; MTDmaximum tolerated dose; Q3W every 3 weeks; QDonce a day; 
RP2Drecommended Phase II dose.


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3.1.1
Dose-Escalation Phase
The dose-escalation phase will determine the RP2D and MTD for venetoclax when given 
in combination with a fixed dose of trastuzumab emtansine (3.6 mg/kg) in patients with 
previously treated, HER2-positive LABC or MBC, irrespective of prior trastuzumab 
emtansine exposure in the metastatic setting. 
The dose-escalation phase will enroll 624 patients and will include 24 cohorts:

Cohort 1A, 400 mg QD Cohort:  Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax
400 mg PO once a day (QD) continuous on Days 121 of each cycle. 

Cohort 1B, 400 mg NC Cohort:  Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 
400 mg PO QD non-continuous on either Days 17 or 114 of each cycle (see 
further description below). 

Cohort 2A, 800 mg QD Cohort: Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 
800 mg PO QD continuous on Days 121 of each cycle.

Cohort 2B, 800 mg NC Cohort:  Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax
800 mg PO QD non-continuous on either Days 17 or 114 of each cycle. 
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator's discretion.  Patients are not required to re-sign the consent form if they 
are re-screened within 30 days after previously signing the consent form. The 
investigator will record reasons for screen failure within the interactive voice or 
web-based response system (IxRS) and electronic Case Report Form (eCRF [see
Section 4.5.1]).
Figure 2 presents an overview of the dose-escalation phase design.  A schedule of 
activities for dose-escalation and expansion phases are provided in Appendix 1 and
Appendix 2, respectively.


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Figure 2
Phase Ib Dose-Escalation Study Schema
DLT dose-limiting toxicity; MTDmaximum tolerated dose; NCnon-continuous; QDonce a day; RP2Drecommended Phase II dose.


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The 400-mg and 800-mg cohorts for dose escalation will be run sequentially (i.e., the 
400-mg cohort followed by the 800-mg cohort). Dose escalation will be performed 
based on a standard 3 3 design. Each cohort will consist of at least 3 patients, unless 
1 of the 3 patients experiences DLTs (refer to Section 3.1.1.1 for DLT criteria), in which
case 3 additional patients will be treated at the same dose level. The dose escalation 
will continue until 2 patients among a cohort of 6 patients experience a DLT (i.e., 33% 
of patients with a DLT at that dose level; refer to dose-escalation rules below). Patients 
who experience a DLT will continue at the same dose level.
Dose de-escalation may be explored by incorporating non-continuous (NC) dosing of 
venetoclax (e.g., less than 21 days of dosing, such as 7 days out of 21 days or 14 days 
out of 21 days) dependent on the severity and timing of DLTs as well as the specific 
adverse events encountered. For example, if DLTs such as a Grade 3 rash occurred
between Day 8 and Day 14, an NC schedule of Days 17 would be tested.  Alternatively, 
if DLTs are thought to be possibly mitigated by a 7-day break such as Grade 3 fatigue 
occurring near the end of the DLT window (e.g., Day 20), then an NC schedule of 
Days 114 could be chosen to be tested. Patients may be treated in up to two NC sub-
cohorts (i.e., either 400 mg NC and/or 800 mg NC; refer to Figure 2). At each dose de-
escalation level, either a Days 17 or Days 114 NC treatment schedule will be 
assessed.
3.1.1.1
Definition of Dose-Limiting Toxicity
Patients will be closely monitored for adverse events during the 21-day DLT assessment 
window. All adverse events, including DLTs, will be graded according to the NCI 
CTCAE v5.0 (Appendix 12) unless otherwise indicated.  If a patient experiences a DLT, 
the patient will be treated according to clinical practice and will be monitored for 
resolution of the toxicity.
For dose-escalation purposes, a DLT will be defined as any one of the following events 
regardless of relationship to study treatment (unless otherwise specified below) 
occurring during the 21-day DLT assessment period, which runs from Days 121 of
Cycle 1:

Grade 4 neutropenia (ANC 500/mm3) lasting >7 days

Grade 4 thrombocytopenia (platelet count 25,000/mm3) or Grade 3 
thrombocytopenia associated with severe bleeding

Grade 4 anemia

Grade 3 febrile neutropenia for 7 days or Grade 4 febrile neutropenia of any 
duration

Treatment related Grade 3 non-hematologic, non-hepatic, and non-cardiac major 
organ toxicity lasting for 72 hours

Grade 3 serum bilirubin, hepatic transaminase (ALT or AST), or ALP lasting for 
72 hours


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For patients with Grade 2 hepatic transaminase or ALP levels at baseline as a 
result of liver metastases or bone metastases, a hepatic transaminase or ALP
level 10 times the upper limit of normal (ULN) will be considered a DLT. For 
patients with abnormal TBILI at baseline an increase of 3.010.0 times baseline 
value will be considered a DLT.

Grade 3 cardiac toxicity (resting ejection fraction [EF] 39%20%; 20% drop from 
baseline; symptomatic heart failure)

Treatment-related death
Adverse events meeting the criteria for DLT within the 21-day assessment period must 
be reported to the Sponsor within 24 hours. 
3.1.1.2
Dose-Escalation Rules, Determination of 
Dose-Limiting Toxicities, and Recommended Phase II Dose
Dose escalation will occur in accordance with the rules listed below:

A minimum of 3 DLT-evaluable patients will initially be enrolled into each cohort.

If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
next cohort at the next dose level may proceed.

If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be 
expanded to 6 patients. If there are no further DLTs in the first 6 DLT-evaluable 
patients, enrollment of the next cohort at the next dose level may proceed.

If 2 or more of the first 6 DLT-evaluable patients in the continuous (QD) dose-
escalation cohorts experience a DLT, an additional 3 patients will be evaluated for 
DLTs at the corresponding NC dose level. If none of the first 3 DLT-evaluable 
patients experiences a DLT, enrollment of the next NC dose level may proceed.

If 1 of the first 3 DLT-evaluable patients experiences a DLT, the NC dose level 
cohort will be expanded to 6 patients. If there are no further DLTs in the first 6 DLT-
evaluable patients, enrollment of the next cohort at the next dose level may proceed.

If 2 or more of the first 6 DLT-evaluable patients in the NC dose-escalation cohort 
experience a DLT, the MTD will have been exceeded and dose escalation will stop. 

If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of
6 DLT-evaluable patients (i.e., 33%) experience a DLT will be declared the MTD.

If the MTD is not exceeded at any dose level, the highest dose administered in this
study will be declared the MTD.
Determination of whether a patient is evaluable for DLT assessment will be made in 
accordance with the following rules:

Patients who receive study treatment (e.g., at least 66% of planned venetoclax 
doses and 1 dose of trastuzumab emtansine) and remain in the study through the 
DLT assessment window will be considered DLT evaluable.


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
Patients who discontinue from treatment with trastuzumab emtansine or venetoclax
treatment prior to completing the DLT assessment window for reasons other than a 
DLT will be considered non-evaluable for dose-escalation decisions and MTD 
determination and will be replaced by an additional patient at that same dose level.

Patients who do not receive at least 66% of planned venetoclax doses (e.g., 14 out 
of 21 days for continuous [QD] dosing, 10 out of 14 days for Days 114 NC, or 5 out 
of 7 days for Days 17 NC) or 1 dose of trastuzumab emtansine during the DLT 
assessment period will be replaced, to ensure that at least 3 patients in each cohort 
have been assessed for the full DLT assessment period of 21 days prior to moving 
to the next dose level.
Patients exhibiting acceptable safety and evidence of clinical benefit (as determined by 
the investigator) may continue to receive study treatment until confirmed objective 
disease progression or unacceptable toxicity, whichever occurs first.
The Sponsor will review cumulative safety data and make recommendations regarding 
dose escalation and overall study conduct on the basis of study safety data to ensure 
patient safety while receiving study treatment. These include recommendations to open 
or suspend patient enrollment in a given dose-escalation cohort based on the overall 
benefitrisk profile of trastuzumab emtansine in combination with venetoclax.
Relevant demographic, adverse event, laboratory, dose administration, and PK data (if 
available) will be reviewed prior to the selection of the RP2D for the expansion and 
randomized phases of the study. The RP2D for both the expansion and randomized 
phases will be the same dose and schedule. The RP2D will be based on the MTD of 
venetoclax when combined with a fixed dose of trastuzumab emtansine and will 
integrate aggregate safety data during treatment. Decision making will be led by the 
Medical Monitor in consultation with the study investigators and a committee composed 
at a minimum of the following Sponsor representatives: statistician, safety scientist, PK 
scientist, and clinical scientist. For example, based upon nonclinical data showing 
similar efficacy of NC versus continuous dosing, as well as the mechanism of action of 
combining venetoclax with a cytotoxic agent such as trastuzumab emtansine, NC dosing 
of 800 mg for 17 days or 114 days would be preferred over 400 mg QD.  Aggregate 
clinical data would be integrated into the decision making, including safety and efficacy 
data.  
3.1.2
Expansion Phase
An expansion phase may be initiated to evaluate the safety, tolerability, and efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine in previously treated 
HER2-positive locally advanced or MBC patients who have received prior trastuzumab 
emtansine or trastuzumab deruxtecan (DS-8201a). 
The decision to open cohorts as part of an expansion phase will be data-driven and 
dependent on the observations made in the dose-escalation phase, emerging data with 


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trastuzumab deruxtecan, as well as other HER2-targeted therapies. The expansion 
phase may run concurrent to and in parallel with the randomized Phase II stage of the 
study.
Approximately 20 patients may be enrolled in each of the expansion cohorts (see
Figure 3).
Figure 3
Phase Ib Expansion Cohorts Study Schema
Bcl-2 B-cell lymphoma 2; DORduration of response; IHC immunohistochemistry; 
INV investigator; MBC metastatic breast cancer; ORR objective response rate; OSoverall 
survival; PFSprogression-free survival; Q3W every 3 weeks; RECIST v1.1 Response 
Evaluation Criteria in Solid Tumors, Version 1.1; RP2D recommended Phase II dose.
a Prior exposure to other HER2-targeted therapies (e.g., trastuzumab, pertuzumab, trastuzumab 
deruxtecan, margetuximab, pyrotinib, tucatinib and/or neratinib) is permitted. 
b Eligibility for this cohort requires prior experience with trastuzumab deruxtecan (DS-8201a) in
any setting. 
3.1.3
Randomized Phase II Stage
The randomized Phase II stage will be initiated once the RP2D has been identified 
based on the cumulative data collected from the dose-escalation phase.  It will consist of 
two interventional arms of trastuzumab emtansine plus placebo or trastuzumab 
emtansine plus venetoclax in patients with previously treated HER2-positive LABC or 
MBC, who have not received prior trastuzumab emtansine therapy.
Approximately 220 patients will be randomized 1:1 to one of the following treatment 
arms:  

Control Arm: Patients will receive trastuzumab emtansine 3.6 mg/kg by IV infusion 
Q3W plus placebo at the RP2D and schedule of venetoclax.


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
Experimental Arm: Patients will receive trastuzumab emtansine 3.6 mg/kg by IV 
infusion Q3W plus venetoclax at the RP2D and schedule.
Each arm will include at least 50% Bcl-2 high patients, and randomization will be based 
on the three stratification factors shown in Figure 4 (see also Section 4.2.1). Crossover 
between treatment arms will not be permitted. A schedule of activities for the 
randomized phase is provided in Appendix 2.


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Figure 4
Phase II Randomized Study Schema
2Lsecond line; Bcl-2 B-cell lymphoma 2; DOR duration of response; IHC immunohistochemistry; INVinvestigator; Nno; ORR objective
response rate; OS overall survival; PFS progression-free survival; Q3W every 3 weeks; RECIST v1.1 Response Evaluation Criteria in Solid 
Tumors, Version 1.1; Rrandomization; RP2D recommended Phase II dose; Yyes.


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3.1.4
Internal Monitoring Committee for the Randomized Phase II 
Stage
An IMC will be established to monitor patient safety as well as efficacy in the randomized 
Phase II stage of the study. The IMC will not be blinded, will help monitor safety of 
enrolled patients, and will conduct periodic interim reviews of safety data during the 
randomized Phase II stage of the study. The frequency of the reviews will be 
determined as needed. The IMC will be external to the study team and will be 
composed of at least one medical doctor and/or clinical science representative, with
representatives from clinical safety, biostatistics, as well as statistical programming and 
analysis, who are not directly involved in the study. A separate IMC charter will outline 
the committee's composition, meeting timelines, and members' roles and responsibilities. 
The committee members will review all potential cases of serious adverse events, Grade 
3 and 4 adverse events, adverse events of special interest, and deaths as specified in 
the IMC charter. The IMC will be apprised of all relevant efficacy and safety data from 
this study and other related clinical trials. Ad hoc meetings may be called as necessary 
in addition to scheduled meetings to provide recommendations on management of any 
new safety issues. The Sponsor will be the final decision maker regarding protocol 
procedures and modifications.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  The end of study is planned to 
occur approximately 24 months after last patient in (LPI).  
In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 48 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Venetoclax Dose Selection in the Phase Ib Dose-
Escalation Phase of the Study
Venetoclax has been investigated and shown to be well tolerated in multiple trials of 
hematopoietic malignancies at doses ranging from 200 mg to 1200 mg, both as a 
monotherapy and in combination with other agents including dexamethasone, rituximab, 
obinutuzumab, bortezomib, and chemotherapy. Venetoclax is approved in the U.S. and 
E.U. for the treatment of adult patients with CLL (or SLL in the U.S.), with or without 17p 
deletion, who have received at least one prior therapy. The recommended dose of 
venetoclax monotherapy in this setting is 400 mg QD in a ramp-up schedule (Venclexta
U.S. Package Insert) and this dosing is maintained during administration with rituximab.
Venetoclax is also approved in combination with azacitidine or decitabine or low-dose 
cytarabine for the treatment of newly-diagnosed AML, with 400 mg QD dosing when in 


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combination with azacitidine or decitabine and 600 mg QD dosing when in combination 
with LDAC in the U.S. 
A Phase I dose-escalation trial investigating combinations of various doses of venetoclax 
(including 200 mg, 400 mg, 600 mg, and 800 mg) with tamoxifen assessed the safety 
and tolerability of venetoclax in combination with that ER modulator in patients with ER,
Bcl-2MBC (Lok et al. 2019).  Venetoclax at the dose of 800 mg PO QD in combination 
with tamoxifen was well tolerated. The nature and frequencies of adverse events were 
consistent with the known safety profiles of venetoclax and tamoxifen, and no Grade 5 
adverse events or DLTs occurred during the DLT observation period, based on the 
preliminary evidence of clinically relevant activity of venetoclax during the dose-
escalation phase. Venetoclax dosing is further informed by the ongoing randomized 
Phase II VERONICA study (WO40181) evaluating venetoclax at 800 mg QD plus 
fulvestrant in patients with HR-positive MBC.
Based on the experience in hematologic malignancies as well as ERBC, and the 
expected limited overlapping toxicities and potential for drugdrug interactions (DDI) 
between venetoclax and trastuzumab emtansine (see Section 3.3.11), two dose levels 
have been selected for the dose-escalation phase of the study. This is based on 
population PK and saturation modeling to assess dose dependency of venetoclax 
exposure with the assumption that CLL/DLBCL modeling can adequately predict solid 
tumors. This modeling has shown limited value of studying a 600 mg dose of venetoclax 
as an intermediate step in a 400 mg to 800 mg dose escalation (internal Genentech 
data). Moreover, the toxicities are considered to be monitorable and manageable, and 
enabling a starting dose of 400 mg continuous QD and moving up to the second dose 
level of 800 mg continuous QD (refer to Section 3.1.1).  
Patients with solid tumors may require a higher dose of venetoclax when compared with 
the 400 mg QD dose in hematologic malignancies such as CLL. This is reflected in the 
lower 50% effective concentration values of venetoclax for circulating lymphocyte counts 
(0.00863 g/mL) compared with tumor size (0.146 g/mL; Freise et al. 2017). Possible 
explanations for this observation include reduced blood flow and subsequent less 
efficient delivery of systemic venetoclax within a tumor, and altered signaling interactions 
between lymphoma cells and the cells of the tumor microenvironment. Therefore, a 
second dose level of 800 mg continuous QD is being evaluated, allowing for increased 
exposure of venetoclax in the tumor compartment.
3.3.2
Rationale for Venetoclax Dose Selection in the Phase II
Randomized Portion of the Study
The dose-escalation phase will provide further information on the venetoclax dose that is 
considered safe and tolerable to be combined with trastuzumab emtansine. The 
venetoclax RP2D and MTD for the combination with trastuzumab emtansine, which will 
be the same for both the expansion and randomized phases, will be determined based 
on the dose-escalation phase of the study (see Section 3.1.1). The RP2D may be lower 


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than the MTD, dependent on the evaluation of the cumulative and aggregated data from
the dose-escalation phase of the study. An IMC will conduct periodic reviews of safety 
data for all patients treated in the randomized Phase II stage of the study in order to 
confirm the safety and tolerability of the combination therapy at the RP2D (see 
Section 3.1.4). 
3.3.3
Rationale for Trastuzumab Emtansine Dose and Schedule
The globally approved and standard-of-care regimen of trastuzumab emtansine is 
3.6 mg/kg Q3W, as confirmed in Study TDM4370g/BO21977 (Verma et al. 2012), the 
pivotal Phase III trial comparing trastuzumab emtansine to lapatinib plus capecitabine in 
patients with HER2MBC who were previously treated with trastuzumab and a taxane.  
3.3.4
Rationale for Dose-Finding Rules
The rules for dose escalation are designed to ensure patient safety while providing an 
opportunity to identify the optimal venetoclax dose and schedule in combination with 
trastuzumab emtansine to maximize the benefitrisk profile of the combination. Key 
elements of dose escalation based on a standard 33 design are described in 
Section 3.1 and depicted in Figure 2.
Rules based on the nature and timing of observed safety events have been implemented.
3.3.5
Rationale for Dosing Schedule
Given the anticipated limited overlapping toxicities between venetoclax and trastuzumab 
emtansine (Section 5), continuous dosing of venetoclax on a 21-day cycle based on the 
trastuzumab emtansine infusion schedule is being evaluated initially. NC 7- or 14-day 
schedules may be evaluated based on the severity and timing of occurrence of adverse 
events experienced.
3.3.6
Rationale for Patient Population
Clinical benefit with trastuzumab emtansine has been demonstrated in a randomized 
study to improve PFS and OS compared to lapatinib pluscapecitabine, for patients with 
HER2-positive MBC who have received prior trastuzumab or taxane (Verma et al. 2012).  
Trastuzumab emtansine is the standard of care in this population; however, the PFS of 
approximately 8.6 months and OS of approximately 30 months for this patient population 
represent a continued unmet medical need.  Despite advances in care for patients with 
HER2-positive MBC, it remains an incurable disease.  Nearly all patients with 
HER2-positive MBC will eventually suffer disease progression and succumb to their 
disease. Thus, there is still a pressing need for more efficacious therapies with 
acceptable safety profiles in patients with HER2-positive disease. 
3.3.7
Rationale for Control Group
This control arm treatment is recognized as the recommended standard of care for 
HER2-positive MBC based on the results from Study TDM4370g/BO21977 (see 


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Section 1.2) (Verma et al. 2012). Trastuzumab emtansine has become widely accepted 
as the standard of care in patients who have been previously exposed to trastuzumab 
alone or trastuzumab and a taxane, which is the patient population being studied in the 
current trial (Cardoso et al. 2018; NCCN 2019). The control arm data will be used to 
ascertain the individual contribution of venetoclax to efficacy with trastuzumab 
emtansine. 
3.3.8
Rationale for Randomization and Blinding
Randomization will minimize differences between treatment groups at the outset of the 
trial and blinding will help prevent differential treatment of the groups later in the trial or 
the differential assessment of outcomes. Both randomization and blinding will mitigate 
bias and will aid to minimize the likelihood of differential treatment or assessments of 
outcomes.
3.3.9
Rationale for Objective Response Rate and Progression-Free 
Survival as Co-Primary Endpoints for the Randomized Phase II 
Stage
Investigator-assessed ORR by RECIST v1.1 and PFS are the co-primary endpoints for 
this study.
ORR (as defined in Section 2.1.1) is an increasingly important endpoint for accelerated 
development of highly active anticancer therapies.  Investigator-assessed ORR by 
RECIST v1.1 has been shown to be a meaningful trial endpoint correlating well with PFS 
and OS endpoints (Oxnard et al. 2016). In this patient population, ORR has been used 
as an early signal of clinical benefit (Verma et al. 2012, Tamura et al. 2019). Therefore,
for this study ORR will be used alongside PFS as a measure of the individual 
contribution of venetoclax to efficacy with trastuzumab emtansine. The clinical 
significance of the ORR will be assessed by the magnitude and duration of response.
PFS is the standard and accepted endpoint reflecting clinical benefit in HER2-positive 
MBC. PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; additionally, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents a
direct clinical benefit or a surrogate for clinical benefit depends upon the magnitude of 
the effect and the benefit-risk of the new treatment compared with available therapies 
(FDA 2007; EMA 2017).   
To ensure the validity of investigator-assessed PFS as the primary endpoint, a number 
of measures have been implemented:  a substantial target magnitude of benefit and 
study assessments that will allow a robust evaluation of benefitrisk. This includes 
conventional criteria using RECIST v1.1 to define radiographic disease progression with 
fixed assessment intervals that are identical in both treatment arms, a robust definition of 
PFS as well as prospectively defined methods to assess, quantify, and analyze PFS, 
including sensitivity analyses.


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3.3.10
Rationale for Pharmacokinetic Assessments
This is the first study for which venetoclax will be given in combination with trastuzumab 
emtansine to patients with MBC.  Accordingly, PK plasma or serum samples will be 
taken to characterize the pharmacokinetics of venetoclax and trastuzumab emtansine 
when given in combination (see Section 4.5.7 for details).  
3.3.11
Rationale for Assessments of DrugDrug Interactions between 
Study Treatments
The potential for venetoclax to affect trastuzumab emtansine pharmacokinetics is 
considered to be low. The antibody component of trastuzumab emtansine is a 
therapeutic protein and therefore is not expected to interact with CYP450 or transporter 
pathways. The potential for DDIs between venetoclax and DM1, the small molecule 
component of trastuzumab emtansine, are also expected to be low based on knowledge 
of the metabolic and transporter pathways for each molecule.  Although venetoclax (a 
P-glycoprotein [P-gp] inhibitor) could potentially affect the pharmacokinetics of DM1 (a 
P-gp substrate) through a transporter-mediated interaction, the potential for a clinically 
meaningful effect is considered to be low, given that the DM1 catabolite of IV 
administered T-DM1 is less likely to be impacted by P-gp inhibition by venetoclax in the 
gut. Additionally, trastuzumab emtansine will be dosed in the linear PK range for this 
study, and co-administration of other anticancer agents with trastuzumab emtansine has
not impacted trastuzumab emtansine pharmacokinetics (see the Trastuzumab 
Emtansine Investigator’s Brochure).  These results suggest that target-mediated 
clearance does not significantly contribute to the overall systemic clearance of 
trastuzumab emtansine, suggesting a low potential for venetoclax to impact trastuzumab 
emtansine PK.
The risk of a clinically significant PK drug interaction for trastuzumab emtansine to alter 
venetoclax pharmacokinetics is expected to be low on the basis of their metabolic 
pathways. Venetoclax is primarily metabolized by CYP3A in vitro and is a reversible 
inhibitor of CYP2C8 and CYP2C9 in vitro. Trastuzumab emtansine is a biologic 
administered intravenously and is not expected to modulate CYP3A activity and affect 
venetoclax metabolism.
Based on the evidence provided above, limited blood samples will be collected to 
characterize the DDI interactions between venetoclax and trastuzumab emtansine when 
given in combination (see Section 4.5.7 for details).  
3.3.12
Rationale for Biomarker Assessments
BC is a heterogeneous disease, and HER2 and Bcl-2 expression have been shown to 
vary among patients (unpublished data).  All patients may not be equally likely to benefit 
from treatment with venetoclax and trastuzumab emtansine.  Predictive biomarker 
samples (tissue and blood) collected prior to dosing will be assessed in an effort to 
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emtansine. PD biomarkers will be assessed to demonstrate evidence of biologic activity 
of venetoclax and trastuzumab emtansine in patients, to support selection of a 
recommended dose and dosing regimen, and to inform potential revisions to the PK 
sample collection schedule. As these biomarkers may also have prognostic value, their 
potential association with disease progression will also be explored.
Currently, there are limited data about the correlation of response to Bcl-2 inhibition in 
BC and Bcl-2 expression levels. Bcl-2 levels are elevated in ER-positive subgroups 
relative to the other molecular subgroups that comprise BC. Furthermore, nonclinical 
data have demonstrated increased antitumor activity in high Bcl-2 expressing BC cell 
lines (see Section 1.5). Therefore, predictive biomarker samples collected prior to 
dosing will be assessed in an effort to identify those patients with Bcl-2-driven 
pathogenesis who are most likely to respond to venetoclax. The study aims to 
prospectively explore if Bcl-2 expression might have predictive or prognostic value or 
may be associated with disease progression in the studied population.
Fresh tissue acquisition in some patients with MBC may not be feasible; consequently, 
assessment of more easily accessible biomarkers in circulation is of high interest. In 
addition to identification of disease-specific, potentially prognostic, or predictive 
biomarkers in predose, baseline blood specimens, on-treatment collection of blood to 
evaluate circulating tumor DNA (ctDNA) may enable identification of biomarkers 
informing the relationship with established clinical response assessments, the monitoring 
of disease progression, and the identification of markers of resistance.
Tumor tissue samples will be analyzed through use of IHC to assess protein expression, 
and/or RNA sequencing to assess gene expression levels. Both tissue and blood 
samples will be analyzed by next-generation sequencing (NGS) to identify somatic 
alterations that are predictive of response to study drug, are associated with progression, 
are associated with acquired resistance to study drug, or can increase the knowledge 
and understanding of disease biology.
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
3.3.13
Rationale for Stratification and Enrichment by B-Cell 
Lymphoma-2 (Bcl-2) Status
Bcl-2 levels are elevated in ER-positive tumors; however, there are scant clinical data 
demonstrating a pathogenic role for Bcl-2 in HER2-positive BC. Venetoclax specifically 
inhibits Bcl-2 activity and there is potential that Bcl-2 target-expression levels may 


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correlate with activity. The role of Bcl-2 in pathogenesis is confounded by the prognostic 
profile associated with the ER-positive subtype. To distinguish the potential for 
predictive value of Bcl-2 expression levels with targeted Bcl-2 inhibition, patients will be 
1) randomized into venetoclax plus trastuzumab emtansine versus trastuzumab 
emtansine plus placebo arms to distinguish prognostic effects; and 2) stratified into Bcl-2
high and Bcl-2 low populations (as defined in Section 4.1.1.1). 
In nonclinical analyses, elevated Bcl-2 expression levels in NHL cell lines correlate with 
venetoclax activity using this high versus low cutoff. Stratification will ensure that the 
relative populations of Bcl-2 high and low are well balanced between both arms and 
therefore enable evaluation of the correlation between Bcl-2 expression and venetoclax 
activity in BC. In addition, specifying a minimum number of Bcl-2 high tumor patients will 
enable evaluation of Bcl-2 status as a potential predictive biomarker.  Responses will be 
evaluated by comparing the two stratified subgroups.
Since a cutoff for Bcl-2 levels in BC has not been established, retrospective analyses 
may also be performed to evaluate alternative cutoffs.
3.3.14
Rationale for Stratification by Visceral Metastases
The site(s) and degree of metastatic dissemination are among the principal prognostic 
factors for patients with MBC. Patients with visceral metastases to the liver and/or lung 
in HER2-positive MBC have been shown to have poor prognosis (Verma et al. 2012; 
Perez et al. 2017; Emens et al. 2019b). In the KATE2 study (Emens et al. 2019b), 
patients treated with trastuzumab emtansine plus placebo harboring visceral disease as 
compared to patients with no evidence of visceral disease performed worse (median 
PFS 4.3 months vs. NE). Visceral disease was defined as the presence of disease in the 
lung, liver, adrenal gland, central nervous system, pleural cavity or peritoneal cavity. All 
locations that included tumors in the breast, bone, bone marrow, lymph nodes, skin and 
soft tissue were classified as non-visceral disease. Moreover, the proportion of patients 
with visceral involvement is expected to be higher than those with non-visceral disease 
(70.8% vs. 29.2%, respectively) in KATE2, further justifying use of visceral disease as a 
stratification factor. 
3.3.15
Rationale for Stratification by HER2 Expression Status
HER2 overexpression is an important prognostic and predictive biomarker in MBC
(Pauletti et al. 2000). Specifically, in the recent KATE2 study (Emens et al. 2019b) 
evaluating trastuzumab emtansine in combination with atezolizumab or atezolizumab
and placebo, higher HER2 expression (IHC 3+) and lower HER2 expression (IHC 
2+/ISH+) demonstrated different prognosis for trastuzumab emtansine outcome (median 
PFS: 8 months. vs 3.2 months, respectively). The majority of patients were IHC 3+ (74%) 
as compared to IHC 2+ (19%). Given the association with variable prognosis as well as 
differences in prevalence, HER2 expression status by IHC has been selected as a 


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stratification factor in the current study. Patients will be stratified based on HER2 IHC 3+ 
status and responses will be evaluated by comparing these two stratified subgroups.
3.3.16
Rationale for Patient-Reported Outcome Assessments
As MBC is not curable with currently approved and available therapies, the main goals of 
treatment are to prolong survival and maintain or improve quality of life (Cardoso et al. 
2018). Examining and measuring patients’ symptoms and their impact of functioning 
and quality of life is important, particularly to inform how delays in radiographic 
progression and PFS might be associated with delays in clinical progression of 
symptoms and their interference with functioning, including maintenance of low disease 
burden. In addition, patients’ reporting of their experience with treatment burden will 
complement the evaluation of treatment tolerability. 
Symptoms, their impact on functioning and quality of life, and treatment burden will be 
assessed using validated patient reported outcome (PRO) measures. The EORTC 
QLQ-C30 will be administered to patients to assess symptoms and their impacts on 
functioning and quality of life (see Section 4.5.9 and Appendix 6), while the EORTC IL46 
will be administered to assess treatment burden.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 226284 patients with previously treated, HER2-positive LABC or MBC 
will be enrolled on this study.
4.1.1
Inclusion Criteria (All Study Phases)
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form 

Ability to comply with the study protocol, in the investigator's judgment

Histologically or cytologically confirmed invasive MBC or LABC that is incurable, 
unresectable, and previously treated with multimodality therapy:
–
Prior treatment for BC in the adjuvant, unresectable locally advanced, or 
metastatic settings, which must include both a taxane and trastuzumab (alone 
or in combination with another agent) 
–
Progression must have occurred during or after most recent treatment for 
LABC/MBC or within 6 months after completing adjuvant therapy

Measurable disease that is evaluable per RECIST v1.1

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Willing to provide tumor biopsy sample at the time of screening


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A tumor biopsy sample (either archival or fresh) must be collected from all 
patients from either the primary tumor or a metastatic site (preferred and within 
6 months of enrollment, if clinically feasible) for determination of HER2 status 
by central laboratory testing for patient eligibility purposes, for Bcl-2 expression,
and for research on biomarkers. 
The tumor specimen must contain adequate evaluable tumor cells (20% tumor 
cells) to enable Bcl-2, HER2, and other relevant biomarker analysis. Samples 
can be a tissue block (preferred) or at least 20 unstained freshly cut serial 
slides, and should be accompanied by an associated pathology report. If fewer
than 20 slides are available, the Sponsor should be consulted. If a tumor 
sample is not available, a fresh biopsy must be collected. 
The specimen must be a formalin-fixed, paraffin-embedded (FFPE) tumor 
specimen, or another appropriate fixative must be used (notation of the type of 
fixative should be included). Cytological or fine-needle aspiration samples are 
not acceptable.

Local histological or cytological confirmation of ER and/or progesterone receptor
status as defined by using IHC per American Society of Clinical Oncology/College of 
American Pathologists criteria (Hammond et al. 2010)

Percentage of ER and/or progesterone receptor positivity, if available

Willing to provide blood samples at the time of screening, on-study, and at 
progression for exploratory research on biomarkers

HER2-positive BC as defined by an IHC score of 3+ or gene amplified by ISH as 
defined by a ratio of 2.0 for the number of HER2 gene copies to the number of 
chromosome 17 copies
For the expansion phase and randomized Phase II stage: Centrally confirmed 
HER2-positive status prospectively tested by a Sponsor-designated central 
laboratory prior to enrollment.
For the dose-escalation phase: Enrollment can be based upon prospective 
central testing or local IHC or ISH results; however, for local IHC or ISH results, 
the same tissue sample must be sent for central HER2 confirmation and the 
testing platform documented in the eCRF.
Both IHC and ISH assays can be performed; however, unless reflex testing is 
necessary, only one positive result is required for eligibility.
If multiple tumor specimens are submitted, the HER2 IHC score and or ISH 
amplification ratio will first be assessed on the most recently obtained specimen 
for the purpose of determining eligibility. For patients with bilateral BC, HER2 
positivity must be demonstrated in both locations for archival tissue or in a 
metastatic biopsy.
Centrally confirmed HER2 results (either IHC or ISH) from a current or previous 
Sponsor study can be used to determine eligibility for this study. Approval must 
be obtained from the Medical Monitor prior to randomization.


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
Adequate hematologic and end-organ function, as evidenced by the following local 
laboratory results obtained within 7 days prior to the first study treatment (Cycle 1, 
Day 1):
–
Absolute neutrophil count 1500 cells/L (without granulocyte-colony 
stimulating factor support within 7 days prior to Cycle 1, Day 1)
–
Platelet count 100,000/L (without transfusion within 7 days prior to 
Cycle 1, Day 1) 
–
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet 
this criterion.
–
Albumin 2.5 g/dL
–
Total bilirubin 1.5ULN with the following exceptions:
Patients with previously documented Gilbert syndrome who may have
bilirubin 5ULN
Patients with documented liver metastases may have bilirubin 
2.5ULN
–
AST, ALT, and ALP 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases may have ALP 
5ULN
–
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min on the 
basis of either 24-hour urine collection or the Cockroft-Gault glomerular 
filtration rate estimation:
(140age)(weight in kg) (0.85 if female)
72(serum creatinine in mg/dL)
–
INR or aPTT 1.5 ULN
For patients requiring anticoagulation therapy with warfarin or other 
coumarins, a stable INR between 2 and 3 is required.  If anti-
coagulation is required for a prosthetic heart valve, then INR should be 
between 2.5 and 3.5.

Screening left ventricular ejection fraction (LVEF) 50% on echocardiogram (ECHO)
or multiple-gated acquisition (MUGA) scan
LVEF assessment may be repeated once up to 3 weeks following the initial 
screening assessment to assess eligibility.

Negative HIV test at screening

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening


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The HBV DNA test will be performed only for patients who have a negative 
HBsAg test and a positive total HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of <1% per year during the treatment period and for at least 30 days after the last 
dose of venetoclax or 7 months after the last dose of trastuzumab emtansine, 
whichever is later. Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state (12 continuous 
months of amenorrhea with no identified cause other than menopause), and 
is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
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 methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below:
With a female partner of childbearing potential who is not pregnant, men 
who are not surgically sterile must remain abstinent or use a condom plus 
an additional contraceptive method that together result in a failure rate of <1% 
per year during the treatment period and for at least 30 days after the last 
dose of venetoclax or 7 months after the last dose of trastuzumab emtansine, 
whichever is later. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 30 days after the last dose of 




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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to 
Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to 
Cycle 1, Day 1

Radiation therapy within 2 weeks prior to Cycle 1, Day 1
The patient must have recovered from any resulting acute toxicity (to Grade 1) 
prior to randomization. 

History of exposure to the following cumulative doses of anthracyclines as specified 
below:
–
Doxorubicin 500 mg/m2
–
Liposomal doxorubicin 500 mg/m2
–
Epirubucin 720 mg/m2
–
Mitoxantrone 120 mg/m2
–
Idarubicin 90 mg/m2
If another anthracycline or more than one anthracycline has been used, then 
the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.

History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
Stage I uterine cancer, or patients who have undergone potentially curative therapy 
with no evidence of disease and are deemed by the treating physician to be at low 
risk for recurrence

Cardiopulmonary dysfunction as defined by:
–
Uncontrolled hypertension (systolic 150 mm Hg and/or diastolic 
100 mm Hg with or without medication)
–
Inadequate LVEF at baseline, 50% by either ECHO or MUGA
–
History of symptomatic congestive heart failure (CHF)-Grade 3 per NCI
CTCAE version 5.0 or Class II New York Heart Association 
–
History of a decrease in LVEF to 40% or symptomatic CHF with prior 
trastuzumab treatment
–
Myocardial infarction or unstable angina within 6 months of randomization
–
Concurrent dyspnea at rest due to complications of advanced malignancy, 
or other disease requiring continuous oxygen therapy
–
Evidence of transmural infarction on ECG
–
Significant symptoms (Grade 2) relating to LVEF, cardiac arrhythmia, or 
cardiac ischemia


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–
High-risk uncontrolled arrhythmias (i.e., supraventricular tachycardia with a 
heart rate 100/min at rest, significant ventricular arrhythmia [ventricular 
tachycardia], or higher-grade atrioventricular [AV]-block [second-degree 
AV-block Type 2 (Mobitz 2) or third-degree AV-block])

Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; 
bone fractures)

Major surgical procedure or significant traumatic injury within 28 days prior to 
randomization or anticipation of the need for major surgery during the course of 
study treatment

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode 
of infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, autoimmune hepatic disorders, sclerosis cholangitis, or active infection with 
HBV or HCV)

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

Known HIV infection or human T-cell leukemia virus 1 infection

Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 2 weeks prior to randomization

Known central nervous system (CNS) disease, except for patients treated and 
currently with asymptomatic CNS metastases, provided that all of the following 
criteria are met:
–
Only supratentorial and cerebellar metastases allowed (i.e., no metastases 
to midbrain, pons, medulla, or spinal cord)
–
No ongoing requirement for corticosteroids as therapy for CNS disease 
–
No stereotactic radiation within 14 days prior to randomization
–
No evidence of interim progression between the completion of CNS-
directed therapy and the screening radiographic study
Note: Patients with new asymptomatic CNS metastases detected at 
the screening scan must receive radiation therapy and/or surgery for 
CNS metastases.  Following treatment, these patients may be eligible 
without the need for an additional brain scan prior to enrollment, if all 
other criteria are met.

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once a month or more frequently)


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Patients with indwelling catheters (e.g., PleurX) are allowed regardless of 
drainage frequency.

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL or 
corrected serum calcium greater than the ULN) or symptomatic hypercalcemia 
requiring continued use of bisphosphonate therapy
Patients who are receiving denosumab must discontinue use of denosumab 
and replace it with a bisphosphonate instead while on study.
Patients who are receiving bisphosphonate therapy specifically to prevent 
skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.

Current Grade 3 peripheral neuropathy (according to the NCI CTCAE v 5.0)

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 
80 or 20 or fusion proteins

Prior allogeneic stem cell or solid organ transplantation

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 30 days after the last dose of venetoclax or 7 months after the last dose of 
trastuzumab emtansine after the final dose of study treatment, whichever is later
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug.

Administration of the following agents within 7 days prior to the first dose of study 
drug:
–
Strong or moderate CYP3A inhibitors (see Appendix 14 for examples)
–
Strong or moderate CYP3A inducers (see Appendix 14 for examples)
Additional restrictions for on-study use of CYP3A inhibitors/inducers are
outlined in Section 4.4.2.

Consumption of grapefruit, grapefruit products, Seville oranges (including
marmalade-containing Seville oranges), or starfruit (carambola) within 3 days before 
anticipated first dose of study drug until the last dose of study drug (see 
Section 4.4.2)

Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the study

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
judgment

Malabsorption syndrome or other condition that would interfere with 
enteral absorption

History of active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative 
colitis) requiring specific medication in the 12 months prior to randomization, or 
active and uncontrolled bowel inflammation (e.g., diverticulitis) at time of 
randomization


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
Inability or unwillingness to swallow a large number of tablets

Known hypersensitivity to venetoclax or trastuzumab emtansine or to any of their 
excipients

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study

Other medical or psychiatric conditions that, in the opinion of the investigator, may 
interfere with the patient’s participation in the study

Blood transfusions if performed within 2 weeks prior to screening 
4.1.2.1
Exclusion Criteria for Randomized Phase II Stage
In addition to the general exclusion criteria, patients in the randomized Phase II stage of 
this study who meet the following criteria will be excluded:

Prior treatment with trastuzumab emtansine in any setting (neoadjuvant/adjuvant or 
advanced/metastatic setting)

Prior treatment with venetoclax in any setting

Prior treatment with anti-HER2 antibody drug conjugates (e.g. trastuzumab 
deruxtecan [DS-8201a]), margetuximab, pyrotinib, or tucatinib
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
(APPLICABLE TO RANDOMIZED PHASE II STAGE ONLY)
4.2.1
Treatment Assignment
The Phase II randomized portion of this study is randomized and double-blind. After 
written informed consent has been obtained, all screening procedures and assessments 
have been completed, and eligibility has been established for a patient, the study site will 
obtain the patient's identification number and treatment assignment from an IxRS.
Patients in the randomized Phase II stage will be randomly assigned to one of two 
treatment arms:  venetoclax in combination with trastuzumab emtansine or trastuzumab 
emtansine plus placebo.  Randomization will occur in a 1:1 ratio through use of a 
permuted-block randomization method to ensure a balanced assignment to each 
treatment arm with respect to pre-specified stratification factors.  Randomization will be 
stratified according to the following criteria:

Bcl-2 status (Bcl-2 high vs. Bcl-2 low; as defined in Section 4.1.1.1)

Visceral disease (Yes vs. No; as defined below)

HER2 status IHC 3+ (Yes vs. No; as defined in Section 4.1.1)
Visceral disease will be defined as the presence of disease in the lung, liver, adrenal 
gland, central nervous system, pleural cavity, or peritoneal cavity. All locations that 
include tumors in the breast, bone, bone marrow, lymph nodes, skin, and soft tissue will 
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cover both visceral and non-visceral disease (e.g., a patient with a tumor in the liver and 
bone lesions) will be designated as having visceral disease for the purposes of the 
analysis.
Patients who are randomized into this study will not be allowed to be re-randomized to 
receive a second course of study treatment. Once a patient has been randomized into 
the study, the IxRS will be used to assign the kit numbers for study drugs to be 
dispensed at each treatment visit.  It is important that the study drugs dispensed for each 
visit are the correct kit number, as assigned by the IxRS.  This will ensure that drug use 
by dates and automatic study drug resupply to sites are managed appropriately via the 
IxRS. 
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and IMC members.
While PK and immunogenicity samples will be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct of the study.  
Laboratories responsible for performing study drug PK and ADA assays will be 
unblinded to patient treatment assignments to identify appropriate samples for analysis.  
PK samples from patients assigned to the comparator arm will not be analyzed for 
venetoclax PK concentration except by request (e.g., to evaluate a possible error in 
dosing).  
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly. The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 


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study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above) will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are venetoclax, trastuzumab 
emtansine, and placebo. 
Rescue medications and pre-medications are considered non-investigational medicinal 
products (NIMPs). In this study, diphenhydramine is considered a NIMP. 
4.3.1.1
Venetoclax and Placebo
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, Inc. and will be supplied 
by the Sponsor as oral film-coated tablets of 100-mg strength. Venetoclax tablets will be 
packaged in high-density polyethylene (PE) plastic bottles to accommodate the study 
design. Venetoclax tablets must be stored at 15C25C (59F77F).
For information on the formulation and handling of venetoclax, see the pharmacy manual 
and the Venetoclax Investigator’s Brochure.
The formulation of placebo is equivalent to venetoclax but without the active agent. The 
handling of placebo is described in the pharmacy manual.
If unblinding occurs, the treatment assignment placebo will no longer be administered to 
patients randomized to Arm A (trastuzumab emtansine and placebo).
4.3.1.2
Trastuzumab Emtansine 
Trastuzumab emtansine will serve as the comparator/active control and will not be 
blinded. Trastuzumab emtansine will be provided as a lyophilized formulation in a 
single-use 20 mL glass vial. Each 20 mL vial contains enough product to deliver 
approximately 160 mg of trastuzumab emtansine. Trastuzumab emtansine vials are to 
be refrigerated at 2C8C (36F46F) and should remain refrigerated until use. Do not 
freeze vials. Trastuzumab emtansine vials should not be used beyond the expiration 
date provided by the manufacturer.
For information on the packaging, reconstitution, and handling of trastuzumab emtansine, 
refer to the pharmacy manual and the Trastuzumab Emtansine Investigator’s Brochure.  


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4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens for the dose-escalation phase, dose-expansion phase, and 
randomized Phase II stage are summarized in Section 3.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration eCRF.  Cases of overdose, medication error, drug abuse, or 
drug misuse, along with any associated adverse events, should be reported as 
described in Section 5.3.5.12.
If trastuzumab emtansine is held, then venetoclax/placebo should continue, provided the 
dosing selected in the dose-escalation phase of this study is continuous. In the case of 
NC dosing of venetoclax/placebo, when trastuzumab emtansine is held, then venetoclax 
placebo should be held as well and restart concomitantly to preserve treatment 
synchronization. If trastuzumab emtansine is permanently discontinued for toxicity, then 
venetoclax/placebo can continue, provided that the patient is deriving clinical benefit 
from venetoclax/placebo, in the opinion of the investigator. Guidelines for dosage 
modification and treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.2.1
Venetoclax and Placebo
At the start of each cycle, patients will be supplied with sufficient venetoclax and placebo 
tablets for that cycle. A drug diary will be provided to the patient to record oral 
administration of doses, including the date and time of dosing. Patients will be instructed 
to return empty bottles or unused tablets.
The investigator is responsible for monitoring patient compliance by monitoring the 
patient diary and counting unused tablets. Patient compliance with the assigned daily 
dose of study medication will be assessed by standard pill counts. Previously distributed 
bottles will be returned to the clinic and tablets counted. Any discrepancy will be 
resolved with the patient at each clinic visit and documented in the patient record.
Each dose of venetoclax or placebo will be taken orally once daily with approximately 
240 mL of water within approximately 30 minutes after the completion of breakfast or 
patient’s first meal of the day. Patients should self-administer venetoclax at 
approximately the same time each morning. On days that PK sampling is required, the 
patient’s first meal of the day and all study treatment doses should occur in the clinic to 
ensure accurate timing of the PK sampling. On those days, the time of each dose of 
venetoclax will be recorded to the nearest minute.
A meal containing approximately 30% of the total caloric content from fat is 
recommended to ensure adequate absorption of venetoclax. The following is an 


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example of a breakfast that contains approximately 520 Kcal and has 30% of the total 
caloric content of the meal from fat that is, approximately 17 grams of fat: one box 
cereal (3040 g), skim milk (240 mL), one boiled egg, one slice of toast (15 g) with 
1 tablespoon of margarine (14 g). The toast and margarine may be replaced with one 
medium croissant or two large pancakes. If there is a substantial period of time between 
the patient’s regular time of breakfast and their venetoclax dosing in the clinic on PK 
sampling days, patients may have a low-fat snack in the morning. Patients must be 
instructed not to take their study treatment with the snack and to take their study 
treatments in the clinic after a meal.
Venetoclax tablets should be swallowed whole and never be chewed, cut, or crushed. If 
vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets are still 
intact, another venetoclax dose should be taken, and the second dose should be noted 
in the drug diary. If tablets are not intact or if vomiting occurs more than 15 minutes after 
taking venetoclax, no replacement dose is to be taken. In cases where a dose of 
venetoclax is missed or forgotten, the patient should take the dose with food as soon as 
possible, ensuring that the dose is taken within 8 hours of the missed dose. Otherwise, 
the dose should not be taken. 
4.3.2.2
Trastuzumab Emtansine
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion Q3W.  The 
initial dose of trastuzumab emtansine will be administered on the basis of the patient’s 
baseline weight.  Weight will be measured at each visit and dose must be re-adjusted for 
weight changes 10% compared to the previous visit or baseline, whichever is most 
recent.  The investigator may choose to recalculate the dose at every cycle using actual 
weight at that time, according to their local practice.  Administration may be delayed to 
assess or treat adverse events.  Dose reduction will be allowed, following the dose 
reduction levels provided in Table 11. Once a dose has been reduced for adverse 
event(s), it must not be re-escalated.  If trastuzumab emtansine is discontinued because 
of toxicity, it should not be re-administered. Guidelines for dosage discontinuation for 
patients who experience adverse events are provided in Section 5.1.3.
If the timing of a protocol-mandated procedure, such as administration of trastuzumab 
emtansine coincides with a holiday that precludes the procedure, the procedure should 
be performed within 3 business days of the scheduled date and, when possible, on the 
earliest following date with subsequent protocol-specified procedures rescheduled 
accordingly.
Refer to Table 1 for guidelines on administration of first and subsequent infusions of 
trastuzumab emtansine.


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Table 1
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine
First Infusion
Subsequent Infusions

No premedication is administered.

Record patient’s vital signs as 
indicated in Appendix 1 and 
Appendix 2.

Administer the initial dose as a 
90-minute IV infusion. 

Patients should be observed during 
the infusion and for at least 
90 minutes following the initial dose 
for fever, chills, or other infusion-
related reactions.

The infusion rate should be slowed or 
interrupted if the patient develops 
infusion-related symptoms.

The infusion site should be closely 
monitored for possible subcutaneous 
infiltration during drug administration.

Record patient’s vital signs as indicated in 
Appendix 1 and Appendix 2.

If prior infusions were well tolerated, subsequent 
doses may be administered as 30-minute 
infusions.

Patient should be observed during the infusions 
and for at least 30 minutes after infusion.
4.3.2.3
Sequence of Study Drug Administration
The oral dose of venetoclax should be administered first, followed by infusion of 
trastuzumab emtansine.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor.  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.
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 Inventory Log.
4.3.3.1
Continued Access to Venetoclax and Trastuzumab Emtansine
The Sponsor will offer continued access to Roche IMPs venetoclax and trastuzumab 
emtansine free of charge to eligible patients in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, as outlined below.


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A patient will be eligible to receive Roche IMPs venetoclax and trastuzumab emtansine
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 Roche IMP 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
A patient will not be eligible to receive Roche IMPs venetoclax and trastuzumab 
emtansine after completing the study if any of the following conditions are met:

The Roche IMP 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 IMP or data suggest that the IMP
is not effective for breast cancer

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
breast cancer 

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
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 to the study completion/treatment discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives with a failure rate of 1% per year (see Section 4.1.1)

Hormone-replacement therapy


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
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) to non-target sites is allowed as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  
Study drug treatment may be continued during palliative radiotherapy.  

Pain medications administered per standard clinical practice 

Inactive influenza vaccinations during influenza season 

Bisphosphonates for prevention of skeletal related events 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
at the discretion of the investigator.
The use of anti-emetics and anti-diarrhea prophylaxis is permitted and should be 
administered per protocol guidelines (see Table 9 and Section 5.1.3 for more details). 
The use of anti-emetics must be documented in the eCRF. Use of prophylactic anti-
microbial agents, TLS prophylaxis and/or treatment, and/or growth factors is also 
recommended according to standard institutional practice and should be documented in 
the eCRF. 
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
Prohibited Food
Use of the following foods is prohibited for at least 3 days prior to initiation of treatment, 
throughout venetoclax administration, and for 28 days after the last dose of study 
treatment:

Constituents of these foods have been shown to inhibit CYP3A4, the major enzyme 
responsible for the metabolism of venetoclax. Consumption of these foods could 
lead to increased venetoclax exposure:
–
Grapefruit
–
Grapefruit products
–
Seville oranges (including marmalade containing Seville oranges)
–
Star fruit (carambola)


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4.4.3
Prohibited and Cautionary Therapy
Use of the following concomitant therapies are prohibited as described below:

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 21 days prior to initiation of study treatment and during study treatment.

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, and herbal therapy) is 
prohibited for various time periods prior to starting study treatment, depending on 
the agent , and during study treatment, until disease progression is documented and 
the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and local therapy under certain circumstances (see Section 4.4.1 for 
details).

The administration of live, attenuated influenza vaccine (e.g., FluMist) is prohibited 
during treatment and within 28 days following the last dose of venetoclax.
Some additional therapies are prohibited only for specific study phases, or are allowed 
with caution, restrictions, and/or dose adjustments.  These are described in Table 7 and 
are to be implemented after relevant exclusion criteria for these medications are met 
(see Section 4.1.1).
Venetoclax is a substrate of CYP3A and therefore venetoclax exposure can be impacted 
by concomitant strong and moderate of CYP3A inducers and inhibitors.  DM1, the 
cytotoxic component of trastuzumab emtansine, is metabolized mainly by CYP3A4 and 
to a lesser extent by CYP3A5. Relevant restrictions and dosing recommendations for 
concurrent CYP3A inhibitors/inducers are described in Table 2.  Medications that should 
be avoided are listed in Appendix 14.
After discontinuation of a moderate or strong CYP3A inhibitor that led to a venetoclax 
dose reduction as per the following guidelines, the investigator should wait for 3 days 
before increasing the venetoclax dose back to the original maintenance/target dose.


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Table 2
Therapies Prohibited for Specific Study Phases, or Allowed with Caution, Restrictions, and/or Dose 
Adjustments  
Therapy
Phase Ib:  Dose-Escalation
Phase Ib: Expansions and
Phase II:  Randomized
DLT Window a
Post DLT Window a at
Cohort-Designated Dose
Cohort-Designated Dose
Strong CYP3A inhibitors
Prohibited
Avoid and consider alternative medications.  Consult with the medical monitor if 
considering use.  If usage is approved by the medical monitor, reduce 
venetoclax dose by at least 4-fold (see Table 3) and follow applicable local 
prescribing information.  Consider delaying T-DM1 treatment until the strong 
CYP3A4 inhibitors have cleared from the circulation (approximately 3 
elimination half-lives of the inhibitors) when possible. If T-DM1 treatment cannot 
be delayed, patients should be closely monitored for adverse reactions. 
Moderate CYP3A inhibitors
Prohibited
Avoid and consider alternative medications.  Consult with the medical monitor if 
considering use.  If usage is approved by the medical monitor, reduce 
venetoclax dose by 2-fold (see Table 3).
Strong CYP3A inducer
Prohibited
Moderate CYP3A inducer
Prohibited
Exclude through completion of the first 
cycle of venetoclax.  After the first cycle, 
avoid and consider alternative 
medications with less induction.  If used, 
contact the Medical Monitor for guidance.
P-gp inhibitors
If P-gp inhibitor must be used, monitor closely for toxicities and follow the applicable local prescribing information
P-gp substrates
Concomitant use of narrow therapeutic index P-gp substrates should be avoided.  If a narrow therapeutic index 
P-gp substrate must be used, it should be taken at least 6 hours before venetoclax.
Warfarin and coumarin 
derivatives (e.g., 
phenprocoumon)
Use with caution with close monitoring of the international normalized ratio (INR).
Excessive alcohol intake
Should be avoided (occasional to moderate use is permitted).
DLT dose-limiting toxicity; P-gpP-glycoprotein.
Note: See Appendix 14 for examples of CYP3A4 inhibitors/inducers and P-gp substrates/inhibitors.
a DLT window applicable to dose-escalation stage only.


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Table 3
Venetoclax Dose Reductions for Strong and Moderate CYP3A 
Inhibitors
Venetoclax 
Assigned Dose (mg)
Venetoclax Reduced Dose (mg)
Strong CYP3A Inhibitors
Moderate CYP3A Inhibitors
100
Consult with Medical Monitor.
Consult with Medical Monitor.
200
Consult with Medical Monitor.
100
400
100
(70 for posaconazole in U.S. and countries 
with USPI-based approval)
200
600
300
800
200
400
U.S.United States; USPI United States Prescribing Information.
Appendix 14 contains examples of CYP3A4 inhibitors/inducers and P-gp 
substrates/inhibitors. Additional examples of these classes of medications are provided 
at the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm
The above lists are not necessarily comprehensive; the investigator should also consult 
the prescribing information for any concomitant medication when determining the drug-
drug interaction potential.    
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed.  A decision may be made to allow the use of prohibited 
medications on a case by case basis, following discussion with the Medical Monitor and 
assessment of the benefit-risk ratio.
Patients who require the use of any therapies when they are prohibited (unless an 
allowance is made after consultation with the medical monitor) will be discontinued from 
study treatment and followed for safety outcomes and followed for safety outcomes for 
4 weeks after the last dose of study treatment or until initiation of another subsequent 
anticancer therapy, whichever comes first.
4.4.3.1
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 (see
Section 4.4.2) may be used during the study at the discretion of the investigator.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1
and Appendix 2.  All activities should be performed and documented for each patient.  


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Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
Prior to signing the main Informed Consent Form for the study, patients may consent to 
the collection of tumor tissue (archival or newly obtained via biopsy) for determination of 
Bcl-2 expression by signing a Prescreening Informed Consent Form.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements, and foods that have been shown to 
inhibit CYP3A4 [Section 4.4.2]) used by the patient within 28 days prior to initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Breast cancer history includes prior cancer therapies and procedures.  
Demographic data will include age, sex, and self-reported race/ethnicity. Local HER2 
testing information will also be collected, if available.
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 at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.


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Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
4.5.5
Tumor and Response Evaluations
All sites of measurable and non-measurable disease must be documented at screening 
and re-assessed at each subsequent tumor evaluation.  Tumor assessments are to be 
performed at the timepoints specified in Appendix 1 and Appendix 2; a time window of 
±7 days is allowed for all timepoints regardless of drug delays or interruptions.  Tumor 
assessments will continue until disease progression, withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first.
Initial screening assessments must include CT scans (with oral or IV contrast unless 
contraindicated) or MRI scans of the chest, abdomen, and pelvis.  A bone scan or 
positron emission tomography (PET) scan should also be performed to evaluate for 
bone metastases. MRI scans of the chest, abdomen, and pelvis or non-contrast CT 
scan may be used in patients for whom CT scans with contrast are contraindicated 
(i.e., patients with contrast allergy or impaired renal clearance).
A CT (with contrast) or MRI scan with contrast (if CT contrast is contraindicated) of the 
head must be done at screening to evaluate CNS metastasis in all patients.  If CT with 
contrast is performed and the presence of brain metastases is considered equivocal, an 
MRI scan of the brain is required to confirm or refute the diagnosis of CNS metastases 
at baseline. Patients with active or untreated symptomatic CNS metastases are not 
eligible for the study (see Section 4.1.1).  Patients with untreated asymptomatic CNS 
metastasis at screening may be eligible.  For untreated patients, brain MRI scan with 
contrast at screening is required, and needs to meet all eligibility criteria as specified in
Section 4.1.
If a CT scan for tumor assessment is performed as part of a PET/CT, the CT acquisition 
must be consistent with the standards for a full-contrast diagnostic CT scan.
Further investigations such as bone scans and CT scans of the neck should also be 
performed if clinically indicated.  At the investigator’s discretion, other methods of 
assessment of measurable disease according to RECIST v1.1 may be used.


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Evaluation of tumor response conforming to RECIST v1.1 (Appendix 11) will be 
performed every 6 weeks (±7 days) following randomization until the primary PFS 
analysis, with additional scans performed as clinically indicated.  The same radiographic 
procedures used to assess measurable disease sites at screening should be used 
throughout the study (e.g., the same contrast protocol for CT and/or MRI scans).  
Following the primary PFS analysis, tumor assessments will be conducted as per 
standard of care and recorded in the eCRF until disease progression.
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Tumor assessments performed after the screening period 
should consist of the following assessments every 6 weeks until the primary PFS 
analysis:  
1.
CT and/or MRI of the chest/abdomen/pelvis, as well as other known sites of disease, 
including brain
2.
If a patient has only bone as a site of involvement at screening, which is determined 
to be measurable disease as per RECIST v1.1, then a bone scan or PET scan is 
mandated at every tumor assessment, or a bone scan or PET scan is to be 
performed as clinically indicated (e.g., suspicion of disease progression)
3.
In cases where patients demonstrate control of their systemic disease but who 
newly develop isolated brain metastases and are eligible to remain on study 
treatment, brain MRI or CT are performed along with regularly scheduled tumor 
assessments
4.
Any other imaging studies felt to be clinically indicated by the treating physician
Response will be assessed by the investigator using RECIST v1.1 (Appendix 11) at 
each tumor assessment.  Assessments should be performed by the same evaluator, if 
possible, to ensure internal consistency across visits.
At the investigator’s discretion, CT or other clinically appropriate scans may be repeated 
at any time if PD is suspected.  If the initial screening bone scan or PET scan indicates 
bone metastases and this is the only site of involvement and is determined to be 
measurable disease per RECIST v1.1, then a bone scan or PET scan needs to be 
performed every 6 weeks.  If the screening scan shows evidence of either non-
measurable bone metastases or no bone metastases, then these procedures do not 
need to be repeated unless clinically indicated or at the treating physician’s discretion.  
If the brain is not identified as a site of involvement at screening, then brain CT or MRI 
only needs to be repeated beyond screening, if clinically indicated.  In cases where a 
patient demonstrates control of their systemic disease but who newly develops isolated 
brain metastases and is eligible to remain on study treatment, brain MRI or CT are 
performed along with regularly scheduled tumor assessments (Section 3.1).


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If study drug treatment is discontinued prior to disease progression according to RECIST 
v1.1, tumor response assessment should continue to be performed as per the schedule 
specified in Appendix 1 and Appendix 2.
4.5.6
Left Ventricular Ejection Fraction Assessment
LVEF will be assessed by ECHO or MUGA.  LVEF will be monitored at baseline and 
every fourth cycle thereafter.  Additional LVEF measurements may be performed if LVEF 
declines are clinically suspected at the discretion of the investigator.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)

Chemistry panel (serum): glucose, BUN or urea, sodium, magnesium, chloride, 
bicarbonate, total bilirubin, ALT, AST, alkaline phosphatase, total protein, and 
albumin
TLS laboratory assessments include serum creatinine, uric acid, potassium, 
calcium, phosphorous, and LDH.

Coagulation: aPTT and INR

HIV serology

HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.  

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and 
blood)

Thyroid function test (thyroid-stimulating hormone [TSH], free T3, and free T4)


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The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis.

Blood samples for exploratory research on biomarkers and biomarker assay
development
Blood samples will be processed to obtain plasma, and serum for the 
determination of baseline level changes in surrogate PD biomarkers.

C-reactive protein

Blood samples for auto-antibody testing
For patients who show evidence of immune-mediated toxicity, additional 
samples may be collected and will be analyzed centrally:

Anti-nuclear antibody

Antidouble-stranded DNA

Circulating anti-neutrophil cytoplasmic antibody

Perinuclear anti-neutrophil cytoplasmic antibody

Plasma samples for venetoclax PK analysis

Serum samples for trastuzumab emtansine PK analysis

Serum samples for total trastuzumab analysis

Serum samples for trastuzumab emtansine immunogenicity analysis
Note:  Alternative PK and ADA assessments may be explored if there is 
substantial difficulty in obtaining the timepoints listed in Appendix 3. Depending 
on the results from interim PK and ADA analyses, the frequency of PK and ADA 
sampling may be reduced or halted later in the study.

Archival or newly collected tumor tissue sample obtained at baseline for 
determination of protein expression of Bcl-2 and HER2 by central laboratory testing 
for patient eligibility purposes and for exploratory research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
20 slides containing unstained, freshly cut, serial sections must be submitted 
along with an associated pathology report prior to study enrollment. If only 
1019 slides are available, the patient may still be eligible for the study, after 
Medical Monitor approval has been obtained.
Tumor tissue should be of good quality based on total and viable tumor content. 
Samples must contain a minimum of ≥20% viable tumor cells that preserve 
cellular context and tissue architecture regardless of needle gauge or retrieval 
method. Samples collected via resection, core-needle biopsy (at least three 
cores, embedded in a single paraffin block), or excisional, incisional, punch, or 
forceps biopsy are acceptable. Fine-needle aspiration (defined as samples that 
do not preserve tissue architecture and yield cell suspension and/or smears), 
brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable. Tumor tissue from bone metastases that have been decalcified is 
not acceptable.


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If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required. A pretreatment tumor 
biopsy may also be performed if a patient's archival tissue test results do not 
meet eligibility criteria.
Exploratory biomarker research may include, but will not be limited to, analysis of tissue 
and ctDNA (i.e., mutation profiles associated with disease) and genes or gene 
signatures associated with apoptosis (i.e., BCL-2 family). Research may involve 
extraction of DNA, ctDNA, or RNA; analysis of somatic mutations; and use of NGS of a 
comprehensive panel of genes. NGS methods will not include whole genome 
sequencing (WGS) or whole exome sequencing (WES). 
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator may obtain an NGS report through Foundation Medicine's web portal.  If 
allowed by local laws, the investigator may share and discuss the results with the patient, 
unless the patient chooses otherwise.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions.  
Results will not be available for samples that do not meet criteria for testing.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11.3), biological samples will be 
destroyed no later than the time of completion of the final Clinical Study Report, with the 
following exceptions:

Serum and plasma samples collected for PK or immunogenicity analysis may be 
needed for additional pharmacokinetics (e.g., PK biomarkers or relevant 
analytes/catabolites/metabolites) and immunogenicity characterization and for PK or 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed, or earlier depending on local regulations.

Tumor tissue and blood samples collected for biomarker research and biomarker 
assay development will be destroyed no later than no later than 5 years after the 
final Clinical Study Report has been completed. However, the storage period will be 
in accordance with the Institutional Review Board/Ethics Committee (IRB/EC)-
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).

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 6 weeks 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 


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samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.8
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1 and Appendix 2), and may be obtained at 
unscheduled timepoints as indicated.
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine 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) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings may be stored at the site. The following should 
be recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and QT interval corrected through use of Fridericia’s formula 
(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 at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified. Standard of care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 


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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).
4.5.9
Patient-Reported Outcome Assessments
PRO instruments will be completed during the randomized Phase II stage of the study to 
assess the treatment benefit and/or more fully characterize the safety profile of 
venetoclax in combination with trastuzumab emtansine compared to trastuzumab 
emtansine plus placebo. In addition, PRO instruments will enable the capture of each 
patient's direct experience with venetoclax in combination with trastuzumab emtansine 
compared to trastuzumab emtansine alone.
PRO data will be collected through use of the following instruments: the EORTC QLQ-
C30 and the EORTC IL46.
4.5.9.1
Data Collection Methods for Clinical Outcome Assessments
PRO instruments, translated into the local language as appropriate, will be self-
administered via paper questionnaires and/or through use of an electronic device 
provided by the Sponsor.  Instructions for completing the questionnaires will be provided 
by the site staff.  The data will be transmitted to a centralized database maintained by 
the electronic device vendor or entered into the study database by site personnel as 
appropriate. The data will be available for access by appropriate study personnel.
The EORTC QLQ-C30 and IL46 assessments will occur as outlined in the schedule of 
activities (Appendix 2). 
To ensure instrument validity and that data standards meet health authority
requirements, questionnaires scheduled for administration during a clinic visit will be
completed in their entirety by the patient prior to receiving any information on disease
status, prior to the performance of non-PRO assessments that could bias patients’
answers, and prior to the administration of study treatment, unless otherwise specified.
During clinic visits, PROs 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 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.


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
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.

If completed on paper, site staff should review and 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.
The questionnaires (EORTC QLQ-C30 and EORTC IL46) will be completed during the 
randomized Phase II stage only: at Cycle 1, Day 1 (baseline) prior to administration of 
study drug; then at every study treatment cycle prior to administration of study drug (i.e., 
on Cycle 2, Day 1; Cycle 3, Day 1; and Cycle 4, Day 1, etc.) and at the study treatment 
discontinuation visit (see Appendix 2). The EORTC QLQ-C30 will be collected at the first 
survival follow-up at 3 months (30 days) and the second survival follow-up at 6 months 
(30 days) following conclusion of treatment or disease progression per RECIST v1.1.
Patients who discontinue study treatment for any reason other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete the 
EORTC QLQ-C30 at each tumor assessment visit until radiographic disease progression 
per RECIST v1.1, death, loss to follow-up, consent withdrawal, or study termination by 
the Sponsor, whichever occurs first.
Patients whose native language is not available with the questionnaires are exempted 
from completing all PRO assessments.
The Sponsor will not derive adverse event reports from PRO data.
4.5.9.2
Description of Clinical Outcome Assessment Instruments
EORTC QLQ-C30
The EORTC QLQ-C30 (see Appendix 6) is a validated and reliable self-report measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999) that consists of 30 questions that assess 
five aspects of patient functioning (physical, emotional, role, cognitive, and social), three 
symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). Scale scores can be obtained for the multi-item scales. The EORTC QLQ-
C30 module takes approximately 15 minutes to complete. 
EORTC IL46
The EORTC IL46 is a validated single-item question assesses overall impact of study 
drug side effects (see Appendix 6). Specifically, the single-item EORTC IL46 
assessment of patient experience with treatment-related side effects will be collected.  


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4.5.10
Optional Tumor Biopsies 
Consenting patients will undergo an optional tumor biopsy (if deemed clinically feasible 
by the investigator) at Cycle 1, Day 1 and/or Cycle 2, Day 1 (see Appendix 1 and 
Appendix 2) and may undergo additional on-treatment biopsies at any other time at the 
investigator’s discretion (if deemed clinically feasible by the investigator). Where fresh 
biopsy is possible, samples collected via resection, core-needle biopsy, or excisional, 
incisional, punch, or forceps biopsy are acceptable. Biopsies collected via fine-needle 
aspirations are not acceptable.
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  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 Optional Biopsy Sample Informed Consent eCRF.
Samples may be used for exploratory biomarker research as described in Section 4.5.7.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.7 for details on duration of sample storage, use 
of samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses. 
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays


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4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's 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 4.5.11)
will not be applicable at that site.
4.5.11.3
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 venetoclax, trastuzumab 
emtansine, disease, or drug safety:

Blood samples collected at baseline

Additional archival tumor tissue samples (e.g., from an earlier biopsy) collected at 
screening

Tumor tissue samples from biopsies performed at the investigator's discretion 
during the study

Leftover blood, serum, plasma, peripheral blood mononuclear cell (PBMC), and 
tumor tissue samples (with the exception of remaining archival tissue blocks, which 
will be returned to sites) and any derivatives thereof (e.g., DNA, RNA, proteins, 
peptides).
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods. Genomics is 
increasingly informing researchers’ understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the IRB/EC
approved- Informed Consent Form and applicable laws (e.g., health authority 
requirements).


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4.5.11.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 


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Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.11.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Use of an anticancer therapy not required per protocol

Radiographic disease progression according to RECIST v1.1
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF. 
Patients who discontinue treatment prematurely during the DLT-evaluation period during 
the dose-escalation phase will be replaced. Patients who discontinue study treatment 
prematurely during the randomized portion of the study will not be replaced.


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Patients will return to the clinic for a treatment completion or treatment discontinuation 
visit 28 days (+14 days) after the last dose of study drug (see Appendix 1 and 
Appendix 2 for additional details). After treatment discontinuation due to disease 
progression, information on survival follow-up and new anticancer therapy will be 
collected via telephone calls, patient medical records, and/or clinic visits approximately 
every 6 months until death, loss to follow-up, withdrawal of consent, or study termination 
by the Sponsor, whichever occurs first.
Patients who are discontinued from study treatment for reasons including disease 
progression and have started follow-on treatment/s will be followed for survival 
approximately every 6 months until death, lost to follow-up, withdrawal of consent, or 
study termination by the Sponsor, whichever occurs first. Patients who are discontinued 
from study treatments for reasons other than disease progression and have not started 
follow-on treatment/s will be followed for disease status every 8 weeks (± 5 days) from 
the date of randomization until Week 24 (± 5) days and every 12 weeks (± 5 days), 
thereafter, until disease progression, loss to follow-up, withdrawal of consent, death or 
study termination by the Sponsor, whichever occurs first (see Appendix 1 and 
Appendix 2 for additional details).
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the study.  
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced.
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.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
GCP

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
Venetoclax has been granted approval in the U.S. (VenclextaU.S. Prescribing 
Information) and by the European Medicines Agency (VenclyxtoE.U. SmPC) for the 
treatment of patients with CLL, with or without 17p deletion, who have received at least 
one prior therapy. Venetoclax has also received accelerated approval in the U.S. in 
combination with azacitidine, decitabine, or LDAC to treat adults with newly diagnosed 
AML.
Venetoclax, however, is not approved for the treatment of BC, and clinical development 
is ongoing. The safety plan for patients in this study is based on clinical experience with 
venetoclax in completed and ongoing studies. The anticipated important safety risks for 
venetoclax are outlined below. Please refer to the most recent version of Venetoclax
Investigator's Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.


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5.1.1
Risks Associated with Venetoclax
Clinical experience gained thus far with venetoclax has demonstrated that it is generally 
well tolerated, and toxicities appear to be mostly manageable and/or reversible; see the 
current Venetoclax Investigator’s Brochure for more information. 
On the basis of clinical data to date, the following known and potential risks with 
venetoclax are described below. Guidelines around the management of these risks 
through dose and schedule modifications are described in Section 5.1.3.
5.1.1.1
Tumor Lysis Syndrome
Available data suggest that in patients with cancers other than CLL, with the exception of 
those with mantle cell lymphoma, the risk of TLS is low. Due to different biology 
between HER2-positive BC and hematological malignancies, the risk of TLS is 
considered to be very low in patients with HER2-positive BC. Therefore, TLS 
prophylaxis is not recommended by any of the international guidelines for patients with 
HER2-positive BC, even in those patients who have developed visceral crisis and are 
receiving chemotherapy.
The target population in this trial is considered to have low disease burden compared 
with patients who have visceral crisis; therefore, TLS risk is negligible (Lok et al. 2019). 
Nevertheless, patients should be advised to remain well hydrated for the first week of 
study drug administration. Although not mandatory, at the discretion of the investigator, 
a prophylactic oral agent (e.g., allopurinol 300 mg QD) may be initiated in patients who 
are deemed to be at risk of TLS in order to reduce the uric acid level. In the dose-
escalation phase, TLS laboratory values obtained before the dose of venetoclax will be 
used to determine whether a patient developed a change related to TLS. Laboratory 
results from 24 hours post-dose must be reviewed before receiving the dose of 
venetoclax for that day. Patients who develop electrolyte changes suggestive of TLS 
should undergo aggressive management and further monitoring per Appendix 7.
Patients with TLS should be treated as per institutional practice and local guidelines, 
including correction of electrolyte abnormalities and monitoring of renal function and fluid 
balance. Recommendations for initial management of electrolyte imbalances and 
prevention of TLS are provided in Appendix 7. In some cases, dialysis may be indicated. 
Guidelines for defining TLS are provided in Appendix 8.
To evaluate any possible risk of TLS with venetoclax in patients with HER2-positive BC, 
patients enrolled in the dose-escalation phase of the study will each have a sample 
collected for a serum chemistry panel 24 hours after the first dose of study drug. The 
Sponsor will review the chemistry panel results and establish a management plan for 
TLS if an increased risk is identified, if needed.


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5.1.1.2
Neutropenia
Neutropenia is an important identified risk for venetoclax. Clinical data from oncology 
studies suggest that neutropenia adverse events are observed among patients who 
receive venetoclax as a single agent or in combination with other therapeutic agents, 
with higher frequency observed in some combination studies. Serious adverse events of 
neutropenia or neutropenia events that lead to discontinuations are few across the entire 
venetoclax oncology program. Neutropenia management guidelines are provided in
Table 6. Granulocyte colony stimulating factors are permitted according to local practice, 
and patients will be monitored and treated promptly in case of infection.
5.1.1.3
Serious Infections
Serious infection is an important identified risk for venetoclax. Infections have been 
reported in oncology clinical studies; however, these events are confounded by the 
underlying disease, comorbidities, and other immunosuppressive medications. To date, 
no clear relationship has been noted between serious infectious events and neutropenia. 
The types of infectious events observed generally have been consistent with those 
anticipated in the elderly population of heavily pretreated patients with hematologic 
malignancies and are similar across all indications. Infections are closely monitored in 
venetoclax program across all indications. Patients should be advised to report fever or 
symptoms suggestive of serious infection and should be assessed for further
management as per standard medical practice. In the oncology studies, 
recommendations are included in the protocol regarding the need for anti-infective 
prophylaxis per standard of care (e.g., NCCN guidelines for oncology subjects).
5.1.1.4
Other Hematological Effects
Anemia has been reported across oncology studies investigating venetoclax, with a 
higher frequency in some studies in which venetoclax is combined with other reference 
therapies; however, most of the events were non-serious and confounded by disease 
factors and prior therapies.
Thrombocytopenia adverse events have been reported in oncology studies 
investigating venetoclax, with a higher frequency in those studies in which venetoclax 
was combined with other chemotherapeutic agents. However, most of the events were 
non-serious and assessment of these events is confounded by the patients' underlying 
hematologic malignancy disease state, prior therapies, and preexisting 
thrombocytopenia, including autoimmune thrombocytopenia in several patients.
Lymphopenia has been observed in nonclinical studies and in the Phase I clinical study 
conducted in heavily pretreated patients with CLL and NHL. While opportunistic 
infections have been reported in the clinical program, data are confounded by the 
patients’ underlying disease and prior therapies. Patients in this study who develop 
lymphopenia are potentially at risk for atypical infections. As such, prophylaxis against 
varicella zoster virus and Pneumocystis jiroveci pneumonia should be considered and 


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implemented (if applicable) as per local institutional practice, although some guidance is 
provided in Appendix 8.
5.1.1.5
Effects on Reproductive System and Pregnancy
This study is open to enrollment of both male and female patients. The effect of Bcl-2
inhibition on pregnancy has not been fully characterized. In animal studies, venetoclax 
resulted in increased post-implantation loss, and decreased fetal body weights were 
observed in the mouse embryo-fetal development study at the highest dosage 
administered. Venetoclax was not teratogenic. Six human pregnancies have been 
reported in the clinical program with venetoclax so far, including two pregnancies 
reported in a partner; in four out of six cases, a live infant with no neonatal complication, 
congenital anomalies, or birth defects was delivered. One out of six cases ended in 
therapeutic abortion in a patient with CLL who experienced progressive disease. One 
out of six cases was reported in a partner of a patient who had not received any study 
drug and for which the projected due date is pending.
In nonclinical studies, both venetoclax and trastuzumab emtansine have shown a 
potential to cause reproductive and embryo-fetal developmental toxicities as single 
agents. Therefore, there is the potential for this combination to cause overlapping or 
additional reproductive and embryo-fetal toxicities compared with the individual 
molecules. Consequently, both venetoclax and trastuzumab emtansine should not 
be administered to pregnant women, and both drugs must be discontinued if a patient 
becomes pregnant. Additionally, patients are advised to remain abstinent (i.e., 
refrain from heterosexual intercourse) or use contraceptive methods with a failure 
rate of <1% per year during the treatment period and for 28 days after the last dose 
of study drug. Please refer to Section 4.1.1 for further details on study eligibility and 
contraceptive requirements for patients.
5.1.1.6
Treatment-Emergent Malignancies (Second Primary 
Malignancies)
Second primary malignancies are important potential risk for venetoclax. Events of 
second primary malignancies have been reported across the venetoclax hematologic 
oncology program. However, no causal association with the venetoclax 
administration has been confirmed, and no pattern has been observed. The overall 
observed incidence rate of malignancy in the venetoclax clinical trial programs were 
comparable to that reported in the general population. Second primary malignancies 
will be closely monitored in this study.
5.1.1.7
Food Effect
Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-
fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to 
5.3-fold compared with fasting conditions. Venetoclax should be administered with a 
meal as described in Section 4.3.2.1.


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5.1.1.8
Concomitant Use with Other Medications
Specific recommendations are provided for co-administration of venetoclax with other 
medications, including inhibitors and inducers of CYP3A (see Section 4.4).
Live, attenuated vaccines should not be administered prior to, during, or after 
treatment with venetoclax until B-cell recovery occurs. The safety and efficacy of 
immunization with live, attenuated vaccines during or following venetoclax therapy 
have not been studied. Patients should be advised that vaccinations may be less 
effective.
Due to possible CYP3A mediated metabolic interaction, certain food items (e.g., 
grapefruit and Seville oranges) should not be consumed during treatment with 
venetoclax. Further details of excluded food items are provided in Section 4.4.
5.1.2
Risks Associated with Trastuzumab Emtansine
5.1.2.1
Pulmonary Toxicity
Cases of ILD, including pneumonitis, some leading to acute respiratory distress 
syndrome or death, have been reported in patients receiving trastuzumab emtansine.  
Signs and symptoms may include dyspnea, cough, fatigue, and pulmonary infiltrates. 
Patients with dyspnea at rest due to complications of advanced malignancy and 
comorbidities may be at risk of pulmonary events.
Patients who have experienced a pulmonary event should be carefully evaluated before 
commencing trastuzumab emtansine treatment.
Guidelines for management of trastuzumab emtansine in patients who develop ILD or 
pneumonitis are provided in Appendix 10.
5.1.2.2
Hepatotoxicity
The following events have been reported with administration of trastuzumab emtansine:

Serious hepatobiliary disorders
Serious hepatobiliary disorders, including NRH of the liver and hepatobiliary 
disorders with a fatal outcome due to drug-induced liver injury, have been
observed in patients treated with trastuzumab emtansine.  Some of the 
observed cases may have been confounded by concomitant medications with 
known hepatotoxic potential.

Increased serum transaminases
Asymptomatic increases in serum transaminase concentration (transaminitis) 
have been observed.  Grade 1 and 2 events have been observed frequently; 
Grade 3 and 4 events have been observed less commonly.  The incidence of 
increased AST was substantially higher than that for increased ALT.  Increases 
in AST and ALT were commonly observed by Day 8 of each cycle and 
generally improved or returned to baseline by Day 21.  A cumulative effect of 
trastuzumab emtansine, that is, an increase in the proportion of patients with 


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Grade 1 or 2 elevations in transaminases with successive cycles has been 
observed; however, there was no increase in the proportion of patients with 
Grade 3 abnormalities over time.

NRH 
NRH is a form of noncirrhotic portal hypertension that can be caused by chronic 
use of medications. NRH typically presents with the insidious or unexpected 
onset of signs or symptoms of portal hypertension (weakness, ascites, 
splenomegaly, esophageal varices) in a patient with little evidence of chronic 
liver disease.
Cases of NRH have been identified from liver biopsies in patients treated with 
trastuzumab emtansine who presented with signs and symptoms of portal 
hypertension.  NRH is a rare liver condition characterized by widespread benign 
transformation of hepatic parenchyma into small regenerative nodules.  NRH 
may lead to non-cirrhotic portal hypertension.  Diagnosis of NRH can only be 
confirmed by histopathology.  Biopsy-confirmed NRH leading to fatal hepatic 
failure has been reported (refer to Appendix 13).
NRH should be considered in all patients with clinical symptoms of portal 
hypertension, even with normal transaminases, and no other manifestations of 
cirrhosis; in patients with a cirrhosis-like pattern seen on a CT scan of the liver; 
and/or in patients with liver failure following long-term treatment with 
trastuzumab emtansine.  
Patients must meet specified hepatic laboratory test requirements to be included in this 
study (Section 4.1.1).
Hepatic laboratory parameters will be monitored as described in the schedule of 
assessments (Appendix 1 and Appendix 2).
Guidelines for management of trastuzumab emtansine in patients who develop
increased serum transaminases, increased serum bilirubin, or NRH are provided 
in (Appendix 10).
5.1.2.3
Left Ventricular Dysfunction
Patients treated with trastuzumab emtansine are at risk of developing left ventricular 
dysfunction.  To date, significant cardiac events, including LVEF of 40%, have been 
observed (infrequently) in clinical trials of trastuzumab emtansine; therefore, 
symptomatic CHF is a potential risk.
Patients must meet specified LVEF requirements to be included in this study 
(Section 4.1).
Left ventricular function will be monitored by measurement of ejection fraction using 
ECHO) or MUGA scans as described in Section 4.5 and the schedule of assessments 
(Appendix 1 and Appendix 2).


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Guidelines for patient monitoring and management of trastuzumab emtansine in patients 
who develop left ventricular dysfunction are provided in (Appendix 10).
5.1.2.4
Infusion-Related Reactions and Hypersensitivity Reactions
Infusion-related reactions (IRRs) and hypersensitivity reactions have been reported with 
administration of trastuzumab emtansine.  Despite the different pathophysiology of IRRs 
(reactions involving cytokine release) and hypersensitivity (allergic) reactions, the clinical 
manifestations are the same.  In general, IRRs are expected to be more frequent and 
severe with the first infusion and to decrease in number and severity over time.  The 
severity of true hypersensitivity reactions would be expected to increase with 
subsequent infusions.
IRRs, characterized by one or more of the following symptomsflushing, chills, pyrexia, 
dyspnea, hypotension, wheezing, bronchospasm, and tachycardiahave been reported 
in clinical trials of trastuzumab emtansine.  In general, these symptoms were not severe.  
In most patients, these reactions resolved over the course of several hours to a day after 
the infusion was terminated.
Hypersensitivity reactions, including serious anaphylactic-like reactions, have been 
observed in clinical trials of trastuzumab emtansine.  Patients with a history of 
intolerance to trastuzumab will be excluded from this study (Section 4.1). 
Administration of trastuzumab emtansine will be performed in a setting with access to 
emergency facilities and staff who are trained to monitor and respond to medical 
emergencies.  Patients should be closely monitored for IRRs during and after each
infusion of trastuzumab emtansine, as described in Section 4.3.2.1.  
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in (Appendix 10).
5.1.2.5
Hematologic Toxicity
Thrombocytopenia has been reported in patients in clinical trials of trastuzumab 
emtansine.  The majority of these patients had Grade 1 or 2 events (platelet count 
50,000/L), with the nadir occurring by Day 8 and generally improving to Grade 0 or 1 
(platelet count 75,000/L) by the next scheduled dose (i.e., within 3 weeks).  In clinical 
trials, the incidence and severity of thrombocytopenia were higher in Asian patients.  
Patients with thrombocytopenia (100,000/mm3) and patients on anticoagulant 
treatment should be monitored closely during treatment with trastuzumab emtansine.  
It is recommended that platelet counts are monitored prior to each trastuzumab 
emtansine dose.  Trastuzumab emtansine has not been studied in patients with platelet 
counts 100,000/mm3 prior to initiation of treatment.  In the event of decreased platelet 
count to Grade 3 or greater (50,000/mm3), do not administer trastuzumab emtansine 
until platelet counts recover to Grade 1 (75,000/mm3).


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Declines in other hematopoietic lineages, for example, leukopenia, neutropenia, and 
anemia, were less frequent than that observed for platelets.
Patients must meet specified hematologic laboratory test requirements to be included in 
this study (Section 4.1). 
Hematologic laboratory parameters will be monitored as described in Section 4.5 and 
the schedule of assessments (Appendix 1 and Appendix 2).  Patients on anticoagulant 
or antiplatelet treatment should be monitored closely. 
Guidelines for management of trastuzumab emtansine in patients who develop
hematologic toxicity are provided in (Table 6).
5.1.2.6
Hemorrhage
Cases of hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported with trastuzumab emtansine.  Some of 
these bleeding events resulted in fatal outcomes.  In some of the observed cases, the 
patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had 
thrombocytopenia; in others, there were no known additional risk factors.  Caution 
should be used with these agents, and additional monitoring should be considered when 
concomitant use with trastuzumab emtansine is medically necessary.
5.1.2.7
Neurotoxicity
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine.  
Patients with Grade 3 peripheral neuropathy will be excluded from this study 
(Section 4.1).
Patients will be clinically monitored on an ongoing basis for signs or symptoms of 
peripheral neuropathy as described in Section 4.5 and the schedule of assessments 
(Appendix 1 and Appendix 2).
Guidelines for management of trastuzumab emtansine in patients who develop
peripheral neuropathy are provided in (Appendix 10).
5.1.2.8
Extravasation
In trastuzumab emtansine clinical studies, reactions secondary to extravasation have 
been observed.  These reactions were usually mild and consisted of erythema, 
tenderness, skin irritation, pain, or swelling at the infusion site.  These reactions have 
been observed more frequently within 24 hours of infusion.
The infusion site will be closely monitored for possible subcutaneous infiltration during 
drug administration, as described in Table 1). Specific treatment for trastuzumab 


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emtansine extravasation is unknown at this time.  Patients should be managed 
symptomatically per local institutional guidelines.
5.1.3
Management of Patients Who Experience Adverse Events
5.1.3.1
Dose Modifications
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v5.0.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.
If, in the opinion of the investigator, a toxicity is considered to be attributable solely to 
one component of the study treatment (i.e., trastuzumab emtansine, venetoclax or 
placebo, then the dose of that component should be delayed or modified in accordance 
with the guidelines below.  If trastuzumab emtansine is held, then venetoclax/placebo 
should continue provided the dosing selected in the dose-escalation phase of this study 
is continuous. In the case of NC dosing of venetoclax/placebo, when trastuzumab 
emtansine is held, then venetoclax placebo should be held as well and restart 
concomitantly to preserve treatment synchronization. If trastuzumab emtansine is
permanently discontinued for toxicity, then venetoclax/placebo can continue provided 
that the patient is deriving clinical benefit from venetoclax/placebo, in the opinion of the 
investigator. Dose interruptions for reason(s) other than adverse events, such as 
surgical procedures, may be allowed with Medical Monitor approval. The acceptable 
length of interruption will depend on agreement between the investigator and the 
Medical Monitor.
Venetoclax Dose Modifications
Although patients with adverse events are to be managed according to the particular 
clinical circumstances based on the investigator’s medical judgement, dose reduction of 
venetoclax by one and, if needed, two dose levels will be allowed depending on the type 
and severity of the toxicity encountered (refer to Table 6 and Appendix 9). The dose 
reduction of venetoclax will occur per Table 4 below. Patients requiring clarification 
regarding management of adverse events and dosing and all patients who received 
starting dose of 800 mg requiring more than three dose reductions should be discussed 
with the Medical Monitor. All dose modifications/adjustments must be clearly 
documented in the patient's source notes and eCRF. Once a dose has been reduced for 
a given patient, all subsequent cycles should be administered at the reduced dose level, 
unless further dose reduction is allowed. Dose re-escalation is not allowed.


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Table 4
Dose Modification Scheme for Venetoclax/Placebo
Dose Reduction Schedule
Dose Level
(mg)
Dose Level
(mg)
Starting dose
800 mg
400 mg
First dose reduction
600 mg
200 mg
Second dose reduction
400 mg
100 mg
Third dose reduction
200 mg
Not Applicable
Requirement for further dose reduction
Discuss with 
Medical Monitor
Not Applicable
Trastuzumab Emtansine Dose Modifications
The dose of trastuzumab emtansine can be reduced by two dose levels for management 
of drug-related toxicities (i.e., from 3.6 mg/kg to 3.0 mg/kg and then from 3.0 mg/kg to 
2.4 mg/kg).  If further dose reduction is indicated after two dose reductions, the patient 
must discontinue trastuzumab emtansine. No dose re-escalation of trastuzumab 
emtansine is permitted in the study.
If significant trastuzumab emtansine-related toxicities have not recovered to Grade 1 or 
baseline, the next scheduled dose may be delayed for up to 42 days after the last dose 
was received.  “Significant” and “related” will be based on the judgment of the 
investigator (in consultation with the Sponsor’s Medical Monitor or designee when 
appropriate).  For example, an adverse event of alopeciaeven if considered related to 
trastuzumab emtansinewould most likely not be considered significant.  Fatigue may 
or may not be considered either related to trastuzumab emtansine or significant. In 
general, when the significant related toxicity (or any other toxicity that the investigator 
chooses to delay dosing for) resolves to Grade 1 or baseline, the patient may resume 
trastuzumab emtansine if the delay is not 42 days from the last dose received. In 
exceptional situations, patients may resume treatment after more than 42 days delay 
with the approval of the Medical Monitor or his delegate. 
Patients should be re-evaluated weekly during the delay, whenever possible.  If dosing 
resumes, the patient may receive trastuzumab emtansine either at the same dose level 
as before or at one lower dose level, at the discretion of the investigator. Subsequent 
cycles should remain Q3W, and patients should be assessed for toxicity as described in 
Section 5.1.3.  If a patient requires a dose reduction, dosing will be reduced by one dose 
level as per Table 5. 


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Table 5
Dose Modification Scheme for Trastuzumab Emtansine
Dose Reduction Schedule
Dose Level
(mg/kg, Q3W)
Starting dose
3.6
First dose reduction
3.0
Second dose reduction
2.4
Requirement for further dose reduction
Discontinue treatment
Q3W every 3 weeks.
Note:  The dose of trastuzumab emtansine, once reduced, may not be re-escalated.  A 
maximum of two dose reductions is allowed; patients with any further requirement for dose 
reduction will discontinue treatment with trastuzumab emtansine.
No dose re-escalation is permitted.  A patient treated with 2.4 mg/kg of trastuzumab 
emtansine who develops an adverse event requiring a dose reduction must discontinue 
study treatment and will be followed for safety, disease progression, and survival 
(Appendix 1 and Appendix 2).
Patients who experience a Grade 3 or 4 hematologic events, other than 
thrombocytopenia, should be checked at least weekly for recovery.  If values do not 
recover to baseline or Grade 1 within 42 days from the last dose received, the patient 
will be discontinued from trastuzumab emtansine. Patients who discontinue 
trastuzumab emtansine can continue venetoclax/placebo provided that, in the opinion of 
the investigator, the patient is deriving clinical benefit from venetoclax/placebo. Patients
who discontinue both study drugs will be followed for safety, disease progression, and 
survival (Appendix 1 and Appendix 2).
5.1.3.2
Treatment Interruption
Patients who interrupt venetoclax secondary to treatment-related adverse events for 
longer than 28 days from the last dose should discontinue venetoclax. However, 
patients who are deriving benefit from the treatment should continue trastuzumab 
emtansine treatment.
If significant trastuzumab emtansinerelated toxicities have not recovered to Grade 1 or 
baseline, the next scheduled dose may be delayed for >42 days after the last dose was 
received. Patients who discontinue trastuzumab emtansine can continue 
venetoclax/placebo provided that, in the opinion of the investigator, the patient is 
deriving clinical benefit from venetoclax/placebo and they are to continue evaluation per 
protocol.
5.1.3.3
Management Guidelines
Guidelines for management of adverse events associated with study treatment are 
provided in Appendix 9 (venetoclax) and in Appendix 10 (trastuzumab emtansine).


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Guidelines for the management of patients who experience specific adverse events are 
provided in Appendix 9, Appendix 10, and Table 6 below and prescribing information, as 
outlined below:
Table 6 below provides guidelines for the management of patients who experience 
the following potential overlapping toxicities for venetoclax and trastuzumab 
emtansine:  hematologic, gastrointestinal, and hepatic events.  It is recommended 
that study treatments be withheld or discontinued per the guidelines below.  For 
these potential overlapping toxicities, refer to guidelines in Table 6.
Appendix 9 provides guidelines for the management of patients who experience 
venetoclax-specific non-hematologic toxicity that is not specifically described in
Table 6. It is recommended that venetoclax be withheld or discontinued per the 
guidelines in Appendix 9.
Appendix 10 provides guidelines for the management of patients who experience 
trastuzumab emtansine-associated adverse events such as left ventricular 
dysfunction, pulmonary toxicity, infusion-related reactions, hypersensitivity, and
NRH reactions.  It is recommended that trastuzumab emtansine be withheld or 
discontinued per the guidelines in Appendix 10.
For cases in which management guidelines are not covered in Table 6, Appendix 9, and 
Appendix 10, patients should be managed and treatments should be withheld or 
discontinued as deemed appropriate by the investigator according to 
best medical judgment.


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Table 6
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Venetoclax and Trastuzumab Emtansine
NCT CTCAE Category
Dose delay or dose modification
Grade 3 febrile
neutropenia
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.
Administer treatment including G-CSF or growth factors for 
neutropenia as indicated and per institutional guidelines.
o
When counts recover to ANC 1 109/L (Grade 2),
resume venetoclax/placebo and trastuzumab emtansine.
For subsequent episodes of Grade 3 febrile neutropenia:
o
Withhold venetoclax/placebo and trastuzumab 
emtansine.
When counts recover to ANC 1 109/L
(Grade 2), resume venetoclax/placebo at one 
dose level reduction (refer to Table 4) and 
trastuzumab emtansine at previous dose.
Grades 3 and 4 
neutropenia
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.
o
When counts recover to ANC 1 109/L (Grade 2), 
resume venetoclax/placebo and trastuzumab emtansine.
For subsequent episodes of Grade 4 neutropenia:
o
Withhold venetoclax/placebo and trastuzumab 
emtansine.
o
Consider secondary prophylaxis with G-CSF as indicated 
or per institutional guidelines.
When counts recover to ANC 1 109/L (Grade 
2), resume venetoclax/placebo at one dose level 
reduction (refer to Table 4) and trastuzumab 
emtansine at previous dose.
Grade 3 thrombocytopenia
(25,000 to 50,000/mm3)
Withhold venetoclax/placebo.  
Withhold trastuzumab emtansine.
o
When platelet count recovers to Grade 1 
(75,000/mm3), resume venetoclax/placebo and 
trastuzumab emtansine at the previous dose level.


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Table 6
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Venetoclax and Trastuzumab Emtansine
(cont.)
NCT CTCAE Category
Dose delay or dose modification
Grade 3 
thrombocytopenia
(platelets 50,000 to 
25,000/L) with clinically 
significant bleeding; or 
Grade 4 
thrombocytopenia
(platelets 25,000/L) 
Withhold venetoclax/placebo.  
Withhold trastuzumab emtansine.
o
Platelets may be transfused if Grade 4 thrombocytopenia is 
associated with symptomatic bleeding or in the case of 
platelet count 10,000/L, or per institutional guidelines.
o
When platelet level rises to 75,000/L, resume
venetoclax/placebo at previous dose. The dose of 
trastuzumab emtansine should be reduced by one dose level 
(refer to Table 5). 
For a subsequent episode of Grade 3 thrombocytopenia with bleeding 
or Grade 4 thrombocytopenia:
o
Withhold both venetoclax/placebo and trastuzumab 
emtansine.
o
Platelets may be transfused if Grade 4 thrombocytopenia is 
associated with symptomatic bleeding or in the case of
platelet count 10,000/L, or per institutional guidelines
o
When platelet level rises to 75, 000/L, resume
venetoclax/placebo at one dose level reduction (refer to 
Table 4). The dose of trastuzumab emtansine should be 
reduced by one dose level (refer to Table 5). 
For recurrent Grade 4 thrombocytopenia in spite of dose reduction
and/or symptomatic bleeding, consult the Medical Monitor regarding 
continuation on study treatment.
Non-hematologic toxicity
Grade 12 Diarrhea
Rule out other or concomitant causes, including medications (e.g., 
stool softeners, laxatives, antacids), infection by C. difficile, 
malabsorption/lactose intolerance, fecal impaction, and dietary 
supplements high in fiber.
Dietary modifications: 
o
Stop all lactose-containing products and eat small meals.
o
The BRAT (banana, rice, apples, toast) diet may be helpful. 
o
Encourage adequate hydration.
Loperamide treatment:
o
Suggested dose of 4 mg followed by 2 mg every 4 hours or 
after every unformed stool, up to a maximum of 16 mg/day.
o
Recommend to continue loperamide treatment until diarrhea-
free for 24 hours.
o
If Grade 2 diarrhea persists after 48 hours total treatment 
with loperamide, consider second-line agents (diphenoxylate 
and atropine or tincture of opium).
No change in study drug dosing will be implemented for Grade 2 
diarrhea; patients should receive maximal supportive care as described 
above.


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Table 6
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Venetoclax and Trastuzumab Emtansine
(cont.)
NCT CTCAE Category
Dose delay or dose modification
Grade 3 Diarrhea 
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.
o
When diarrhea has improved to Grade 1, restart 
venetoclax/placebo and trastuzumab emtansine at the 
previous dose level.
If Grade 3 diarrhea recurs:
o
Withhold venetoclax/placebo.
o
Withhold trastuzumab emtansine.
When diarrhea has improved to Grade 1, 
resume venetoclax/placebo at one dose level 
reduction (refer to Table 4). Resume
trastuzumab emtansine at the previous dose 
level.
Grade 3 increased 
transaminase (AST/ALT)
(5 to 20ULN)
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.  
o
When AST/ALT recovers to Grade 2, resume
trastuzumab emtansine reduced by one dose level (refer 
to Table 5). Resume venetoclax/placebo at previous 
dose. 
Grade 4 increased 
transaminase (AST/ALT)
(20ULN)
Discontinue both trastuzumab emtansine and venetoclax/placebo. 
o
Laboratory tests may be repeated (within 24 hours) to 
exclude laboratory error prior to discontinuing 
trastuzumab emtansine.
TBILI increase 1.5 ULN 
to 3 ULN (Grade 2)
Withhold both venetoclax/placebo.
Withhold trastuzumab emtansine.
When TBILI recovers to 1.5 ULN, resume 
venetoclax/placebo and trastuzumab emtansine 
at the previous dose level.
TBILI increase 3 ULN 
to 10 ULN (Grade 3)
Withhold both venetoclax/placebo. 
Withhold trastuzumab emtansine. 
o
When TBILI recovers to 1.5 ULN, resume venetoclax 
at the previous dose level and trastuzumab emtansine 
with one dose level reduction (refer Table 5).  
o
Discontinue trastuzumab emtansine if the event has not 
resolved to 1.5 ULN within 42 days after the last 
dose received.
TBILI increase 10 ULN 
(Grade 4)
Discontinue venetoclax/placebo and trastuzumab emtansine.
TBILI total bilirubin; ULN upper limit of normal.


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Recommendations for the initial management of electrolyte imbalances and prevention 
of TLS are provided in Appendix 7. Additional guidelines are provided in the subsections 
below.
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 GCP, 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 5.3.5.10 and 
Section 5.3.5.11 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
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:

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 5.3.5.8)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

TLS

Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with 
symptomatic bleeding

Grade 3 diarrhea

Pneumonitis


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
Grade 3 infusion-related reaction or hypersensitivity reaction

Grade 4 febrile neutropenia
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 the 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, discontinuation of medications) should be reported (see 
Section 5.2.3 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
last dose of study drug or initiation of another anticancer therapy (whichever occurs first).
Serious adverse events and adverse events of special interest will continue to be
reported (independent of causality) until 90 days after the last dose of study drug or until
initiation of new systemic anticancer therapy, whichever occurs first.
The Sponsor should be notified if the investigator becomes aware of any serious
adverse event or adverse event of special interest that occur after the end of the adverse
event reporting period (defined as 90 days after the last dose of study drug), if the event
is believed to be related to prior treatment with study drug, regardless if the patient has
initiated another anticancer therapy treatment (Section 5.2.3).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of 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?" 


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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 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 7
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 
ageappropriate- instrumental activities of daily living a
3
Severe or medically significant, but not immediately lifethreatening-; 
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"
accordingly.  The following guidance should be taken into consideration:

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


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
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
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
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 as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF.
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 timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
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 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).


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5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
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 HER2-positive MBC 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). An IMC will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.


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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Metastatic Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on both clinical and laboratory findings (physical exam, biopsy, 
breast imaging, radiologic evidence, etc.).  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 preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying MBC
An event that leads to hospitalization under the following circumstances is not 
considered to be serious adverse event, but should be reported as adverse events 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours


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Hospitalization for a minor condition for which the patient suffers an adverse event, 
but does not meet the definition of an overnight admission (e.g., tooth extraction)
5.3.5.12
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose}

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm}

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, 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 
trastuzumab emtansine, venetoclax or matching placebo, adverse events associated 
with special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.


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
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 trastuzumab emtansine, venetoclax or 
matching placebo, 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.

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.


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5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
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 5.2.2; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional 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
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
, M.D.
Mobile Telephone No.:
Alternate Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
, M.D., Ph.D.
Mobile Telephone No.:


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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug after the final
dose of study drug or until initiation of another anticancer therapy, whichever occurs first.  
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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study treatment 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 to immediately inform the 
investigator if they become pregnant during the study or within 30 days after the final 
dose of venetoclax or 7 months after the last dose of trastuzumab emtansine, whichever 


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occurs last.  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.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
7 months after the last dose of trastuzumab emtansine.  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.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
drug.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy 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.


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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 study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 28 days after the final
dose of study drug), 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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
Trastuzumab emtansine
Trastuzumab Emtansine Investigator's Brochure
Venetoclax
Venetoclax Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An IMC will monitor efficacy and safety data during the study.  An aggregate report of 
any clinically relevant imbalances that do not favor the test product will be submitted to 
health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The analysis populations are defined as follows:

The ITT population for the Phase II portion of the study is defined as all randomized 
patients, whether or not they were assigned to the arm where the study drug was 
administered.

The ITT population for the non-randomized cohorts is defined as all enrolled
patients who received any drug.

The Bcl-2 high population consists of patients within the ITT population with 50% 
of tumor cells stained with an intensity of IHC 2+ or 3+.

The safety-evaluable population is defined as patients who received any amount of 
any component of the investigational or non-investigational study treatments.
The ITT population is the primary analysis population for efficacy for the study, and 
efficacy analyses will be analyzed according to the intended treatment. Efficacy
analyses will also be performed in the Bcl-2 high population. Safety analyses will be 
performed in the safety population according to treatment received. 


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Analyses will be performed separately for the dose-escalation phase, expansion phase, 
and randomized Phase II stage of the study.
The primary efficacy analysis will be performed in the ITT population of the randomized 
Phase II stage, which will be based on the co-primary endpoints of ORR and PFS. A 
key secondary efficacy analysis will be efficacy analyses in the Bcl-2 high population of 
the randomized Phase II stage.  Descriptive efficacy analyses will also be performed on 
the non-randomized cohorts.
6.1
DETERMINATION OF SAMPLE SIZE
6.1.1
Dose-Escalation Phase
The sample size for the dose-escalation phase is based on the dose-escalation rules 
described in the protocol. The planned enrollment for the dose-escalation phase is 
approximately 624 patients enrolled across 24 dose-escalation treatment groups. 
6.1.2
Expansion Phase
Approximately 20 patients each may be enrolled in the expansion phase (trastuzumab 
emtansine-experienced cohort and trastuzumab deruxtecan-experienced cohort).
With 20 patients per cohort and an observed ORR of 60%, the exact 90% Clopper-
Pearson confidence interval for the ORR would be 39%78%, which would rule out an 
ORR of 35% or less.
Table 8 provides exact 90% confidence intervals for a range of observed proportions of 
ORR based on a sample size of 20 patients.
Table 8
Potential 90% Confidence Interval Estimated for the True ORR
Observed ORR
Exact 90% Confidence Interval for 
the True ORR
40%
(22%, 61%)
50%
(30%, 70%)
55%
(34%, 74%)
60%
(39%, 78%)
65%
(44%, 82%)
70%
(50%, 70%)
ORR objective response rate.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of 
observing at least one such event in a cohort of 20 patients is 87.8%, 64.2%, and 18.2%, 
respectively.  Table 9 describes exact 90% confidence intervals for a range of observed 
proportions of adverse events based on a sample size of 20 patients.


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Table 9
Potential 90% Confidence Interval Estimates for Adverse Event 
Rates
Observed Event Rate
Exact 90% Confidence Interval for 
the True ORR
1%
(0%, 16%)
5%
(0%, 22%)
10%
(2%, 28%)
20%
(7%, 40%)
30%
(14%, 51%)
ORR objective response rate.
6.1.3
Randomized Phase II Stage
After the RP2D has been determined for venetoclax when given in combination with a 
fixed dose of trastuzumab emtansine, a total of 220 patients will be enrolled in the 
randomized Phase II stage of the study. The purpose of the randomized Phase II stage
is estimation and hypothesis generation regarding the effect of venetoclax in 
combination with trastuzumab emtansine on ORR and duration of PFS relative to 
trastuzumab emtansine plus placebo.  The point and interval estimates of the true 
underlying HR will be obtained.  
For the co-primary endpoints of ORR and PFS in the primary efficacy analysis 
population, the trial will have:

85% power (0.05) to detect a 20% improvement in ORR (i.e., ORR ) (assuming 
a 44% ORR in the trastuzumab emtansine plus placebo arm). In the meantime, a 
20% improvement in ORR will have a 95% CI of (7%, 33%).

90% power (0.05) to detect a PFS HR of 0.6 venetoclax plus trastuzumab 
emtansine arm relative to the trastuzumab emtansine plus placebo arm, when 
approximately 161 total PFS events have occurred. In the meantime, a PFS HR of 
0.6 will have a 95% CI of (0.44, 0.82). The assumptions of the sample size 
calculation are that the median PFS in the control arm is 6.8 months and that 
enrollment would occur non-uniformly over 24 months. Enrollment is anticipated to 
be lower during the second half of the enrolment period because it will be restricted 
to the Bcl-2 high population.
Within the Bcl-2 high population the study will have:

85% power (0.05) to detect a PFS HR of 0.5 venetoclax plus trastuzumab 
emtansine arm relative to the trastuzumab emtansine plus placebo arm, when 
approximately 75 total PFS events have occurred. In the meantime, a PFS HR of 
0.5 will have a 95% CI of (0.32, 0.79).


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The study will not, however, have adequate power to detect all potentially clinically 
meaningful differences in ORR and PFS.  For example, within the entire ITT population:

With 110 patients in each arm, there is only 60% power (0.05) to detect a 15% 
improvement in ORR (assuming a 44% ORR in the trastuzumab emtansine plus 
placebo arm), and 

With approximately 161 total PFS events, only 62% power (0.05) to detect an HR 
of 0.70, in venetoclax plus trastuzumab emtansine arm relative to the trastuzumab 
emtansine plus placebo arm.  
Thus, a statistically negative outcome in any of the co-primary endpoints does not 
necessarily rule out a clinically meaningful outcome. The below tables show the power 
and CIs for several possible true underlying improvements in ORR and PFS in favor of 
the venetoclax plus trastuzumab emtansine arm. 
Due to the smaller sample size of the Bcl-2 high population the power to detect a HR of 
0.60 in the Bcl-2 population is 60% compared to 90% for the entire ITT population. The 
study has adequate power (85%) to detect a HR of 0.5 in the Bcl-2 high population.
Table 10 Operating Characteristics for Proposed Study Design for 
Possible True Underlying ORR Values
True Underlying ORR 
15%
20%
25%
Power to detect ORR a
60%
85%
96%
95% confidence interval 
for true ORR b
(2%, 28%)
(7%, 33%)
(12%, 38%)
ORR objective response rate.
Note:  trastuzumab emtansine plus placebo arm is assumed to have an ORR of 44%. Results are 
based on 110 patients in each arm.
a
Two-sided 0.05.
b
Confidence intervals are based on the assumption that the point estimate is equal to the true underlying 
value of the ORR in each column.


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Table 11 Operating Characteristics for Proposed Study Design for 
Possible True Underlying PFS Hazard Ratio Values
True Underlying Hazard Ratio
0.60
0.65
0.70
0.75
Power of log-rank test a
90%
78%
62%
44%
95% confidence interval 
for true hazard ratio b
(0.44, 0.82)
(0.48, 0.89)
(0.51, 0.95)
(0.55, 1.00)
Note:  Operating characteristics are based on the following assumptions:  event times are exponentially 
distributed, median PFS in the trastuzumab emtansine plus placebo arm is 6.8 months, 161 total PFS 
events.
a
Two-sided 0.05.
b
Confidence intervals are based on the assumption that the point estimate is equal to the true underlying 
value of the hazard ratio in each column.
Table 12 Operating Characteristics in the Bcl-2 High Group for Proposed 
Study Design for Possible True Underlying PFS Hazard Ratio 
Values
True Underlying Hazard Ratio
0.50
0.55
0.60
0.65
Power of log-rank test a
85%
73%
60%
46%
95% confidence interval 
for true hazard ratio b
(0.32, 0.79)
(0.35, 0.86)
(0.38, 0.94)
(0.41, 1.00)
Note:  Operating characteristics are based on the following assumptions:  event times are exponentially 
distributed, median PFS in the trastuzumab emtansine plus placebo arm is 6.8 months, 75 total PFS events.
a
Two-sided 0.05.
b
Confidence intervals are based on the assumption that the point estimate is equal to the true underlying value 
of the hazard ratio in each column.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized by treatment arm and for all randomized patients within each phase of the 
study. 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 DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race, lines of prior 
therapy, rapid disease progression to first-line therapy, Bcl-2 status, ER status, site of 
disease, and presence of visceral/liver metastases) will be summarized using means, 


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standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables, as appropriate.  Summaries will be presented overall and by 
treatment group.
6.4
EFFICACY ANALYSES (RANDOMIZED PHASE II STAGE ONLY)
The primary efficacy analysis population will consist of all randomized patients, with 
patients grouped according to their assigned treatment (the ITT population).
The primary efficacy analysis will occur when 161 patients have experienced a PFS 
event. It is anticipated that this will occur six months after the last patient enters 
treatment.
6.4.1
Co-Primary Efficacy Endpoints
6.4.1.1
Objective Response Rate
The co-primary endpoint ORR is defined as the proportion of patients with CR or PR as 
assessed by the investigator on two consecutive assessments at least 28 days apart 
using the criteria in RECIST v1.1. Patients with no disease assessments for any reason 
will be classified as non-responders. An estimate of ORR with 95% CI will be calculated 
for each treatment arm using the normal approximation to the binomial distribution. An 
estimate and 95% CI for the difference in ORR between the two treatment groups will be 
presented based on the normal approximation to the binomial distribution.
6.4.1.2
Progression-Free Survival
The co-primary efficacy endpoint PFS is defined as the time from randomization to the 
first occurrence of disease progression (as defined by the investigator according to 
RECIST v1.1) or death from any cause, whichever comes first. Data for patients without 
the occurrence of disease progression or death as of the clinical data cut-off date will be 
censored at the time of last tumor assessment (or the time of randomization plus 1 day if 
no tumor assessment was performed after the baseline visit).
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm. 
Kaplan-Meier curves of time to PFS for each treatment group will be provided. The Cox 
proportional hazards model stratified by the randomization stratification factors (Bcl-2
status [high, low], visceral disease [yes, no], and HER2 status IHC 3+ [yes, no] will be 
used to provide an estimate of the hazard ratio of venetoclax plus trastuzumab 
emtansine to placebo plus trastuzumab emtansine with associated 95% CI and p-value. 
The unstratified hazard ratio estimate and 95% CI will also be presented. 
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Duration of Objective Response
DOR is defined as the time from the first documented objective response (CR or PR) to 
the time of first documented disease progression (as determined by the investigator 
using RECIST v1.1) or death from any cause, whichever occurs first. Data for patients 


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without the occurrence of disease progression or death as of the clinical data cut-off will 
be censored at the time of the last tumor assessment.
DOR will be estimated using the Kaplan-Meier methodology. Only patients achieving a 
CR or PR will be included in the assessment of DOR. No formal hypothesis testing will 
be performed due to the non-randomized population.
6.4.2.2
Overall Survival
OS is defined as time from randomization to death from any cause. Data for patients 
who are alive at the time of the analysis data cut-off will be censored at the last date they 
were known to be alive. Data from patients without postbaseline information will be 
censored at the date of randomization plus 1 day.
OS will be analyzed using the same methodology as PFS (see Section 6.4.1).
6.4.3
Exploratory Efficacy Endpoints
6.4.3.1
Clinical Benefit Rate
CBR is defined as CR or PR (as defined in Section 6.4.1) or achieving SD lasting 
6 months from randomization as assessed by the investigator using RECIST v1.1.
Patients with no disease assessments for any reason will be classified as non-
responders.
CBR will be analyzed using the same methodology as ORR (see Section 6.4.1).
6.4.3.2
Patient-Reported Outcomes Data
Summary statistics and the mean change from baseline of linear-transformed scores will 
be reported for all of the items and subscales of the EORTC QLQ-C30 and EORTC IL46 
(an item for trouble with side effects) questionnaires at each timepoint, at the end of 
treatment, at the time of progression, and at the time of clinical progression (if different 
from time to progression). In addition, mean scores for global health status, physical 
functioning, and selected symptom scales will be presented. The scores will be derived 
according to the EORTC scoring manual guidelines. 
Completion and compliance rates will be summarized at each timepoint by treatment 
arm. The analysis populations for PRO changes will be all randomized patients with a 
non-missing baseline assessment and at least one non-missing post-baseline 
assessment.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received. 


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6.5.1
Analyses of Exposure, Adverse Event, Laboratory, and Vital 
Sign Data
Safety will be assessed separately for each study phase through summaries of exposure 
to study treatment, adverse events, changes in laboratory test results, and changes in 
vital signs and ECGs.
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  All adverse events, serious adverse events, adverse 
events leading to death, adverse events of special interest, and adverse events leading 
to study treatment discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized. 
6.6
PHARMACOKINETIC ANALYSES
Individual pharmacokinetic concentration data will be tabulated and summarized (e.g., 
mean, standard deviation, coefficient of variation, median, minimum, and maximum) 
after appropriate grouping.  Pharmacokinetic parameters may also be calculated as data 
allow (e.g., Cmax, AUC, clearance, volume of distribution, half-life, etc.) and tabulated 
and/or summarized after appropriate grouping.  Population PK analyses of concentration 
data (with or without the PK data from other studies) may be conducted as appropriate. 
Potential PK DDIs may be assessed by comparison with relevant historical data for 
venetoclax and/or trastuzumab emtansine. Potential correlations between exposure and 
response (e.g., PD, efficacy, ECG, and safety endpoints) may also be explored, if 
warranted.  
The results of population PK analyses and exploratory exposure-response analyses may 
be reported separately from the clinical study report.  At the discretion of the Sponsor, all 
analyses may be extended to include relevant biotransformation products of venetoclax 
and/or trastuzumab emtansine.


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6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients for
trastuzumab emtansine at baseline (baseline prevalence) and after drug administration 
(postbaseline incidence) will be summarized by treatment group.  When determining 
postbaseline incidence, patients are considered to be ADA positive if: 1) they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response) or 2) they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all postbaseline samples are negative, or if they are ADA positive at 
baseline but do not have any postbaseline samples with a titer that is at least 0.60 titer 
unit greater than the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies to better understand disease pathobiology and guide the development of new 
therapeutic approaches. Exploratory biomarker analyses may be performed in an effort 
to understand the association of these biomarkers with study treatment response. 
Results will be presented in a separate report.
6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analyses (Randomized Phase II Stage Only)
Periodic analyses of cumulative safety data and one interim analysis is planned for this 
study. Given the hypothesis-generating nature of this study, the Sponsor considers the 
interim efficacy analysis as exploratory.
The planned interim efficacy analysis of cumulative safety, ORR, and PFS will occur 
when approximately 56 PFS events have occurred. This is expected to occur after the 
enrollment of the first 110 patients who have been followed up for at least 6 months.
If the interim analysis coincides within approximately 1 month of a planned safety review, 
the safety review may be combined with the efficacy interim analyses.  Outcomes from 
these reviews that may affect study conduct will be communicated in a timely manner to 
the investigators, and IRBs/ECs will be notified.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
Where PRO data (EORTC QLQ-C30 and IL46) are captured via paper questionnaires, 
data will be entered into the EDC system by site staff. Otherwise, PRO data will be 
collected through the use of an electronic device provided by a vendor (see Section 7.3
for details).
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 Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT REPORTED OUTCOME DATA
Where an electronic device is be used to capture PRO data, the device will be designed 
for entry of data in a way that is attributable, secure, and accurate, in compliance with 
U.S. FDA regulations for electronic records (21 CFR Part 11).  The data will be 
transmitted to a centralized database maintained by the electronic device vendor.
Where a device-based system is employed, the electronic data will be available for view 
access only, via a secure web server. Only identified and trained users may view the 


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data, and their actions will become part of the audit trail.  The Sponsor will have view 
access only.  System backups for data stored by the Sponsor and records retention for 
the study data will be consistent with the Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format.
7.4
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.
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 7.6.
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.
7.5
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 


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of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.


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


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The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
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
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication (see Section 9.5).
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 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 9.5).


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.


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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
In the U.S., this trial will be sponsored and managed by Genentech. F. Hoffmann-La 
Roche Ltd will sponsor this trial outside of the U.S. with management responsibilities 
being shared by Genentech and Roche. Genentech and Roche have authorized Roche 
Registrations, a company formed under the laws of England, to act as their legally 
authorized representative for the purposes of Article 19 of Directive 2001/20/EC relating 
to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use. Reference to “Sponsor” in this protocol will mean Genentech for the United 
States and F. Hoffmann−La Roche Ltd for all countries outside of the United States.
Approximately 145 sites globally will participate in this study to enroll approximately 284
patients. Data will be recorded via an EDC system from Medidata Solutions (New York, 
NY, with use of eCRFs; see Section 7.2). Central laboratories will be used for the 
analyses of and/or management of PK, PD, genotyping, and tissue samples. An IxRS 
will be used for patient registration, patient number, and dose assignment.
An IMC will review data on a regular basis at predefined timepoints during the study. 
The IMC will review results from the analyses of unblinded safety data and make 
recommendations to the Sponsor regarding continuation and/or modification of the study. 
The final decision on the IMC recommendation will be made by the Sponsor. The details 
of the composition, roles, and responsibilities of the IMC will be documented in detail in 
the IMC charter and submitted to Health Authorities as applicable.
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 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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 


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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.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1:  Schedule of Activities: Dose Escalation (cont.)
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148/Protocol CO41863, Version 1
h
A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Limited, symptom-directed physical examinations should be performed at specified postbaseline visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF.
j
Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline and/or previous cycle.
k
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature. Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
l
Hematology includes CBC, with RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
and other cells), and platelet count. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may 
be done on the day of randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to 
administration of the first dose of study treatment. Hematologic evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 
3 days before).
m Serum chemistry includes glucose, BUN or urea, sodium, magnesium, chloride, bicarbonate, total bilirubin, ALT, AST, alkaline phosphatase, total protein, and 
albumin. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may be done on the day of 
randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to administration of the first dose 
of study treatment. Chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).
n
TLS laboratory assessments collected during dose escalation include serum creatinine, uric acid, potassium, calcium, phosphorous and LDH. If the screening 
assessments were done within 3 days prior to Cycle 1, Day 1, there is no need to repeat the TLS panel at Cycle 1, Day 1. Refer to Appendix 8 for further 
instructions.
o
All patients will be tested for HIV prior to the inclusion into the study; HIV-positive patients will be excluded from the study. HBV serology includes HBsAg, total 
HBcAb, and (if HBsAg test is negative and total HBcAb test is positive) HBV DNA. HBV DNA must be collected on or before Cycle 1, Day 1, in patients who 
have negative serology for hepatitis B surface antigen and positive serology for anti-HBc. HCV serology includes HCV antibody and (if HCV antibody test is 
positive) HCV RNA.
p
Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.
q
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  During the treatment period, a
urine pregnancy test in women of childbearing potential in all treatment arms must be performed within 3 days prior study drug administration of every 3rd cycle
of protocol-mandated therapy. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. For patients who discontinue therapy 
before end of planned therapy, a pregnancy test must be done at the completion/early termination visit (within 28 days after the last dose of HER2-targeted 
therapy), at 3 months, and additionally at 6 months after the discontinuation of study treatment.


Appendix 1:  Schedule of Activities: Dose Escalation (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
149/Protocol CO41863, Version 1
r
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1, may be used rather than repeating 
tests. All measurable and evaluable lesions should be assessed and documented at the screening visit. See Section 4.5.5 for details on imaging and tumor 
assessments. Tumor response will be evaluated using RECIST v1.1 (Appendix 11). In the absence of disease progression, tumor assessments should continue 
regardless of whether patients discontinue study treatment, unless they withdraw consent or the study is terminated by the Sponsor, whichever occurs first. 
Results must be reviewed by the investigator before dosing at the next cycle. All tumor assessments should be documented in the eCRF before and after the 
primary PFS analysis.
s
A bone scan is to be performed within 28 days prior to Cycle 1, Day 1 (see Section 4.5.5 for further instructions).
t
CT/MRI scan of the brain is mandatory at screening and should be performed 1) with scheduled tumor assessments when identified as a site of involvement at 
baseline, 2) as clinically indicated, or 3) if a patient demonstrates control of systemic disease but has a newly developed isolated brain metastases and is eligible 
to remain on study treatment, a brain MRI or CT will be performed along with regularly scheduled tumor assessments.
u
A 12-lead ECG is required at screening. Subsequent ECGs may be performed as clinically indicated. ECGs for each patient should be obtained from the same 
machine wherever possible. ECG recordings must be performed after the patient has been resting in a supine position for at least 10 minutes.
v
LVEF assessment by ECHO is preferred, but LVEF may also be assessed by MUGA scan. The same method should be used throughout the study for each 
patient and preferably performed and evaluated by the same assessor.
w Venetoclax will be administered on a once daily dosing schedule.
x
Trastuzumab emtansine will be administered second by IV infusion at a dose of 3.6 mg/kg on Cycle 1 Day 1, and on Day 1 of each 21-day cycle thereafter. 
Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-related adverse events, over 
approximately 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. Patients will be monitored for 
any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related events, for a 
minimum of 30 minutes at subsequent infusions.
y
Auto-antibody testing includes anti-nuclear antibody, anti-double-stranded DNA, and circulating and perinuclear anti-neutrophil cytoplasmic antibody.  The 
baseline sample will be obtained pre-treatment at Cycle 1, Day 1, before the first dose of study drug. For patients who show evidence of immune-mediated 
toxicity, additional samples may be collected. All samples will be analyzed centrally.
z
At screening, the FFPE archival tumor block from the most recently collected, available tumor tissue or fresh core biopsy (3 cores) is mandated. If more than 
one FFPE block exists from different timepoints (e.g., initial diagnosis vs. metastatic disease tissue), the most recent block is mandatory to be sent. If the FFPE 
block from the earlier timepoint is available, then this would be requested to also be sent. In the cases of bilateral breast cancer, an additional 8 unstained slides 
from the contralateral breast to where FFPE block have been provided. At least 20 freshly serial cut, unstained slides will be acceptable in lieu of the FFPE 
block. Optional core biopsies will be obtained at Cycle 1, Day 1 and on Day 1 of any subsequent on treatment cycle (± 3 days) if patient consented. At the study 
drug discontinuation/early study completion visit, if reason for discontinuation is disease progression, a biopsy must be taken (if deemed clinically feasible) 
before next line of therapy begins, unless purely anti-hormonal therapy.






Appendix 2:  Schedule of Activities: Expansion Cohorts/Randomized Phase II (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
152/Protocol CO41863, Version 1
ADAanti-drug antibody; Bcl-2B-cell lymphoma 2; BSAbody surface area; C cycle; CT computed tomography; D day; ECG electrocardiogram; 
ECHOechocardiogram; ECOGEastern Cooperative Oncology Group; eCRF electronic Case Report Form; FFPEformalin-fixed, paraffin-embedded; 
HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; HER2human epidermal growth factor 
receptor 2; LVEFleft ventricular ejection fraction; MRImagnetic resonance imaging; MUGAmultiple-gated acquisition; NCnon-continuous; NYHANew York 
Heart Association; PETpositron emission tomography; PFSprogression-free survival; PKpharmacokinetic; RECISTResponse Evaluation Criteria in Solid 
Tumors; TLStumor lysis syndrome; TSHthyroid-stimulating hormone; ULNupper limit of normal.
Notes: With the exception of Day 1 of Cycle 1, all assessments should be performed within 3 days of the scheduled visit, unless otherwise specified. On treatment 
days, all assessments should be performed prior to dosing, unless otherwise specified. If the timing of a protocol-mandated procedure coincides with a holiday or 
weekend, it should be performed on the nearest following date. Results of standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 28 days prior to enrollment may be used; such tests do not need to be repeated for screening.
a
Visit Dates for Cycle 2 and subsequent cycles must be calculated utilizing the previous visit date ±3 days.
b
The treatment completion/discontinuation visit will optimally be scheduled for ≤30 days after last dose of study treatment.
c
Patients will be followed for survival, serious adverse events, and adverse events of special interest considered as related to study drug (Section 5.4.2). 
Subsequent anticancer therapies (not all concomitant medications) need to be reported approximately every 3 months starting from the study drug completion 
visit until death, loss to follow-up, withdrawal of consent, or study discontinuation by the Sponsor. Survival follow-up information will be collected every 6 months 
via telephone calls, patient medical records, and/or clinic visits.  Study staff may use a public information source (e.g., county records) to obtain information 
about survival status only where permitted.
d
Written informed consent must be obtained before any study-specific screening assessments are performed.
e
Demographics include age, sex, and self-reported race/ethnicity.
f
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive status. In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements, and foods that have been 
shown to inhibit CYP3A4 [Section 4.4.2]) used by the patient within 28 days prior to the Cycle 1, Day 1 visit. Breast cancer history includes prior cancer 
therapies and procedures.
g
Refer to Appendix 4 or tissue requirements related to eligibility. HER2 and or Bcl-2 status are required and must be centrally confirmed prior to treatment. 
h
A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Limited, symptom-directed physical examinations should be performed at specified postbaseline visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF.
j
Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline and/or previous cycle.
k
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature. Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.


Appendix 2:  Schedule of Activities: Expansion Cohorts/Randomized Phase II (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
153/Protocol CO41863, Version 1
l
Hematology includes CBC, with RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
and other cells), and platelet count. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may 
be done on the day of randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to 
administration of the first dose of study treatment. Hematologic evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 
3 days before).
m Serum chemistry includes glucose, BUN or urea, sodium, magnesium, chloride, bicarbonate, total bilirubin, ALT, AST, alkaline phosphatase, total protein, and 
albumin. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may be done on the day of 
randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to administration of the first 
dose of study treatment. Chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).
n
TLS assessment frequency during the dose-expansion and randomized phases will be determined based on a comprehensive review of data in the dose-
escalation phase. TLS laboratory assessments include serum creatinine, uric acid, potassium, calcium, phosphorous and LDH. If the screening assessments 
were done within 3 days prior to Cycle 1 Day 1, there is no need to repeat the TLS panel at Cycle 1 Day 1. Refer to Appendix 8 for further instructions.
o
All patients will be tested for HIV prior to the inclusion into the study; HIV-positive patients will be excluded from the study. HBV DNA must be collected on or 
before Cycle 1, Day 1, in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.
p
Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.
q
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  During the treatment period, a
urine pregnancy test in women of childbearing potential in all treatment arms must be performed within 3 days prior study drug administration of every 3rd cycle 
of protocol-mandated therapy. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. For patients who discontinue therapy 
before end of planned therapy, a pregnancy test must be done at the completion/early termination visit (within 28 days after the last dose of HER2-targeted 
therapy), at 3 months, and additionally at 6 months after the discontinuation of study treatment.
r
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1, may be used rather than repeating 
tests. All measurable and evaluable lesions should be assessed and documented at the screening visit. See Section 4.5.5 for details on imaging and tumor 
assessments. Tumor response will be evaluated using RECIST v1.1 (Appendix 11). In the absence of disease progression, tumor assessments should continue 
regardless of whether patients discontinue study treatment, unless they withdraw consent or the study is terminated by the Sponsor, whichever occurs first. 
Results must be reviewed by the investigator before dosing at the next cycle. All tumor assessments should be documented in the eCRF before and after the 
primary PFS analysis.
s
CT/MRI scan of the brain is mandatory at screening and should be performed 1) with scheduled tumor assessments when identified as a site of involvement at 
baseline, 2) as clinically indicated, or 3) if a patient demonstrates control of systemic disease but has a newly developed isolated brain metastases and is eligible 
to remain on study treatment, a brain MRI or CT will be performed along with regularly scheduled tumor assessments.
t
A bone scan is to be performed within 28 days prior to Cycle 1, Day 1 (see Section 4.5.5 for further instructions).
u
A 12-lead ECG is required at screening. Subsequent ECGs may be performed as clinically indicated. ECGs for each patient should be obtained from the same 
machine wherever possible. ECG recordings must be performed after the patient has been resting in a supine position for at least 10 minutes.
v
LVEF assessment by ECHO is preferred, but LVEF may also be assessed by MUGA scan. The same method should be used throughout the study for each 
patient and preferably performed and evaluated by the same assessor.


Appendix 2:  Schedule of Activities: Expansion Cohorts/Randomized Phase II (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
154/Protocol CO41863, Version 1
w ECHO or MUGA assessments will be performed every fourth cycle. Additional LVEF or MUGA measurements may be performed at the discretion of the 
investigator if LVEF declines are clinically suspected.  
x
Venetoclax/placebo will be administered on a once daily dosing schedule.  
y
Trastuzumab emtansine will be administered second by IV infusion at a dose of 3.6 mg/kg on Cycle 1 Day 1, and on Day 1 of each 21-day cycle thereafter. 
Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-related adverse events, over 
approximately 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. Patients will be monitored for 
any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related events, for a 
minimum of 30 minutes at subsequent infusions.
z
Serum and plasma samples for PK/ADA analysis will take place on Cycle 1, Day 1 for all patients and on Cycle 1, Day 8 for NC patients.
aa Blood for biomarker analysis will take place on Cycle 1, Day 1.
bb Auto-antibody testing includes anti-nuclear antibody, anti-double-stranded DNA, and circulating and perinuclear anti-neutrophil cytoplasmic antibody.  The 
baseline sample will be obtained pre-treatment at Cycle 1, Day 1, before the first dose of study drug. For patients who show evidence of immune-mediated 
toxicity, additional samples may be collected. All samples will be analyzed centrally.
cc At screening, the FFPE archival tumor block from the most recently collected, available tumor tissue or fresh core biopsy (3 cores) is mandated. If more than 
one FFPE block exists from different timepoints (e.g., initial diagnosis vs. metastatic disease tissue), the most recent block is mandatory to be sent. If the FFPE 
block from the earlier timepoint is available, then this would be requested to also be sent. In cases of bilateral breast cancer, an additional 8 unstained slides 
from the contralateral breast to where FFPE block have been provided. At least 20 freshly serial cut, unstained slides will be acceptable in lieu of the FFPE 
block. Optional core biopsies will be obtained at Cycle 1, Day 1 and on Day 1 of any subsequent on treatment cycle (3 days) if patient consented. At the study 
drug discontinuation/early study completion visit, if reason for discontinuation is disease progression, a biopsy must be taken (if deemed clinically feasible) 
before next line of therapy begins, unless purely anti-hormonal therapy.




Appendix 3:  Schedule of Pharmacokinetic and Immunogenicity Samples (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
156/Protocol CO41863, Version 1
ADA anti-therapeutic antibody; hr hour; min minute; PK pharmacokinetic.
Notes: PK and ADA samples are to be collected, prepared, and shipped according to procedures outlined in the separate laboratory manual.  
Record exact date and time of venetoclax dosing on the day of and the day prior to the date of PK sampling.  Patients should record venetoclax 
doses taken at home in a dosing diary. Record exact date and time of all PK and ADA sample collections.  Sample collection times are relative to 
the administration of the study drug being measured.
a Venetoclax should be administered in the clinic on days that venetoclax PK sample is to be taken. Venetoclax PK will be collected for patients 
enrolled in all study phases.
b Total trastuzumab PK will be collected for patients enrolled in all study phases.
c Trastuzumab emtansine PK and ADA to trastuzumab emtansine samples will only be collected for patients enrolled in the randomized Phase II 
stage.




Appendix 3:  Schedule of Pharmacokinetic and Immunogenicity Samples (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
158/Protocol CO41863, Version 1
ADA anti-therapeutic antibody; discon discontinuation; hr hour; min minute; PK pharmacokinetic.
Notes: PK and ADA samples are to be collected, prepared, and shipped according to procedures outlined in the separate laboratory manual.
Record exact date and time of venetoclax dosing on the day of and the day prior to the date of PK sampling.  Patients should record venetoclax 
doses taken at home in a dosing diary. Record exact date and time of all PK and ADA sample collections.  Sample collection times are relative to 
the administration of the study drug being measured.
a Venetoclax should be administered in the clinic on days that venetoclax PK sample is to be taken. Venetoclax PK will be collected for patients 
enrolled in all study phases.
b Total trastuzumab PK will be collected for patients enrolled in all study phases.
c Trastuzumab emtansine PK and ADA to trastuzumab emtansine samples will only be collected for patients enrolled in the randomized Phase II 
stage.
d
For a 7 out of 21 day venetoclax dosing schedule, where no dose is scheduled on Day 8 of each cycle, samples should be drawn on Day 7 of 
the cycle, with allowance to collect on Day 5 or 6 to avoid a weekend or holiday. 






Venetoclax—F. Hoffmann-La Roche Ltd
161/Protocol CO41863, Version 1
Appendix 5
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:

Stop the study treatment infusion.

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.


Venetoclax—F. Hoffmann-La Roche Ltd
162/Protocol CO41863, Version 1
Appendix 6
Patient-Reported Outcomes Questionnaires
Figure 1
EORTC QLQ-30 (Version 3)


Appendix 6:  Patient-Reported Outcomes Questionnaires (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
163/Protocol CO41863, Version 1
Figure 1
EORTC QLQ-30 (Version 3) (cont.)


Appendix 6:  Patient-Reported Outcomes Questionnaires (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
164/Protocol CO41863, Version 1
Figure 2
EORTC IL46


Venetoclax—F. Hoffmann-La Roche Ltd
165/Protocol CO41863, Version 1
Appendix 7
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome 
FIRST DOSE OF VENETOCLAX 

Within the first 24 hours after the first dose, if any laboratory criteria below are met, 
the patient should be hospitalized for monitoring and the investigator notified.  No 
additional venetoclax doses should be administered until resolution.  A rapidly rising 
serum potassium level is a medical emergency. 

Nephrology (or acute dialysis service) must be consulted/contacted on admission
(per institutional standards to ensure emergency dialysis is available). 

IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/h 
rounded to the nearest 10 mL (target 150200 mL/hr; not 50 mL/hr).  Modification 
of fluid rate should also be considered for individuals with specific medical needs. 

Monitor for symptoms or signs of tumor lysis syndrome (TLS) (e.g., fever, chills, 
tachycardia, nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches, 
weakness, paresthesias, mental status changes, confusion, and seizures).  If any 
clinical features are observed, recheck potassium, phosphorus, uric acid, calcium, 
and creatinine within 1 hour STAT. 

Vital signs should be taken at time of all blood draws or any intervention. 

The management recommendations below focus on the minimum initial responses
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and 
multidisciplinary management will be as per institutional protocols. 
In addition to the recommendations for patients receiving first dose of venetoclax: 

For potassium increase 0.5 mmol/L from baseline, or any value 5.0 mmol/L, 
recheck potassium, phosphorus, uric acid, calcium, and creatinine within 1 hour 
STAT and follow first guideline. 

For phosphorus increase of 0.5 mg/dL AND 4.5 mg/dL, administer phosphate
binder and recheck potassium, phosphorus, uric acid, calcium, and creatinine within 
1 hour STAT. 
The Sponsor may explore a different TLS lab schedule in the randomized Phase II 
expansion portion of the study based on findings in dose-escalation phase.


Venetoclax—F. Hoffmann-La Roche Ltd
166/Protocol CO41863, Version 1
Appendix 8
Guidelines for Defining Tumor Lysis Syndrome
All tumor lysis syndrome events should be graded per the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0 criteria.
Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring 
during the same 24-hour period within 3 days before the start of therapy or 7 days after 
the start of therapy.  For the purposes of this study, this window applies to the initiation 
of any study therapy and each dose escalation of venetoclax.  Furthermore, this 
assessment assumes that a patient has or will receive adequate hydration 
(alkalinization) and a hypouricemic agent(s).
Table 1
Howard Definition of Laboratory Tumor Lysis Syndrome
Laboratory Assessment
Range
Uric acid
476 mol/L (8.0 mg/dL)
Potassium
6.0 mmol/L (6.0 mEq/L)
Phosphorous
1.5 mmol/L (4.5 mg/dL)
Corrected calcium
1.75 mmol/L (7.0 mg/dL) or ionized calcium 1.12 (0.3 mmol/L) a
Note:  Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring during the 
same 24-hour period within 3 days before the start of therapy or 7 days afterward. For the 
purposes of this study, this window applies to the initiation of any study therapy and each dose 
escalation of venetoclax. Furthermore, this assessment assumes that a patient has or will 
receive adequate hydration (± alkalinization) and a hypouricemic agent(s).
a The corrected calcium level in mg/dL is the measured calcium in mg/dL(0.8[4-albumin in 
g/dL]).


Appendix 8:  Guidelines for Defining Tumor Lysis Syndrome (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
167/Protocol CO41863, Version 1
Table 2
Howard Definition of Clinical Tumor Lysis Syndrome
The presence of laboratory TLS and one or more of the following criteria:
Creatinine a:  An increase in serum creatinine level of 0.3 mg/dL (26.5 µmol/L); a single value 
1.5 times the ULN of the age appropriate normal range if no baseline creatinine measurement 
is available; or the presence of oliguria, defined as average urine output of 0.5 mL/kg/hour for 
6 hours
Cardiac dysrhythmia or sudden death probably or definitely caused by hyperkalemia
Cardiac dysrhythmia, sudden death, seizure, neuromuscular irritability (tetany, paresthesias, 
muscle twitching, carpopedal spasm, Trousseau’s sign, Chvostek’s sign, layngospasm or 
bronchospasm), hypotension, or heart failure probably or definitely caused by hypocalcemiab
TLStumor lysis syndrome; ULNupper limit of normal.
a Acute kidney injury is defined as an increase in the creatinine level of 0.3 mg/dL 
(26.5 umol/L) or a period of oliguria lasting 6 hours.  By definition, if acute kidney injury is 
present, the patient has clinical TLS.
b Not directly attributable to a therapeutic agent.
REFERENCE
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. New Engl J Med 
2011;364:184454.


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Appendix 9
Management of Venetoclax-Specific Adverse Events
Event
Action to Be Taken
Non-hematologic toxicity
(Not specifically described 
in Table 6)
Grade 3 or 4 
non-hematologic events 
Delay venetoclax for a maximum of 28 days.
First episode:  If improvement to Grade 1 or baseline, resume 
previous doses of venetoclax.
For subsequent episodes:  If improvement to Grade 1 or 
baseline, restart venetoclax at one dose level reduction.
Certain treatment emergent non-hematologic adverse events 
(e.g., venous thromboembolic events) may be managed and 
become clinically stable following medical intervention but may 
not improve to Grade 1 according to the NCI CTCAE definitions.  
In such cases, if a patient is clinically stable, resumption of study 
drug may be possible after consultation with the Medical Monitor.
Grade 2 related non-
hematologic toxicity
Delay treatment with venetoclax until resolution to Grade 1 (or 
baseline status) for a maximum of 28 days. 
After resolution, resume full dose of venetoclax.
Grade 1 non-hematologic 
toxicity
No dose reduction or delay.


Venetoclax—F. Hoffmann-La Roche Ltd
169/Protocol CO41863, Version 1
Appendix 10
Management of Trastuzumab Emtansine-Specific Adverse Events
Event
Action to Be Taken
Left ventricular dysfunction
Symptomatic congestive heart failure
Discontinue trastuzumab emtansine.
Asymptomatic LVEF decrease
LVEF 45%
Continue trastuzumab emtansine at the same dose level.
LVEF 40% to 45% and decrease 
from baseline of 10% points
Withhold trastuzumab emtansine.  Repeat LVEF assessment within 3 weeks.  If LVEF decrease from 
baseline of 10% points is confirmed, discontinue trastuzumab emtansine.
LVEF 40% to 45% and decrease 
from baseline of 10% points
Continue trastuzumab emtansine at the same dose level.  Repeat LVEF assessment within 3 weeks.
LVEF 40%
Withhold trastuzumab emtansine.  Repeat LVEF assessment within 3 weeks.  If LVEF 40% is confirmed, 
discontinue trastuzumab emtansine.
Infusion-related reaction (caused by cytokine release) or hypersensitivity (allergic) reaction
Grade 2 reaction
Decrease trastuzumab emtansine infusion rate or interrupt infusion.  Administer supportive care with oxygen, 
-agonists, antihistamines, antipyretics, or corticosteroids, as appropriate, at the investigator’s discretion.  
Monitor patient until complete resolution of symptoms.  
May continue trastuzumab emtansine at the same dose level at the investigator’s discretion.   In the event of 
a true hypersensitivity reaction (in which severity of reaction increases with subsequent infusions), 
discontinue trastuzumab emtansine.
Premedication for infusion reactions (e.g., antihistamines such as diphenhydramine or corticosteroids) may be 
given at the investigator’s discretion.
Grade 3 reaction
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s discretion.  Monitor patient until complete 
resolution of symptoms.  
May continue trastuzumab emtansine at the same dose level at the investigator’s discretion.  In the event of a 
true hypersensitivity reaction (in which severity of reaction increases with subsequent infusions), discontinue 
trastuzumab emtansine.
Premedication for infusion reactions (e.g., antihistamines such as diphenhydramine or corticosteroids) may 


Appendix 10:  Management of Trastuzumab Emtansine-Specific Adverse Events (cont.)
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Event
Action to Be Taken
be given at the investigator’s discretion.
Grade 4 reaction
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s discretion.  Monitor patient until complete 
resolution of symptoms.
Discontinue trastuzumab emtansine.
Neurotoxicity
Grade 3 peripheral neuropathy
Withhold trastuzumab emtansine until recovery to Grade 2.  
Following recovery, resume trastuzumab emtansine at the same dose level or with one dose level reduction, 
at the investigator's discretion.  
Discontinue trastuzumab emtansine if the event has not resolved to Grade 2 within 42 days after the last 
dose received.
Interstitial Lung Disease and Pneumonitis
Grades 14
Discontinue trastuzumab emtansine treatment.  
NRH
If there are signs of portal hypertension (e.g., ascites and/or varices) and/or a cirrhosis-like pattern is seen on 
a CT scan of the liver, the possibility of NRH should be considered.  
Discontinue trastuzumab emtansine treatment and have the patient evaluated by a hepatologist.
LVEF left ventricular ejection fraction, LVSD left ventricular systolic dysfunction; NRH Nodular Regenerative Hyperplasia. 


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Appendix 11
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.


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DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
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 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 


Appendix 11:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (cont.)
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METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 


Appendix 11:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (cont.)
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non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation .
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 


Appendix 11:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (cont.)
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but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple 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").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked).


Appendix 11:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (cont.)
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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the CRF as part of the assessment of non-
target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline) 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD


Appendix 11:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (cont.)
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CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities.

CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
"new" cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 


Appendix 11:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (cont.)
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there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 1
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and during the study only two lesions were assessed, but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 


Appendix 11:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (cont.)
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progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  


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Appendix 12
National Cancer Institute Common Terminology Criteria
In the present study, toxicities will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 
A pdf of the NCI CTCAE v5.0 can be downloaded from the following website:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Investigators who do not have access to Internet can contact the Data Center to receive 
a hard copy of this document by mail.


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Appendix 13
Guidelines for Liver Biopsy
Because nodular regenerative hyperplasia (NRH) can be a very subtle diagnosis to 
make on liver biopsy, every attempt should be made to maximize the amount of tissue 
obtained.  
The needle used should be at least 18 gauge, and percutaneous biopsies of length at 
least 1.5 cm are recommended, if clinically appropriate.  In order to diagnose NRH, 
reticulin and trichrome stains are necessary.
Smaller biopsies obtained via a transjugular approach and smaller biopsy gun needle 
biopsies are discouraged.  Small wedge biopsies should also be discouraged.






FINAL PROTOCOL APPROVAL
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.
Venetoclax F. Hoffmann-La Roche Ltd
Protocol CO41863, Version 2 (VHP)
PROTOCOL
TITLE:
A PHASE Ib/II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
EVALUATING THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF VENETOCLAX 
IN COMBINATION WITH TRASTUZUMAB EMTANSINE IN 
PATIENTS WITH PREVIOUSLY TREATED HER2-POSITIVE 
LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER
PROTOCOL NUMBER:
CO41863
VERSION NUMBER:
2 (VHP)
EUDRACT NUMBER:
2019-004200-35
IND NUMBER:
137088
NCT NUMBER:
NCT04298918
TEST PRODUCT:
Venetoclax (RO5537382)
Trastuzumab emtansine (RO5304020)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
06-Apr-2020 20:30:50
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Venetoclax—F. Hoffmann-La Roche Ltd
2/Protocol CO41863, Version 2 (VHP)
PROTOCOL HISTORY
Protocol
Version
Date Final
1
19 December 2019


Venetoclax—F. Hoffmann-La Roche Ltd
3/Protocol CO41863, Version 2 (VHP)
PROTOCOL AMENDMENT, VERSION 2 (VHP):
RATIONALE
Protocol CO41863 has been amended to address a request from the Italian Health 
Authority, the reference competent authority in this Voluntary Harmonisation Procedure
(VHP).  Changes to the protocol, along with a rationale for each change, are 
summarized below:

Section 3.1.1 has been revised to clarify that the dose de-escalation decision will 
depend on the severity and timing of the DLTs as well as the specific adverse 
events, including those that result in dose interruption and modifications.

Section 4.1.1 has been updated to add inclusion criteria requiring prior exposure to 
pertuzumab.

Section 4.1.1.1 has been updated to add inclusion criteria specific to the 
dose-escalation phase requiring prior exposure to trastuzumab emtansine.

Sections 4.5.9.1 and 7.3 have been amended to remove text relating to electronic 
collection of patient reported outcome data.

Section 5.1.1.1 has been revised to include tumor lysis syndrome (TLS) language 
and literature references more appropriate for the target population in this trial.

Section 5.1.1.1 has been updated to provide guidance on potential predisposing risk 
factors for TLS for the target population in this trial.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 32
1.1
Background on HER2-Positive Breast Cancer ...................... 32
1.2
BCL-2 Signaling Pathway and HER2-Positive 
Breast Cancer........................................................................ 33
1.3
Background on Trastuzumab Emtansine............................... 34
1.3.1
Study TDM4370g/BO21977 (EMILIA) ................................... 34
1.3.2
Study WO30085 (KATE2)...................................................... 35
1.3.3
Study TDM4997g/BO25734 (TH3RESA)............................... 36
1.3.4
Study BO27938 (KATHERINE) ............................................. 37
1.4
Background On Venetoclax................................................... 37
1.5
Study Rationale and Benefit-Risk Assessment...................... 39
2.
OBJECTIVES AND ENDPOINTS ............................................................... 41
2.1
Objectives And Endpoints for Dose-Escalation 
Phase .................................................................................... 42
2.1.1
Primary Safety Objective ....................................................... 42
2.1.2
Exploratory Efficacy Objective............................................... 42
2.1.3
Pharmacokinetic Objective .................................................... 42
2.1.4
Biomarker Objective .............................................................. 43
2.2
Objectives and Endpoints for Expansion Phase.................... 43
2.2.1
Primary Efficacy Objective..................................................... 43
2.2.2
Secondary Efficacy Objective................................................ 43
2.2.3
Safety Objective .................................................................... 43
2.2.4
Pharmacokinetic Objective .................................................... 44
2.2.5
Biomarker Objective .............................................................. 44
2.3
Objectives and Endpoints for Randomized Phase 
II Stage .................................................................................. 44
2.3.1
Primary Efficacy Objective..................................................... 44
2.3.2
Secondary Efficacy Objective................................................ 44
2.3.3
Exploratory Efficacy Objective............................................... 45


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2.3.4
Safety Objective .................................................................... 45
2.3.5
Pharmacokinetic Objective .................................................... 45
2.3.6
Immunogenicity Objectives.................................................... 45
2.3.7
Biomarker Objective .............................................................. 46
2.3.8
Patient Reported Outcome Objective .................................... 46
3.
STUDY DESIGN......................................................................................... 46
3.1
Description of the Study......................................................... 46
3.1.1
Dose-Escalation Phase ......................................................... 48
3.1.1.1
Definition of Dose-Limiting Toxicity........................................ 50
3.1.1.2
Dose-Escalation Rules, Determination of 
Dose-Limiting Toxicities, and Recommended 
Phase II Dose........................................................................ 51
3.1.2
Expansion Phase................................................................... 52
3.1.3
Randomized Phase II Stage.................................................. 53
3.1.4
Internal Monitoring Committee for the 
Randomized Phase II Stage.................................................. 56
3.2
End of Study and Length of Study......................................... 56
3.3
Rationale for Study Design.................................................... 56
3.3.1
Rationale for Venetoclax Dose Selection in the 
Phase Ib Dose-Escalation Phase of the Study ...................... 56
3.3.2
Rationale for Venetoclax Dose Selection in the 
Phase II Randomized Portion of the Study............................ 57
3.3.3
Rationale for Trastuzumab Emtansine Dose and 
Schedule................................................................................ 58
3.3.4
Rationale for Dose-Finding Rules.......................................... 58
3.3.5
Rationale for Dosing Schedule .............................................. 58
3.3.6
Rationale for Patient Population ............................................ 58
3.3.7
Rationale for Control Group................................................... 58
3.3.8
Rationale for Randomization and Blinding............................. 59
3.3.9
Rationale for Objective Response Rate and 
Progression-Free Survival as Co-Primary 
Endpoints for the Randomized Phase II Stage...................... 59
3.3.10
Rationale for Pharmacokinetic Assessments......................... 60
3.3.11
Rationale for Assessments of DrugDrug 
Interactions between Study Treatments ................................ 60


Venetoclax—F. Hoffmann-La Roche Ltd
6/Protocol CO41863, Version 2 (VHP)
3.3.12
Rationale for Biomarker Assessments................................... 60
3.3.13
Rationale for Stratification and Enrichment by B-
Cell Lymphoma-2 (Bcl-2) Status............................................ 61
3.3.14
Rationale for Stratification by Visceral 
Metastases ............................................................................ 62
3.3.15
Rationale for Stratification by HER2 Expression 
Status .................................................................................... 62
3.3.16
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 63
4.
MATERIALS AND METHODS .................................................................... 63
4.1
Patients.................................................................................. 63
4.1.1
Inclusion Criteria (All Study Phases) ..................................... 63
4.1.1.1
Inclusion Criteria for Dose-Escalation Phase Only ................ 67
4.1.1.2
Inclusion Criteria for Expansion Phase Only.......................... 67
4.1.1.3
Inclusion Criteria for Randomized Phase II Stage ................. 68
4.1.2
Exclusion Criteria................................................................... 68
4.1.2.1
Exclusion Criteria for Randomized Phase II 
Stage ..................................................................................... 71
4.2
Method of Treatment Assignment and Blinding 
(Applicable to Randomized Phase II Stage ONLY)
.............................................................................................. 71
4.2.1
Treatment Assignment........................................................... 71
4.2.2
Blinding.................................................................................. 72
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 73
4.3.1.1
Venetoclax and Placebo........................................................ 73
4.3.1.2
Trastuzumab Emtansine........................................................ 73
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 74
4.3.2.1
Venetoclax and Placebo........................................................ 74
4.3.2.2
Trastuzumab Emtansine........................................................ 75
4.3.2.3
Sequence of Study Drug Administration................................ 76
4.3.3
Investigational Medicinal Product Accountability ................... 76
4.3.3.1
Continued Access to Venetoclax and 
Trastuzumab Emtansine........................................................ 76


Venetoclax—F. Hoffmann-La Roche Ltd
7/Protocol CO41863, Version 2 (VHP)
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 77
4.4.1
Permitted Therapy................................................................. 77
4.4.2
Prohibited Food ..................................................................... 78
4.4.3
Prohibited and Cautionary Therapy....................................... 79
4.4.3.1
Herbal Therapies................................................................... 81
4.5
Study Assessments ............................................................... 81
4.5.1
Informed Consent Forms and Screening Log........................ 82
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 82
4.5.3
Physical Examinations........................................................... 82
4.5.4
Vital Signs.............................................................................. 83
4.5.5
Tumor and Response Evaluations......................................... 83
4.5.6
Left Ventricular Ejection Fraction Assessment ...................... 85
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 85
4.5.8
Electrocardiograms................................................................ 88
4.5.9
Patient-Reported Outcome Assessments.............................. 89
4.5.9.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 89
4.5.9.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 90
4.5.10
Optional Tumor Biopsies ....................................................... 91
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 91
4.5.11.1
Overview of the Research Biosample Repository.................. 91
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 92
4.5.11.3
Sample Collection.................................................................. 92
4.5.11.4
Confidentiality........................................................................ 93
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 93
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 93
4.5.11.7
Monitoring and Oversight....................................................... 94


Venetoclax—F. Hoffmann-La Roche Ltd
8/Protocol CO41863, Version 2 (VHP)
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 94
4.6.1
Study Treatment Discontinuation........................................... 94
4.6.2
Patient Discontinuation from the Study.................................. 95
4.6.3
Study Discontinuation............................................................ 96
4.6.4
Site Discontinuation............................................................... 96
5.
ASSESSMENT OF SAFETY....................................................................... 96
5.1
Safety Plan ............................................................................ 96
5.1.1
Risks Associated with Venetoclax ......................................... 97
5.1.1.1
Tumor Lysis Syndrome.......................................................... 97
5.1.1.2
Neutropenia........................................................................... 98
5.1.1.3
Serious Infections.................................................................. 98
5.1.1.4
Other Hematological Effects.................................................. 98
5.1.1.5
Effects on Reproductive System and Pregnancy................... 99
5.1.1.6
Treatment-Emergent Malignancies (Second 
Primary Malignancies) ........................................................... 99
5.1.1.7
Food Effect ............................................................................ 99
5.1.1.8
Concomitant Use with Other Medications............................ 100
5.1.2
Risks Associated with Trastuzumab Emtansine .................. 100
5.1.2.1
Pulmonary Toxicity .............................................................. 100
5.1.2.2
Hepatotoxicity...................................................................... 100
5.1.2.3
Left Ventricular Dysfunction................................................. 101
5.1.2.4
Infusion-Related Reactions and Hypersensitivity 
Reactions............................................................................. 102
5.1.2.5
Hematologic Toxicity ........................................................... 102
5.1.2.6
Hemorrhage......................................................................... 103
5.1.2.7
Neurotoxicity........................................................................ 103
5.1.2.8
Extravasation....................................................................... 103
5.1.3
Management of Patients Who Experience 
Adverse Events ................................................................... 104
5.1.3.1
Dose Modifications .............................................................. 104
5.1.3.2
Treatment Interruption ......................................................... 106
5.1.3.3
Management Guidelines...................................................... 106
5.2
Safety Parameters and Definitions ...................................... 111


Venetoclax—F. Hoffmann-La Roche Ltd
9/Protocol CO41863, Version 2 (VHP)
5.2.1
Adverse Events ................................................................... 111
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 111
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 112
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 113
5.3.1
Adverse Event Reporting Period ......................................... 113
5.3.2
Eliciting Adverse Event Information..................................... 113
5.3.3
Assessment of Severity of Adverse Events ......................... 114
5.3.4
Assessment of Causality of Adverse Events ....................... 114
5.3.5
Procedures for Recording Adverse Events.......................... 115
5.3.5.1
Infusion-Related Reactions.................................................. 115
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 115
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 115
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 116
5.3.5.5
Abnormal Laboratory Values ............................................... 116
5.3.5.6
Abnormal Vital Sign Values ................................................. 117
5.3.5.7
Abnormal Liver Function Tests............................................ 118
5.3.5.8
Deaths ................................................................................. 118
5.3.5.9
Preexisting Medical Conditions............................................ 118
5.3.5.10
Lack of Efficacy or Worsening of Metastatic 
Breast Cancer...................................................................... 119
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 119
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse ........................................................ 120
5.3.5.13
Safety Biomarker Data......................................................... 122
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 122
5.4.1
Emergency Medical Contacts.............................................. 122
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 123
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 123
5.4.2.2
Events That Occur after Study Drug Initiation...................... 123


Venetoclax—F. Hoffmann-La Roche Ltd
10/Protocol CO41863, Version 2 (VHP)
5.4.3
Reporting Requirements for Pregnancies............................ 123
5.4.3.1
Pregnancies in Female Patients.......................................... 123
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 124
5.4.3.3
Abortions ............................................................................. 124
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 125
5.5
Follow-Up of Patients after Adverse Events ........................ 125
5.5.1
Investigator Follow-Up......................................................... 125
5.5.2
Sponsor Follow-Up .............................................................. 125
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 125
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 126
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 126
6.1
Determination of Sample Size ............................................. 127
6.1.1
Dose-Escalation Phase ....................................................... 127
6.1.2
Expansion Phase................................................................. 127
6.1.3
Randomized Phase II Stage................................................ 128
6.2
Summaries of Conduct of Study.......................................... 130
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 130
6.4
Efficacy Analyses (Randomized Phase II Stage 
Only).................................................................................... 131
6.4.1
Co-Primary Efficacy Endpoints............................................ 131
6.4.1.1
Objective Response Rate.................................................... 131
6.4.1.2
Progression-Free Survival ................................................... 131
6.4.2
Secondary Efficacy Endpoints............................................. 131
6.4.2.1
Duration of Objective Response.......................................... 131
6.4.2.2
Overall Survival ................................................................... 132
6.4.3
Exploratory Efficacy Endpoints............................................ 132
6.4.3.1
Clinical Benefit Rate ............................................................ 132
6.4.3.2
Patient-Reported Outcomes Data........................................ 132
6.5
Safety Analyses................................................................... 132


Venetoclax—F. Hoffmann-La Roche Ltd
11/Protocol CO41863, Version 2 (VHP)
6.5.1
Analyses of Exposure, Adverse Event, 
Laboratory, and Vital Sign Data........................................... 133
6.6
Pharmacokinetic Analyses................................................... 133
6.7
Immunogenicity Analyses.................................................... 134
6.8
Biomarker Analyses............................................................. 134
6.9
Interim Analyses .................................................................. 134
6.9.1
Planned Interim Analyses (Randomized Phase II 
Stage Only).......................................................................... 134
7.
DATA COLLECTION AND MANAGEMENT ............................................. 135
7.1
Data Quality Assurance....................................................... 135
7.2
Electronic Case Report Forms............................................. 135
7.3
Source Data Documentation................................................ 135
7.4
Use of Computerized Systems ............................................ 136
7.5
Retention of Records........................................................... 136
8.
ETHICAL CONSIDERATIONS.................................................................. 137
8.1
Compliance with Laws and Regulations .............................. 137
8.2
Informed Consent................................................................ 137
8.3
Institutional Review Board or Ethics Committee.................. 138
8.4
Confidentiality...................................................................... 139
8.5
Financial Disclosure ............................................................ 139
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 140
9.1
Study Documentation .......................................................... 140
9.2
Protocol Deviations.............................................................. 140
9.3
Management of Study Quality ............................................. 140
9.4
Site Inspections ................................................................... 140
9.5
Administrative Structure....................................................... 140
9.6
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 141
9.7
Protocol Amendments ......................................................... 142
10. REFERENCES ......................................................................................... 143


Venetoclax—F. Hoffmann-La Roche Ltd
12/Protocol CO41863, Version 2 (VHP)
LIST OF TABLES
Table 1
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine ............................................................. 76
Table 2
Therapies Prohibited for Specific Study Phases, or Allowed 
with Caution, Restrictions, and/or Dose Adjustments ................. 80
Table 3
Venetoclax Dose Reductions for Strong and Moderate 
CYP3A Inhibitors......................................................................... 81
Table 4
Dose Modification Scheme for Venetoclax/Placebo.................. 105
Table 5
Dose Modification Scheme for Trastuzumab Emtansine .......... 106
Table 6
Guidelines for Management of Patients Who Experience 
Specific Adverse Events with Venetoclax and Trastuzumab 
Emtansine................................................................................. 108
Table 7
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 114
Table 8
Potential 90% Confidence Interval Estimated for the True 
ORR.......................................................................................... 127
Table 9
Potential 90% Confidence Interval Estimates for Adverse 
Event Rates .............................................................................. 128
Table 10
Operating Characteristics for Proposed Study Design for 
Possible True Underlying ORR Values.................................. 129
Table 11
Operating Characteristics for Proposed Study Design for 
Possible True Underlying PFS Hazard Ratio Values ................ 130
Table 12
Operating Characteristics in the Bcl-2 High Group for 
Proposed Study Design for Possible True Underlying PFS 
Hazard Ratio Values................................................................. 130
LIST OF FIGURES
Figure 1
Overall Study Schema ................................................................ 47
Figure 2
Phase Ib Dose-Escalation Study Schema .................................. 49
Figure 3
Phase Ib Expansion Cohorts Study Schema .............................. 53
Figure 4
Phase II Randomized Study Schema ......................................... 55
LIST OF APPENDICES
Appendix 1
Schedule of Activities: Dose Escalation.................................... 147
Appendix 2
Schedule of Activities: Expansion Cohorts/Randomized 
Phase II..................................................................................... 152
Appendix 3
Schedule of Pharmacokinetic and Immunogenicity Samples.... 158
Appendix 4
Biomarker Assessments ........................................................... 162


Venetoclax—F. Hoffmann-La Roche Ltd
13/Protocol CO41863, Version 2 (VHP)
Appendix 5
Anaphylaxis Precautions........................................................... 164
Appendix 6
Patient-Reported Outcomes Questionnaires............................. 165
Appendix 7
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome............. 168
Appendix 8
Guidelines for Defining Tumor Lysis Syndrome........................ 169
Appendix 9
Management of Venetoclax-Specific Adverse Events............... 171
Appendix 10
Management of Trastuzumab Emtansine-Specific Adverse 
Events....................................................................................... 172
Appendix 11
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 174
Appendix 12
National Cancer Institute Common Terminology Criteria .......... 183
Appendix 13
Guidelines for Liver Biopsy ....................................................... 184
Appendix 14
Sample List of Excluded and Cautionary Medications .............. 185


Venetoclax—F. Hoffmann-La Roche Ltd
14/Protocol CO41863, Version 2 (VHP)
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IB/II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
EVALUATING THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF 
VENETOCLAX IN COMBINATION WITH 
TRASTUZUMAB EMTANSINE IN PATIENTS WITH 
PREVIOUSLY TREATED HER2-POSITIVE 
LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER
PROTOCOL NUMBER:
CO41863
VERSION NUMBER:
2 (VHP)
EUDRACT NUMBER:
2019-004200-35
IND NUMBER:
137088
NCT NUMBER:
NCT04298918
TEST PRODUCT:
Venetoclax (RO5537382)
Trastuzumab emtansine (RO5304020)
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)
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.


Venetoclax—F. Hoffmann-La Roche Ltd
15/Protocol CO41863, Version 2 (VHP)
PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY EVALUATING THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF 
VENETOCLAX IN COMBINATION WITH TRASTUZUMAB 
EMTANSINE IN PATIENTS WITH PREVIOUSLY TREATED HER2-
POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER
PROTOCOL NUMBER:
CO41863
VERSION NUMBER:
2 (VHP)
EUDRACT NUMBER:
2019-004200-35
IND NUMBER:
137088
NCT NUMBER:
NCT04298918
TEST PRODUCT:
Venetoclax (RO5537382)
Trastuzumab emtansine (RO5304020)
PHASE:
Ib/II
INDICATION:
Locally advanced or metastatic breast cancer 
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-controlled, 
double-blind, multicenter stage (hereafter referred to as the “randomized Phase II stage”).  
The dose-escalation phase will assess safety and tolerability, determine the maximum tolerated 
dose (MTD) and the recommended Phase II dose (RP2D), and evaluate the preliminary efficacy 
of trastuzumab emtansine in combination with venetoclax in patients with previously treated 
HER2-positive unresectable locally advanced breast cancer (LABC) or metastatic breast cancer 
(MBC) who have received prior trastuzumab emtansine in the metastatic setting.  
Once the RP2D is established, additional patients may be enrolled in the expansion phase to 
evaluate the safety, tolerability, and efficacy of trastuzumab emtansine in combination with 
venetoclax at the RP2D in patients with previously treated HER2-positive LABC or MBC who 
have previously received either trastuzumab emtansine or trastuzumab deruxtecan (DS-8201a).  
The decision to open these cohorts will be data-driven and dependent on the observations 
made in the dose-escalation phase, as well as emerging data about trastuzumab deruxtecan 
and other HER 2-targeted therapies.  Importantly, the expansion phase may run concurrent to 
and in parallel with the randomized Phase II stage of the study. 
The randomized Phase II stage will aim to evaluate the safety, tolerability, pharmacokinetics, 
and efficacy of trastuzumab emtansine in combination with venetoclax at the RP2D compared 
with trastuzumab emtansine plus placebo in patients with previously treated HER2-positive 
LABC or MBC who have not received prior trastuzumab emtansine therapy, either alone or in 
combination with other anticancer therapies.  Specific objectives and corresponding endpoints 
for the study are outlined below.


Venetoclax—F. Hoffmann-La Roche Ltd
16/Protocol CO41863, Version 2 (VHP)
Objectives and Endpoints for Dose-Escalation Phase
Primary Safety Objective
The safety objective for the dose-escalation phase is to evaluate the safety and tolerability of 
trastuzumab emtansine in combination with venetoclaxincluding estimation of the MTD, 
determination of the RP2D, and characterization of dose-limiting toxicities (DLTs)on the basis 
of the following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0) 

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Exploratory Efficacy Objective
The exploratory efficacy objective for the dose-escalation phase is to make a preliminary 
assessment of the anti-tumor activity of trastuzumab emtansine and venetoclax on the basis of 
the following endpoints:

Objective response rate (ORR), defined as the proportion of patients with complete 
response (CR) or partial response (PR) on two consecutive assessments, at least 28 days 
apart, as determined by investigator assessment using Response Evaluation Criteria in 
Solid Tumors, Version 1.1 (RECIST v1.1)

Duration of response (DOR), defined as the time from the first occurrence of a documented 
objective response to disease progression as determined by the investigator using 
RECIST v1.1, or death from any cause, whichever occurs first
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for the dose-escalation phase of this study is to 
characterize the pharmacokinetics of venetoclax when given in combination with trastuzumab 
emtansine on the basis of the following endpoint:

Plasma concentrations of venetoclax at specified timepoints
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or evaluate 
biomarkers that are predictive of response to venetoclax in combination with trastuzumab 
emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to trastuzumab emtansine and venetoclax, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of venetoclax and/or trastuzumab 
emtansine activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the knowledge and 
understanding of disease biology and drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
Objectives and Endpoints for Expansion Phase
Primary Efficacy Objective
The primary efficacy objective for the expansion phase is to evaluate the efficacy of venetoclax 
at the RP2D in combination with trastuzumab emtansine on the basis of the following endpoint:

ORR
Secondary Efficacy Objective
The secondary efficacy objective for the expansion phase is to evaluate the efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoint:

DOR


Venetoclax—F. Hoffmann-La Roche Ltd
17/Protocol CO41863, Version 2 (VHP)
Safety Objective
The safety objective for the expansion phase is to evaluate the safety and tolerability of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to NCI CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Pharmacokinetic Objective
The PK objective for the expansion phase of the study is to characterize the pharmacokinetics 
of venetoclax when given in combination with trastuzumab emtansine on the basis of the 
following endpoint:

Plasma concentrations of venetoclax at specified timepoints
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or evaluate 
biomarkers that are predictive of response to venetoclax in combination with trastuzumab 
emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to trastuzumab emtansine and venetoclax, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of venetoclax and/or trastuzumab 
emtansine activity (i.e., PD biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
Objectives and Endpoints for Randomized Phase II Stage
Primary Efficacy Objective
The primary efficacy objective for the randomized Phase II stage is to evaluate the efficacy of 
trastuzumab emtansine in combination with venetoclax compared with trastuzumab emtansine 
plus placebo on the basis of the following co-primary endpoints:

ORR

Progression-free survival (PFS) after randomization, 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
Secondary Efficacy Objective
The secondary efficacy objective for the randomized Phase II stage is to evaluate the efficacy of 
trastuzumab emtansine in combination with venetoclax compared with trastuzumab emtansine 
plus placebo on the basis of the following endpoints:

DOR

Overall survival (OS) after randomization, defined as the time from randomization to death 
from any cause
Exploratory Efficacy Objective
The exploratory efficacy objective for the randomized Phase II stage is to evaluate the efficacy 
of trastuzumab emtansine in combination with venetoclax compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoints:

Clinical benefit rate (CBR), defined as the proportion of patients with CR, PR, or stable 
disease (SD) at 6 months after randomization, as determined by the investigator according 
to RECIST v1.1


Venetoclax—F. Hoffmann-La Roche Ltd
18/Protocol CO41863, Version 2 (VHP)
Safety Objective
The safety objective for the randomized Phase II stage is to evaluate safety of trastuzumab 
emtansine in combination with venetoclax compared with trastuzumab emtansine plus placebo 
on the basis of the following endpoints:

Incidence and severity of adverse events with severity determined according to 
NCI CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Pharmacokinetic Objective
The PK objective for the randomized Phase II stage of this study is to characterize the 
pharmacokinetics of trastuzumab emtansine and venetoclax when given in combination on the 
basis of the following endpoints:

Serum concentrations of trastuzumab emtansine at specified timepoints

Plasma concentrations of venetoclax at specified timepoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to trastuzumab 
emtansine when given with placebo or in combination with venetoclax on the basis of the 
following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or evaluate 
biomarkers that are predictive of response to venetoclax in combination with trastuzumab 
emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to trastuzumab emtansine and venetoclax, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of venetoclax and/or trastuzumab 
emtansine activity (i.e., PD biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
Patient Reported Outcome Objective
The patient-reported outcome objective for the randomized Phase II stage is to evaluate the 
efficacy of trastuzumab emtansine in combination with venetoclax compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoint:

Change from baseline in patient-reported symptoms and their impact on functioning and 
health-related quality of life, and overall burden of side effects, as measured by the 
European Organisation for Research and Treatment of Cancer Quality of Life Core 30 
Questionnaire (EORTC QLQ-C30) and EORTC Item List 46 (EORTC IL46) item


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Study Design
Description of Study
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-controlled, 
double-blind, multicenter stage (hereafter referred to as the “randomized Phase II stage”). The 
expansion phase may run concurrent to and in parallel with the randomized Phase II stage.
Dose-Escalation Phase
The dose-escalation phase will determine the RP2D and MTD for venetoclax when given in 
combination with a fixed dose of trastuzumab emtansine (3.6 mg/kg) in patients with previously 
treated, HER2-positive LABC or MBC having received prior trastuzumab emtansine in the 
metastatic setting. 
The dose-escalation phase will enroll 624 patients and will include 24 cohorts:

Cohort 1A, 400 mg QD Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (every 3 weeks [Q3W]) and venetoclax 400 mg 
orally (PO) once a day (QD) continuous on Days 121 of each cycle. 

Cohort 1B, 400 mg NC Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 400 mg PO QD non-
continuous (NC) on either Days 17 or 114 of each cycle.

Cohort 2A, 800 mg QD Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 800 mg PO QD 
continuous on Days 121 of each cycle.

Cohort 2B, 800 mg NC Cohort:  Patients will receive trastuzumab emtansine 3.6 mg/kg by 
IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 800 mg PO QD non-
continuous on either Days 17 or 114 of each cycle.
The 400-mg and 800-mg cohorts for dose escalation will be run sequentially (i.e., the 400-mg 
cohort followed by the 800-mg cohort).  Dose escalation will be performed based on a standard 
3 3 design.  Each cohort will consist of at least 3 patients, unless 1 of the 3 patients
experiences DLTs (refer to the protocol for DLT criteria), in which case 3 additional patients will 
be treated at the same dose level.  The dose escalation will continue until 2 patients among a 
cohort of 6 patients experience a DLT (i.e., 33% of patients with a DLT at that dose level; refer 
to dose-escalation rules in the protocol).  Patients who experience a DLT will continue at the 
same dose level.
Dose de-escalation may be explored by incorporating non-continuous (NC) dosing of 
venetoclax (e.g., less than 21 days of dosing, such as 7 days out of 21 days or 14 days out of 
21 days) dependent on the severity and timing of DLTs as well as the specific adverse events, 
including those that result in dose interruptions or dose modifications.  For example, if DLTs 
such as a Grade 3 rash occurred between Day 8 and Day 14, an NC schedule of Days 17 
would be tested.  Alternatively, if DLTs are thought to be possibly mitigated by a 7-day break 
such as Grade 3 fatigue occurring near the end of the DLT window (e.g., Day 20), then an NC 
schedule of Days 114 could be chosen to be tested. Patients may be treated in up to two NC 
sub-cohorts (i.e., either 400 mg NC and/or 800 mg NC).  At each dose de-escalation level, 
either a Days 17 or Days 114 NC treatment schedule will be assessed.
Refer to the protocol for definition of DLT, dose-escalation rules, and determination of DLTs and 
RP2D. 
Expansion Phase
An expansion phase may be initiated to evaluate the safety, tolerability, and efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine in previously treated HER2-
positive locally advanced or MBC patients who have received prior trastuzumab emtansine or 
trastuzumab deruxtecan (DS-8201a). 
The decision to open cohorts as part of an expansion phase will be data-driven and dependent 
on the observations made in the dose-escalation phase, emerging data with trastuzumab 
deruxtecan, as well as other HER2-targeted therapies.  The expansion phase may run 
concurrent to and in parallel with the randomized Phase II stage of the study.


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Randomized Phase II Stage
The randomized Phase II stage will be initiated once the RP2D has been identified based on the 
cumulative data collected from the dose-escalation phase.  It will consist of two interventional 
arms of trastuzumab emtansine plus placebo or trastuzumab emtansine plus venetoclax in 
patients with previously treated HER2-positive LABC or MBC, who have not received prior 
trastuzumab emtansine therapy.
Approximately 220 patients will be randomized 1:1 to one of the following treatment arms:  

Control Arm:  Patients will receive trastuzumab emtansine 3.6 mg/kg by IV infusion Q3W 
plus placebo at the RP2D and schedule of venetoclax. 

Experimental Arm:  Patients will receive trastuzumab emtansine 3.6 mg/kg by IV infusion 
Q3W plus venetoclax at the RP2D and schedule. 
Each arm will include at least 50% Bcl-2 high patients. Randomization will be stratified 
according to the following criteria:

Bcl-2 status (Bcl-2 high vs. Bcl-2 low)

Visceral disease (Yes vs. No)

HER2 status IHC 3+ (Yes vs. No)
Number of Patients
Approximately 226284 patients will be enrolled in this study across approximately 145 sites 
globally. The study will enroll 624 patients in Part 1 of the study and approximately 
220 patients in Part 2. An additional approximately 2040 patients may be enrolled in the 
expansion cohorts.
Target Population
Inclusion Criteria (All Study Phases)
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form 

Ability to comply with the study protocol, in the investigator's judgment

Histologically or cytologically confirmed invasive MBC or LABC that is incurable, 
unresectable, and previously treated with multimodality therapy:

Prior treatment for BC in the adjuvant, unresectable locally advanced, or 
metastatic settings, which must include a taxane, trastuzumab (alone or in 
combination with another agent), and pertuzumab
o
For patients who have not received pertuzumab in early breast cancer 
setting, prior treatment with pertuzumab in the metastatic setting is 
required prior to enrollment

Progression must have occurred during or after most recent treatment for 
LABC/MBC or within 6 months after completing adjuvant therapy

Measurable disease that is evaluable per RECIST v1.1

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Willing to provide tumor biopsy sample at the time of screening
A tumor biopsy sample (either archival or fresh) must be collected from all patients 
from either the primary tumor or a metastatic site (preferred and within 6 months of 
enrollment, if clinically feasible) for determination of HER2 status by central laboratory 
testing for patient eligibility purposes, for Bcl-2 expression, and for research on 
biomarkers. 
The tumor specimen must contain adequate evaluable tumor cells (20% tumor cells) 
to enable Bcl-2, HER2, and other relevant biomarker analysis. Samples can be a 
tissue block (preferred) or at least 20 unstained freshly cut serial slides.  If fewer than 
20 slides are available, the Sponsor should be consulted. If a tumor sample is not 
available, a fresh biopsy must be collected. 


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The specimen must be a formalin-fixed, paraffin-embedded (FFPE) tumor specimen, or 
another appropriate fixative must be used (notation of the type of fixative should be 
included).  Cytological or fine-needle aspiration samples are not acceptable.

Local histological or cytological confirmation of estrogen receptor (ER) and/or progesterone 
receptor status as defined by using IHC per American Society of Clinical Oncology/College 
of American Pathologists criteria

Percentage of ER and/or progesterone receptor positivity, if available

Willing to provide blood samples at the time of screening, on-study, and at progression for 
exploratory research on biomarkers

HER2-positive breast cancer (BC) as defined by an IHC score of 3+ or gene amplified by in 
situ hybridization (ISH) as defined by a ratio of 2.0 for the number of HER2 gene copies to 
the number of chromosome 17 copies
For the expansion phase and randomized Phase II stage:  Centrally confirmed HER2-
positive status prospectively tested by a Sponsor-designated central laboratory prior to 
enrollment.
For the dose-escalation phase:  Enrollment can be based upon prospective central 
testing or local IHC or ISH results; however, for local IHC or ISH results, the same 
tissue sample must be sent for central HER2 confirmation and the testing platform 
documented in the eCRF.
Both IHC and ISH assays can be performed; however, unless reflex testing is 
necessary, only one positive result is required for eligibility.
If multiple tumor specimens are submitted, the HER2 IHC score and or ISH 
amplification ratio will first be assessed on the most recently obtained specimen for the 
purpose of determining eligibility.  For patients with bilateral BC, HER2 positivity must 
be demonstrated in both locations for archival tissue or in a metastatic biopsy.
Centrally confirmed HER2 results (either IHC or ISH) from a current or previous 
Sponsor study can be used to determine eligibility for this study.  Approval must be 
obtained from the Medical Monitor prior to randomization.

Adequate hematologic and end-organ function, as evidenced by the following local 
laboratory results obtained within 7 days prior to the first study treatment (Cycle 1, Day 1):

Absolute neutrophil count 1500 cells/L (without granulocyte-colony 
stimulating factor support within 7 days prior to Cycle 1, Day 1)

Platelet count 100,000/L (without transfusion within 7 days prior to Cycle 1, 
Day 1)

Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet 
this criterion.

Albumin 25 g/L (2.5 g/dL)

Total bilirubin 1.5 ULN with the following exceptions:
Patients with previously documented Gilbert syndrome who may have
bilirubin 5 ULN
Patients with documented liver metastases may have bilirubin 
2.5 ULN

AST, ALT, and ALP 2.5 ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases may have ALP 
5 ULN

Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min on the basis 
of either 24-hour urine collection or the Cockroft-Gault glomerular filtration 
rate estimation:


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(140 age) (weight in kg) (0.85 if female)
72 (serum creatinine in mg/dL)

INR or aPTT 1.5 ULN
For patients requiring anticoagulation therapy with warfarin or other 
coumarins, a stable INR between 2 and 3 is required.  If anti-coagulation 
is required for a prosthetic heart valve, then INR should be between 2.5 
and 3.5.

Screening left ventricular ejection fraction (LVEF) 50% on echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan
LVEF assessment may be repeated once up to 3 weeks following the initial screening 
assessment to assess eligibility.

Negative HIV test at screening

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening
The HBV DNA test will be performed only for patients who have a negative HBsAg test 
and a positive total HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive HCV 
antibody test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 
1% per year during the treatment period and for at least 30 days after the last dose of 
venetoclax or 7 months after the last dose of trastuzumab emtansine, whichever is later.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or regulations.
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 methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men who are not 
surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for at least 30 days after the last dose of venetoclax or 7 months 
after the last dose of trastuzumab emtansine, whichever is later. 


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With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 30 days after the last dose of venetoclax or 7 
months after the last dose of trastuzumab emtansine, whichever is later to avoid 
exposing the embryo.
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 acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.
Inclusion Criteria for Dose-Escalation Phase Only
In addition to the general inclusion criteria, patients in the dose-escalation phase of the study 
must also meet the following criteria for study entry:

Prior exposure to trastuzumab emtansine in any setting (advanced/metastatic or early 
breast cancer) is required     
Inclusion Criteria for Expansion Phase Only
In addition to the general inclusion criteria, patients in the expansion phase of the study must 
also meet the following criteria for study entry:

Trastuzumab emtansine experienced cohort:

Disease progression during or after trastuzumab emtansine treatment in the
advanced/metastatic setting or disease recurrence in the neoadjuvant/adjuvant 
setting  

At least 50% patients in the expansion cohort (e.g., 10 out of 20) must have 
tumor that is Bcl-2 high. 
Bcl-2 high is defined as 50% of tumor cells stained with an intensity of 
IHC 2+ or 3+, and Bcl-2 low is defined as IHC 0 or 1+ or < 50% of tumor 
cells stained with an intensity of IHC 2+ or 3+.

Trastuzumab deruxtecan (DS-8201a) experienced cohort:

Disease progression during or after trastuzumab deruxtecan in the 
advanced/metastatic setting

Prior trastuzumab emtansine in any setting is allowed

At least 50% patients in the expansion cohort (e.g., 10 out of 20) must have 
tumor that is Bcl-2 high. 
Inclusion Criteria for Randomized Phase II Stage
In addition to the general inclusion criteria, patients in the randomized Phase II stage of the 
study must also meet the following criteria for study entry:

Bcl-2 expression status by IHC either from fresh tissue or the most recent archival tissue 
(see criteria for all study phases) by a central laboratory using the Ventana Bcl-2 IHC assay 
prior to randomization.  
At least 50% of patients in the randomized Phase II (e.g., 110 out of 220 patients) must 
be Bcl-2 high.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to Cycle 1, 
Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1

Radiation therapy within 2 weeks prior to Cycle 1, Day 1

The patient must have recovered from any resulting acute toxicity (to Grade 1) prior to 
randomization. 

History of exposure to the following cumulative doses of anthracyclines as specified below:


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
Doxorubicin 500 mg/m2

Liposomal doxorubicin 500 mg/m2

Epirubucin 720 mg/m2

Mitoxantrone 120 mg/m2

Idarubicin 90 mg/m2
If another anthracycline or more than one anthracycline has been used, then the 
cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.

History of other malignancy within the previous 5 years, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or 
patients who have undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to be at low risk for recurrence

Cardiopulmonary dysfunction as defined by:

Uncontrolled hypertension (systolic 150 mm Hg and/or diastolic 
100 mm Hg with or without medication)

Inadequate LVEF at baseline, 50% by either ECHO or MUGA

History of symptomatic congestive heart failure (CHF)-Grade 3 per NCI
CTCAE version 5.0 or Class II New York Heart Association 

History of a decrease in LVEF to 40% or symptomatic CHF with prior 
trastuzumab treatment

Myocardial infarction or unstable angina within 6 months of randomization

Concurrent dyspnea at rest due to complications of advanced malignancy, or 
other disease requiring continuous oxygen therapy

Evidence of transmural infarction on ECG

Significant symptoms (Grade 2) relating to LVEF, cardiac arrhythmia, or 
cardiac ischemia

High-risk uncontrolled arrhythmias (i.e., supraventricular tachycardia with a 
heart rate 100/min at rest, significant ventricular arrhythmia [ventricular 
tachycardia], or higher-grade atrioventricular [AV]-block [second-degree AV-
block Type 2 (Mobitz 2) or third-degree AV-block])

Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, 
pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures)

Major surgical procedure or significant traumatic injury within 28 days prior to randomization 
or anticipation of the need for major surgery during the course of study treatment

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding 
fungal infections of nail beds) at study enrollment, or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the completion of the 
course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, 
autoimmune hepatic disorders, sclerosis cholangitis, or active infection with HBV or HCV)

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

Known HIV infection or human T-cell leukemia virus 1 infection

Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for 2 weeks prior to randomization

Known central nervous system (CNS) disease, except for patients treated and currently with 
asymptomatic CNS metastases, provided that all of the following criteria are met:

Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord)

No ongoing requirement for corticosteroids as therapy for CNS disease 


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
No stereotactic radiation within 14 days prior to randomization

No evidence of interim progression between the completion of CNS-directed
therapy and the screening radiographic study
Note: Patients with new asymptomatic CNS metastases detected at the 
screening scan must receive radiation therapy and/or surgery for CNS 
metastases.  Following treatment, these patients may be eligible without 
the need for an additional brain scan prior to enrollment, if all other 
criteria are met.

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once a month or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed regardless of drainage 
frequency.

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL or 
corrected serum calcium greater than the ULN) or symptomatic hypercalcemia requiring 
continued use of bisphosphonate therapy
Patients who are receiving denosumab must discontinue use of denosumab and 
replace it with a bisphosphonate instead while on study.
Patients who are receiving bisphosphonate therapy specifically to prevent skeletal 
events and who do not have a history of clinically significant hypercalcemia are eligible.

Current Grade 3 peripheral neuropathy (according to the NCI CTCAE v 5.0)

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion 
proteins

Prior allogeneic stem cell or solid organ transplantation

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
30 days after the last dose of venetoclax or 7 months after the last dose of trastuzumab 
emtansine after the final dose of study treatment, whichever is later
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

Administration of the following agents within 7 days prior to the first dose of study drug:

Strong or moderate CYP3A inhibitors

Strong or moderate CYP3A inducers
Additional restrictions for on-study use of CYP3A inhibitors/inducers are outlined in the 
protocol.

Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade-
containing Seville oranges), or starfruit (carambola) within 3 days before anticipated first 
dose of study drug until the last dose of study drug

Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the study

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
judgment

Malabsorption syndrome or other condition that would interfere with enteral absorption

History of active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) 
requiring specific medication in the 12 months prior to randomization, or active and 
uncontrolled bowel inflammation (e.g., diverticulitis) at time of randomization

Inability or unwillingness to swallow a large number of tablets

Known hypersensitivity to venetoclax or trastuzumab emtansine or to any of their excipients


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
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study

Other medical or psychiatric conditions that, in the opinion of the investigator, may interfere 
with the patient’s participation in the study

Blood transfusions if performed within 2 weeks prior to screening
Exclusion Criteria for Randomized Phase II Stage
In addition to the general exclusion criteria, patients in the randomized Phase II stage of this 
study who meet the following criteria will be excluded:

Prior treatment with trastuzumab emtansine in any setting (neoadjuvant/adjuvant or 
advanced/metastatic setting)

Prior treatment with venetoclax in any setting

Prior treatment with anti-HER2 antibody drug conjugates (e.g. trastuzumab deruxtecan [DS-
8201a]), margetuximab, pyrotinib, or tucatinib. 
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later.  The end of study is planned to occur approximately 
24 months after last patient in (LPI). In addition, the Sponsor may decide to terminate the study 
at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 48 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, Inc. and will be supplied by the 
Sponsor as oral film-coated tablets of 100-mg strength. Each dose of venetoclax will be taken 
orally once daily.  The venetoclax treatment regimens for the dose-escalation phase, dose-
expansion phase, and randomized Phase II stage are summarized in the Description of Study
above.
Comparator
The formulation of placebo is equivalent to venetoclax but without the active agent.  Each dose 
of placebo will be taken orally once daily.  The placebo treatment regimen for the randomized 
Phase II stage is summarized in the Description of Study above.
Trastuzumab emtansine will serve as the comparator/active control and will not be blinded.
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion Q3W.
The oral dose of venetoclax should be administered first, followed by infusion of trastuzumab 
emtansine.
Statistical Methods
Primary Analysis for Dose-Escalation Phase
The primary objective for the dose-escalation phase is to evaluate the safety and tolerability of 
trastuzumab emtansine in combination with venetoclax, including estimation of the MTD, 
determination of the RP2D, and characterization of DLTs.  The safety analysis population will 
consist of all randomized patients who received at least one dose of study drug, with patients 
grouped according to treatment received.  Safety will be assessed separately for each study 
phase through summaries of exposure to study treatment, adverse events, changes in 
laboratory test results, and changes in vital signs and ECGs.  Study treatment exposure (such 
as treatment duration, total dose received, and number of cycles and dose modifications) will be 
summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms, and adverse event severity will be graded according to NCI 


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CTCAE v5.0.  All adverse events, serious adverse events, adverse events leading to death, 
adverse events of special interest, and adverse events leading to study treatment 
discontinuation that occur on or after the first dose of study treatment (i.e., treatment emergent 
adverse events) will be summarized by mapped term, appropriate thesaurus level, and severity 
grade.  For events of varying severity, the highest grade will be used in the summaries.  Deaths 
and cause of death will be summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse oximetry, and 
temperature), and ECG data will be displayed by time, with grades identified where appropriate.  
Additionally, a shift table of selected laboratory tests will be used to summarize the baseline and 
maximum postbaseline severity grade.  Changes in vital signs and ECGs will be summarized.
Primary Analysis for Randomized Phase II Stage
The co-primary endpoints for the randomized Phase II stage are ORR and PFS.  The primary 
efficacy analysis population will consist of all randomized patients, with patients grouped 
according to their assigned treatment (the intent-to-treat [ITT] population).  The primary efficacy 
analysis will occur when 161 patients have experienced a PFS event.  It is anticipated that this 
will occur six months after the last patient enters treatment.  Patients with no disease 
assessments for any reason will be classified as non-responders.  An estimate of ORR with 95% 
CI will be calculated for each treatment arm using the normal approximation to the binomial 
distribution.  An estimate and 95% CI for the difference in ORR between the two treatment 
groups will be presented based on the normal approximation to the binomial distribution.
PFS is defined as the time from randomization to the first occurrence of disease progression (as 
defined by the investigator according to RECIST v1.1) or death from any cause, whichever 
comes first.  Data for patients without the occurrence of disease progression or death as of the 
clinical data cut-off date will be censored at the time of last tumor assessment (or the time of 
randomization plus 1 day if no tumor assessment was performed after the baseline visit).
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm. 
Kaplan-Meier curves of time to PFS for each treatment group will be provided.  The Cox 
proportional hazards model stratified by the randomization stratification factors (Bcl-2 status 
[high, low], visceral disease [yes, no], and HER2 status IHC 3+ [yes, no] will be used to provide 
an estimate of the hazard ratio of venetoclax plus trastuzumab emtansine to placebo plus 
trastuzumab emtansine with associated 95% CI and p-value.  The unstratified hazard ratio 
estimate and 95% CI will also be presented.
Determination of Sample Size  
The sample size for the dose-escalation phase is based on the dose-escalation rules described 
in the protocol.  The planned enrollment for the dose-escalation phase is approximately 
624 patients enrolled across 24 dose-escalation treatment groups.  
Approximately 20 patients each may be enrolled in the expansion phase (trastuzumab 
emtansine-experienced cohort and trastuzumab deruxtecan-experienced cohort).
With 20 patients per cohort and an observed ORR of 60%, the exact 90% Clopper-Pearson 
confidence interval for the ORR would be 39%78%, which would rule out an ORR of 35% or 
less.  The protocol provides exact 90% confidence intervals for a range of observed proportions 
of ORR based on a sample size of 20 patients.  For a given adverse event with a true rate of 
10%, 5%, or 1%, the probability of observing at least one such event in a cohort of 20 patients is 
87.8%, 64.2%, and 18.2%, respectively.  The protocol describes exact 90% confidence intervals 
for a range of observed proportions of adverse events based on a sample size of 20 patients.
After the RP2D has been determined for venetoclax when given in combination with a fixed 
dose of trastuzumab emtansine, a total of 220 patients will be enrolled in the randomized 
Phase II stage of the study.  The purpose of the randomized Phase II stage is estimation and 
hypothesis generation regarding the effect of venetoclax in combination with trastuzumab 
emtansine on ORR and duration of PFS relative to trastuzumab emtansine plus placebo.  The 
point and interval estimates of the true underlying HR will be obtained.  
For the co-primary endpoints of ORR and PFS in the primary efficacy analysis population, the 
trial will have:

85% power (0.05) to detect a 20% improvement in ORR (i.e., ORR ) (assuming a 44% 
ORR in the trastuzumab emtansine plus placebo arm).  In the meantime, a 20% 
improvement in ORR will have a 95% CI of (7%, 33%).


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
90% power (0.05) to detect a PFS HR of 0.6 venetoclax plus trastuzumab emtansine 
arm relative to the trastuzumab emtansine plus placebo arm, when approximately 161 total 
PFS events have occurred. In the meantime, a PFS HR of 0.6 will have a 95% CI of (0.44, 
0.82).  The assumptions of the sample size calculation are that the median PFS in the 
control arm is 6.8 months and that enrollment would occur non-uniformly over 24 months.  
Enrollment is anticipated to be lower during the second half of the enrolment period 
because it will be restricted to the Bcl-2 high population.
Within the Bcl-2 high population the study will have:

85% power (0.05) to detect a PFS HR of 0.5 venetoclax plus trastuzumab emtansine 
arm relative to the trastuzumab emtansine plus placebo arm, when approximately 75 total 
PFS events have occurred.  In the meantime, a PFS HR of 0.5 will have a 95% CI of (0.32, 
0.79).
The study will not, however, have adequate power to detect all potentially clinically meaningful 
differences in ORR and PFS.  For example, within the entire ITT population:

With 110 patients in each arm, there is only 60% power (0.05) to detect a 15% 
improvement in ORR (assuming a 44% ORR in the trastuzumab emtansine plus placebo 
arm), and 

With approximately 161 total PFS events, only 62% power (0.05) to detect an HR of 0.70, 
in venetoclax plus trastuzumab emtansine arm relative to the trastuzumab emtansine plus 
placebo arm.  
Thus, a statistically negative outcome in any of the co-primary endpoints does not necessarily 
rule out a clinically meaningful outcome.  The protocol describes the power and CIs for several 
possible true underlying improvements in ORR and PFS in favor of the venetoclax plus 
trastuzumab emtansine arm. 
Due to the smaller sample size of the Bcl-2 high population the power to detect a HR of 0.60 in 
the Bcl-2 population is 60% compared to 90% for the entire ITT population. The study has 
adequate power (85%) to detect a HR of 0.5 in the Bcl-2 high population.
Interim Analyses (Randomized Phase II Stage Only)
Periodic analyses of cumulative safety data and one interim analysis is planned for this study.  
Given the hypothesis-generating nature of this study, the Sponsor considers the interim efficacy 
analysis as exploratory.
The planned interim efficacy analysis of cumulative safety, ORR, and PFS will occur when 
approximately 56 PFS events have occurred.  This is expected to occur after the enrollment of 
the first 110 patients who have been followed up for at least 6 months.
If the interim analysis coincides within approximately 1 month of a planned safety review, the 
safety review may be combined with the efficacy interim analyses.  Outcomes from these 
reviews that may affect study conduct will be communicated in a timely manner to the 
investigators, and IRBs/ECs will be notified.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
AML
acute myeloid leukemia
AV
atrioventricular
BC
breast cancer
Bcl-2
B-cell lymphoma 2
CBR
clinical benefit rate
CHF
congestive heart failure
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
CLL
chronic lymphocytic leukemia
CNS
central nervous system
CR
complete response
CT
computed tomography (scan)
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
DDI
drugdrug interaction
DLT
dose-limiting toxicity
DOR
duration of response
EBC
early breast cancer
EC
Ethics Committee
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of Cancer
EORTC IL46
EORTC Item List 46
EORTC QLQ-C30
EORTC Quality of LifeCore 30 Questionnaire
ER
estrogen receptor
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio


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Abbreviation
Definition
ICH
International Council for Harmonisation
IHC
immunohistochemistry
IL46
Item List 46
ILD
interstitial lung disease
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
infusion-related reaction
ISH
in situ hybridization
ITT
intent-to-treat (population)
IxRS
interactive voice or web-based response system
LABC
locally advanced breast cancer
LDAC
low-dose cytarabine
LVEF
left ventricular ejection fraction
MBC
metastatic breast cancer
MM
multiple myeloma
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition (scan)
NC
non-continuous (dose)
NCI
National Cancer Institute
NCI CTCAE v5.0
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0
NGS
next-generation sequencing
NHL
non-Hodgkin lymphoma
NIMP
non-investigational medicinal product
NRH
nodular regenerative hyperplasia
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic
PDX
patient-derived xenograft
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
PO
by mouth; orally


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Abbreviation
Definition
PR
partial response
PRO
patient-reported outcome
Q3W
every 3 weeks
QD
once a day
QLQ-C30
Quality of LifeCore 30 Questionnaire
QTcF
QT interval corrected through use of Fridericia's formula
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase II dose
SD
stable disease
SLL
small lymphocytic lymphoma
SmPC
Summary of Product Characteristics
TGI
tumor growth inhibition
TIL
tumor-infiltrating lymphocyte
TLS
tumor lysis syndrome
TPC
treatment of physician’s choice
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON HER2-POSITIVE BREAST CANCER
Breast cancer (BC) is the most common cancer among women in the world, with an 
estimated 2.09 million cases diagnosed globally per year and a mortality rate of 
approximately 627,000 deaths (Bray et al. 2018).  While advances in early diagnosis and 
adjuvant therapy have led to a decrease in mortality rates from BC in developed 
countries, the prevalence of metastatic breast cancer (MBC) is still high and it is not 
curable, with the main goals of treatment being to prolong survival while maintaining or
improving patients’ quality of life (Cardoso et al. 2018).
BC risk assessment, prognosis, and treatment strategy rely on the status of key 
biomarkers: hormonal receptors (estrogen receptor [ER] and progesterone receptor) and 
HER2, also known as erbB2, neu, and p185HER2. Approximately 15%20% of patients 
with primary invasive BC overexpress the HER2 receptor (Reese and Slamon 1997; 
Owens et al. 2004; Wolff et al. 2013; Zhang et al. 2015).  Before HER2-targeted therapy
became available, primary BCs that overexpressed HER2 were associated with a poorer 
prognosis, including a greater risk of relapse and shortened survival compared with that 
of HER2-negative tumors (Slamon et al. 1987; Toikkanen et al. 1992; Andrulis et al. 
1998; Pauletti et al. 2000; Rubin and Yarden 2001). That changed with the introduction 
of trastuzumab, the first anti-HER2 therapy approved for HER2-positive BC, with HER2 
positivity being designated as an immunohistochemistry (IHC) score of 3+ or HER2 gene 
amplification ratio of 2.0 by in situ hybridization (ISH).
Until recently, for patients with HER2-positive MBC, the combination of trastuzumab and 
a taxane was widely accepted as the first-line treatment option of choice on the basis of 
the survival advantage demonstrated in two large pivotal trials (Studies H0648g [Slamon 
et al. 2001] and M77001 [Marty et al. 2005]).  More recently, the regimen of pertuzumab 
in combination with trastuzumab and docetaxel has shown clear superiority in terms of 
both progression-free survival (PFS) and overall survival (OS) with a generally similar 
safety profile (Study WO20698/TOC4129g [Baselga et al. 2012]), and became the new 
standard of care for first-line HER2-positive MBC.
In patients with HER2-positive advanced BC previously treated with trastuzumab and a 
taxane, trastuzumab emtansine has significantly prolonged PFS (up to 3 months
improvement) and OS (up to 7 months increase) with a more favorable safety profile 
than lapatinib plus capecitabine (Study BO21977/TDM4370g, EMILIA [Verma et al.
2012]) or compared with a treatment of physicians’ choice (TPC) in patients who 
previously received trastuzumab, taxane, and lapatinib (Wildiers et al. 2015). 
Trastuzumab emtansine is considered the standard of care in the aforementioned 
patient population (Cardoso et al. 2018; National Comprehensive Cancer Network 
[NCCN] 2019).


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Based on the clinical data mentioned above, for patients with HER2-positive BC, the 
continuous blockage of HER2 through the initial lines of therapy in the metastatic setting 
is recommended (NCCN 2019). Even though the survival time of patients with HER2-
positive BC has been prolonged in recent years, there remains a significant need for 
further outcome improvement. This could be achieved with the addition of new agents 
with novel mechanisms of action and acceptable toxicity, such as the pro-apoptotic 
molecule venetoclax, that can be combined with established HER2-targeted therapies.
1.2
BCL-2 SIGNALING PATHWAY AND HER2-POSITIVE BREAST 
CANCER
Cancer cells are characterized by their capacity for relentless growth, survival, and 
evasion of cell death (Adams and Cory 2007; Strasser et al. 2011). Apoptosis is the 
dominant mode of programmed cell death with two distinct pathways: the intrinsic 
mitochondrial pathway and the extrinsic death receptor pathway (Strasser et al. 2011). 
Intrinsic apoptosis is regulated by the B-cell lymphoma 2 (Bcl-2) family of anti-apoptotic 
proteins of which key members are Bcl-2, Bcl-XL, Bcl-w, A1, and MCL-1 (Cory et al.
2003). Bcl-2 family proteins have been described to be overexpressed in numerous 
cancer types. BCL-2 overexpression has been described in approximately 54%75% of 
BC cases.
Bcl-2 is a relevant therapeutic target in hematologic malignancies, including chronic 
lymphocytic leukemia (CLL])/small lymphocytic lymphoma (SLL), non-Hodgkin 
lymphoma (NHL), multiple myeloma (MM), myelodysplastic syndrome, and acute 
myeloid leukemia (AML) (Perini et al. 2018), and may have an important role in the 
survival of solid tumors such as BC and lung cancer. For example, patient-derived 
xenograft (PDX) tumor models of luminal B BC have demonstrated significant 
improvement in tumor responses and OS when treated with the dual BCL-2/BCL-XL
inhibitor ABT-737 in combination with tamoxifen, compared with tamoxifen alone (Oakes 
et al. 2012; Vaillant et al. 2013). Similar efficacy was observed using the Bcl-2specific 
inhibitor venetoclax (GDC-0199/ABT-199), suggesting that Bcl-2 may be a critical target 
(Vaillant et al. 2013; Lok et al. 2019) in patients with ER-positive, Bcl-2positive MBC. 
The combination appears to show preliminary efficacy as well as a favorable toxicity 
profile when compared with other adjunctive therapies used with endocrine therapy, 
such as the mTOR, PIK3CA, and CDK4/6 inhibitors (Lok et al. 2019). 
Bcl-2 is believed to be an important target in HER2-positive BC. Internal Genentech and 
Roche biomarker data in HER2-positive BC suggest that higher levels of Bcl-2
expression may be a poor prognostic factor in early breast cancer (EBC).  Analysis of 
EBC tumor samples demonstrated that 24% of HER2-positive tumors were Bcl-2 high by 
IHC analysis (Genentech internal, unpublished).  These data are consistent with 
previously reported data indicating that 21%26% of HER2-positive samples are Bcl-
2positive (Honma et al. 2015; Eom et al. 2016).


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1.3
BACKGROUND ON TRASTUZUMAB EMTANSINE
Trastuzumab emtansine (Kadcyla®) is a regulatory authorityapproved antibody-drug 
conjugate.  Linkage of a cytotoxic agent to highly specific monoclonal antibodies 
targeting unique and/or overexpressed cell-surface tumor antigens focuses the delivery 
of such agents to tumor cells, creating a more favorable therapeutic window than can be 
achieved by their administration as free drugs.  Trastuzumab emtansine is specifically 
designed for the treatment of HER2-positive cancer.  It is composed of the cytotoxic 
agent DM1 (a thiol-containing maytansinoid anti-microtubule agent; N2'deacetyl-N2'-[3-
mercapto-1-oxopropyl]-maytansine) conjugated to trastuzumab via lysine side chains, 
with an average drug-to-antibody ratio of approximately 3.5:1.
Trastuzumab emtansine binds to HER2 with an affinity similar to that of trastuzumab; 
such binding is required for its anti-tumor activity.  After binding to HER2, trastuzumab 
emtansine undergoes receptor-mediated internalization, followed by intracellular release 
of DM1 and subsequent cytotoxicity.
Based on Phase I, II, and III studies in which trastuzumab emtansine demonstrated 
clinical activity, it is currently approved as a single agent for the treatment of patients 
with HER2-positive MBC who previously received trastuzumab and a taxane, separately 
or in combination (Kadcyla U.S. Package Insert; E.U. Summary of Product 
Characteristics [SmPC]). Trastuzumab emtansine is also approved for the adjuvant 
treatment of patients with HER2-positive EBC who have residual invasive disease after 
neoadjuvant taxane and trastuzumab-based treatment. Data from clinical trials of 
trastuzumab emtansine that are relevant to the design of the current trial are 
summarized in the following sections.  Refer to the most recent version of the 
Trastuzumab Emtansine Investigator’s Brochure for further information on all of the 
completed and ongoing trastuzumab emtansine studies.
1.3.1
Study TDM4370g/BO21977 (EMILIA)
Study TDM4370g/BO21977 was a randomized Phase III study of trastuzumab 
emtansine versus lapatinib plus capecitabine in patients with HER2-positive, 
unresectable locally advanced BC (LABC) or MBC previously treated with trastuzumab 
and a taxane (n991).  Patients received trastuzumab emtansine (3.6 mg/kg IV every
3 weeks [Q3W]) or capecitabine (1000 mg/m2 orally [PO] twice a day, Days 114 Q3W) 
plus lapatinib (1250 mg PO once a day [QD]) until progressive disease or unmanageable 
toxicity.
Primary endpoints were PFS by independent review, OS, and safety. A total of 
991 patients were enrolled, and 978 patients received treatment.  Baseline patient 
demographics, prior therapy, and disease characteristics were balanced.  There was a 
significant improvement in PFS favoring trastuzumab emtansine (hazard ratio 
[HR]0.650; 95% CI:0.549 to 0.771; p0.0001; median PFS: 9.6 vs. 6.4 months).  
Objective response rate (ORR) was 43.6% for the trastuzumab emtansine arm versus 


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30.8% for the lapatinibpluscapecitabine arm, with a median duration of response (DOR) 
of 12.6 months versus 6.5 months, respectively. Final OS analysis showed a consistent 
survival benefit for trastuzumab emtansine compared with lapatinibpluscapecitabine 
(median OS 29.9 vs. 25.9 months; stratified HR0.75), despite 27% of patients 
crossing over from the control arm to trastuzumab emtansine (Diéras et al. 2017).
Trastuzumab emtansine was well tolerated, with no unexpected safety signals.  The 
most common Grade 3 adverse events in the trastuzumab emtansine arm were 
thrombocytopenia (12.9% vs. 0.2%, respectively), increased AST (4.3% vs. 0.8%), and 
increased ALT (2.9% vs. 1.4%); the most common Grade 3 adverse events in the 
lapatinibpluscapecitabine arm were diarrhea (20.7% vs. 1.6%), palmar plantar 
erythrodysesthesia (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).  The incidence of 
Grade 3 adverse events in the trastuzumab emtansine arm was 40.8% versus 57.0% in 
the lapatinibpluscapecitabine arm (Verma et al. 2012). Based on the results of the 
EMILIA study, trastuzumab emtansine was granted regulatory approval in the U.S. and 
E.U. for treatment-refractory HER2-positive LABC or MBC.
1.3.2
Study WO30085 (KATE2)
Study WO30085 (KATE2) is an ongoing, randomized, multicenter, double-blind, 
placebo-controlled Phase II study of the efficacy and safety of trastuzumab emtansine 
(3.6 mg/kg IV Q3W) in combination with atezolizumab (1200 mg IV Q3W) or 
trastuzumab emtansine plus placebo in patients with HER2-positive LABC or MBC who 
have received prior trastuzumab and taxane-based therapy. A total of 202 patients have 
been randomized to study treatment in a 2:1 ratio. Based on the primary efficacy 
endpoint of PFS, as determined by investigator-assessed Response Evaluation Criteria 
in Solid Tumors, Version 1.1 (RECIST v1.1), the study did not demonstrate a statistically 
significant benefit from the addition of atezolizumab to trastuzumab emtansine in the 
intent-to-treat (ITT) population. The stratified PFS HR was 0.82 (95% CI: 0.55 to 1.23), 
and p-value was 0.3332, with a median PFS of 8.2 months (95% CI: 5.8 to 10.7 months) 
for the treatment arm versus 6.8 months (95% CI: 4.011.1 months) for the control arm.
However, in the exploratory analysis of the PD-L1 immune cell-positive subgroup, the 
stratified HR was 0.60 (95% CI: 0.32–1.11) with a median PFS of 8.5 months (95% CI: 
5.7 months to non-evaluable) for the treatment arm versus 4.1 months (95% CI: 2.7 to 
11.1 months) for the control arm, suggesting a potential benefit for this patient subgroup
(Emens et al. 2019b). 
The ORR as assessed by investigator using RECIST v1.1 was similar between the 
treatment arms (43.5% vs. 45.5%). Of the 69 patients with measurable disease at 
baseline in the trastuzumab emtansine plus placebo arm, 36.2% had a partial response 
(PR) and 7.2% had a complete response (CR). Of the 132 patients with measurable 
disease at baseline in the trastuzumab emtansine plus atezolizumab arm, 39.4% had a 
PR and 6.1% had a CR. The DOR data based on investigator assessment in both arms 
were immature at the primary cancer-related causes of death with low event rates in 


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each arm (26.7% in the trastuzumab emtansine plus placebo arm vs. 28.3% in the 
trastuzumab emtansine plus atezolizumab arm). The median DOR was not reached.
At a second planned analysis (Emens et al. 2019a) with at least 18 months of follow-up 
in the ITT population, the median OS was not reached in either arm, but numerically 
favored the trastuzumab emtansine plus atezolizumab arm. One-year survival was 89.1% 
versus 89.0% (stratified HR0.74; 95% CI: 0.42 to 1.30) in the trastuzumab emtansine 
plus atezolizumab and trastuzumab emtansine plus placebo arms, respectively. In PD-
L1selected patients, 1-year survival rates were higher with trastuzumab emtansine plus 
atezolizumab as compared with trastuzumab emtansine plus placebo (94.3% vs. 87.9%;
stratified HR0.55; 95% CI: 0.22 to 1.38). All biomarkers of T-cell activation and 
quantity were enriched in the PD-L1selected subgroup. This included higher 
expression of PD-L1, Teff signature, and CD8 RNA, as well as greater numbers of 
tumor-infiltrating lymphocytes (TILs) observed in PD-L1positive tumors. Overall, the 
safety profile of the combination was consistent with the known safety profile of each 
drug.  Rate of high-grade adverse events (Grade 3) was 53% versus 45% in the 
trastuzumab emtansine plus atezolizumab as compared with trastuzumab emtansine 
plus placebo. Fatal Grade 5 events were similar in the two arms at 1.5% versus 1.5%. 
Adverse events leading to discontinuation of any study treatment was higher in the in the 
trastuzumab emtansine plus atezolizumab arm as compared with trastuzumab 
emtansine plus placebo arm (29% vs. 15%, respectively).
1.3.3
Study TDM4997g/BO25734 (TH3RESA)
Study TDM4997g/BO25734 was a Phase III, randomized, open-label trial to evaluate 
trastuzumab emtansine compared with TPC (these were approved or standard-of-care 
therapies based on frequently used regimens) in patients with HER2-positive MBC.  
Patients had received prior treatments with trastuzumab, lapatinib, and a taxane in any 
setting, and disease progression occurred after at least two regimens of HER2-directed 
therapy in the metastatic or unresectable locally advanced/recurrent setting.
The study demonstrated a statistically significant and clinically meaningful improvement 
in PFS for trastuzumab emtansine compared with TPC.  The median PFS was 
6.2 months for the trastuzumab emtansine arm and 3.3 months for the TPC arm, with a 
stratified HR of 0.528 (95% CI: 0.422, 0.661); p0.0001.  The ORR was 31% for the 
trastuzumab emtansine arm versus 9% for the TPC arm, resulting in an ORR difference 
of 22.7% (95% CI: 16.2 to 29.2; p0·0001).  
At the final OS analysis with a median 30.5 months of follow-up, trastuzumab emtansine 
demonstrated a clinically meaningful and statistically significant improvement in OS 
compared with TPC. The median OS improved from 15.8 months (95% CI: 13.5 to 
18.7 months) with TPC to 22.7 months (95% CI: 19.4 to 27.5 months) with trastuzumab 
emtansine. The stratified HR was 0.68 (95% CI: 0.54 to 0.85; p0.0007).  Despite the 
longer treatment duration relative to control (4.1 months; [0.0331.2]), trastuzumab 


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emtansine (7.9 months [0.0338]) had a favorable safety profile, which was consistent 
with prior studies (Krop et al. 2017).
In the updated safety analysis, fewer patients receiving trastuzumab emtansine than 
those receiving TPC had Grade 3 adverse events (40% vs. 47%). The most common 
Grade 3 adverse events (affecting 2% of patients in either group) that were more 
frequent with trastuzumab emtansine included thrombocytopenia (6% vs. 3%) and 
hemorrhage of any type (4% vs. 1%). Serious adverse events were reported in 25% of 
patients in the trastuzumab emtansine group and 22% in the TPC group. Deaths from 
adverse events were reported in 3 patients (2%) in the TPC group (of which 1 death was 
judged to be treatment related) and 9 patients (2%) in the trastuzumab emtansine group
(of which 3 deaths were judged to be treatment related) (Krop et al. 2017).
1.3.4
Study BO27938 (KATHERINE)
Study BO27938 is a multicenter, Phase III, randomized, open-label trial to evaluate 
patients with HER2-positive EBC who had residual invasive disease after completion of 
neoadjuvant therapy. At the interim analysis, among 1486 randomly assigned patients 
(743 in the trastuzumab emtansine group and 743 in the trastuzumab group), invasive 
disease or death had occurred in 91 patients in the trastuzumab emtansine group 
(12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage 
of patients who were free of invasive disease at 3 years was 88.3% in the trastuzumab 
emtansine group and 77.0% in the trastuzumab group. Invasive disease-free survival 
was significantly higher in the trastuzumab emtansine group than in the trastuzumab 
group (HR for invasive disease or death was 0.50; 95% CI: 0.390.64; p0.001). Distant 
recurrence as the first invasive-disease event occurred in 10.5% of patients in the 
trastuzumab emtansine group and 15.9% of those in the trastuzumab group. The safety 
data were consistent with the known safety profile of trastuzumab emtansine, with more 
adverse events associated with trastuzumab emtansine than with trastuzumab alone.
As of December 2019, based on the results of the KATHERINE study, trastuzumab 
emtansine (Kadcyla) was approved in the U.S. and has received recommendation for 
approval in the E.U. from the Committee for Medicinal Products for Human Use for the 
adjuvant treatment of patients with HER2-positive EBC who have residual invasive 
disease after neoadjuvant taxane and trastuzumab-based treatment.
1.4
BACKGROUND ON VENETOCLAX
Venetoclax (also referred to as GDC-0199, RO5537382, ABT-199, A-1195425.0, 
Venclexta, and Venclyxto) is an orally bioavailable, selective small-molecule inhibitor 
of Bcl-2 in the biaryl acylsulfonamide chemical class. Venetoclax binds with high affinity 
(Ki0.01 nM) to the anti-apoptotic protein Bcl-2 and with lower affinity to other anti-
apoptotic Bcl-2 family proteins such as Bcl-XL and Bcl-w (4,000-fold and 2,000- to 
20,000-fold lower affinity than to Bcl-2, respectively; Souers et al. 2013). Survival of 
platelets depends on Bcl-XL, and thrombocytopenia is therefore a major dose-limiting 
toxicity (DLT) caused by inhibition of BCL-XL in the clinic. Venetoclax has an improved 


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therapeutic index by maintaining efficacy against tumor cells while avoiding dose-limiting 
thrombocytopenia.
Venetoclax has been extensively studied in oncology, particularly in hematologic
malignancies but also in some solid tumors. Efficacy data indicate that venetoclax, both 
as a monotherapy and in combination with other therapeutic agents, shows promising 
safety, tolerability, pharmacokinetics, and efficacy. This includes combinations with 
rituximab; obinutuzumab; bendamustine plus rituximab; O6-benzylguanine; rituxan plus 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); obinutuzumab 
plus CHOP (G-CHOP); bortezomib plus dexamethasone, azacitidine, or decitabine; and 
cytarabine in patients with hematologic malignancies, including CLL/SLL, NHL, MM, 
myelodysplastic syndrome, and AML. 
In the United States, venetoclax (Venclexta) is indicated for the treatment of adult 
patients with CLL or SLL. In addition, it is approved in combination with azacitidine or 
decitabine or low-dose cytarabine (LDAC) for the treatment of adults with newly
diagnosed AML who are age 75 years or older or who have comorbidities that preclude 
use of intensive induction chemotherapy. The AML indication is approved under 
accelerated approval based on response rates. Continued approval for this indication 
may be contingent upon verification and description of clinical benefit in confirmatory 
trials.
In the European Union, venetoclax (Venclyxto) in combination with rituximab is 
indicated for the treatment of adult patients with CLL who have received at least one
prior therapy. Monotherapy is indicated for the treatment of CLL in the presence of 17p 
deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell 
receptor pathway inhibitor, or in the absence of 17p deletion or TP53 mutation in adult 
patients who have failed both chemoimmunotherapy and a B-cell receptor pathway 
inhibitor.
In solid tumors, such as ER-positive, Bcl-2 positive MBC, venetoclax has shown 
promising activity (Lok et al. 2019). In a Phase Ib dose-escalation study, venetoclax 
administered at 200, 400, 600, or 800 mg QD in combination with tamoxifen at 20 mg
QD was shown to be well tolerated.  No DLTs, including Grade 3 toxicity, were
observed in any of the cohorts and the maximum tolerated dose (MTD) was not reached. 
The 800 mg QD dose was selected as the recommended Phase II dose (RP2D).
Efficacy was promising with 54% ORR and a clinical benefit rate (CBR) of 75% for the 
800 mg QD cohort, comparing favorably with historical studies of patients treated with 
tamoxifen in the first-line relapse setting (e.g., ORR 17%33% and CBR 38%56%).
The combination of venetoclax plus hormonal therapy (fulvestrant) in ER-positive MBC is 
being further evaluated in the ongoing randomized Phase II Study WO40181 
(VERONICA). Study results will be reported in the Venetoclax Investigator’s Brochure(s) 
when available.


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Refer to the Venetoclax Investigator's Brochure(s) for details on nonclinical and clinical 
studies.
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Trastuzumab emtansine is an active regimen and the standard of care in second-line
HER2-positive MBC (Verma et al. 2012). The safety of trastuzumab emtansine is well 
established, having been evaluated in over 2000 patients with BC in clinical studies.  
Trastuzumab emtansine is generally well tolerated, with the most common adverse 
events being nausea, fatigue, and headache.  Adverse events of particular relevance 
include thrombocytopenia, hemorrhage, hepatotoxicity (increases in serum 
transaminases and nodular regenerative hyperplasia [NRH] of the liver), infusion
related-reactions/hypersensitivity, cardiac dysfunction (left ventricular dysfunction), 
peripheral neuropathy, and pulmonary toxicity (interstitial lung disease [ILD].  
Venetoclax has been evaluated in a variety of oncological indications, particularly in 
hematological malignancies, and has been generally well tolerated as a single agent as 
well as in combination with targeted therapies and chemotherapy (refer to the 
Venetoclax Investigator’s Brochure for more details). Adverse events commonly 
observed with venetoclax include nausea, vomiting, diarrhea, and myelotoxicity 
(including anemia, thrombocytopenia, and leukopenia). To date, the majority of these 
adverse events have been manageable without requiring treatment discontinuation. 
Important identified risks for venetoclax include tumor lysis syndrome (TLS), particularly 
in CLL and mantle cell lymphoma, and neutropenia. Serious infection is also an 
identified risk. Of note, cytopenias and TLS are commonly observed in hematologic 
malignances and in some cases independently of treatment, and their prevalence in 
solid tumors remains to be elucidated.
Nonclinical data indicate a potential synergistic mechanism of action between venetoclax 
and trastuzumab emtansine. Microtubule inhibitors, such as taxanes and vinca alkaloids, 
have been described to promote degradation of the anti-apoptotic protein MCL-1 (Wertz 
et al. 2011), which can be a resistance factor for venetoclax monotherapy (Bose et al. 
2017). The mechanism of DM1 inhibition of microtubules is similar to that of vinca
alkaloids and, as such, DM1 also induces degradation of MCL-1 (Genentech 
unpublished data). Direct inhibition of MCL-1 in combination with venetoclax has been 
shown to be synergistic nonclinically across various hematologic and solid tumor
malignancies (Phillips et al. 2015; Li et al. 2019; Moujalled et al. 2019). These
nonclinical data support the investigation of venetoclax with combination partners that 
inhibit MCL-1, either directly or indirectly, and provide scientific rationale to test the 
combination of trastuzumab emtansine (via MCL-1 degradation) and venetoclax. 
Further, Bcl-2 upregulation has been associated with resistance to trastuzumab 
emtansine in various BC cell lines (unpublished data; Saatci et al. 2018).  Combining
venetoclax with trastuzumab emtansine was shown to enhance apoptosis in vitro
compared to single agent treatments in these trastuzumab emtansineresistant cell lines 


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(Genentech unpublished data). The combination of trastuzumab emtansine and 
venetoclax has been tested in vivo in trastuzumab emtansine naive and resistant models,
and the results of the data are summarized as follows (Genentech unpublished data):

In the MDA-MB-361 HER2-positive trastuzumab emtansine naiveBC xenografts 
grown orthotopically in NOD-SCID mice, trastuzumab emtansine administered 
intravenously once in combination with venetoclax administered PO QD for 21 days 
demonstrated enhanced tumor growth inhibition (TGI) compared to trastuzumab 
emtansine or venetoclax monotherapy. TGI on Day 21 of the dosing period was 38% 
for trastuzumab emtansine, 34% for venetoclax, and 70% for the combination of 
trastuzumab emtansine and venetoclax.  

KPL-4 trastuzumab emtansineresistant cell line clones were generated to be 
trastuzumab emtansine resistant in vitro through long-term drug treatment. KPL-4 
clones 8 and 17 demonstrated upregulation of Bcl-2 protein at resistance. The 
combination of trastuzumab emtansine and venetoclax showed enhanced 
anti-tumor efficacy for both clones when grown orthotopically as xenografts in NOD-
SCID mice. Trastuzumab emtansine was administered once intravenously and 
venetoclax was administered PO QD for 21 days. For KPL-4 clone 17, TGI on 
Day 21 of the dosing period was 27% for trastuzumab emtansine, 3% for venetoclax,
and 74% for the combination of trastuzumab emtansine and venetoclax. For KPL-4 
clone 8, TGI 2 days after end of treatment (Study Day 23) was 93% for trastuzumab 
emtansine, 8% for venetoclax, and 143% for the combination of trastuzumab 
emtansine and venetoclax.
Importantly, in vivo assessment of altering venetoclax schedules dosed for either 10 or 
21 consecutive days has demonstrated equivalent anti-tumor efficacy when 
administered in combination with trastuzumab emtansine (Genentech unpublished data). 
Furthermore, a shorter schedule of venetoclax dosing (5 continuous days) was also 
shown to improve responses in combination with trastuzumab emtansine in 
HER2-positive BC PDX models that are sensitive as well as resistant to trastuzumab 
emtansine (unpublished data). In separate studies using additional HER2-positive PDX 
models, inhibition of Bcl-2 and Bcl-XL with navitoclax (ABT-263) significantly enhanced 
cytotoxicity of trastuzumab emtansine (Zoeller et al. 2019). The nonclinical data cited 
herein provide rationale for testing continuous and non-continuous schedules of 
venetoclax in combination with trastuzumab emtansine. Therefore, this study will offer 
an opportunity to evaluate the safety and activity of a promising novel approach 
combining venetoclax and trastuzumab emtansine for the treatment of HER2-positive 
MBC in the clinical setting.
The safety and tolerability of the combination of trastuzumab emtansine and venetoclax 
is currently unknown and will be evaluated in the Phase Ib portion of this study. 
Although the combination is expected to have limited overlapping toxicities, there 
remains the potential for unknown toxicities. Key overlapping toxicities for the 
combination include hematologic toxicities, such as neutropenia, febrile neutropenia, 
thrombocytopenia, and gastrointestinal toxicities (e.g., nausea, vomiting, diarrhea).


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To minimize this risk, stringent inclusion and exclusion criteria (Sections 4.1.1 and 4.2.2) 
and close safety monitoring (Section 5.1), together with rules for dose modifications and 
safety management guidelines for known risks of single-agent trastuzumab emtansine 
and venetoclax, have been implemented in the current study.  Furthermore, guidance on 
management of potential overlapping toxicities is described in Section 5.1.3.3.  
Specifically, during the Phase Ib portion of this study, safety review will be led by the 
Medical Monitor in consultation with the study investigators and a committee composed 
at a minimum of the following Sponsor representatives: statistician, safety scientist, PK 
scientist, and clinical scientist. During the randomized Phase II stage of the study, an 
Internal Monitoring Committee (IMC; Section 3.1.4) has also been incorporated into the 
trial design to periodically review aggregate efficacy and safety data (refer to the IMC 
charter for a detailed monitoring plan). 
HER2-positive MBC remains an incurable disease despite advances in patient care.  
Nearly all patients with HER2-positive MBC will eventually suffer disease progression 
and succumb to their disease. There continues to be a need for more efficacious 
therapies with acceptable safety profiles in patients with HER2-positive disease. 
Therefore, the addition of venetoclax based on its pro-apoptotic mechanism of action 
and potential to overcome resistance to trastuzumab emtansine, as well as a
manageable safety profile, can represent a potential valuable treatment option and offers
a favorable benefitrisk balance for patients in this study.
2.
OBJECTIVES AND ENDPOINTS
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-
controlled, double-blind, multicenter stage (hereafter referred to as the “randomized 
Phase II stage”). 
The dose-escalation phase will assess safety and tolerability, determine the MTD and 
the RP2D, and evaluate the preliminary efficacy of trastuzumab emtansine in 
combination with venetoclax in patients with previously treated HER2-positive LABC or 
MBC who have received prior trastuzumab emtansine in the metastatic setting.  
Once the RP2D is established, additional patients may be enrolled in the expansion 
phase to evaluate the safety, tolerability, and efficacy of trastuzumab emtansine in 
combination with venetoclax at the RP2D in patients with previously treated HER2-
positive LABC or MBC who have previously received either trastuzumab emtansine or 
trastuzumab deruxtecan (DS-8201a). The decision to open these cohorts will be data-
driven and dependent on the observations made in the dose-escalation phase, as well 
as emerging data about trastuzumab deruxtecan and other HER2-targeted therapies.
Importantly, the expansion phase may run concurrent to and in parallel with the 
randomized Phase II stage of the study. 


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The randomized Phase II stage will aim to evaluate the safety, tolerability, 
pharmacokinetics, and efficacy of trastuzumab emtansine in combination with 
venetoclax at the RP2D compared with trastuzumab emtansine plus placebo in patients 
with previously treated HER2-positive LABC or MBC who have not received prior 
trastuzumab emtansine therapy, either alone or in combination with other anticancer 
therapies.
Specific objectives and corresponding endpoints for the study are outlined below.
2.1
OBJECTIVES AND ENDPOINTS FOR DOSE-ESCALATION 
PHASE
2.1.1
Primary Safety Objective
The safety objective for the dose-escalation phase is to evaluate the safety and 
tolerability of trastuzumab emtansine in combination with venetoclaxincluding 
estimation of the MTD, determination of the RP2D, and characterization of DLTs (see 
Section 3.1.1.1)on the basis of the following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0 (NCI CTCAE v5.0)

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
2.1.2
Exploratory Efficacy Objective
The exploratory efficacy objective for the dose-escalation phase is to make a preliminary 
assessment of the anti-tumor activity of trastuzumab emtansine and venetoclax on the 
basis of the following endpoints:

ORR, defined as the proportion of patients with CR or PR on two consecutive 
assessments, at least 28 days apart, as determined by investigator assessment 
using RECIST v1.1 (see Appendix 11)

DOR, defined as the time from the first occurrence of a documented objective 
response to disease progression as determined by the investigator using RECIST 
v1.1, or death from any cause, whichever occurs first
2.1.3
Pharmacokinetic Objective
The PK objective for the dose-escalation phase of this study is to characterize the 
pharmacokinetics of venetoclax when given in combination with trastuzumab emtansine 
on the basis of the following endpoint:

Plasma concentrations of venetoclax at specified timepoints


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2.1.4
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or 
evaluate biomarkers that are predictive of response to venetoclax in combination with 
trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to trastuzumab emtansine and venetoclax, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of venetoclax and/or trastuzumab emtansine activity (i.e., pharmacodynamic [PD] 
biomarkers), or can increase the knowledge and understanding of disease biology and 
drug safety, on the basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab 
emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue (see 
Section 4.5.7) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
2.2
OBJECTIVES AND ENDPOINTS FOR EXPANSION PHASE
2.2.1
Primary Efficacy Objective
The primary efficacy objective for the expansion phase is to evaluate the efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoint:

ORR
2.2.2
Secondary Efficacy Objective
The secondary efficacy objective for the expansion phase is to evaluate the efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoint:

DOR
2.2.3
Safety Objective
The safety objective for the expansion phase is to evaluate the safety and tolerability of 
venetoclax at the RP2D in combination with trastuzumab emtansine on the basis of the 
following endpoints:

Incidence and severity of adverse events, including DLTs, with severity determined 
according to NCI CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results


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2.2.4
Pharmacokinetic Objective
The PK objective for the expansion phase of the study is to characterize the 
pharmacokinetics of venetoclax when given in combination with trastuzumab emtansine 
on the basis of the following endpoint:

Plasma concentrations of venetoclax at specified timepoints
2.2.5
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or 
evaluate biomarkers that are predictive of response to venetoclax in combination with 
trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to trastuzumab emtansine and venetoclax, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of venetoclax and/or trastuzumab emtansine activity (i.e., PD biomarkers), or can 
increase the knowledge and understanding of disease biology and drug safety, on the 
basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab 
emtansine

Relationship between biomarkers in blood, plasma, and tumor tissue (see 
Section 4.5.7) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
2.3
OBJECTIVES AND ENDPOINTS FOR RANDOMIZED PHASE II 
STAGE
2.3.1
Primary Efficacy Objective
The primary efficacy objective for the randomized Phase II stage is to evaluate the 
efficacy of trastuzumab emtansine in combination with venetoclax compared with 
trastuzumab emtansine plus placebo on the basis of the following co-primary endpoints:

ORR

PFS after randomization, 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
2.3.2
Secondary Efficacy Objective
The secondary efficacy objective for the randomized Phase II stage is to evaluate the 
efficacy of trastuzumab emtansine in combination with venetoclax compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoints:

DOR


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
OS after randomization, defined as the time from randomization to death from any 
cause
2.3.3
Exploratory Efficacy Objective 
The exploratory efficacy objective for the randomized Phase II stage is to evaluate the 
efficacy of trastuzumab emtansine in combination with venetoclax compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoints:

CBR, defined as the proportion of patients with CR, PR, or stable disease (SD) at 
6 months after randomization, as determined by the investigator according to 
RECIST v1.1
2.3.4
Safety Objective
The safety objective for the randomized Phase II stage is to evaluate safety of 
trastuzumab emtansine in combination with venetoclax compared with trastuzumab 
emtansine plus placebo on the basis of the following endpoints:

Incidence and severity of adverse events with severity determined according to NCI 
CTCAE v5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
2.3.5
Pharmacokinetic Objective
The PK objective for the randomized Phase II stage of this study is to characterize the 
pharmacokinetics of trastuzumab emtansine and venetoclax when given in combination 
on the basis of the following endpoints:

Serum concentrations of trastuzumab emtansine at specified timepoints

Plasma concentrations of venetoclax at specified timepoints
2.3.6
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to
trastuzumab emtansine when given with placebo or in combination with venetoclax on 
the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during 
the study
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints


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2.3.7
Biomarker Objective
The exploratory biomarker objective for all phases in this study is to identify and/or 
evaluate biomarkers that are predictive of response to venetoclax in combination with 
trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with acquired resistance to trastuzumab emtansine and venetoclax, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of venetoclax and/or trastuzumab emtansine activity (i.e., PD biomarkers), or can 
increase the knowledge and understanding of disease biology and drug safety, on the 
basis of the following endpoints:

Changes in expression levels of biomarkers or biomarker panels during and after 
investigational treatment with venetoclax in combination with trastuzumab 
emtansine

The relationship between biomarkers in blood, plasma, and tumor tissue (see 
Section 4.5.7) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
2.3.8
Patient Reported Outcome Objective
The patient reported outcome objective for the randomized Phase II stage is to evaluate 
the efficacy of trastuzumab emtansine in combination with venetoclax compared with 
trastuzumab emtansine plus placebo on the basis of the following endpoint:

Change from baseline in patient-reported symptoms and their impact on functioning 
and health-related quality of life, and the overall burden of side effects, as measured 
by the European Organisation for Research and Treatment of Cancer Quality of Life 
Core 30 Questionnaire (EORTC QLQ-C30) and EORTC Item List 46 (EORTC IL46)
item
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This two-part study is composed of two stages: a Phase Ib stage consisting of a dose-
escalation phase and an expansion phase; and a Phase II, randomized, placebo-
controlled, double-blind, multicenter stage (hereafter referred to as the “randomized 
Phase II stage”).  The expansion phase may run concurrent to and in parallel with the 
randomized Phase II stage.
Approximately 226284 patients will be enrolled in this study across approximately 
145 sites globally. The study will enroll 624 patients in the Phase Ib dose-escalation 
phase and approximately 220 patients in the Phase II stage.  An additional 
approximately 2040 patients may be enrolled in the Phase Ib expansion cohorts.


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Figure 1
Overall Study Schema
MBCmetastatic breast cancer; MTDmaximum tolerated dose; Q3W every 3 weeks; QDonce a day; RP2Drecommended Phase II dose.


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3.1.1
Dose-Escalation Phase
The dose-escalation phase will determine the RP2D and MTD for venetoclax when given 
in combination with a fixed dose of trastuzumab emtansine (3.6 mg/kg) in patients with 
previously treated, HER2-positive LABC or MBC who have received prior trastuzumab
emtansine in the metastatic setting. 
The dose-escalation phase will enroll 624 patients and will include 24 cohorts:

Cohort 1A, 400 mg QD Cohort:  Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax
400 mg PO once a day (QD) continuous on Days 121 of each cycle. 

Cohort 1B, 400 mg NC Cohort:  Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 
400 mg PO QD non-continuous on either Days 17 or 114 of each cycle (see 
further description below). 

Cohort 2A, 800 mg QD Cohort: Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax 
800 mg PO QD continuous on Days 121 of each cycle.

Cohort 2B, 800 mg NC Cohort:  Patients will receive trastuzumab emtansine 
3.6 mg/kg by IV infusion on Day 1 of each 21-day cycle (Q3W) and venetoclax
800 mg PO QD non-continuous on either Days 17 or 114 of each cycle. 
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator's discretion.  Patients are not required to re-sign the consent form if they 
are re-screened within 30 days after previously signing the consent form. The 
investigator will record reasons for screen failure within the interactive voice or 
web-based response system (IxRS) and electronic Case Report Form (eCRF [see
Section 4.5.1]).
Figure 2 presents an overview of the dose-escalation phase design.  A schedule of 
activities for dose-escalation and expansion phases are provided in Appendix 1 and
Appendix 2, respectively.


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Figure 2
Phase Ib Dose-Escalation Study Schema
DLT dose-limiting toxicity; MTDmaximum tolerated dose; NCnon-continuous; QDonce a day; RP2Drecommended Phase II dose.


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The 400-mg and 800-mg cohorts for dose escalation will be run sequentially (i.e., the 
400-mg cohort followed by the 800-mg cohort). Dose escalation will be performed 
based on a standard 3 3 design. Each cohort will consist of at least 3 patients, unless 
1 of the 3 patients experiences DLTs (refer to Section 3.1.1.1 for DLT criteria), in which
case 3 additional patients will be treated at the same dose level. The dose escalation 
will continue until 2 patients among a cohort of 6 patients experience a DLT (i.e., 33% 
of patients with a DLT at that dose level; refer to dose-escalation rules below). Patients 
who experience a DLT will continue at the same dose level.
Dose de-escalation may be explored by incorporating non-continuous (NC) dosing of 
venetoclax (e.g., less than 21 days of dosing, such as 7 days out of 21 days or 14 days 
out of 21 days) dependent on the severity and timing of DLTs as well as the specific 
adverse events, including those that result in dose interruptions or dose modifications. 
For example, if DLTs such as a Grade 3 rash occurred between Day 8 and Day 14, an
NC schedule of Days 17 would be tested.  Alternatively, if DLTs are thought to be 
possibly mitigated by a 7-day break such as Grade 3 fatigue occurring near the end of 
the DLT window (e.g., Day 20), then an NC schedule of Days 114 could be chosen to 
be tested. Patients may be treated in up to two NC sub-cohorts (i.e., either 400 mg NC 
and/or 800 mg NC; refer to Figure 2). At each dose de-escalation level, either a Days
17 or Days 114 NC treatment schedule will be assessed.
3.1.1.1
Definition of Dose-Limiting Toxicity
Patients will be closely monitored for adverse events during the 21-day DLT assessment 
window. All adverse events, including DLTs, will be graded according to the NCI 
CTCAE v5.0 (Appendix 12) unless otherwise indicated.  If a patient experiences a DLT, 
the patient will be treated according to clinical practice and will be monitored for 
resolution of the toxicity.
For dose-escalation purposes, a DLT will be defined as any one of the following events 
regardless of relationship to study treatment (unless otherwise specified below) 
occurring during the 21-day DLT assessment period, which runs from Days 121 of
Cycle 1:

Grade 4 neutropenia (ANC 500/mm3) lasting >7 days

Grade 4 thrombocytopenia (platelet count 25,000/mm3) or Grade 3 
thrombocytopenia associated with severe bleeding

Grade 4 anemia

Grade 3 febrile neutropenia for 7 days or Grade 4 febrile neutropenia of any 
duration

Treatment related Grade 3 non-hematologic, non-hepatic, and non-cardiac major 
organ toxicity lasting for 72 hours

Grade 3 serum bilirubin, hepatic transaminase (ALT or AST), or ALP lasting for 
72 hours


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For patients with Grade 2 hepatic transaminase or ALP levels at baseline as a 
result of liver metastases or bone metastases, a hepatic transaminase or ALP
level 10 times the upper limit of normal (ULN) will be considered a DLT. For 
patients with abnormal TBILI at baseline an increase of 3.010.0 times baseline 
value will be considered a DLT.

Grade 3 cardiac toxicity (resting ejection fraction [EF] 39%20%; 20% drop from 
baseline; symptomatic heart failure)

Treatment-related death
Adverse events meeting the criteria for DLT within the 21-day assessment period must 
be reported to the Sponsor within 24 hours. 
3.1.1.2
Dose-Escalation Rules, Determination of 
Dose-Limiting Toxicities, and Recommended Phase II Dose
Dose escalation will occur in accordance with the rules listed below:

A minimum of 3 DLT-evaluable patients will initially be enrolled into each cohort.

If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
next cohort at the next dose level may proceed.

If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be 
expanded to 6 patients. If there are no further DLTs in the first 6 DLT-evaluable 
patients, enrollment of the next cohort at the next dose level may proceed.

If 2 or more of the first 6 DLT-evaluable patients in the continuous (QD) dose-
escalation cohorts experience a DLT, an additional 3 patients will be evaluated for 
DLTs at the corresponding NC dose level. If none of the first 3 DLT-evaluable 
patients experiences a DLT, enrollment of the next NC dose level may proceed.

If 1 of the first 3 DLT-evaluable patients experiences a DLT, the NC dose level 
cohort will be expanded to 6 patients. If there are no further DLTs in the first 6 DLT-
evaluable patients, enrollment of the next cohort at the next dose level may proceed.

If 2 or more of the first 6 DLT-evaluable patients in the NC dose-escalation cohort 
experience a DLT, the MTD will have been exceeded and dose escalation will stop. 

If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of
6 DLT-evaluable patients (i.e., 33%) experience a DLT will be declared the MTD.

If the MTD is not exceeded at any dose level, the highest dose administered in this
study will be declared the MTD.
Determination of whether a patient is evaluable for DLT assessment will be made in 
accordance with the following rules:

Patients who receive study treatment (e.g., at least 66% of planned venetoclax 
doses and 1 dose of trastuzumab emtansine) and remain in the study through the 
DLT assessment window will be considered DLT evaluable.


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
Patients who discontinue from treatment with trastuzumab emtansine or venetoclax
treatment prior to completing the DLT assessment window for reasons other than a 
DLT will be considered non-evaluable for dose-escalation decisions and MTD 
determination and will be replaced by an additional patient at that same dose level.

Patients who do not receive at least 66% of planned venetoclax doses (e.g., 14 out 
of 21 days for continuous [QD] dosing, 10 out of 14 days for Days 114 NC, or 5 out 
of 7 days for Days 17 NC) or 1 dose of trastuzumab emtansine during the DLT 
assessment period will be replaced, to ensure that at least 3 patients in each cohort 
have been assessed for the full DLT assessment period of 21 days prior to moving 
to the next dose level.
Patients exhibiting acceptable safety and evidence of clinical benefit (as determined by 
the investigator) may continue to receive study treatment until confirmed objective 
disease progression or unacceptable toxicity, whichever occurs first.
The Sponsor will review cumulative safety data and make recommendations regarding 
dose escalation and overall study conduct on the basis of study safety data to ensure 
patient safety while receiving study treatment. These include recommendations to open 
or suspend patient enrollment in a given dose-escalation cohort based on the overall 
benefitrisk profile of trastuzumab emtansine in combination with venetoclax.
Relevant demographic, adverse event, laboratory, dose administration, and PK data (if 
available) will be reviewed prior to the selection of the RP2D for the expansion and 
randomized phases of the study. The RP2D for both the expansion and randomized 
phases will be the same dose and schedule. The RP2D will be based on the MTD of 
venetoclax when combined with a fixed dose of trastuzumab emtansine and will 
integrate aggregate safety data during treatment. Decision making will be led by the 
Medical Monitor in consultation with the study investigators and a committee composed 
at a minimum of the following Sponsor representatives: statistician, safety scientist, PK 
scientist, and clinical scientist. For example, based upon nonclinical data showing 
similar efficacy of NC versus continuous dosing, as well as the mechanism of action of 
combining venetoclax with a cytotoxic agent such as trastuzumab emtansine, NC dosing 
of 800 mg for 17 days or 114 days would be preferred over 400 mg QD.  Aggregate 
clinical data would be integrated into the decision making, including safety and efficacy 
data.  
3.1.2
Expansion Phase
An expansion phase may be initiated to evaluate the safety, tolerability, and efficacy of 
venetoclax at the RP2D in combination with trastuzumab emtansine in previously treated 
HER2-positive locally advanced or MBC patients who have received prior trastuzumab 
emtansine or trastuzumab deruxtecan (DS-8201a). 
The decision to open cohorts as part of an expansion phase will be data-driven and 
dependent on the observations made in the dose-escalation phase, emerging data with 


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trastuzumab deruxtecan, as well as other HER2-targeted therapies. The expansion 
phase may run concurrent to and in parallel with the randomized Phase II stage of the 
study.
Approximately 20 patients may be enrolled in each of the expansion cohorts (see
Figure 3).
Figure 3
Phase Ib Expansion Cohorts Study Schema
Bcl-2 B-cell lymphoma 2; DORduration of response; IHC immunohistochemistry; 
INV investigator; MBC metastatic breast cancer; ORR objective response rate; OSoverall 
survival; PFSprogression-free survival; Q3W every 3 weeks; RECIST v1.1 Response 
Evaluation Criteria in Solid Tumors, Version 1.1; RP2D recommended Phase II dose.
a Prior exposure to other HER2-targeted therapies (e.g., trastuzumab, pertuzumab, trastuzumab 
deruxtecan, margetuximab, pyrotinib, tucatinib and/or neratinib) is permitted. 
b Eligibility for this cohort requires prior experience with trastuzumab deruxtecan (DS-8201a) in
any setting. 
3.1.3
Randomized Phase II Stage
The randomized Phase II stage will be initiated once the RP2D has been identified 
based on the cumulative data collected from the dose-escalation phase.  It will consist of 
two interventional arms of trastuzumab emtansine plus placebo or trastuzumab 
emtansine plus venetoclax in patients with previously treated HER2-positive LABC or 
MBC, who have not received prior trastuzumab emtansine therapy.
Approximately 220 patients will be randomized 1:1 to one of the following treatment 
arms:  

Control Arm: Patients will receive trastuzumab emtansine 3.6 mg/kg by IV infusion 
Q3W plus placebo at the RP2D and schedule of venetoclax.


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
Experimental Arm: Patients will receive trastuzumab emtansine 3.6 mg/kg by IV 
infusion Q3W plus venetoclax at the RP2D and schedule.
Each arm will include at least 50% Bcl-2 high patients, and randomization will be based 
on the three stratification factors shown in Figure 4 (see also Section 4.2.1). Crossover 
between treatment arms will not be permitted. A schedule of activities for the 
randomized phase is provided in Appendix 2.


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Figure 4
Phase II Randomized Study Schema
Bcl-2 B-cell lymphoma 2; DOR duration of response; IHC immunohistochemistry; INV investigator; Nno; ORR objective response rate; 
OS overall survival; PFS progression-free survival; Q3W every 3 weeks; RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 
1.1; Rrandomization; RP2D recommended Phase II dose; Yyes.


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3.1.4
Internal Monitoring Committee for the Randomized Phase II 
Stage
An IMC will be established to monitor patient safety as well as efficacy in the randomized 
Phase II stage of the study. The IMC will not be blinded, will help monitor safety of 
enrolled patients, and will conduct periodic interim reviews of safety data during the 
randomized Phase II stage of the study. The frequency of the reviews will be 
determined as needed. The IMC will be external to the study team and will be 
composed of at least one medical doctor and/or clinical science representative, with
representatives from clinical safety, biostatistics, as well as statistical programming and 
analysis, who are not directly involved in the study. A separate IMC charter will outline 
the committee's composition, meeting timelines, and members' roles and responsibilities. 
The committee members will review all potential cases of serious adverse events, Grade 
3 and 4 adverse events, adverse events of special interest, and deaths as specified in 
the IMC charter. The IMC will be apprised of all relevant efficacy and safety data from 
this study and other related clinical trials. Ad hoc meetings may be called as necessary 
in addition to scheduled meetings to provide recommendations on management of any 
new safety issues. The Sponsor will be the final decision maker regarding protocol 
procedures and modifications.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  The end of study is planned to 
occur approximately 24 months after last patient in (LPI).  
In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 48 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Venetoclax Dose Selection in the Phase Ib Dose-
Escalation Phase of the Study
Venetoclax has been investigated and shown to be well tolerated in multiple trials of 
hematopoietic malignancies at doses ranging from 200 mg to 1200 mg, both as a 
monotherapy and in combination with other agents including dexamethasone, rituximab, 
obinutuzumab, bortezomib, and chemotherapy. Venetoclax is approved in the U.S. and 
E.U. for the treatment of adult patients with CLL (or SLL in the U.S.), with or without 17p 
deletion, who have received at least one prior therapy. The recommended dose of 
venetoclax monotherapy in this setting is 400 mg QD in a ramp-up schedule (Venclexta
U.S. Package Insert) and this dosing is maintained during administration with rituximab.
Venetoclax is also approved in combination with azacitidine or decitabine or low-dose 
cytarabine for the treatment of newly-diagnosed AML, with 400 mg QD dosing when in 


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combination with azacitidine or decitabine and 600 mg QD dosing when in combination 
with LDAC in the U.S. 
A Phase I dose-escalation trial investigating combinations of various doses of venetoclax 
(including 200 mg, 400 mg, 600 mg, and 800 mg) with tamoxifen assessed the safety 
and tolerability of venetoclax in combination with that ER modulator in patients with ER,
Bcl-2MBC (Lok et al. 2019).  Venetoclax at the dose of 800 mg PO QD in combination 
with tamoxifen was well tolerated. The nature and frequencies of adverse events were 
consistent with the known safety profiles of venetoclax and tamoxifen, and no Grade 5 
adverse events or DLTs occurred during the DLT observation period, based on the 
preliminary evidence of clinically relevant activity of venetoclax during the dose-
escalation phase. Venetoclax dosing is further informed by the ongoing randomized 
Phase II VERONICA study (WO40181) evaluating venetoclax at 800 mg QD plus 
fulvestrant in patients with HR-positive MBC.
Based on the experience in hematologic malignancies as well as ERBC, and the 
expected limited overlapping toxicities and potential for drugdrug interactions (DDI) 
between venetoclax and trastuzumab emtansine (see Section 3.3.11), two dose levels 
have been selected for the dose-escalation phase of the study. This is based on 
population PK and saturation modeling to assess dose dependency of venetoclax 
exposure with the assumption that CLL/DLBCL modeling can adequately predict solid 
tumors. This modeling has shown limited value of studying a 600 mg dose of venetoclax 
as an intermediate step in a 400 mg to 800 mg dose escalation (internal Genentech 
data). Moreover, the toxicities are considered to be monitorable and manageable, and 
enabling a starting dose of 400 mg continuous QD and moving up to the second dose 
level of 800 mg continuous QD (refer to Section 3.1.1).  
Patients with solid tumors may require a higher dose of venetoclax when compared with 
the 400 mg QD dose in hematologic malignancies such as CLL. This is reflected in the 
lower 50% effective concentration values of venetoclax for circulating lymphocyte counts 
(0.00863 g/mL) compared with tumor size (0.146 g/mL; Freise et al. 2017). Possible 
explanations for this observation include reduced blood flow and subsequent less 
efficient delivery of systemic venetoclax within a tumor, and altered signaling interactions 
between lymphoma cells and the cells of the tumor microenvironment. Therefore, a 
second dose level of 800 mg continuous QD is being evaluated, allowing for increased 
exposure of venetoclax in the tumor compartment.
3.3.2
Rationale for Venetoclax Dose Selection in the Phase II
Randomized Portion of the Study
The dose-escalation phase will provide further information on the venetoclax dose that is 
considered safe and tolerable to be combined with trastuzumab emtansine. The 
venetoclax RP2D and MTD for the combination with trastuzumab emtansine, which will 
be the same for both the expansion and randomized phases, will be determined based 
on the dose-escalation phase of the study (see Section 3.1.1). The RP2D may be lower 


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than the MTD, dependent on the evaluation of the cumulative and aggregated data from
the dose-escalation phase of the study. An IMC will conduct periodic reviews of safety 
data for all patients treated in the randomized Phase II stage of the study in order to 
confirm the safety and tolerability of the combination therapy at the RP2D (see 
Section 3.1.4). 
3.3.3
Rationale for Trastuzumab Emtansine Dose and Schedule
The globally approved and standard-of-care regimen of trastuzumab emtansine is 
3.6 mg/kg Q3W, as confirmed in Study TDM4370g/BO21977 (Verma et al. 2012), the 
pivotal Phase III trial comparing trastuzumab emtansine to lapatinib plus capecitabine in 
patients with HER2MBC who were previously treated with trastuzumab and a taxane.  
3.3.4
Rationale for Dose-Finding Rules
The rules for dose escalation are designed to ensure patient safety while providing an 
opportunity to identify the optimal venetoclax dose and schedule in combination with 
trastuzumab emtansine to maximize the benefitrisk profile of the combination. Key 
elements of dose escalation based on a standard 33 design are described in 
Section 3.1 and depicted in Figure 2.
Rules based on the nature and timing of observed safety events have been implemented.
3.3.5
Rationale for Dosing Schedule
Given the anticipated limited overlapping toxicities between venetoclax and trastuzumab 
emtansine (Section 5), continuous dosing of venetoclax on a 21-day cycle based on the 
trastuzumab emtansine infusion schedule is being evaluated initially. NC 7- or 14-day 
schedules may be evaluated based on the severity and timing of occurrence of adverse 
events experienced.
3.3.6
Rationale for Patient Population
Clinical benefit with trastuzumab emtansine has been demonstrated in a randomized 
study to improve PFS and OS compared to lapatinib pluscapecitabine, for patients with 
HER2-positive MBC who have received prior trastuzumab or taxane (Verma et al. 2012).  
Trastuzumab emtansine is the standard of care in this population; however, the PFS of 
approximately 8.6 months and OS of approximately 30 months for this patient population 
represent a continued unmet medical need.  Despite advances in care for patients with 
HER2-positive MBC, it remains an incurable disease.  Nearly all patients with 
HER2-positive MBC will eventually suffer disease progression and succumb to their 
disease. Thus, there is still a pressing need for more efficacious therapies with 
acceptable safety profiles in patients with HER2-positive disease. 
3.3.7
Rationale for Control Group
This control arm treatment is recognized as the recommended standard of care for 
HER2-positive MBC based on the results from Study TDM4370g/BO21977 (see 


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Section 1.2) (Verma et al. 2012). Trastuzumab emtansine has become widely accepted 
as the standard of care in patients who have been previously exposed to trastuzumab 
alone or trastuzumab and a taxane, which is the patient population being studied in the 
current trial (Cardoso et al. 2018; NCCN 2019). The control arm data will be used to 
ascertain the individual contribution of venetoclax to efficacy with trastuzumab 
emtansine. 
3.3.8
Rationale for Randomization and Blinding
Randomization will minimize differences between treatment groups at the outset of the 
trial and blinding will help prevent differential treatment of the groups later in the trial or 
the differential assessment of outcomes. Both randomization and blinding will mitigate 
bias and will aid to minimize the likelihood of differential treatment or assessments of 
outcomes.
3.3.9
Rationale for Objective Response Rate and Progression-Free 
Survival as Co-Primary Endpoints for the Randomized Phase II 
Stage
Investigator-assessed ORR by RECIST v1.1 and PFS are the co-primary endpoints for 
this study.
ORR (as defined in Section 2.1.1) is an increasingly important endpoint for accelerated 
development of highly active anticancer therapies.  Investigator-assessed ORR by 
RECIST v1.1 has been shown to be a meaningful trial endpoint correlating well with PFS 
and OS endpoints (Oxnard et al. 2016). In this patient population, ORR has been used 
as an early signal of clinical benefit (Verma et al. 2012, Tamura et al. 2019). Therefore,
for this study ORR will be used alongside PFS as a measure of the individual 
contribution of venetoclax to efficacy with trastuzumab emtansine. The clinical 
significance of the ORR will be assessed by the magnitude and duration of response.
PFS is the standard and accepted endpoint reflecting clinical benefit in HER2-positive 
MBC. PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; additionally, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents a 
direct clinical benefit or a surrogate for clinical benefit depends upon the magnitude of 
the effect and the benefit-risk of the new treatment compared with available therapies 
(FDA 2007; EMA 2017).   
To ensure the validity of investigator-assessed PFS as the primary endpoint, a number 
of measures have been implemented:  a substantial target magnitude of benefit and 
study assessments that will allow a robust evaluation of benefitrisk. This includes 
conventional criteria using RECIST v1.1 to define radiographic disease progression with 
fixed assessment intervals that are identical in both treatment arms, a robust definition of 
PFS as well as prospectively defined methods to assess, quantify, and analyze PFS, 
including sensitivity analyses.


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3.3.10
Rationale for Pharmacokinetic Assessments
This is the first study for which venetoclax will be given in combination with trastuzumab 
emtansine to patients with MBC.  Accordingly, PK plasma or serum samples will be 
taken to characterize the pharmacokinetics of venetoclax and trastuzumab emtansine 
when given in combination (see Section 4.5.7 for details).  
3.3.11
Rationale for Assessments of DrugDrug Interactions between 
Study Treatments
The potential for venetoclax to affect trastuzumab emtansine pharmacokinetics is 
considered to be low. The antibody component of trastuzumab emtansine is a 
therapeutic protein and therefore is not expected to interact with CYP450 or transporter 
pathways. The potential for DDIs between venetoclax and DM1, the small molecule 
component of trastuzumab emtansine, are also expected to be low based on knowledge 
of the metabolic and transporter pathways for each molecule.  Although venetoclax (a 
P-glycoprotein [P-gp] inhibitor) could potentially affect the pharmacokinetics of DM1 (a 
P-gp substrate) through a transporter-mediated interaction, the potential for a clinically 
meaningful effect is considered to be low, given that the DM1 catabolite of IV 
administered T-DM1 is less likely to be impacted by P-gp inhibition by venetoclax in the 
gut. Additionally, trastuzumab emtansine will be dosed in the linear PK range for this 
study, and co-administration of other anticancer agents with trastuzumab emtansine has
not impacted trastuzumab emtansine pharmacokinetics (see the Trastuzumab 
Emtansine Investigator’s Brochure).  These results suggest that target-mediated 
clearance does not significantly contribute to the overall systemic clearance of 
trastuzumab emtansine, suggesting a low potential for venetoclax to impact trastuzumab 
emtansine PK.
The risk of a clinically significant PK drug interaction for trastuzumab emtansine to alter 
venetoclax pharmacokinetics is expected to be low on the basis of their metabolic 
pathways. Venetoclax is primarily metabolized by CYP3A in vitro and is a reversible 
inhibitor of CYP2C8 and CYP2C9 in vitro. Trastuzumab emtansine is a biologic 
administered intravenously and is not expected to modulate CYP3A activity and affect 
venetoclax metabolism.
Based on the evidence provided above, limited blood samples will be collected to 
characterize the DDI interactions between venetoclax and trastuzumab emtansine when 
given in combination (see Section 4.5.7 for details).  
3.3.12
Rationale for Biomarker Assessments
BC is a heterogeneous disease, and HER2 and Bcl-2 expression have been shown to 
vary among patients (unpublished data).  All patients may not be equally likely to benefit 
from treatment with venetoclax and trastuzumab emtansine.  Predictive biomarker 
samples (tissue and blood) collected prior to dosing will be assessed in an effort to 
identify those patients who are most likely to respond to venetoclax and trastuzumab 


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emtansine. PD biomarkers will be assessed to demonstrate evidence of biologic activity 
of venetoclax and trastuzumab emtansine in patients, to support selection of a 
recommended dose and dosing regimen, and to inform potential revisions to the PK 
sample collection schedule. As these biomarkers may also have prognostic value, their 
potential association with disease progression will also be explored.
Currently, there are limited data about the correlation of response to Bcl-2 inhibition in 
BC and Bcl-2 expression levels. Bcl-2 levels are elevated in ER-positive subgroups 
relative to the other molecular subgroups that comprise BC. Furthermore, nonclinical 
data have demonstrated increased antitumor activity in high Bcl-2 expressing BC cell 
lines (see Section 1.5). Therefore, predictive biomarker samples collected prior to 
dosing will be assessed in an effort to identify those patients with Bcl-2-driven 
pathogenesis who are most likely to respond to venetoclax. The study aims to 
prospectively explore if Bcl-2 expression might have predictive or prognostic value or 
may be associated with disease progression in the studied population.
Fresh tissue acquisition in some patients with MBC may not be feasible; consequently, 
assessment of more easily accessible biomarkers in circulation is of high interest. In 
addition to identification of disease-specific, potentially prognostic, or predictive 
biomarkers in predose, baseline blood specimens, on-treatment collection of blood to 
evaluate circulating tumor DNA (ctDNA) may enable identification of biomarkers 
informing the relationship with established clinical response assessments, the monitoring 
of disease progression, and the identification of markers of resistance.
Tumor tissue samples will be analyzed through use of IHC to assess protein expression, 
and/or RNA sequencing to assess gene expression levels. Both tissue and blood 
samples will be analyzed by next-generation sequencing (NGS) to identify somatic 
alterations that are predictive of response to study drug, are associated with progression, 
are associated with acquired resistance to study drug, or can increase the knowledge 
and understanding of disease biology.
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
3.3.13
Rationale for Stratification and Enrichment by B-Cell 
Lymphoma-2 (Bcl-2) Status
Bcl-2 levels are elevated in ER-positive tumors; however, there are scant clinical data 
demonstrating a pathogenic role for Bcl-2 in HER2-positive BC. Venetoclax specifically 
inhibits Bcl-2 activity and there is potential that Bcl-2 target-expression levels may 


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correlate with activity. The role of Bcl-2 in pathogenesis is confounded by the prognostic 
profile associated with the ER-positive subtype. To distinguish the potential for 
predictive value of Bcl-2 expression levels with targeted Bcl-2 inhibition, patients will be 
1) randomized into venetoclax plus trastuzumab emtansine versus trastuzumab 
emtansine plus placebo arms to distinguish prognostic effects; and 2) stratified into Bcl-2
high and Bcl-2 low populations (as defined in Section 4.1.1.1). 
In nonclinical analyses, elevated Bcl-2 expression levels in NHL cell lines correlate with 
venetoclax activity using this high versus low cutoff. Stratification will ensure that the 
relative populations of Bcl-2 high and low are well balanced between both arms and 
therefore enable evaluation of the correlation between Bcl-2 expression and venetoclax 
activity in BC. In addition, specifying a minimum number of Bcl-2 high tumor patients will 
enable evaluation of Bcl-2 status as a potential predictive biomarker.  Responses will be 
evaluated by comparing the two stratified subgroups.
Since a cutoff for Bcl-2 levels in BC has not been established, retrospective analyses 
may also be performed to evaluate alternative cutoffs.
3.3.14
Rationale for Stratification by Visceral Metastases
The site(s) and degree of metastatic dissemination are among the principal prognostic 
factors for patients with MBC. Patients with visceral metastases to the liver and/or lung 
in HER2-positive MBC have been shown to have poor prognosis (Verma et al. 2012; 
Perez et al. 2017; Emens et al. 2019b). In the KATE2 study (Emens et al. 2019b), 
patients treated with trastuzumab emtansine plus placebo harboring visceral disease as 
compared to patients with no evidence of visceral disease performed worse (median 
PFS 4.3 months vs. NE). Visceral disease was defined as the presence of disease in the 
lung, liver, adrenal gland, central nervous system, pleural cavity or peritoneal cavity. All 
locations that included tumors in the breast, bone, bone marrow, lymph nodes, skin and 
soft tissue were classified as non-visceral disease. Moreover, the proportion of patients 
with visceral involvement is expected to be higher than those with non-visceral disease 
(70.8% vs. 29.2%, respectively) in KATE2, further justifying use of visceral disease as a 
stratification factor. 
3.3.15
Rationale for Stratification by HER2 Expression Status
HER2 overexpression is an important prognostic and predictive biomarker in MBC
(Pauletti et al. 2000). Specifically, in the recent KATE2 study (Emens et al. 2019b) 
evaluating trastuzumab emtansine in combination with atezolizumab or atezolizumab
and placebo, higher HER2 expression (IHC 3+) and lower HER2 expression (IHC 
2+/ISH+) demonstrated different prognosis for trastuzumab emtansine outcome (median 
PFS: 8 months. vs 3.2 months, respectively). The majority of patients were IHC 3+ (74%) 
as compared to IHC 2+ (19%). Given the association with variable prognosis as well as 
differences in prevalence, HER2 expression status by IHC has been selected as a 


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stratification factor in the current study. Patients will be stratified based on HER2 IHC 3+ 
status and responses will be evaluated by comparing these two stratified subgroups.
3.3.16
Rationale for Patient-Reported Outcome Assessments
As MBC is not curable with currently approved and available therapies, the main goals of 
treatment are to prolong survival and maintain or improve quality of life (Cardoso et al. 
2018). Examining and measuring patients’ symptoms and their impact of functioning 
and quality of life is important, particularly to inform how delays in radiographic 
progression and PFS might be associated with delays in clinical progression of 
symptoms and their interference with functioning, including maintenance of low disease 
burden. In addition, patients’ reporting of their experience with treatment burden will 
complement the evaluation of treatment tolerability. 
Symptoms, their impact on functioning and quality of life, and treatment burden will be 
assessed using validated patient reported outcome (PRO) measures. The EORTC 
QLQ-C30 will be administered to patients to assess symptoms and their impacts on 
functioning and quality of life (see Section 4.5.9 and Appendix 6), while the EORTC IL46 
will be administered to assess treatment burden.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 226284 patients with previously treated, HER2-positive LABC or MBC 
will be enrolled on this study.
4.1.1
Inclusion Criteria (All Study Phases)
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form 

Ability to comply with the study protocol, in the investigator's judgment

Histologically or cytologically confirmed invasive MBC or LABC that is incurable, 
unresectable, and previously treated with multimodality therapy:
–
Prior treatment for BC in the adjuvant, unresectable locally advanced, or 
metastatic settings, which must include a taxane, trastuzumab (alone or in 
combination with another agent), and pertuzumab
o
For patients who have not received pertuzumab in early breast cancer 
setting, prior treatment with pertuzumab in the metastatic setting is 
required prior to enrollment
–
Progression must have occurred during or after most recent treatment for 
LABC/MBC or within 6 months after completing adjuvant therapy

Measurable disease that is evaluable per RECIST v1.1

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1


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
Willing to provide tumor biopsy sample at the time of screening
A tumor biopsy sample (either archival or fresh) must be collected from all 
patients from either the primary tumor or a metastatic site (preferred and within 
6 months of enrollment, if clinically feasible) for determination of HER2 status 
by central laboratory testing for patient eligibility purposes, for Bcl-2 expression,
and for research on biomarkers. 
The tumor specimen must contain adequate evaluable tumor cells (20% tumor 
cells) to enable Bcl-2, HER2, and other relevant biomarker analysis. Samples 
can be a tissue block (preferred) or at least 20 unstained freshly cut serial 
slides. If fewer than 20 slides are available, the Sponsor should be consulted. 
If a tumor sample is not available, a fresh biopsy must be collected. 
The specimen must be a formalin-fixed, paraffin-embedded (FFPE) tumor 
specimen, or another appropriate fixative must be used (notation of the type of 
fixative should be included). Cytological or fine-needle aspiration samples are 
not acceptable.

Local histological or cytological confirmation of ER and/or progesterone receptor
status as defined by using IHC per American Society of Clinical Oncology/College of 
American Pathologists criteria (Hammond et al. 2010)

Percentage of ER and/or progesterone receptor positivity, if available

Willing to provide blood samples at the time of screening, on-study, and at 
progression for exploratory research on biomarkers

HER2-positive BC as defined by an IHC score of 3+ or gene amplified by ISH as 
defined by a ratio of 2.0 for the number of HER2 gene copies to the number of 
chromosome 17 copies
For the expansion phase and randomized Phase II stage: Centrally confirmed 
HER2-positive status prospectively tested by a Sponsor-designated central 
laboratory prior to enrollment.
For the dose-escalation phase: Enrollment can be based upon prospective 
central testing or local IHC or ISH results; however, for local IHC or ISH results, 
the same tissue sample must be sent for central HER2 confirmation and the 
testing platform documented in the eCRF.
Both IHC and ISH assays can be performed; however, unless reflex testing is 
necessary, only one positive result is required for eligibility.
If multiple tumor specimens are submitted, the HER2 IHC score and or ISH 
amplification ratio will first be assessed on the most recently obtained specimen 
for the purpose of determining eligibility. For patients with bilateral BC, HER2 
positivity must be demonstrated in both locations for archival tissue or in a 
metastatic biopsy.
Centrally confirmed HER2 results (either IHC or ISH) from a current or previous 
Sponsor study can be used to determine eligibility for this study. Approval must 
be obtained from the Medical Monitor prior to randomization.


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
Adequate hematologic and end-organ function, as evidenced by the following local 
laboratory results obtained within 7 days prior to the first study treatment (Cycle 1, 
Day 1):
–
Absolute neutrophil count 1500 cells/L (without granulocyte-colony 
stimulating factor support within 7 days prior to Cycle 1, Day 1)
–
Platelet count 100,000/L (without transfusion within 7 days prior to 
Cycle 1, Day 1) 
–
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet 
this criterion.
–
Albumin 25 g/L (2.5 g/dL)
–
Total bilirubin 1.5ULN with the following exceptions:
Patients with previously documented Gilbert syndrome who may have
bilirubin 5ULN
Patients with documented liver metastases may have bilirubin 
2.5ULN
–
AST, ALT, and ALP 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases may have ALP 
5ULN
–
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min on the 
basis of either 24-hour urine collection or the Cockroft-Gault glomerular 
filtration rate estimation:
(140age)(weight in kg) (0.85 if female)
72(serum creatinine in mg/dL)
–
INR or aPTT 1.5 ULN
For patients requiring anticoagulation therapy with warfarin or other 
coumarins, a stable INR between 2 and 3 is required.  If anti-
coagulation is required for a prosthetic heart valve, then INR should be 
between 2.5 and 3.5.

Screening left ventricular ejection fraction (LVEF) 50% on echocardiogram (ECHO)
or multiple-gated acquisition (MUGA) scan
LVEF assessment may be repeated once up to 3 weeks following the initial 
screening assessment to assess eligibility.

Negative HIV test at screening

Negative hepatitis B surface antigen (HBsAg) test at screening

Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening


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The HBV DNA test will be performed only for patients who have a negative 
HBsAg test and a positive total HBcAb test.

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test.

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of <1% per year during the treatment period and for at least 30 days after the last 
dose of venetoclax or 7 months after the last dose of trastuzumab emtansine, 
whichever is later. Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state (12 continuous 
months of amenorrhea with no identified cause other than menopause), and 
is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
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 methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below:
With a female partner of childbearing potential who is not pregnant, men 
who are not surgically sterile must remain abstinent or use a condom plus 
an additional contraceptive method that together result in a failure rate of <1% 
per year during the treatment period and for at least 30 days after the last 
dose of venetoclax or 7 months after the last dose of trastuzumab emtansine, 
whichever is later. 
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 30 days after the last dose of 


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venetoclax or 7 months after the last dose of trastuzumab emtansine, 
whichever is later to avoid exposing the embryo.
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 acceptable methods of 
contraception. If required per local guidelines or regulations, locally 
recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.
4.1.1.1
Inclusion Criteria for Dose-Escalation Phase Only
In addition to the general inclusion criteria, patients in the dose-escalation phase of the 
study must also meet the following criteria for study entry:

Prior exposure to trastuzumab emtansine in any setting (advanced/metastatic or 
early breast cancer) is required      
4.1.1.2
Inclusion Criteria for Expansion Phase Only
In addition to the general inclusion criteria, patients in the expansion phase of the study 
must also meet the following criteria for study entry:

Trastuzumab emtansine experienced cohort:
–
Disease progression during or after trastuzumab emtansine treatment in 
the advanced/metastatic setting or disease recurrence in the 
neoadjuvant/adjuvant setting  
–
At least 50% patients in the expansion cohort (e.g., 10 out of 20) must have 
tumor that is Bcl-2 high. 
Bcl-2 high is defined as 50% of tumor cells stained with an intensity 
of IHC 2+ or 3+, and Bcl-2 low is defined as IHC 0 or 1+ or < 50% of 
tumor cells stained with an intensity of IHC 2+ or 3+.

Trastuzumab deruxtecan (DS-8201a) experienced cohort:
–
Disease progression during or after trastuzumab deruxtecan in the 
advanced/ metastatic setting
–
Prior trastuzumab emtansine in any setting is allowed
–
At least 50% patients in the expansion cohort (e.g., 10 out of 20) must have 
tumor that is Bcl-2 high (as defined above). 


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4.1.1.3
Inclusion Criteria for Randomized Phase II Stage
In addition to the general inclusion criteria, patients in the randomized Phase II stage of 
the study must also meet the following criteria for study entry:

Bcl-2 expression status by IHC either from fresh tissue or the most recent archival 
tissue (see criteria in Section 4.1.1) by a central laboratory using the Ventana Bcl-2
IHC assay prior to randomization.  
At least 50% of patients in the randomized Phase II (e.g., 110 out of 220 
patients) must be Bcl-2 high (as defined in Section 4.1.1.1).
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to 
Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to 
Cycle 1, Day 1

Radiation therapy within 2 weeks prior to Cycle 1, Day 1
The patient must have recovered from any resulting acute toxicity (to Grade 1) 
prior to randomization. 

History of exposure to the following cumulative doses of anthracyclines as specified 
below:
–
Doxorubicin 500 mg/m2
–
Liposomal doxorubicin 500 mg/m2
–
Epirubucin 720 mg/m2
–
Mitoxantrone 120 mg/m2
–
Idarubicin 90 mg/m2
If another anthracycline or more than one anthracycline has been used, then 
the cumulative dose must not exceed the equivalent of 500 mg/m2 doxorubicin.

History of other malignancy within the previous 5 years, except for appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
Stage I uterine cancer, or patients who have undergone potentially curative therapy 
with no evidence of disease and are deemed by the treating physician to be at low 
risk for recurrence

Cardiopulmonary dysfunction as defined by:
–
Uncontrolled hypertension (systolic 150 mm Hg and/or diastolic 
100 mm Hg with or without medication)
–
Inadequate LVEF at baseline, 50% by either ECHO or MUGA
–
History of symptomatic congestive heart failure (CHF)-Grade 3 per NCI
CTCAE version 5.0 or Class II New York Heart Association 
–
History of a decrease in LVEF to 40% or symptomatic CHF with prior 
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–
Myocardial infarction or unstable angina within 6 months of randomization
–
Concurrent dyspnea at rest due to complications of advanced malignancy, 
or other disease requiring continuous oxygen therapy
–
Evidence of transmural infarction on ECG
–
Significant symptoms (Grade 2) relating to LVEF, cardiac arrhythmia, or 
cardiac ischemia
–
High-risk uncontrolled arrhythmias (i.e., supraventricular tachycardia with a 
heart rate 100/min at rest, significant ventricular arrhythmia [ventricular 
tachycardia], or higher-grade atrioventricular [AV]-block [second-degree 
AV-block Type 2 (Mobitz 2) or third-degree AV-block])

Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; 
bone fractures)

Major surgical procedure or significant traumatic injury within 28 days prior to 
randomization or anticipation of the need for major surgery during the course of 
study treatment

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode 
of infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

Clinically significant history of liver disease, including cirrhosis, current alcohol 
abuse, autoimmune hepatic disorders, sclerosis cholangitis, or active infection with 
HBV or HCV)

Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

Known HIV infection or human T-cell leukemia virus 1 infection

Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 2 weeks prior to randomization

Known central nervous system (CNS) disease, except for patients treated and 
currently with asymptomatic CNS metastases, provided that all of the following 
criteria are met:
–
Only supratentorial and cerebellar metastases allowed (i.e., no metastases 
to midbrain, pons, medulla, or spinal cord)
–
No ongoing requirement for corticosteroids as therapy for CNS disease 
–
No stereotactic radiation within 14 days prior to randomization
–
No evidence of interim progression between the completion of CNS-
directed therapy and the screening radiographic study
Note: Patients with new asymptomatic CNS metastases detected at 
the screening scan must receive radiation therapy and/or surgery for 
CNS metastases.  Following treatment, these patients may be eligible 


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without the need for an additional brain scan prior to enrollment, if all 
other criteria are met.

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once a month or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed regardless of 
drainage frequency.

Uncontrolled hypercalcemia (1.5 mmol/L ionized calcium or calcium 12 mg/dL or 
corrected serum calcium greater than the ULN) or symptomatic hypercalcemia 
requiring continued use of bisphosphonate therapy
Patients who are receiving denosumab must discontinue use of denosumab 
and replace it with a bisphosphonate instead while on study.
Patients who are receiving bisphosphonate therapy specifically to prevent 
skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.

Current Grade 3 peripheral neuropathy (according to the NCI CTCAE v 5.0)

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 
80 or 20 or fusion proteins

Prior allogeneic stem cell or solid organ transplantation

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 30 days after the last dose of venetoclax or 7 months after the last dose of 
trastuzumab emtansine after the final dose of study treatment, whichever is later
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study drug.

Administration of the following agents within 7 days prior to the first dose of study 
drug:
–
Strong or moderate CYP3A inhibitors (see Appendix 14 for examples)
–
Strong or moderate CYP3A inducers (see Appendix 14 for examples)
Additional restrictions for on-study use of CYP3A inhibitors/inducers are
outlined in Section 4.4.2.

Consumption of grapefruit, grapefruit products, Seville oranges (including
marmalade-containing Seville oranges), or starfruit (carambola) within 3 days before 
anticipated first dose of study drug until the last dose of study drug (see 
Section 4.4.2)

Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment or anticipation of need for such a vaccine during the study

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
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
Malabsorption syndrome or other condition that would interfere with 
enteral absorption

History of active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative 
colitis) requiring specific medication in the 12 months prior to randomization, or 
active and uncontrolled bowel inflammation (e.g., diverticulitis) at time of 
randomization

Inability or unwillingness to swallow a large number of tablets

Known hypersensitivity to venetoclax or trastuzumab emtansine or to any of their 
excipients

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study

Other medical or psychiatric conditions that, in the opinion of the investigator, may 
interfere with the patient’s participation in the study

Blood transfusions if performed within 2 weeks prior to screening 
4.1.2.1
Exclusion Criteria for Randomized Phase II Stage
In addition to the general exclusion criteria, patients in the randomized Phase II stage of 
this study who meet the following criteria will be excluded:

Prior treatment with trastuzumab emtansine in any setting (neoadjuvant/adjuvant or 
advanced/metastatic setting)

Prior treatment with venetoclax in any setting

Prior treatment with anti-HER2 antibody drug conjugates (e.g. trastuzumab 
deruxtecan [DS-8201a]), margetuximab, pyrotinib, or tucatinib
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
(APPLICABLE TO RANDOMIZED PHASE II STAGE ONLY)
4.2.1
Treatment Assignment
The Phase II randomized portion of this study is randomized and double-blind. After 
written informed consent has been obtained, all screening procedures and assessments 
have been completed, and eligibility has been established for a patient, the study site will 
obtain the patient's identification number and treatment assignment from an IxRS.
Patients in the randomized Phase II stage will be randomly assigned to one of two 
treatment arms:  venetoclax in combination with trastuzumab emtansine or trastuzumab 
emtansine plus placebo.  Randomization will occur in a 1:1 ratio through use of a 
permuted-block randomization method to ensure a balanced assignment to each 
treatment arm with respect to pre-specified stratification factors.  Randomization will be 
stratified according to the following criteria:

Bcl-2 status (Bcl-2 high vs. Bcl-2 low; as defined in Section 4.1.1.1)

Visceral disease (Yes vs. No; as defined below)


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
HER2 status IHC 3+ (Yes vs. No; as defined in Section 4.1.1)
Visceral disease will be defined as the presence of disease in the lung, liver, adrenal 
gland, central nervous system, pleural cavity, or peritoneal cavity. All locations that 
include tumors in the breast, bone, bone marrow, lymph nodes, skin, and soft tissue will 
be classified as non-visceral disease. Patients with tumors in multiple locations that 
cover both visceral and non-visceral disease (e.g., a patient with a tumor in the liver and 
bone lesions) will be designated as having visceral disease for the purposes of the 
analysis.
Patients who are randomized into this study will not be allowed to be re-randomized to 
receive a second course of study treatment. Once a patient has been randomized into 
the study, the IxRS will be used to assign the kit numbers for study drugs to be 
dispensed at each treatment visit.  It is important that the study drugs dispensed for each 
visit are the correct kit number, as assigned by the IxRS.  This will ensure that drug use 
by dates and automatic study drug resupply to sites are managed appropriately via the 
IxRS. 
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and IMC members.
While PK and immunogenicity samples will be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct of the study.  
Laboratories responsible for performing study drug PK and ADA assays will be 
unblinded to patient treatment assignments to identify appropriate samples for analysis.  
PK samples from patients assigned to the comparator arm will not be analyzed for 
venetoclax PK concentration except by request (e.g., to evaluate a possible error in 
dosing).  
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly. The 


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investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above) will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are venetoclax, trastuzumab 
emtansine, and placebo. 
Rescue medications and pre-medications are considered non-investigational medicinal 
products (NIMPs). In this study, diphenhydramine is considered a NIMP. 
4.3.1.1
Venetoclax and Placebo
Venetoclax (GDC-0199/ABT-0199) is manufactured by AbbVie, Inc. and will be supplied 
by the Sponsor as oral film-coated tablets of 100-mg strength. Venetoclax tablets will be 
packaged in high-density polyethylene (PE) plastic bottles to accommodate the study 
design. Venetoclax tablets must be stored at 15C25C (59F77F).
For information on the formulation and handling of venetoclax, see the pharmacy manual 
and the Venetoclax Investigator’s Brochure.
The formulation of placebo is equivalent to venetoclax but without the active agent. The 
handling of placebo is described in the pharmacy manual.
If unblinding occurs, the treatment assignment placebo will no longer be administered to 
patients randomized to Arm A (trastuzumab emtansine and placebo).
4.3.1.2
Trastuzumab Emtansine 
Trastuzumab emtansine will serve as the comparator/active control and will not be 
blinded. Trastuzumab emtansine will be provided as a lyophilized formulation in a 
single-use 20 mL glass vial. Each 20 mL vial contains enough product to deliver 
approximately 160 mg of trastuzumab emtansine. Trastuzumab emtansine vials are to 
be refrigerated at 2C8C (36F46F) and should remain refrigerated until use. Do not 
freeze vials. Trastuzumab emtansine vials should not be used beyond the expiration 
date provided by the manufacturer.


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For information on the packaging, reconstitution, and handling of trastuzumab emtansine, 
refer to the pharmacy manual and the Trastuzumab Emtansine Investigator’s Brochure.  
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens for the dose-escalation phase, dose-expansion phase, and 
randomized Phase II stage are summarized in Section 3.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration eCRF.  Cases of overdose, medication error, drug abuse, or 
drug misuse, along with any associated adverse events, should be reported as 
described in Section 5.3.5.12.
If trastuzumab emtansine is held, then venetoclax/placebo should continue, provided the 
dosing selected in the dose-escalation phase of this study is continuous. In the case of 
NC dosing of venetoclax/placebo, when trastuzumab emtansine is held, then venetoclax 
placebo should be held as well and restart concomitantly to preserve treatment 
synchronization. If trastuzumab emtansine is permanently discontinued for toxicity, then 
venetoclax/placebo can continue, provided that the patient is deriving clinical benefit 
from venetoclax/placebo, in the opinion of the investigator. Guidelines for dosage 
modification and treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.2.1
Venetoclax and Placebo
At the start of each cycle, patients will be supplied with sufficient venetoclax and placebo 
tablets for that cycle. A drug diary will be provided to the patient to record oral 
administration of doses, including the date and time of dosing. Patients will be instructed 
to return empty bottles or unused tablets.
The investigator is responsible for monitoring patient compliance by monitoring the 
patient diary and counting unused tablets. Patient compliance with the assigned daily 
dose of study medication will be assessed by standard pill counts. Previously distributed 
bottles will be returned to the clinic and tablets counted. Any discrepancy will be 
resolved with the patient at each clinic visit and documented in the patient record.
Each dose of venetoclax or placebo will be taken orally once daily with approximately 
240 mL of water within approximately 30 minutes after the completion of breakfast or 
patient’s first meal of the day. Patients should self-administer venetoclax at 
approximately the same time each morning. On days that PK sampling is required, the 
patient’s first meal of the day and all study treatment doses should occur in the clinic to 
ensure accurate timing of the PK sampling. On those days, the time of each dose of 
venetoclax will be recorded to the nearest minute.


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A meal containing approximately 30% of the total caloric content from fat is 
recommended to ensure adequate absorption of venetoclax. The following is an 
example of a breakfast that contains approximately 520 Kcal and has 30% of the total 
caloric content of the meal from fat that is, approximately 17 grams of fat: one box 
cereal (3040 g), skim milk (240 mL), one boiled egg, one slice of toast (15 g) with 
1 tablespoon of margarine (14 g). The toast and margarine may be replaced with one 
medium croissant or two large pancakes. If there is a substantial period of time between 
the patient’s regular time of breakfast and their venetoclax dosing in the clinic on PK 
sampling days, patients may have a low-fat snack in the morning. Patients must be 
instructed not to take their study treatment with the snack and to take their study 
treatments in the clinic after a meal.
Venetoclax tablets should be swallowed whole and never be chewed, cut, or crushed. If 
vomiting occurs within 15 minutes after taking venetoclax and all expelled tablets are still 
intact, another venetoclax dose should be taken, and the second dose should be noted 
in the drug diary. If tablets are not intact or if vomiting occurs more than 15 minutes after 
taking venetoclax, no replacement dose is to be taken. In cases where a dose of 
venetoclax is missed or forgotten, the patient should take the dose with food as soon as 
possible, ensuring that the dose is taken within 8 hours of the missed dose. Otherwise, 
the dose should not be taken. 
4.3.2.2
Trastuzumab Emtansine
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion Q3W.  The 
initial dose of trastuzumab emtansine will be administered on the basis of the patient’s 
baseline weight.  Weight will be measured at each visit and dose must be re-adjusted for 
weight changes 10% compared to the previous visit or baseline, whichever is most 
recent.  The investigator may choose to recalculate the dose at every cycle using actual 
weight at that time, according to their local practice.  Administration may be delayed to 
assess or treat adverse events.  Dose reduction will be allowed, following the dose 
reduction levels provided in Table 5. Once a dose has been reduced for adverse 
event(s), it must not be re-escalated.  If trastuzumab emtansine is discontinued because 
of toxicity, it should not be re-administered. Guidelines for dosage discontinuation for 
patients who experience adverse events are provided in Section 5.1.3.
If the timing of a protocol-mandated procedure, such as administration of trastuzumab 
emtansine coincides with a holiday that precludes the procedure, the procedure should 
be performed within 3 business days of the scheduled date and, when possible, on the 
earliest following date with subsequent protocol-specified procedures rescheduled 
accordingly.
Refer to Table 1 for guidelines on administration of first and subsequent infusions of 
trastuzumab emtansine.


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Table 1
Administration of First and Subsequent Infusions of 
Trastuzumab Emtansine
First Infusion
Subsequent Infusions

No premedication is administered.

Record patient’s vital signs as 
indicated in Appendix 1 and 
Appendix 2.

Administer the initial dose as a 
90-minute IV infusion. 

Patients should be observed during 
the infusion and for at least 
90 minutes following the initial dose 
for fever, chills, or other infusion-
related reactions.

The infusion rate should be slowed or 
interrupted if the patient develops 
infusion-related symptoms.

The infusion site should be closely 
monitored for possible subcutaneous 
infiltration during drug administration.

Record patient’s vital signs as indicated in 
Appendix 1 and Appendix 2.

If prior infusions were well tolerated, subsequent 
doses may be administered as 30-minute 
infusions.

Patient should be observed during the infusions 
and for at least 30 minutes after infusion.
4.3.2.3
Sequence of Study Drug Administration
The oral dose of venetoclax should be administered first, followed by infusion of 
trastuzumab emtansine.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor.  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.
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 Inventory Log.
4.3.3.1
Continued Access to Venetoclax and Trastuzumab Emtansine
The Sponsor will offer continued access to Roche IMPs venetoclax and trastuzumab 
emtansine free of charge to eligible patients in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, as outlined below.


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A patient will be eligible to receive Roche IMPs venetoclax and trastuzumab emtansine
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 Roche IMP 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
A patient will not be eligible to receive Roche IMPs venetoclax and trastuzumab 
emtansine after completing the study if any of the following conditions are met:

The Roche IMP 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 IMP or data suggest that the IMP
is not effective for breast cancer

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
breast cancer 

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
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 to the study completion/treatment discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives with a failure rate of 1% per year (see Section 4.1.1)

Hormone-replacement therapy


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
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) to non-target sites is allowed as outlined below:
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  
Study drug treatment may be continued during palliative radiotherapy.  

Pain medications administered per standard clinical practice 

Inactive influenza vaccinations during influenza season 

Bisphosphonates for prevention of skeletal related events 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
at the discretion of the investigator.
The use of anti-emetics and anti-diarrhea prophylaxis is permitted and should be 
administered per protocol guidelines (see Table 9 and Section 5.1.3 for more details). 
The use of anti-emetics must be documented in the eCRF. Use of prophylactic anti-
microbial agents, TLS prophylaxis and/or treatment, and/or growth factors is also 
recommended according to standard institutional practice and should be documented in 
the eCRF. 
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
Prohibited Food
Use of the following foods is prohibited for at least 3 days prior to initiation of treatment, 
throughout venetoclax administration, and for 28 days after the last dose of study 
treatment:

Constituents of these foods have been shown to inhibit CYP3A4, the major enzyme 
responsible for the metabolism of venetoclax. Consumption of these foods could 
lead to increased venetoclax exposure:
–
Grapefruit
–
Grapefruit products
–
Seville oranges (including marmalade containing Seville oranges)
–
Star fruit (carambola)


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4.4.3
Prohibited and Cautionary Therapy
Use of the following concomitant therapies are prohibited as described below:

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 21 days prior to initiation of study treatment and during study treatment.

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, and herbal therapy) is 
prohibited for various time periods prior to starting study treatment, depending on 
the agent , and during study treatment, until disease progression is documented and 
the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and local therapy under certain circumstances (see Section 4.4.1 for 
details).

The administration of live, attenuated influenza vaccine (e.g., FluMist) is prohibited 
during treatment and within 28 days following the last dose of venetoclax.
Some additional therapies are prohibited only for specific study phases, or are allowed 
with caution, restrictions, and/or dose adjustments.  These are described in Table 7 and 
are to be implemented after relevant exclusion criteria for these medications are met 
(see Section 4.1.1).
Venetoclax is a substrate of CYP3A and therefore venetoclax exposure can be impacted 
by concomitant strong and moderate of CYP3A inducers and inhibitors.  DM1, the 
cytotoxic component of trastuzumab emtansine, is metabolized mainly by CYP3A4 and 
to a lesser extent by CYP3A5. Relevant restrictions and dosing recommendations for 
concurrent CYP3A inhibitors/inducers are described in Table 2.  Examples of CYP3A4 
inhibitors/inducers and P-gp substrates/inhibitors are listed in Appendix 14.
After discontinuation of a moderate or strong CYP3A inhibitor that led to a venetoclax 
dose reduction as per the following guidelines, the investigator should wait for 3 days 
before increasing the venetoclax dose back to the original maintenance/target dose.


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Table 2
Therapies Prohibited for Specific Study Phases, or Allowed with Caution, Restrictions, and/or Dose 
Adjustments  
Therapy
Phase Ib:  Dose-Escalation
Phase Ib: Expansions and
Phase II:  Randomized
DLT Window a
Post DLT Window a at
Cohort-Designated Dose
Cohort-Designated Dose
Strong CYP3A inhibitors
Prohibited
Avoid and consider alternative medications.  Consult with the medical monitor if 
considering use.  If usage is approved by the medical monitor, reduce 
venetoclax dose by at least 4-fold (see Table 3) and follow applicable local 
prescribing information.  Consider delaying T-DM1 treatment until the strong 
CYP3A4 inhibitors have cleared from the circulation (approximately 3 
elimination half-lives of the inhibitors) when possible. If T-DM1 treatment cannot 
be delayed, patients should be closely monitored for adverse reactions. 
Moderate CYP3A inhibitors
Prohibited
Avoid and consider alternative medications.  Consult with the medical monitor if 
considering use.  If usage is approved by the medical monitor, reduce 
venetoclax dose by 2-fold (see Table 3).
Strong CYP3A inducer
Prohibited
Moderate CYP3A inducer
Prohibited
Exclude through completion of the first 
cycle of venetoclax.  After the first cycle, 
avoid and consider alternative 
medications with less induction.  If used, 
contact the Medical Monitor for guidance.
P-gp inhibitors
If P-gp inhibitor must be used, monitor closely for toxicities and follow the applicable local prescribing information
P-gp substrates
Concomitant use of narrow therapeutic index P-gp substrates should be avoided.  If a narrow therapeutic index 
P-gp substrate must be used, it should be taken at least 6 hours before venetoclax.
Warfarin and coumarin 
derivatives (e.g., 
phenprocoumon)
Use with caution with close monitoring of the international normalized ratio (INR).
Excessive alcohol intake
Should be avoided (occasional to moderate use is permitted).
DLT dose-limiting toxicity; P-gpP-glycoprotein.
Note: See Appendix 14 for examples of CYP3A4 inhibitors/inducers and P-gp substrates/inhibitors.
a DLT window applicable to dose-escalation stage only.


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Table 3
Venetoclax Dose Reductions for Strong and Moderate CYP3A 
Inhibitors
Venetoclax 
Assigned Dose (mg)
Venetoclax Reduced Dose (mg)
Strong CYP3A Inhibitors
Moderate CYP3A Inhibitors
100
Consult with Medical Monitor.
Consult with Medical Monitor.
200
Consult with Medical Monitor.
100
400
100
(70 for posaconazole in U.S. and countries 
with USPI-based approval)
200
600
300
800
200
400
U.S.United States; USPI United States Prescribing Information.
Appendix 14 contains examples of CYP3A4 inhibitors/inducers and P-gp 
substrates/inhibitors. Additional examples of these classes of medications are provided 
at the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm
The above lists are not necessarily comprehensive; the investigator should also consult 
the prescribing information for any concomitant medication when determining the drug-
drug interaction potential.    
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed.  A decision may be made to allow the use of prohibited 
medications on a case by case basis, following discussion with the Medical Monitor and 
assessment of the benefit-risk ratio.
Patients who require the use of any therapies when they are prohibited (unless an 
allowance is made after consultation with the medical monitor) will be discontinued from 
study treatment and followed for safety outcomes and followed for safety outcomes for 
4 weeks after the last dose of study treatment or until initiation of another subsequent 
anticancer therapy, whichever comes first.
4.4.3.1
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 (see
Section 4.4.2) may be used during the study at the discretion of the investigator.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1
and Appendix 2.  All activities should be performed and documented for each patient.  


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Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
Prior to signing the main Informed Consent Form for the study, patients may consent to 
the collection of tumor tissue (archival or newly obtained via biopsy) for determination of 
Bcl-2 expression by signing a Prescreening Informed Consent Form.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements, and foods that have been shown to 
inhibit CYP3A4 [Section 4.4.2]) used by the patient within 28 days prior to initiation of 
study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Breast cancer history includes prior cancer therapies and procedures.  
Demographic data will include age, sex, and self-reported race/ethnicity. Local HER2 
testing information will also be collected, if available.
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 at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.


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Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
4.5.5
Tumor and Response Evaluations
All sites of measurable and non-measurable disease must be documented at screening 
and re-assessed at each subsequent tumor evaluation.  Tumor assessments are to be 
performed at the timepoints specified in Appendix 1 and Appendix 2; a time window of 
±7 days is allowed for all timepoints regardless of drug delays or interruptions.  Tumor 
assessments will continue until disease progression, withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first.
Initial screening assessments must include CT scans (with oral or IV contrast unless 
contraindicated) or MRI scans of the chest, abdomen, and pelvis.  A bone scan or 
positron emission tomography (PET) scan should also be performed to evaluate for 
bone metastases.  MRI scans of the chest, abdomen, and pelvis or non-contrast CT 
scan may be used in patients for whom CT scans with contrast are contraindicated 
(i.e., patients with contrast allergy or impaired renal clearance).
A CT (with contrast) or MRI scan with contrast (if CT contrast is contraindicated) of the 
head must be done at screening to evaluate CNS metastasis in all patients.  If CT with 
contrast is performed and the presence of brain metastases is considered equivocal, an 
MRI scan of the brain is required to confirm or refute the diagnosis of CNS metastases 
at baseline. Patients with active or untreated symptomatic CNS metastases are not 
eligible for the study (see Section 4.1.1).  Patients with untreated asymptomatic CNS 
metastasis at screening may be eligible.  For untreated patients, brain MRI scan with 
contrast at screening is required, and needs to meet all eligibility criteria as specified in
Section 4.1.
If a CT scan for tumor assessment is performed as part of a PET/CT, the CT acquisition 
must be consistent with the standards for a full-contrast diagnostic CT scan.
Further investigations such as bone scans and CT scans of the neck should also be 
performed if clinically indicated.  At the investigator’s discretion, other methods of 
assessment of measurable disease according to RECIST v1.1 may be used.


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Evaluation of tumor response conforming to RECIST v1.1 (Appendix 11) will be 
performed every 6 weeks (±7 days) following randomization until the primary PFS 
analysis, with additional scans performed as clinically indicated.  The same radiographic 
procedures used to assess measurable disease sites at screening should be used 
throughout the study (e.g., the same contrast protocol for CT and/or MRI scans).  
Following the primary PFS analysis, tumor assessments will be conducted as per 
standard of care and recorded in the eCRF until disease progression.
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Tumor assessments performed after the screening period 
should consist of the following assessments every 6 weeks until the primary PFS 
analysis:  
1.
CT and/or MRI of the chest/abdomen/pelvis, as well as other known sites of disease, 
including brain
2.
If a patient has only bone as a site of involvement at screening, which is determined 
to be measurable disease as per RECIST v1.1, then a bone scan or PET scan is 
mandated at every tumor assessment, or a bone scan or PET scan is to be 
performed as clinically indicated (e.g., suspicion of disease progression)
3.
In cases where patients demonstrate control of their systemic disease but who 
newly develop isolated brain metastases and are eligible to remain on study 
treatment, brain MRI or CT are performed along with regularly scheduled tumor
assessments
4.
Any other imaging studies felt to be clinically indicated by the treating physician
Response will be assessed by the investigator using RECIST v1.1 (Appendix 11) at 
each tumor assessment.  Assessments should be performed by the same evaluator, if 
possible, to ensure internal consistency across visits.
At the investigator’s discretion, CT or other clinically appropriate scans may be repeated 
at any time if PD is suspected.  If the initial screening bone scan or PET scan indicates 
bone metastases and this is the only site of involvement and is determined to be 
measurable disease per RECIST v1.1, then a bone scan or PET scan needs to be 
performed every 6 weeks.  If the screening scan shows evidence of either non-
measurable bone metastases or no bone metastases, then these procedures do not 
need to be repeated unless clinically indicated or at the treating physician’s discretion.  
If the brain is not identified as a site of involvement at screening, then brain CT or MRI 
only needs to be repeated beyond screening, if clinically indicated.  In cases where a 
patient demonstrates control of their systemic disease but who newly develops isolated 
brain metastases and is eligible to remain on study treatment, brain MRI or CT are 
performed along with regularly scheduled tumor assessments (Section 3.1).


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If study drug treatment is discontinued prior to disease progression according to RECIST 
v1.1, tumor response assessment should continue to be performed as per the schedule 
specified in Appendix 1 and Appendix 2.
4.5.6
Left Ventricular Ejection Fraction Assessment
LVEF will be assessed by ECHO or MUGA.  LVEF will be monitored at baseline and 
every fourth cycle thereafter.  Additional LVEF measurements may be performed if LVEF 
declines are clinically suspected at the discretion of the investigator.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)

Chemistry panel (serum): glucose, BUN or urea, sodium, magnesium, chloride, 
bicarbonate, total bilirubin, ALT, AST, alkaline phosphatase, total protein, and 
albumin
TLS laboratory assessments include serum creatinine, uric acid, potassium, 
calcium, phosphorous, and LDH.

Coagulation: aPTT and INR

HIV serology

HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.  

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and 
blood)

Thyroid function test (thyroid-stimulating hormone [TSH], free T3, and free T4)


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The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis.

Blood samples for exploratory research on biomarkers and biomarker assay
development
Blood samples will be processed to obtain plasma, and serum for the 
determination of baseline level changes in surrogate PD biomarkers.

C-reactive protein

Blood samples for auto-antibody testing
For patients who show evidence of immune-mediated toxicity, additional 
samples may be collected and will be analyzed centrally:

Anti-nuclear antibody

Antidouble-stranded DNA

Circulating anti-neutrophil cytoplasmic antibody

Perinuclear anti-neutrophil cytoplasmic antibody

Plasma samples for venetoclax PK analysis

Serum samples for trastuzumab emtansine PK analysis

Serum samples for total trastuzumab analysis

Serum samples for trastuzumab emtansine immunogenicity analysis
Note:  Alternative PK and ADA assessments may be explored if there is 
substantial difficulty in obtaining the timepoints listed in Appendix 3. Depending 
on the results from interim PK and ADA analyses, the frequency of PK and ADA 
sampling may be reduced or halted later in the study.

Archival or newly collected tumor tissue sample obtained at baseline for 
determination of protein expression of Bcl-2 and HER2 by central laboratory testing 
for patient eligibility purposes and for exploratory research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
20 slides containing unstained, freshly cut. If only 1019 slides are available, 
the patient may still be eligible for the study, after Medical Monitor approval has 
been obtained.
Tumor tissue should be of good quality based on total and viable tumor content. 
Samples must contain a minimum of ≥20% viable tumor cells that preserve 
cellular context and tissue architecture regardless of needle gauge or retrieval 
method. Samples collected via resection, core-needle biopsy (at least three 
cores, embedded in a single paraffin block), or excisional, incisional, punch, or 
forceps biopsy are acceptable. Fine-needle aspiration (defined as samples that 
do not preserve tissue architecture and yield cell suspension and/or smears), 
brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable. Tumor tissue from bone metastases that have been decalcified is 
not acceptable.


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If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required. A pretreatment tumor 
biopsy may also be performed if a patient's archival tissue test results do not 
meet eligibility criteria.
Exploratory biomarker research may include, but will not be limited to, analysis of tissue 
and ctDNA (i.e., mutation profiles associated with disease) and genes or gene 
signatures associated with apoptosis (i.e., BCL-2 family). Research may involve 
extraction of DNA, ctDNA, or RNA; analysis of somatic mutations; and use of NGS of a 
comprehensive panel of genes. NGS methods will not include whole genome 
sequencing (WGS) or whole exome sequencing (WES). 
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator may obtain an NGS report through Foundation Medicine's web portal.  If 
allowed by local laws, the investigator may share and discuss the results with the patient, 
unless the patient chooses otherwise.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions.  
Results will not be available for samples that do not meet criteria for testing.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11.3), biological samples will be 
destroyed no later than the time of completion of the final Clinical Study Report, with the 
following exceptions:

Serum and plasma samples collected for PK or immunogenicity analysis may be 
needed for additional pharmacokinetics (e.g., PK biomarkers or relevant 
analytes/catabolites/metabolites) and immunogenicity characterization and for PK or 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed, or earlier depending on local regulations.

Tumor tissue and blood samples collected for biomarker research and biomarker 
assay development will be destroyed no later than no later than 5 years after the 
final Clinical Study Report has been completed. However, the storage period will be 
in accordance with the Institutional Review Board/Ethics Committee (IRB/EC)-
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).

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 6 weeks 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 


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samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.8
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1 and Appendix 2), and may be obtained at 
unscheduled timepoints as indicated.
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine 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) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings may be stored at the site. The following should 
be recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and QT interval corrected through use of Fridericia’s formula 
(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 at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified. Standard of care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that timepoint, an unscheduled PK sample should be obtained.  A decision on study 


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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).
4.5.9
Patient-Reported Outcome Assessments
PRO instruments will be completed during the randomized Phase II stage of the study to 
assess the treatment benefit and/or more fully characterize the safety profile of 
venetoclax in combination with trastuzumab emtansine compared to trastuzumab 
emtansine plus placebo. In addition, PRO instruments will enable the capture of each 
patient's direct experience with venetoclax in combination with trastuzumab emtansine 
compared to trastuzumab emtansine alone.
PRO data will be collected through use of the following instruments:  the EORTC QLQ-
C30 questionnaire and the EORTC IL46 item.
4.5.9.1
Data Collection Methods for Clinical Outcome Assessments
PRO instruments, translated into the local language as appropriate, will be self-
administered via paper questionnaires.  Instructions for completing the questionnaires 
will be provided by the site staff.  The data will be transmitted to a centralized database 
maintained by the electronic device vendor or entered into the study database by site 
personnel as appropriate. The data will be available for access by appropriate study 
personnel.
The EORTC QLQ-C30 and IL46 assessments will occur as outlined in the schedule of 
activities (Appendix 2). 
To ensure instrument validity and that data standards meet health authority
requirements, questionnaires scheduled for administration during a clinic visit will be
completed in their entirety by the patient prior to receiving any information on disease
status, prior to the performance of non-PRO assessments that could bias patients’
answers, and prior to the administration of study treatment, unless otherwise specified.
During clinic visits, PROs 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 minutes at each specified visit.

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions.


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
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.

If completed on paper, site staff should review and 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.
The questionnaires (EORTC QLQ-C30 and EORTC IL46 item) will be completed during 
the randomized Phase II stage only: at Cycle 1, Day 1 (baseline) prior to administration 
of study drug; then at every study treatment cycle prior to administration of study drug 
(i.e., on Cycle 2, Day 1; Cycle 3, Day 1; and Cycle 4, Day 1, etc.) and at the study 
treatment discontinuation visit (see Appendix 2).
Patients who discontinue study treatment for any reason other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete the 
EORTC QLQ-C30 at each tumor assessment visit until radiographic disease progression 
per RECIST v1.1, death, loss to follow-up, consent withdrawal, or study termination by 
the Sponsor, whichever occurs first.
Patients whose native language is not available with the questionnaires are exempted 
from completing all PRO assessments.
The Sponsor will not derive adverse event reports from PRO data.
4.5.9.2
Description of Clinical Outcome Assessment Instruments
EORTC QLQ-C30
The EORTC QLQ-C30 (see Appendix 6) is a validated and reliable self-report measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999) that consists of 30 questions that assess 
five aspects of patient functioning (physical, emotional, role, cognitive, and social), three 
symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). Scale scores can be obtained for the multi-item scales. The EORTC QLQ-
C30 module takes approximately 15 minutes to complete. 
EORTC IL46
The EORTC IL46 is a validated single-item question assessing the overall burden or 
impact of study drug side effects (see Appendix 6), i.e., patient experience of tolerability.  


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4.5.10
Optional Tumor Biopsies 
Consenting patients will undergo an optional tumor biopsy (if deemed clinically feasible 
by the investigator) at Cycle 1, Day 1 and/or Cycle 2, Day 1 (see Appendix 1 and 
Appendix 2) and may undergo additional on-treatment biopsies at any other time at the 
investigator’s discretion (if deemed clinically feasible by the investigator). Where fresh 
biopsy is possible, samples collected via resection, core-needle biopsy, or excisional, 
incisional, punch, or forceps biopsy are acceptable. Biopsies collected via fine-needle 
aspirations are not acceptable.
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  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 Optional Biopsy Sample Informed Consent eCRF.
Samples may be used for exploratory biomarker research as described in Section 4.5.7.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.7 for details on duration of sample storage, use 
of samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses. 
4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
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4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's 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 4.5.11)
will not be applicable at that site.
4.5.11.3
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 venetoclax, trastuzumab 
emtansine, disease, or drug safety:

Blood samples collected at baseline

Additional archival tumor tissue samples (e.g., from an earlier biopsy) collected at 
screening

Tumor tissue samples from biopsies performed at the investigator's discretion 
during the study

Leftover blood, serum, plasma, peripheral blood mononuclear cell (PBMC), and 
tumor tissue samples (with the exception of remaining archival tissue blocks, which 
will be returned to sites) and any derivatives thereof (e.g., DNA, RNA, proteins, 
peptides).
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods. Genomics is 
increasingly informing researchers’ understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the IRB/EC
approved- Informed Consent Form and applicable laws (e.g., health authority 
requirements).


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4.5.11.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 


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Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.11.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Use of an anticancer therapy not required per protocol

Radiographic disease progression according to RECIST v1.1
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF. 
Patients who discontinue treatment prematurely during the DLT-evaluation period during 
the dose-escalation phase will be replaced. Patients who discontinue study treatment 
prematurely during the randomized portion of the study will not be replaced.


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Patients will return to the clinic for a treatment completion or treatment discontinuation 
visit 28 days (+14 days) after the last dose of study drug (see Appendix 1 and 
Appendix 2 for additional details). After treatment discontinuation due to disease 
progression, information on survival follow-up and new anticancer therapy will be 
collected via telephone calls, patient medical records, and/or clinic visits approximately 
every 6 months until death, loss to follow-up, withdrawal of consent, or study termination 
by the Sponsor, whichever occurs first.
Patients who are discontinued from study treatment for reasons including disease 
progression and have started follow-on treatment/s will be followed for survival 
approximately every 6 months until death, lost to follow-up, withdrawal of consent, or 
study termination by the Sponsor, whichever occurs first. Patients who are discontinued 
from study treatments for reasons other than disease progression and have not started 
follow-on treatment/s will be followed for disease status every 8 weeks (± 5 days) from 
the date of randomization until Week 24 (± 5 days) and every 12 weeks (± 5 days), 
thereafter, until disease progression, loss to follow-up, withdrawal of consent, death or 
study termination by the Sponsor, whichever occurs first (see Appendix 1 and 
Appendix 2 for additional details).
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the study.  
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced.
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.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
GCP

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
Venetoclax has been granted approval in the U.S. (VenclextaU.S. Prescribing 
Information) and by the European Medicines Agency (VenclyxtoE.U. SmPC) for the 
treatment of patients with CLL, with or without 17p deletion, who have received at least 
one prior therapy. Venetoclax has also received accelerated approval in the U.S. in 
combination with azacitidine, decitabine, or LDAC to treat adults with newly diagnosed 
AML.
Venetoclax, however, is not approved for the treatment of BC, and clinical development 
is ongoing. The safety plan for patients in this study is based on clinical experience with 
venetoclax in completed and ongoing studies. The anticipated important safety risks for 
venetoclax are outlined below. Please refer to the most recent version of Venetoclax
Investigator's Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.


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5.1.1
Risks Associated with Venetoclax
Clinical experience gained thus far with venetoclax has demonstrated that it is generally 
well tolerated, and toxicities appear to be mostly manageable and/or reversible; see the 
current Venetoclax Investigator’s Brochure for more information. 
On the basis of clinical data to date, the following known and potential risks with 
venetoclax are described below. Guidelines around the management of these risks 
through dose and schedule modifications are described in Section 5.1.3.
5.1.1.1
Tumor Lysis Syndrome
Available data suggest that in patients with cancers other than CLL, with the exception of 
those with mantle cell lymphoma, the risk of TLS is low. Due to different biology 
between HER2-positive BC and hematological malignancies, the risk of TLS is 
considered to be very low in patients with HER2-positive BC. Therefore, TLS 
prophylaxis is not recommended by any of the international guidelines for patients with 
HER2-positive BC, even in those patients who have developed visceral crisis and are 
receiving chemotherapy.
TLS is rarely observed in solid tumors such as breast cancer (Aslam et al. 2019; Cairo 
et al. 2009). In addition, as the target population in this trial would have received 
treatment for their HER2+ BC prior to enrollment, these patients would be considered 
to have low risk of developing TLS. Nevertheless, patients should be advised to remain 
well hydrated for the first week of study drug administration. Although not mandatory, at 
the discretion of the investigator, a prophylactic oral agent (e.g., allopurinol 300 mg QD) 
may be initiated in patients who are deemed to be at risk of TLS in order to reduce the 
uric acid level. In the dose-escalation phase, TLS laboratory values obtained before the 
dose of venetoclax will be used to determine whether a patient developed a change 
related to TLS. Laboratory results from 24 hours post-dose must be reviewed before 
receiving the dose of venetoclax for that day. Patients who develop electrolyte changes 
suggestive of TLS should undergo aggressive management and further monitoring per 
Appendix 7.
Patients with TLS should be treated as per institutional practice and local guidelines, 
including correction of electrolyte abnormalities and monitoring of renal function and fluid 
balance. In general, patients with baseline elevation of uric acid, dehydration, oliguria, 
renal dysfunction, and/or hypotension are considered to be more prone to TLS. 
Additionally, patients with bulky disease with extensive metastases to the liver, lungs,
or bone marrow may be at an increased risk of developing TLS. Recommendations for 
initial management of electrolyte imbalances and prevention of TLS are provided in
Appendix 7. In some cases, dialysis may be indicated. Guidelines for defining TLS are 
provided in Appendix 8.
To evaluate any possible risk of TLS with venetoclax in patients with HER2-positive BC, 
patients enrolled in the dose-escalation phase of the study will each have a sample 


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collected for a serum chemistry panel 24 hours after the first dose of study drug. The 
Sponsor will review the chemistry panel results and establish a management plan for 
TLS if an increased risk is identified, if needed.
5.1.1.2
Neutropenia
Neutropenia is an important identified risk for venetoclax. Clinical data from oncology 
studies suggest that neutropenia adverse events are observed among patients who 
receive venetoclax as a single agent or in combination with other therapeutic agents, 
with higher frequency observed in some combination studies. Serious adverse events of 
neutropenia or neutropenia events that lead to discontinuations are few across the entire 
venetoclax oncology program. Neutropenia management guidelines are provided in
Table 6. Granulocyte colony stimulating factors are permitted according to local practice, 
and patients will be monitored and treated promptly in case of infection.
5.1.1.3
Serious Infections
Serious infection is an important identified risk for venetoclax. Infections have been 
reported in oncology clinical studies; however, these events are confounded by the 
underlying disease, comorbidities, and other immunosuppressive medications. To date, 
no clear relationship has been noted between serious infectious events and neutropenia. 
The types of infectious events observed generally have been consistent with those 
anticipated in the elderly population of heavily pretreated patients with hematologic 
malignancies and are similar across all indications. Infections are closely monitored in 
venetoclax program across all indications. Patients should be advised to report fever or 
symptoms suggestive of serious infection and should be assessed for further
management as per standard medical practice. In the oncology studies, 
recommendations are included in the protocol regarding the need for anti-infective 
prophylaxis per standard of care (e.g., NCCN guidelines for oncology subjects).
5.1.1.4
Other Hematological Effects
Anemia has been reported across oncology studies investigating venetoclax, with a 
higher frequency in some studies in which venetoclax is combined with other reference 
therapies; however, most of the events were non-serious and confounded by disease 
factors and prior therapies.
Thrombocytopenia adverse events have been reported in oncology studies 
investigating venetoclax, with a higher frequency in those studies in which venetoclax 
was combined with other chemotherapeutic agents. However, most of the events were 
non-serious and assessment of these events is confounded by the patients' underlying 
hematologic malignancy disease state, prior therapies, and preexisting 
thrombocytopenia, including autoimmune thrombocytopenia in several patients.
Lymphopenia has been observed in nonclinical studies and in the Phase I clinical study 
conducted in heavily pretreated patients with CLL and NHL. While opportunistic 
infections have been reported in the clinical program, data are confounded by the 


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patients’ underlying disease and prior therapies. Patients in this study who develop 
lymphopenia are potentially at risk for atypical infections. As such, prophylaxis against 
varicella zoster virus and Pneumocystis jiroveci pneumonia should be considered and 
implemented (if applicable) as per local institutional practice, although some guidance is 
provided in Appendix 8.
5.1.1.5
Effects on Reproductive System and Pregnancy
This study is open to enrollment of both male and female patients. The effect of Bcl-2
inhibition on pregnancy has not been fully characterized. In animal studies, venetoclax 
resulted in increased post-implantation loss, and decreased fetal body weights were 
observed in the mouse embryo-fetal development study at the highest dosage 
administered. Venetoclax was not teratogenic. Six human pregnancies have been 
reported in the clinical program with venetoclax so far, including two pregnancies 
reported in a partner; in four out of six cases, a live infant with no neonatal complication, 
congenital anomalies, or birth defects was delivered. One out of six cases ended in 
therapeutic abortion in a patient with CLL who experienced progressive disease. One 
out of six cases was reported in a partner of a patient who had not received any study 
drug and for which the projected due date is pending.
In nonclinical studies, both venetoclax and trastuzumab emtansine have shown a 
potential to cause reproductive and embryo-fetal developmental toxicities as single 
agents. Therefore, there is the potential for this combination to cause overlapping or 
additional reproductive and embryo-fetal toxicities compared with the individual 
molecules. Consequently, both venetoclax and trastuzumab emtansine should not 
be administered to pregnant women, and both drugs must be discontinued if a patient 
becomes pregnant. Additionally, patients are advised to remain abstinent (i.e., 
refrain from heterosexual intercourse) or use contraceptive methods with a failure 
rate of <1% per year during the treatment period and for 28 days after the last dose 
of study drug. Please refer to Section 4.1.1 for further details on study eligibility and 
contraceptive requirements for patients.
5.1.1.6
Treatment-Emergent Malignancies (Second Primary 
Malignancies)
Second primary malignancies are important potential risk for venetoclax. Events of 
second primary malignancies have been reported across the venetoclax hematologic 
oncology program. However, no causal association with the venetoclax 
administration has been confirmed, and no pattern has been observed. The overall 
observed incidence rate of malignancy in the venetoclax clinical trial programs were 
comparable to that reported in the general population. Second primary malignancies 
will be closely monitored in this study.
5.1.1.7
Food Effect
Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-
fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to 


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5.3-fold compared with fasting conditions. Venetoclax should be administered with a 
meal as described in Section 4.3.2.1.
5.1.1.8
Concomitant Use with Other Medications
Specific recommendations are provided for co-administration of venetoclax with other 
medications, including inhibitors and inducers of CYP3A (see Section 4.4).
Live, attenuated vaccines should not be administered prior to, during, or after 
treatment with venetoclax until B-cell recovery occurs. The safety and efficacy of 
immunization with live, attenuated vaccines during or following venetoclax therapy 
have not been studied. Patients should be advised that vaccinations may be less 
effective.
Due to possible CYP3A mediated metabolic interaction, certain food items (e.g., 
grapefruit and Seville oranges) should not be consumed during treatment with 
venetoclax. Further details of excluded food items are provided in Section 4.4.
5.1.2
Risks Associated with Trastuzumab Emtansine
5.1.2.1
Pulmonary Toxicity
Cases of ILD, including pneumonitis, some leading to acute respiratory distress 
syndrome or death, have been reported in patients receiving trastuzumab emtansine.  
Signs and symptoms may include dyspnea, cough, fatigue, and pulmonary infiltrates.  
Patients with dyspnea at rest due to complications of advanced malignancy and 
comorbidities may be at risk of pulmonary events.
Patients who have experienced a pulmonary event should be carefully evaluated before 
commencing trastuzumab emtansine treatment.
Guidelines for management of trastuzumab emtansine in patients who develop ILD or 
pneumonitis are provided in Appendix 10.
5.1.2.2
Hepatotoxicity
The following events have been reported with administration of trastuzumab emtansine:

Serious hepatobiliary disorders
Serious hepatobiliary disorders, including NRH of the liver and hepatobiliary 
disorders with a fatal outcome due to drug-induced liver injury, have been 
observed in patients treated with trastuzumab emtansine.  Some of the 
observed cases may have been confounded by concomitant medications with 
known hepatotoxic potential.

Increased serum transaminases
Asymptomatic increases in serum transaminase concentration (transaminitis) 
have been observed.  Grade 1 and 2 events have been observed frequently; 
Grade 3 and 4 events have been observed less commonly.  The incidence of 
increased AST was substantially higher than that for increased ALT.  Increases 


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in AST and ALT were commonly observed by Day 8 of each cycle and 
generally improved or returned to baseline by Day 21.  A cumulative effect of 
trastuzumab emtansine, that is, an increase in the proportion of patients with 
Grade 1 or 2 elevations in transaminases with successive cycles has been 
observed; however, there was no increase in the proportion of patients with 
Grade 3 abnormalities over time.

NRH 
NRH is a form of noncirrhotic portal hypertension that can be caused by chronic 
use of medications. NRH typically presents with the insidious or unexpected 
onset of signs or symptoms of portal hypertension (weakness, ascites, 
splenomegaly, esophageal varices) in a patient with little evidence of chronic 
liver disease.
Cases of NRH have been identified from liver biopsies in patients treated with 
trastuzumab emtansine who presented with signs and symptoms of portal 
hypertension.  NRH is a rare liver condition characterized by widespread benign 
transformation of hepatic parenchyma into small regenerative nodules.  NRH 
may lead to non-cirrhotic portal hypertension.  Diagnosis of NRH can only be 
confirmed by histopathology.  Biopsy-confirmed NRH leading to fatal hepatic 
failure has been reported (refer to Appendix 13).
NRH should be considered in all patients with clinical symptoms of portal 
hypertension, even with normal transaminases, and no other manifestations of 
cirrhosis; in patients with a cirrhosis-like pattern seen on a CT scan of the liver; 
and/or in patients with liver failure following long-term treatment with 
trastuzumab emtansine.  
Patients must meet specified hepatic laboratory test requirements to be included in this 
study (Section 4.1.1).
Hepatic laboratory parameters will be monitored as described in the schedule of 
assessments (Appendix 1 and Appendix 2).
Guidelines for management of trastuzumab emtansine in patients who develop
increased serum transaminases, increased serum bilirubin, or NRH are provided 
in (Appendix 10).
5.1.2.3
Left Ventricular Dysfunction
Patients treated with trastuzumab emtansine are at risk of developing left ventricular 
dysfunction.  To date, significant cardiac events, including LVEF of 40%, have been 
observed (infrequently) in clinical trials of trastuzumab emtansine; therefore, 
symptomatic CHF is a potential risk.
Patients must meet specified LVEF requirements to be included in this study 
(Section 4.1).


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Left ventricular function will be monitored by measurement of ejection fraction using 
ECHO) or MUGA scans as described in Section 4.5 and the schedule of assessments 
(Appendix 1 and Appendix 2).
Guidelines for patient monitoring and management of trastuzumab emtansine in patients 
who develop left ventricular dysfunction are provided in (Appendix 10).
5.1.2.4
Infusion-Related Reactions and Hypersensitivity Reactions
Infusion-related reactions (IRRs) and hypersensitivity reactions have been reported with 
administration of trastuzumab emtansine.  Despite the different pathophysiology of IRRs 
(reactions involving cytokine release) and hypersensitivity (allergic) reactions, the clinical 
manifestations are the same.  In general, IRRs are expected to be more frequent and 
severe with the first infusion and to decrease in number and severity over time.  The 
severity of true hypersensitivity reactions would be expected to increase with 
subsequent infusions.
IRRs, characterized by one or more of the following symptomsflushing, chills, pyrexia, 
dyspnea, hypotension, wheezing, bronchospasm, and tachycardiahave been reported 
in clinical trials of trastuzumab emtansine.  In general, these symptoms were not severe.  
In most patients, these reactions resolved over the course of several hours to a day after 
the infusion was terminated.
Hypersensitivity reactions, including serious anaphylactic-like reactions, have been 
observed in clinical trials of trastuzumab emtansine.  Patients with a history of 
intolerance to trastuzumab will be excluded from this study (Section 4.1). 
Administration of trastuzumab emtansine will be performed in a setting with access to 
emergency facilities and staff who are trained to monitor and respond to medical 
emergencies.  Patients should be closely monitored for IRRs during and after each 
infusion of trastuzumab emtansine, as described in Section 4.3.2.1.  
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in (Appendix 10).
5.1.2.5
Hematologic Toxicity
Thrombocytopenia has been reported in patients in clinical trials of trastuzumab 
emtansine.  The majority of these patients had Grade 1 or 2 events (platelet count 
50,000/L), with the nadir occurring by Day 8 and generally improving to Grade 0 or 1 
(platelet count 75,000/L) by the next scheduled dose (i.e., within 3 weeks).  In clinical 
trials, the incidence and severity of thrombocytopenia were higher in Asian patients.  
Patients with thrombocytopenia (100,000/mm3) and patients on anticoagulant 
treatment should be monitored closely during treatment with trastuzumab emtansine.  
It is recommended that platelet counts are monitored prior to each trastuzumab 
emtansine dose.  Trastuzumab emtansine has not been studied in patients with platelet 


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counts 100,000/mm3 prior to initiation of treatment.  In the event of decreased platelet 
count to Grade 3 or greater (50,000/mm3), do not administer trastuzumab emtansine 
until platelet counts recover to Grade 1 (75,000/mm3).
Declines in other hematopoietic lineages, for example, leukopenia, neutropenia, and 
anemia, were less frequent than that observed for platelets.
Patients must meet specified hematologic laboratory test requirements to be included in 
this study (Section 4.1). 
Hematologic laboratory parameters will be monitored as described in Section 4.5 and 
the schedule of assessments (Appendix 1 and Appendix 2).  Patients on anticoagulant 
or antiplatelet treatment should be monitored closely. 
Guidelines for management of trastuzumab emtansine in patients who develop
hematologic toxicity are provided in (Table 6).
5.1.2.6
Hemorrhage
Cases of hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported with trastuzumab emtansine.  Some of 
these bleeding events resulted in fatal outcomes.  In some of the observed cases, the 
patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had 
thrombocytopenia; in others, there were no known additional risk factors.  Caution 
should be used with these agents, and additional monitoring should be considered when 
concomitant use with trastuzumab emtansine is medically necessary.
5.1.2.7
Neurotoxicity
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine.  
Patients with Grade 3 peripheral neuropathy will be excluded from this study 
(Section 4.1).
Patients will be clinically monitored on an ongoing basis for signs or symptoms of 
peripheral neuropathy as described in Section 4.5 and the schedule of assessments 
(Appendix 1 and Appendix 2).
Guidelines for management of trastuzumab emtansine in patients who develop
peripheral neuropathy are provided in (Appendix 10).
5.1.2.8
Extravasation
In trastuzumab emtansine clinical studies, reactions secondary to extravasation have 
been observed.  These reactions were usually mild and consisted of erythema, 
tenderness, skin irritation, pain, or swelling at the infusion site.  These reactions have 
been observed more frequently within 24 hours of infusion.


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The infusion site will be closely monitored for possible subcutaneous infiltration during 
drug administration, as described in Table 1). Specific treatment for trastuzumab 
emtansine extravasation is unknown at this time.  Patients should be managed 
symptomatically per local institutional guidelines.
5.1.3
Management of Patients Who Experience Adverse Events
5.1.3.1
Dose Modifications
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF. 
The severity of adverse events will be graded according to the NCI CTCAE v5.0.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.
If, in the opinion of the investigator, a toxicity is considered to be attributable solely to 
one component of the study treatment (i.e., trastuzumab emtansine, venetoclax or 
placebo, then the dose of that component should be delayed or modified in accordance 
with the guidelines below.  If trastuzumab emtansine is held, then venetoclax/placebo 
should continue provided the dosing selected in the dose-escalation phase of this study 
is continuous. In the case of NC dosing of venetoclax/placebo, when trastuzumab 
emtansine is held, then venetoclax placebo should be held as well and restart 
concomitantly to preserve treatment synchronization. If trastuzumab emtansine is
permanently discontinued for toxicity, then venetoclax/placebo can continue provided 
that the patient is deriving clinical benefit from venetoclax/placebo, in the opinion of the 
investigator. Dose interruptions for reason(s) other than adverse events, such as 
surgical procedures, may be allowed with Medical Monitor approval. The acceptable 
length of interruption will depend on agreement between the investigator and the 
Medical Monitor.
Venetoclax Dose Modifications
Although patients with adverse events are to be managed according to the particular 
clinical circumstances based on the investigator’s medical judgement, dose reduction of 
venetoclax by one and, if needed, two dose levels will be allowed depending on the type 
and severity of the toxicity encountered (refer to Table 6 and Appendix 9). The dose 
reduction of venetoclax will occur per Table 4 below. Patients requiring clarification 
regarding management of adverse events and dosing and all patients who received 
starting dose of 800 mg requiring more than three dose reductions should be discussed 
with the Medical Monitor. All dose modifications/adjustments must be clearly 
documented in the patient's source notes and eCRF. Once a dose has been reduced for 
a given patient, all subsequent cycles should be administered at the reduced dose level, 
unless further dose reduction is allowed. Dose re-escalation is not allowed.


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Table 4
Dose Modification Scheme for Venetoclax/Placebo
Dose Reduction Schedule
Dose Level
(mg)
Dose Level
(mg)
Starting dose
800 mg
400 mg
First dose reduction
600 mg
200 mg
Second dose reduction
400 mg
100 mg
Third dose reduction
200 mg
Not Applicable
Requirement for further dose reduction
Discuss with 
Medical Monitor
Not Applicable
Trastuzumab Emtansine Dose Modifications
The dose of trastuzumab emtansine can be reduced by two dose levels for management 
of drug-related toxicities (i.e., from 3.6 mg/kg to 3.0 mg/kg and then from 3.0 mg/kg to 
2.4 mg/kg).  If further dose reduction is indicated after two dose reductions, the patient 
must discontinue trastuzumab emtansine. No dose re-escalation of trastuzumab 
emtansine is permitted in the study.
If significant trastuzumab emtansine-related toxicities have not recovered to Grade 1 or 
baseline, the next scheduled dose may be delayed for up to 42 days after the last dose 
was received.  “Significant” and “related” will be based on the judgment of the 
investigator (in consultation with the Sponsor’s Medical Monitor or designee when 
appropriate).  For example, an adverse event of alopeciaeven if considered related to 
trastuzumab emtansinewould most likely not be considered significant.  Fatigue may 
or may not be considered either related to trastuzumab emtansine or significant. In 
general, when the significant related toxicity (or any other toxicity that the investigator 
chooses to delay dosing for) resolves to Grade 1 or baseline, the patient may resume 
trastuzumab emtansine if the delay is not 42 days from the last dose received. In 
exceptional situations, patients may resume treatment after more than 42 days delay 
with the approval of the Medical Monitor or his delegate. 
Patients should be re-evaluated weekly during the delay, whenever possible.  If dosing 
resumes, the patient may receive trastuzumab emtansine either at the same dose level 
as before or at one lower dose level, at the discretion of the investigator. Subsequent 
cycles should remain Q3W, and patients should be assessed for toxicity as described in 
Section 5.1.3.  If a patient requires a dose reduction, dosing will be reduced by one dose 
level as per Table 5. 


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Table 5
Dose Modification Scheme for Trastuzumab Emtansine
Dose Reduction Schedule
Dose Level
(mg/kg, Q3W)
Starting dose
3.6
First dose reduction
3.0
Second dose reduction
2.4
Requirement for further dose reduction
Discontinue treatment
Q3W every 3 weeks.
Note:  The dose of trastuzumab emtansine, once reduced, may not be re-escalated.  A 
maximum of two dose reductions is allowed; patients with any further requirement for dose 
reduction will discontinue treatment with trastuzumab emtansine.
No dose re-escalation is permitted.  A patient treated with 2.4 mg/kg of trastuzumab 
emtansine who develops an adverse event requiring a dose reduction must discontinue
study treatment and will be followed for safety, disease progression, and survival 
(Appendix 1 and Appendix 2).
Patients who experience a Grade 3 or 4 hematologic events, other than 
thrombocytopenia, should be checked at least weekly for recovery.  If values do not 
recover to baseline or Grade 1 within 42 days from the last dose received, the patient 
will be discontinued from trastuzumab emtansine. Patients who discontinue 
trastuzumab emtansine can continue venetoclax/placebo provided that, in the opinion of 
the investigator, the patient is deriving clinical benefit from venetoclax/placebo. Patients
who discontinue both study drugs will be followed for safety, disease progression, and 
survival (Appendix 1 and Appendix 2).
5.1.3.2
Treatment Interruption
Patients who interrupt venetoclax secondary to treatment-related adverse events for 
longer than 28 days from the last dose should discontinue venetoclax. However, 
patients who are deriving benefit from the treatment should continue trastuzumab 
emtansine treatment.
If significant trastuzumab emtansinerelated toxicities have not recovered to Grade 1 or 
baseline, the next scheduled dose may be delayed for >42 days after the last dose was 
received. Patients who discontinue trastuzumab emtansine can continue 
venetoclax/placebo provided that, in the opinion of the investigator, the patient is 
deriving clinical benefit from venetoclax/placebo and they are to continue evaluation per 
protocol.
5.1.3.3
Management Guidelines
Guidelines for management of adverse events associated with study treatment are 
provided in Appendix 9 (venetoclax) and in Appendix 10 (trastuzumab emtansine).


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Guidelines for the management of patients who experience specific adverse events are 
provided in Appendix 9, Appendix 10, and Table 6 below and prescribing information, as 
outlined below:
Table 6 below provides guidelines for the management of patients who experience 
the following potential overlapping toxicities for venetoclax and trastuzumab 
emtansine:  hematologic, gastrointestinal, and hepatic events.  It is recommended 
that study treatments be withheld or discontinued per the guidelines below.  For 
these potential overlapping toxicities, refer to guidelines in Table 6.
Appendix 9 provides guidelines for the management of patients who experience 
venetoclax-specific non-hematologic toxicity that is not specifically described in
Table 6. It is recommended that venetoclax be withheld or discontinued per the 
guidelines in Appendix 9.
Appendix 10 provides guidelines for the management of patients who experience 
trastuzumab emtansine-associated adverse events such as left ventricular 
dysfunction, pulmonary toxicity, infusion-related reactions, hypersensitivity, and
NRH reactions.  It is recommended that trastuzumab emtansine be withheld or 
discontinued per the guidelines in Appendix 10.
For cases in which management guidelines are not covered in Table 6, Appendix 9, and 
Appendix 10, patients should be managed and treatments should be withheld or 
discontinued as deemed appropriate by the investigator according to 
best medical judgment.


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Table 6
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Venetoclax and Trastuzumab Emtansine
NCT CTCAE Category
Dose delay or dose modification
Grade 3 febrile
neutropenia
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.
Administer treatment including G-CSF or growth factors for 
neutropenia as indicated and per institutional guidelines.
o
When counts recover to ANC 1 109/L (Grade 2),
resume venetoclax/placebo and trastuzumab emtansine.
For subsequent episodes of Grade 3 febrile neutropenia:
o
Withhold venetoclax/placebo and trastuzumab 
emtansine.
When counts recover to ANC 1 109/L
(Grade 2), resume venetoclax/placebo at one 
dose level reduction (refer to Table 4) and 
trastuzumab emtansine at previous dose.
Grades 3 and 4 
neutropenia
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.
o
When counts recover to ANC 1 109/L (Grade 2), 
resume venetoclax/placebo and trastuzumab emtansine.
For subsequent episodes of Grade 4 neutropenia:
o
Withhold venetoclax/placebo and trastuzumab 
emtansine.
o
Consider secondary prophylaxis with G-CSF as indicated 
or per institutional guidelines.
When counts recover to ANC 1 109/L (Grade 
2), resume venetoclax/placebo at one dose level 
reduction (refer to Table 4) and trastuzumab 
emtansine at previous dose.
Grade 3 thrombocytopenia
(25,000 to 50,000/mm3)
Withhold venetoclax/placebo.  
Withhold trastuzumab emtansine.
o
When platelet count recovers to Grade 1 
(75,000/mm3), resume venetoclax/placebo and 
trastuzumab emtansine at the previous dose level.


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Table 6
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Venetoclax and Trastuzumab Emtansine
(cont.)
NCT CTCAE Category
Dose delay or dose modification
Grade 3 
thrombocytopenia
(platelets 50,000 to 
25,000/L) with clinically 
significant bleeding; or 
Grade 4 
thrombocytopenia
(platelets 25,000/L) 
Withhold venetoclax/placebo.  
Withhold trastuzumab emtansine.
o
Platelets may be transfused if Grade 4 thrombocytopenia is 
associated with symptomatic bleeding or in the case of 
platelet count 10,000/L, or per institutional guidelines.
o
When platelet level rises to 75,000/L, resume
venetoclax/placebo at previous dose. The dose of 
trastuzumab emtansine should be reduced by one dose level 
(refer to Table 5). 
For a subsequent episode of Grade 3 thrombocytopenia with bleeding 
or Grade 4 thrombocytopenia:
o
Withhold both venetoclax/placebo and trastuzumab 
emtansine.
o
Platelets may be transfused if Grade 4 thrombocytopenia is 
associated with symptomatic bleeding or in the case of
platelet count 10,000/L, or per institutional guidelines
o
When platelet level rises to 75, 000/L, resume
venetoclax/placebo at one dose level reduction (refer to 
Table 4). The dose of trastuzumab emtansine should be 
reduced by one dose level (refer to Table 5). 
For recurrent Grade 4 thrombocytopenia in spite of dose reduction
and/or symptomatic bleeding, consult the Medical Monitor regarding 
continuation on study treatment.
Non-hematologic toxicity
Grade 12 Diarrhea
Rule out other or concomitant causes, including medications (e.g., 
stool softeners, laxatives, antacids), infection by C. difficile, 
malabsorption/lactose intolerance, fecal impaction, and dietary 
supplements high in fiber.
Dietary modifications: 
o
Stop all lactose-containing products and eat small meals.
o
The BRAT (banana, rice, apples, toast) diet may be helpful. 
o
Encourage adequate hydration.
Loperamide treatment:
o
Suggested dose of 4 mg followed by 2 mg every 4 hours or 
after every unformed stool, up to a maximum of 16 mg/day.
o
Recommend to continue loperamide treatment until diarrhea-
free for 24 hours.
o
If Grade 2 diarrhea persists after 48 hours total treatment 
with loperamide, consider second-line agents (diphenoxylate 
and atropine or tincture of opium).
No change in study drug dosing will be implemented for Grade 2 
diarrhea; patients should receive maximal supportive care as described 
above.


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Table 6
Guidelines for Management of Patients Who Experience Specific 
Adverse Events with Venetoclax and Trastuzumab Emtansine
(cont.)
NCT CTCAE Category
Dose delay or dose modification
Grade 3 Diarrhea 
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.
o
When diarrhea has improved to Grade 1, restart 
venetoclax/placebo and trastuzumab emtansine at the 
previous dose level.
If Grade 3 diarrhea recurs:
o
Withhold venetoclax/placebo.
o
Withhold trastuzumab emtansine.
When diarrhea has improved to Grade 1, 
resume venetoclax/placebo at one dose level 
reduction (refer to Table 4). Resume
trastuzumab emtansine at the previous dose 
level.
Grade 3 increased 
transaminase (AST/ALT)
(5 to 20ULN)
Withhold venetoclax/placebo.
Withhold trastuzumab emtansine.  
o
When AST/ALT recovers to Grade 2, resume
trastuzumab emtansine reduced by one dose level (refer 
to Table 5). Resume venetoclax/placebo at previous 
dose. 
Grade 4 increased 
transaminase (AST/ALT)
(20ULN)
Discontinue both trastuzumab emtansine and venetoclax/placebo. 
o
Laboratory tests may be repeated (within 24 hours) to 
exclude laboratory error prior to discontinuing 
trastuzumab emtansine.
TBILI increase 1.5 ULN 
to 3 ULN (Grade 2)
Withhold both venetoclax/placebo.
Withhold trastuzumab emtansine.
When TBILI recovers to 1.5 ULN, resume 
venetoclax/placebo and trastuzumab emtansine 
at the previous dose level.
TBILI increase 3 ULN 
to 10 ULN (Grade 3)
Withhold both venetoclax/placebo. 
Withhold trastuzumab emtansine. 
o
When TBILI recovers to 1.5 ULN, resume venetoclax 
at the previous dose level and trastuzumab emtansine 
with one dose level reduction (refer Table 5).  
o
Discontinue trastuzumab emtansine if the event has not 
resolved to 1.5 ULN within 42 days after the last 
dose received.
TBILI increase 10 ULN 
(Grade 4)
Discontinue venetoclax/placebo and trastuzumab emtansine.
TBILI total bilirubin; ULN upper limit of normal.


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Recommendations for the initial management of electrolyte imbalances and prevention 
of TLS are provided in Appendix 7. Additional guidelines are provided in the subsections 
below.
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 GCP, 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 5.3.5.10 and 
Section 5.3.5.11 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
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:

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 5.3.5.8)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

TLS

Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with 
symptomatic bleeding

Grade 3 diarrhea

Pneumonitis


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Grade 3 infusion-related reaction or hypersensitivity reaction

Grade 4 febrile neutropenia
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 the 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, discontinuation of medications) should be reported (see 
Section 5.2.3 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
last dose of study drug or initiation of another anticancer therapy (whichever occurs first).
Serious adverse events and adverse events of special interest will continue to be
reported (independent of causality) until 90 days after the last dose of study drug or until
initiation of new systemic anticancer therapy, whichever occurs first.
The Sponsor should be notified if the investigator becomes aware of any serious
adverse event or adverse event of special interest that occur after the end of the adverse
event reporting period (defined as 90 days after the last dose of study drug), if the event
is believed to be related to prior treatment with study drug, regardless if the patient has
initiated another anticancer therapy treatment (Section 5.2.3).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of 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?" 


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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 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 7
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 
ageappropriate- instrumental activities of daily living a
3
Severe or medically significant, but not immediately lifethreatening-; 
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"
accordingly.  The following guidance should be taken into consideration:

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


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
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
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
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 as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF.
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 timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
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 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).


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5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
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 HER2-positive MBC 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). An IMC will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.


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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Metastatic Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on both clinical and laboratory findings (physical exam, biopsy, 
breast imaging, radiologic evidence, etc.).  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 preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying MBC
An event that leads to hospitalization under the following circumstances is not 
considered to be serious adverse event, but should be reported as adverse events 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours


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
Hospitalization for a minor condition for which the patient suffers an adverse event, 
but does not meet the definition of an overnight admission (e.g., tooth extraction)
5.3.5.12
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose}

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm}

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, 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 
trastuzumab emtansine, venetoclax or matching placebo, adverse events associated 
with special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.


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
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 trastuzumab emtansine, venetoclax or 
matching placebo, 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.

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.


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5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
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 5.2.2; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional 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
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
, M.D.
Mobile Telephone No.:
Alternate Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
, M.D., Ph.D.
Mobile Telephone No.:


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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug after the final
dose of study drug or until initiation of another anticancer therapy, whichever occurs first.  
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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study treatment 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 to immediately inform the 
investigator if they become pregnant during the study or within 30 days after the final 
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occurs last.  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.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
7 months after the last dose of trastuzumab emtansine.  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.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
drug.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy 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.


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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 study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 28 days after the final
dose of study drug), 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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
Trastuzumab emtansine
Trastuzumab Emtansine Investigator's Brochure
Venetoclax
Venetoclax Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An IMC will monitor efficacy and safety data during the study.  An aggregate report of 
any clinically relevant imbalances that do not favor the test product will be submitted to 
health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The analysis populations are defined as follows:

The ITT population for the Phase II portion of the study is defined as all randomized 
patients, whether or not they were assigned to the arm where the study drug was 
administered.

The ITT population for the non-randomized cohorts is defined as all enrolled
patients who received any drug.

The Bcl-2 high population consists of patients within the ITT population with 50% 
of tumor cells stained with an intensity of IHC 2+ or 3+.

The safety-evaluable population is defined as patients who received any amount of 
any component of the investigational or non-investigational study treatments.
The ITT population is the primary analysis population for efficacy for the study, and 
efficacy analyses will be analyzed according to the intended treatment. Efficacy
analyses will also be performed in the Bcl-2 high population. Safety analyses will be 
performed in the safety population according to treatment received. 


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Analyses will be performed separately for the dose-escalation phase, expansion phase, 
and randomized Phase II stage of the study.
The primary efficacy analysis will be performed in the ITT population of the randomized 
Phase II stage, which will be based on the co-primary endpoints of ORR and PFS. A 
key secondary efficacy analysis will be efficacy analyses in the Bcl-2 high population of 
the randomized Phase II stage.  Descriptive efficacy analyses will also be performed on 
the non-randomized cohorts.
6.1
DETERMINATION OF SAMPLE SIZE
6.1.1
Dose-Escalation Phase
The sample size for the dose-escalation phase is based on the dose-escalation rules 
described in the protocol. The planned enrollment for the dose-escalation phase is 
approximately 624 patients enrolled across 24 dose-escalation treatment groups. 
6.1.2
Expansion Phase
Approximately 20 patients each may be enrolled in the expansion phase (trastuzumab 
emtansine-experienced cohort and trastuzumab deruxtecan-experienced cohort).
With 20 patients per cohort and an observed ORR of 60%, the exact 90% Clopper-
Pearson confidence interval for the ORR would be 39%78%, which would rule out an 
ORR of 35% or less.
Table 8 provides exact 90% confidence intervals for a range of observed proportions of 
ORR based on a sample size of 20 patients.
Table 8
Potential 90% Confidence Interval Estimated for the True ORR
Observed ORR
Exact 90% Confidence Interval for 
the True ORR
40%
(22%, 61%)
50%
(30%, 70%)
55%
(35%, 74%)
60%
(39%, 78%)
65%
(44%, 82%)
70%
(49%, 86%)
ORR objective response rate.
For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of 
observing at least one such event in a cohort of 20 patients is 87.8%, 64.2%, and 18.2%, 
respectively.  Table 9 describes exact 90% confidence intervals for a range of observed 
proportions of adverse events based on a sample size of 20 patients.


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Table 9
Potential 90% Confidence Interval Estimates for Adverse Event 
Rates
Observed Event Rate
Exact 90% Confidence Interval for 
the True ORR
1%
(0%, 16%)
5%
(0%, 22%)
10%
(2%, 28%)
20%
(7%, 40%)
30%
(14%, 51%)
ORR objective response rate.
6.1.3
Randomized Phase II Stage
After the RP2D has been determined for venetoclax when given in combination with a 
fixed dose of trastuzumab emtansine, a total of 220 patients will be enrolled in the 
randomized Phase II stage of the study. The purpose of the randomized Phase II stage
is estimation and hypothesis generation regarding the effect of venetoclax in 
combination with trastuzumab emtansine on ORR and duration of PFS relative to 
trastuzumab emtansine plus placebo.  The point and interval estimates of the true 
underlying HR will be obtained.  
For the co-primary endpoints of ORR and PFS in the primary efficacy analysis 
population, the trial will have:

85% power (0.05) to detect a 20% improvement in ORR (i.e., ORR ) (assuming 
a 44% ORR in the trastuzumab emtansine plus placebo arm). In the meantime, a 
20% improvement in ORR will have a 95% CI of (7%, 33%).

90% power (0.05) to detect a PFS HR of 0.6 venetoclax plus trastuzumab 
emtansine arm relative to the trastuzumab emtansine plus placebo arm, when 
approximately 161 total PFS events have occurred. In the meantime, a PFS HR of 
0.6 will have a 95% CI of (0.44, 0.82). The assumptions of the sample size 
calculation are that the median PFS in the control arm is 6.8 months and that 
enrollment would occur non-uniformly over 24 months. Enrollment is anticipated to 
be lower during the second half of the enrolment period because it will be restricted 
to the Bcl-2 high population.
Within the Bcl-2 high population the study will have:

85% power (0.05) to detect a PFS HR of 0.5 venetoclax plus trastuzumab 
emtansine arm relative to the trastuzumab emtansine plus placebo arm, when 
approximately 75 total PFS events have occurred. In the meantime, a PFS HR of 
0.5 will have a 95% CI of (0.32, 0.79).


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The study will not, however, have adequate power to detect all potentially clinically 
meaningful differences in ORR and PFS.  For example, within the entire ITT population:

With 110 patients in each arm, there is only 60% power (0.05) to detect a 15% 
improvement in ORR (assuming a 44% ORR in the trastuzumab emtansine plus 
placebo arm), and 

With approximately 161 total PFS events, only 62% power (0.05) to detect an HR 
of 0.70, in venetoclax plus trastuzumab emtansine arm relative to the trastuzumab 
emtansine plus placebo arm.  
Thus, a statistically negative outcome in any of the co-primary endpoints does not 
necessarily rule out a clinically meaningful outcome. The below tables show the power 
and CIs for several possible true underlying improvements in ORR and PFS in favor of 
the venetoclax plus trastuzumab emtansine arm. 
Due to the smaller sample size of the Bcl-2 high population the power to detect a HR of 
0.60 in the Bcl-2 population is 60% compared to 90% for the entire ITT population. The 
study has adequate power (85%) to detect a HR of 0.5 in the Bcl-2 high population.
Table 10 Operating Characteristics for Proposed Study Design for 
Possible True Underlying ORR Values
True Underlying ORR 
15%
20%
25%
Power to detect ORR a
60%
85%
96%
95% confidence interval 
for true ORR b
(2%, 28%)
(7%, 33%)
(12%, 38%)
ORR objective response rate.
Note:  trastuzumab emtansine plus placebo arm is assumed to have an ORR of 44%. Results are 
based on 110 patients in each arm.
a
Two-sided 0.05.
b
Confidence intervals are based on the assumption that the point estimate is equal to the true underlying 
value of the ORR in each column.


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Table 11 Operating Characteristics for Proposed Study Design for 
Possible True Underlying PFS Hazard Ratio Values
True Underlying Hazard Ratio
0.60
0.65
0.70
0.75
Power of log-rank test a
90%
78%
62%
44%
95% confidence interval 
for true hazard ratio b
(0.44, 0.82)
(0.48, 0.89)
(0.51, 0.95)
(0.55, 1.00)
Note:  Operating characteristics are based on the following assumptions:  event times are exponentially 
distributed, median PFS in the trastuzumab emtansine plus placebo arm is 6.8 months, 161 total PFS 
events.
a
Two-sided 0.05.
b
Confidence intervals are based on the assumption that the point estimate is equal to the true underlying 
value of the hazard ratio in each column.
Table 12 Operating Characteristics in the Bcl-2 High Group for Proposed 
Study Design for Possible True Underlying PFS Hazard Ratio 
Values
True Underlying Hazard Ratio
0.50
0.55
0.60
0.65
Power of log-rank test a
85%
73%
60%
46%
95% confidence interval 
for true hazard ratio b
(0.32, 0.79)
(0.35, 0.86)
(0.38, 0.94)
(0.41, 1.00)
Note:  Operating characteristics are based on the following assumptions:  event times are exponentially 
distributed, median PFS in the trastuzumab emtansine plus placebo arm is 6.8 months, 75 total PFS events.
a
Two-sided 0.05.
b
Confidence intervals are based on the assumption that the point estimate is equal to the true underlying value 
of the hazard ratio in each column.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized by treatment arm and for all randomized patients within each phase of the 
study. 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 DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race, lines of prior 
therapy, rapid disease progression to first-line therapy, Bcl-2 status, ER status, site of 
disease, and presence of visceral/liver metastases) will be summarized using means, 


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standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables, as appropriate.  Summaries will be presented overall and by 
treatment group.
6.4
EFFICACY ANALYSES (RANDOMIZED PHASE II STAGE ONLY)
The primary efficacy analysis population will consist of all randomized patients, with 
patients grouped according to their assigned treatment (the ITT population).
The primary efficacy analysis will occur when 161 patients have experienced a PFS 
event. It is anticipated that this will occur six months after the last patient enters 
treatment.
6.4.1
Co-Primary Efficacy Endpoints
6.4.1.1
Objective Response Rate
The co-primary endpoint ORR is defined as the proportion of patients with CR or PR as 
assessed by the investigator on two consecutive assessments at least 28 days apart 
using the criteria in RECIST v1.1. Patients with no disease assessments for any reason 
will be classified as non-responders. An estimate of ORR with 95% CI will be calculated 
for each treatment arm using the normal approximation to the binomial distribution. An 
estimate and 95% CI for the difference in ORR between the two treatment groups will be 
presented based on the normal approximation to the binomial distribution.
6.4.1.2
Progression-Free Survival
The co-primary efficacy endpoint PFS is defined as the time from randomization to the 
first occurrence of disease progression (as defined by the investigator according to 
RECIST v1.1) or death from any cause, whichever comes first. Data for patients without 
the occurrence of disease progression or death as of the clinical data cut-off date will be 
censored at the time of last tumor assessment (or the time of randomization plus 1 day if 
no tumor assessment was performed after the baseline visit).
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm. 
Kaplan-Meier curves of time to PFS for each treatment group will be provided. The Cox 
proportional hazards model stratified by the randomization stratification factors (Bcl-2
status [high, low], visceral disease [yes, no], and HER2 status IHC 3+ [yes, no] will be 
used to provide an estimate of the hazard ratio of venetoclax plus trastuzumab 
emtansine to placebo plus trastuzumab emtansine with associated 95% CI and p-value. 
The unstratified hazard ratio estimate and 95% CI will also be presented. 
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Duration of Objective Response
DOR is defined as the time from the first documented objective response (CR or PR) to 
the time of first documented disease progression (as determined by the investigator 
using RECIST v1.1) or death from any cause, whichever occurs first. Data for patients 


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without the occurrence of disease progression or death as of the clinical data cut-off will 
be censored at the time of the last tumor assessment.
DOR will be estimated using the Kaplan-Meier methodology. Only patients achieving a 
CR or PR will be included in the assessment of DOR. No formal hypothesis testing will 
be performed due to the non-randomized population.
6.4.2.2
Overall Survival
OS is defined as time from randomization to death from any cause. Data for patients 
who are alive at the time of the analysis data cut-off will be censored at the last date they 
were known to be alive. Data from patients without postbaseline information will be 
censored at the date of randomization plus 1 day.
OS will be analyzed using the same methodology as PFS (see Section 6.4.1).
6.4.3
Exploratory Efficacy Endpoints
6.4.3.1
Clinical Benefit Rate
CBR is defined as CR or PR (as defined in Section 6.4.1) or achieving SD lasting 
6 months from randomization as assessed by the investigator using RECIST v1.1.
Patients with no disease assessments for any reason will be classified as non-
responders.
CBR will be analyzed using the same methodology as ORR (see Section 6.4.1).
6.4.3.2
Patient-Reported Outcomes Data
Summary statistics and the mean change from baseline of linear-transformed scores will 
be reported for all of the items and subscales of the EORTC QLQ-C30 and EORTC IL46 
(an item for trouble with side effects) questionnaires at each timepoint, at the end of 
treatment, at the time of progression, and at the time of clinical progression (if different 
from time to progression). In addition, mean scores for global health status, physical 
functioning, and selected symptom scales will be presented. The scores will be derived 
according to the EORTC scoring manual guidelines. 
Completion and compliance rates will be summarized at each timepoint by treatment 
arm. The analysis populations for PRO changes will be all randomized patients with a 
non-missing baseline assessment and at least one non-missing post-baseline 
assessment.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received. 


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6.5.1
Analyses of Exposure, Adverse Event, Laboratory, and Vital 
Sign Data
Safety will be assessed separately for each study phase through summaries of exposure 
to study treatment, adverse events, changes in laboratory test results, and changes in 
vital signs and ECGs.
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  All adverse events, serious adverse events, adverse 
events leading to death, adverse events of special interest, and adverse events leading 
to study treatment discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized. 
6.6
PHARMACOKINETIC ANALYSES
Individual pharmacokinetic concentration data will be tabulated and summarized (e.g., 
mean, standard deviation, coefficient of variation, median, minimum, and maximum) 
after appropriate grouping.  Pharmacokinetic parameters may also be calculated as data 
allow (e.g., Cmax, AUC, clearance, volume of distribution, half-life, etc.) and tabulated 
and/or summarized after appropriate grouping.  Population PK analyses of concentration 
data (with or without the PK data from other studies) may be conducted as appropriate. 
Potential PK DDIs may be assessed by comparison with relevant historical data for 
venetoclax and/or trastuzumab emtansine. Potential correlations between exposure and 
response (e.g., PD, efficacy, ECG, and safety endpoints) may also be explored, if 
warranted.  
The results of population PK analyses and exploratory exposure-response analyses may 
be reported separately from the clinical study report.  At the discretion of the Sponsor, all 
analyses may be extended to include relevant biotransformation products of venetoclax 
and/or trastuzumab emtansine.


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6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients for
trastuzumab emtansine at baseline (baseline prevalence) and after drug administration 
(postbaseline incidence) will be summarized by treatment group.  When determining 
postbaseline incidence, patients are considered to be ADA positive if: 1) they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response) or 2) they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all postbaseline samples are negative, or if they are ADA positive at 
baseline but do not have any postbaseline samples with a titer that is at least 0.60 titer 
unit greater than the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies to better understand disease pathobiology and guide the development of new 
therapeutic approaches. Exploratory biomarker analyses may be performed in an effort 
to understand the association of these biomarkers with study treatment response. 
Results will be presented in a separate report.
6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analyses (Randomized Phase II Stage Only)
Periodic analyses of cumulative safety data and one interim analysis is planned for this 
study. Given the hypothesis-generating nature of this study, the Sponsor considers the 
interim efficacy analysis as exploratory.
The planned interim efficacy analysis of cumulative safety, ORR, and PFS will occur 
when approximately 56 PFS events have occurred. This is expected to occur after the 
enrollment of the first 110 patients who have been followed up for at least 6 months.
If the interim analysis coincides within approximately 1 month of a planned safety review, 
the safety review may be combined with the efficacy interim analyses.  Outcomes from 
these reviews that may affect study conduct will be communicated in a timely manner to 
the investigators, and IRBs/ECs will be notified.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
PRO data (EORTC QLQ-C30 and IL46) will be captured via paper questionnaires, with
data entered into the EDC system by site staff. 
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 Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 


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evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial
related- monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
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, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.


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Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP 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, 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 or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 


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to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
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. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from Foundation 
Medicine).  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication (see Section 9.5).
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 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 9.5).
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).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
In the U.S., this trial will be sponsored and managed by Genentech. F. Hoffmann-La 
Roche Ltd will sponsor this trial outside of the U.S. with management responsibilities 
being shared by Genentech and Roche. Genentech and Roche have authorized Roche 


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Registrations, a company formed under the laws of England, to act as their legally 
authorized representative for the purposes of Article 19 of Directive 2001/20/EC relating 
to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use. Reference to “Sponsor” in this protocol will mean Genentech for the United 
States and F. Hoffmann−La Roche Ltd for all countries outside of the United States.
Approximately 145 sites globally will participate in this study to enroll approximately 284
patients. Data will be recorded via an EDC system from Medidata Solutions (New York, 
NY, with use of eCRFs; see Section 7.2). Central laboratories will be used for the 
analyses of and/or management of PK, PD, genotyping, and tissue samples. An IxRS 
will be used for patient registration, patient number, and dose assignment.
An IMC will review data on a regular basis at predefined timepoints during the study. 
The IMC will review results from the analyses of unblinded safety data and make 
recommendations to the Sponsor regarding continuation and/or modification of the study. 
The final decision on the IMC recommendation will be made by the Sponsor. The details 
of the composition, roles, and responsibilities of the IMC will be documented in detail in 
the IMC charter and submitted to Health Authorities as applicable.
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 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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 


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


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10.
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Appendix 1:  Schedule of Activities: Dose Escalation (cont.)
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h
A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Limited, symptom-directed physical examinations should be performed at specified postbaseline visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF.
j
Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline and/or previous cycle.
k
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature. Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
l
Hematology includes CBC, with RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
and other cells), and platelet count. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may 
be done on the day of randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to 
administration of the first dose of study treatment. Hematologic evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 
3 days before).
m Serum chemistry includes glucose, BUN or urea, sodium, magnesium, chloride, bicarbonate, total bilirubin, ALT, AST, alkaline phosphatase, total protein, and 
albumin. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may be done on the day of 
randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to administration of the first dose 
of study treatment. Chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).
n
TLS laboratory assessments collected during dose escalation include serum creatinine, uric acid, potassium, calcium, phosphorous and LDH. If the screening 
assessments were done within 3 days prior to Cycle 1, Day 1, there is no need to repeat the TLS panel at Cycle 1, Day 1. Refer to Appendix 8 for further 
instructions.
o
All patients will be tested for HIV prior to the inclusion into the study; HIV-positive patients will be excluded from the study. HBV serology includes HBsAg, total 
HBcAb, and (if HBsAg test is negative and total HBcAb test is positive) HBV DNA. HBV DNA must be collected on or before Cycle 1, Day 1, in patients who 
have negative serology for hepatitis B surface antigen and positive serology for anti-HBc. HCV serology includes HCV antibody and (if HCV antibody test is 
positive) HCV RNA.
p
Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.
q
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  During the treatment period, a
urine pregnancy test in women of childbearing potential in all treatment arms must be performed within 3 days prior study drug administration of every 3rd cycle
of protocol-mandated therapy. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. For patients who discontinue therapy 
before end of planned therapy, a pregnancy test must be done at the completion/early termination visit (within 28 days after the last dose of HER2-targeted 
therapy), at 3 months, and additionally at 6 months after the discontinuation of study treatment.


Appendix 1:  Schedule of Activities: Dose Escalation (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
151/Protocol CO41863, Version 2 (VHP)
r
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1, may be used rather than repeating 
tests. All measurable and evaluable lesions should be assessed and documented at the screening visit. See Section 4.5.5 for details on imaging and tumor 
assessments. Tumor response will be evaluated using RECIST v1.1 (Appendix 11) every 6 weeks (7 days). In the absence of disease progression, tumor 
assessments should continue regardless of whether patients discontinue study treatment, unless they withdraw consent or the study is terminated by the 
Sponsor, whichever occurs first. Results must be reviewed by the investigator before dosing at the next cycle. All tumor assessments should be documented in 
the eCRF before and after the primary PFS analysis. Patients who discontinue from study treatments for reasons other than disease progression and have 
not started follow-on treatment(s) will be followed for disease status every 8 weeks (5 days) from the date of randomization until Week 24 (5 days) and 
then every 12 weeks (5 days), thereafter, until disease progression, loss to follow-up, withdrawal of consent, death or study termination by the Sponsor 
(whichever occurs first).
s
A bone scan is to be performed within 28 days prior to Cycle 1, Day 1 (see Section 4.5.5 for further instructions).
t
CT/MRI scan of the brain is mandatory at screening and should be performed 1) with scheduled tumor assessments when identified as a site of involvement at 
baseline, 2) as clinically indicated, or 3) if a patient demonstrates control of systemic disease but has a newly developed isolated brain metastases and is eligible 
to remain on study treatment, a brain MRI or CT will be performed along with regularly scheduled tumor assessments.
u
A 12-lead ECG is required at screening. Subsequent ECGs may be performed as clinically indicated. ECGs for each patient should be obtained from the same 
machine wherever possible. ECG recordings must be performed after the patient has been resting in a supine position for at least 10 minutes.
v
LVEF assessment by ECHO is preferred, but LVEF may also be assessed by MUGA scan. The same method should be used throughout the study for each 
patient and preferably performed and evaluated by the same assessor.
w Venetoclax will be administered on a once daily dosing schedule.
x
Trastuzumab emtansine will be administered second by IV infusion at a dose of 3.6 mg/kg on Cycle 1 Day 1, and on Day 1 of each 21-day cycle thereafter.  
Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-related adverse events, over 
approximately 30 minutes in subsequent doses.  Vital signs should be taken before and after the trastuzumab emtansine infusion.  Patients will be monitored for 
any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related events, for a 
minimum of 30 minutes at subsequent infusions.
y
Auto-antibody testing includes anti-nuclear antibody, anti-double-stranded DNA, and circulating and perinuclear anti-neutrophil cytoplasmic antibody.  The 
baseline sample will be obtained any time during screening and prior to treatment (Cycle 1, Day 1), before the first dose of study drug. For patients who show 
evidence of immune-mediated toxicity, additional samples may be collected. All samples will be analyzed centrally.
z
At screening, the FFPE archival tumor block from the most recently collected, available tumor tissue or fresh core biopsy (3 cores) is mandated. If more than 
one FFPE block exists from different timepoints (e.g., initial diagnosis vs. metastatic disease tissue), the most recent block is mandatory to be sent. If the FFPE 
block from the earlier timepoint is available, then this would be requested to also be sent. In the cases of bilateral breast cancer, an additional 8 unstained slides 
from the contralateral breast to where FFPE block have been provided. At least 20 freshly serial cut, unstained slides will be acceptable in lieu of the FFPE 
block. Optional core biopsies will be obtained at Cycle 1, Day 1 and on Day 1 of any subsequent on treatment cycle (± 3 days) if patient consented. At the study 
drug discontinuation/early study completion visit, if reason for discontinuation is disease progression, a biopsy must be taken (if deemed clinically feasible) 
before next line of therapy begins, unless purely anti-hormonal therapy.








Appendix 2:  Schedule of Activities: Expansion Cohorts/Randomized Phase II (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
155/Protocol CO41863, Version 2 (VHP)
f
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive status. In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements, and foods that have been 
shown to inhibit CYP3A4 [Section 4.4.2]) used by the patient within 28 days prior to the Cycle 1, Day 1 visit. Breast cancer history includes prior cancer 
therapies and procedures.
g
Refer to Appendix 4 or tissue requirements related to eligibility. HER2 and or Bcl-2 status are required and must be centrally confirmed prior to treatment. 
h
A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Limited, symptom-directed physical examinations should be performed at specified postbaseline visits and as clinically indicated.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse 
Event eCRF.
j
Weight is to be measured up to 3 days prior to Day 1 of each cycle and compared with baseline and/or previous cycle.
k
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature. Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
l
Hematology includes CBC, with RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
and other cells), and platelet count. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may 
be done on the day of randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to 
administration of the first dose of study treatment. Hematologic evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 
3 days before).
m Serum chemistry includes glucose, BUN or urea, sodium, magnesium, chloride, bicarbonate, total bilirubin, ALT, AST, alkaline phosphatase, total protein, and 
albumin. Screening laboratory tests are to be performed within 7 days prior to randomization. Screening laboratory assessments may be done on the day of 
randomization, and their results may be used for randomization visit purposes. Results must be reviewed and documented prior to administration of the first 
dose of study treatment. Chemistry evaluations should be completed prior to dosing on Day 1 of each indicated cycle (or up to 3 days before).
n
TLS assessment frequency during the dose-expansion and randomized phases will be determined based on a comprehensive review of data in the dose-
escalation phase. TLS laboratory assessments include serum creatinine, uric acid, potassium, calcium, phosphorous and LDH. If the screening assessments 
were done within 3 days prior to Cycle 1 Day 1, there is no need to repeat the TLS panel at Cycle 1 Day 1. Refer to Appendix 8 for further instructions.
o
All patients will be tested for HIV prior to the inclusion into the study; HIV-positive patients will be excluded from the study. HBV DNA must be collected on or 
before Cycle 1, Day 1, in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.
p
Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.


Appendix 2:  Schedule of Activities: Expansion Cohorts/Randomized Phase II (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
156/Protocol CO41863, Version 2 (VHP)
q
All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  During the treatment period, a
urine pregnancy test in women of childbearing potential in all treatment arms must be performed within 3 days prior study drug administration of every 3rd cycle 
of protocol-mandated therapy. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. For patients who discontinue therapy 
before end of planned therapy, a pregnancy test must be done at the completion/early termination visit (within 28 days after the last dose of HER2-targeted 
therapy), at 3 months, and additionally at 6 months after the discontinuation of study treatment.
r
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1, may be used rather than repeating 
tests. All measurable and evaluable lesions should be assessed and documented at the screening visit. See Section 4.5.5 for details on imaging and tumor 
assessments. Tumor response will be evaluated using RECIST v1.1 (Appendix 11) every 6 weeks (7 days). In the absence of disease progression, tumor 
assessments should continue regardless of whether patients discontinue study treatment, unless they withdraw consent or the study is terminated by the 
Sponsor, whichever occurs first. Results must be reviewed by the investigator before dosing at the next cycle. All tumor assessments should be documented in 
the eCRF before and after the primary PFS analysis. Patients who discontinue from study treatments for reasons other than disease progression and have 
not started follow-on treatment(s) will be followed for disease status every 8 weeks (5 days) from the date of randomization until Week 24 (5 days) and 
then every 12 weeks (5 days), thereafter, until disease progression, loss to follow-up, withdrawal of consent, death or study termination by the Sponsor 
(whichever occurs first).
s
CT/MRI scan of the brain is mandatory at screening and should be performed 1) with scheduled tumor assessments when identified as a site of involvement at 
baseline, 2) as clinically indicated, or 3) if a patient demonstrates control of systemic disease but has a newly developed isolated brain metastases and is eligible 
to remain on study treatment, a brain MRI or CT will be performed along with regularly scheduled tumor assessments.
t
A bone scan is to be performed within 28 days prior to Cycle 1, Day 1 (see Section 4.5.5 for further instructions).
u
A 12-lead ECG is required at screening. Subsequent ECGs may be performed as clinically indicated. ECGs for each patient should be obtained from the same 
machine wherever possible. ECG recordings must be performed after the patient has been resting in a supine position for at least 10 minutes.
v
LVEF assessment by ECHO is preferred, but LVEF may also be assessed by MUGA scan. The same method should be used throughout the study for each 
patient and preferably performed and evaluated by the same assessor. 
w ECHO or MUGA assessments will be performed every fourth cycle. Additional LVEF or MUGA measurements may be performed at the discretion of the 
investigator if LVEF declines are clinically suspected.  
x
Venetoclax/placebo will be administered on a once daily dosing schedule.  
y
Trastuzumab emtansine will be administered second by IV infusion at a dose of 3.6 mg/kg on Cycle 1 Day 1, and on Day 1 of each 21-day cycle thereafter. 
Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-related adverse events, over 
approximately 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. Patients will be monitored for 
any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related events, for a 
minimum of 30 minutes at subsequent infusions.
z
Auto-antibody testing includes anti-nuclear antibody, anti-double-stranded DNA, and circulating and perinuclear anti-neutrophil cytoplasmic antibody.  The 
baseline sample will be obtained any time during screening and prior to treatment (Cycle 1, Day 1), before the first dose of study drug. For patients who show 
evidence of immune-mediated toxicity, additional samples may be collected. All samples will be analyzed centrally.


Appendix 2:  Schedule of Activities: Expansion Cohorts/Randomized Phase II (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
157/Protocol CO41863, Version 2 (VHP)
aa At screening, the FFPE archival tumor block from the most recently collected, available tumor tissue or fresh core biopsy (3 cores) is mandated. If more than 
one FFPE block exists from different timepoints (e.g., initial diagnosis vs. metastatic disease tissue), the most recent block is mandatory to be sent. If the FFPE 
block from the earlier timepoint is available, then this would be requested to also be sent. In cases of bilateral breast cancer, an additional 8 unstained slides 
from the contralateral breast to where FFPE block have been provided. At least 20 freshly serial cut, unstained slides will be acceptable in lieu of the FFPE 
block. Optional core biopsies will be obtained at Cycle 1, Day 1 and on Day 1 of any subsequent on treatment cycle (3 days) if patient consented. At the study 
drug discontinuation/early study completion visit, if reason for discontinuation is disease progression, a biopsy must be taken (if deemed clinically feasible) 
before next line of therapy begins, unless purely anti-hormonal therapy.
bb The questionnaires (EORTC QLQ-C30 and EORTC IL46 item) are to be completed during the randomized Phase II stage only:  at Cycle 1, Day 1 (baseline) 
prior to administration of study drug; then at every study treatment cycle prior to administration of study drug (i.e., on Cycle 2, Day 1; Cycle 3, Day 1; 
and Cycle 4, Day 1, etc.) and at the study treatment discontinuation visit.




Appendix 3:  Schedule of Pharmacokinetic and Immunogenicity Samples (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
159/Protocol CO41863, Version 2 (VHP)
ADA anti-therapeutic antibody; hr hour; min minute; PK pharmacokinetic.
Notes: PK and ADA samples are to be collected, prepared, and shipped according to procedures outlined in the separate laboratory manual.  
Record exact date and time of venetoclax dosing on the day of and the day prior to the date of PK sampling.  Patients should record venetoclax 
doses taken at home in a dosing diary. Record exact date and time of all PK and ADA sample collections.  Sample collection times are relative to 
the administration of the study drug being measured.
a Venetoclax should be administered in the clinic on days that venetoclax PK sample is to be taken. Venetoclax PK will be collected for patients 
enrolled in all study phases.
b Total trastuzumab PK will be collected for patients enrolled in all study phases.
c Trastuzumab emtansine PK and ADA to trastuzumab emtansine samples will only be collected for patients enrolled in the randomized Phase II 
stage.




Appendix 3:  Schedule of Pharmacokinetic and Immunogenicity Samples (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
161/Protocol CO41863, Version 2 (VHP)
ADA anti-therapeutic antibody; discon discontinuation; hr hour; min minute; PK pharmacokinetic.
Notes: PK and ADA samples are to be collected, prepared, and shipped according to procedures outlined in the separate laboratory manual.
Record exact date and time of venetoclax dosing on the day of and the day prior to the date of PK sampling.  Patients should record venetoclax 
doses taken at home in a dosing diary. Record exact date and time of all PK and ADA sample collections.  Sample collection times are relative to 
the administration of the study drug being measured.
a Venetoclax should be administered in the clinic on days that venetoclax PK sample is to be taken. Venetoclax PK will be collected for patients 
enrolled in all study phases.
b Total trastuzumab PK will be collected for patients enrolled in all study phases.
c Trastuzumab emtansine PK and ADA to trastuzumab emtansine samples will only be collected for patients enrolled in the randomized Phase II 
stage.
d
For a 7 out of 21 day venetoclax dosing schedule, where no dose is scheduled on Day 8 of each cycle, samples should be drawn on Day 7 of 
the cycle, with allowance to collect on Day 5 or 6 to avoid a weekend or holiday. 






Venetoclax—F. Hoffmann-La Roche Ltd
164/Protocol CO41863, Version 2 (VHP)
Appendix 5
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:

Stop the study treatment infusion.

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.


Venetoclax—F. Hoffmann-La Roche Ltd
165/Protocol CO41863, Version 2 (VHP)
Appendix 6
Patient-Reported Outcomes Questionnaires
Figure 1
EORTC QLQ-30 (Version 3)


Appendix 6:  Patient-Reported Outcomes Questionnaires (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
166/Protocol CO41863, Version 2 (VHP)
Figure 1
EORTC QLQ-30 (Version 3) (cont.)


Appendix 6:  Patient-Reported Outcomes Questionnaires (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
167/Protocol CO41863, Version 2 (VHP)
Figure 2
EORTC IL46


Venetoclax—F. Hoffmann-La Roche Ltd
168/Protocol CO41863, Version 2 (VHP)
Appendix 7
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome 
FIRST DOSE OF VENETOCLAX 

Within the first 24 hours after the first dose, if any laboratory criteria below are met, 
the patient should be hospitalized for monitoring and the investigator notified.  No 
additional venetoclax doses should be administered until resolution.  A rapidly rising 
serum potassium level is a medical emergency. 

Nephrology (or acute dialysis service) must be consulted/contacted on admission
(per institutional standards to ensure emergency dialysis is available). 

IV fluids (e.g., D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/h 
rounded to the nearest 10 mL (target 150200 mL/hr; not 50 mL/hr).  Modification 
of fluid rate should also be considered for individuals with specific medical needs. 

Monitor for symptoms or signs of tumor lysis syndrome (TLS) (e.g., fever, chills, 
tachycardia, nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches, 
weakness, paresthesias, mental status changes, confusion, and seizures).  If any 
clinical features are observed, recheck potassium, phosphorus, uric acid, calcium, 
and creatinine within 1 hour STAT. 

Vital signs should be taken at time of all blood draws or any intervention. 

The management recommendations below focus on the minimum initial responses
required.  If a diagnosis of TLS is established, ongoing intensive monitoring and 
multidisciplinary management will be as per institutional protocols. 
In addition to the recommendations for patients receiving first dose of venetoclax: 

For potassium increase 0.5 mmol/L from baseline, or any value 5.0 mmol/L, 
recheck potassium, phosphorus, uric acid, calcium, and creatinine within 1 hour 
STAT and follow first guideline. 

For phosphorus increase of 0.5 mg/dL AND 4.5 mg/dL, administer phosphate
binder and recheck potassium, phosphorus, uric acid, calcium, and creatinine within 
1 hour STAT. 
The Sponsor may explore a different TLS lab schedule in the randomized Phase II 
expansion portion of the study based on findings in dose-escalation phase.


Venetoclax—F. Hoffmann-La Roche Ltd
169/Protocol CO41863, Version 2 (VHP)
Appendix 8
Guidelines for Defining Tumor Lysis Syndrome
All tumor lysis syndrome events should be graded per the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0 criteria.
Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring 
during the same 24-hour period within 3 days before the start of therapy or 7 days after 
the start of therapy.  For the purposes of this study, this window applies to the initiation 
of any study therapy and each dose escalation of venetoclax.  Furthermore, this 
assessment assumes that a patient has or will receive adequate hydration 
(alkalinization) and a hypouricemic agent(s).
Table 1
Howard Definition of Laboratory Tumor Lysis Syndrome
Laboratory Assessment
Range
Uric acid
476 mol/L (8.0 mg/dL)
Potassium
6.0 mmol/L (6.0 mEq/L)
Phosphorous
1.5 mmol/L (4.5 mg/dL)
Corrected calcium
1.75 mmol/L (7.0 mg/dL) or ionized calcium 1.12 (0.3 mmol/L) a
Note:  Howard et al. (2011) defined laboratory tumor lysis syndrome as the presence of two or 
more electrolyte changes above or below the thresholds described above occurring during the 
same 24-hour period within 3 days before the start of therapy or 7 days afterward. For the 
purposes of this study, this window applies to the initiation of any study therapy and each dose 
escalation of venetoclax. Furthermore, this assessment assumes that a patient has or will 
receive adequate hydration (± alkalinization) and a hypouricemic agent(s).
a The corrected calcium level in mg/dL is the measured calcium in mg/dL(0.8[4-albumin in 
g/dL]).


Appendix 8:  Guidelines for Defining Tumor Lysis Syndrome (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
170/Protocol CO41863, Version 2 (VHP)
Table 2
Howard Definition of Clinical Tumor Lysis Syndrome
The presence of laboratory TLS and one or more of the following criteria:
Creatinine a:  An increase in serum creatinine level of 0.3 mg/dL (26.5 µmol/L); a single value 
1.5 times the ULN of the age appropriate normal range if no baseline creatinine measurement 
is available; or the presence of oliguria, defined as average urine output of 0.5 mL/kg/hour for 
6 hours
Cardiac dysrhythmia or sudden death probably or definitely caused by hyperkalemia
Cardiac dysrhythmia, sudden death, seizure, neuromuscular irritability (tetany, paresthesias, 
muscle twitching, carpopedal spasm, Trousseau’s sign, Chvostek’s sign, layngospasm or 
bronchospasm), hypotension, or heart failure probably or definitely caused by hypocalcemiab
TLStumor lysis syndrome; ULNupper limit of normal.
a Acute kidney injury is defined as an increase in the creatinine level of 0.3 mg/dL 
(26.5 umol/L) or a period of oliguria lasting 6 hours.  By definition, if acute kidney injury is 
present, the patient has clinical TLS.
b Not directly attributable to a therapeutic agent.
REFERENCE
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. New Engl J Med 
2011;364:184454.


Venetoclax—F. Hoffmann-La Roche Ltd
171/Protocol CO41863, Version 2 (VHP)
Appendix 9
Management of Venetoclax-Specific Adverse Events
Event
Action to Be Taken
Non-hematologic toxicity
(Not specifically described 
in Table 6)
Grade 3 or 4 
non-hematologic events 
Delay venetoclax for a maximum of 28 days.
First episode:  If improvement to Grade 1 or baseline, resume 
previous doses of venetoclax.
For subsequent episodes:  If improvement to Grade 1 or 
baseline, restart venetoclax at one dose level reduction.
Certain treatment emergent non-hematologic adverse events 
(e.g., venous thromboembolic events) may be managed and 
become clinically stable following medical intervention but may 
not improve to Grade 1 according to the NCI CTCAE definitions.  
In such cases, if a patient is clinically stable, resumption of study 
drug may be possible after consultation with the Medical Monitor.
Grade 2 related non-
hematologic toxicity
Delay treatment with venetoclax until resolution to Grade 1 (or 
baseline status) for a maximum of 28 days. 
After resolution, resume full dose of venetoclax.
Grade 1 non-hematologic 
toxicity
No dose reduction or delay.


Venetoclax—F. Hoffmann-La Roche Ltd
172/Protocol CO41863, Version 2 (VHP)
Appendix 10
Management of Trastuzumab Emtansine-Specific Adverse Events
Event
Action to Be Taken
Left ventricular dysfunction
Symptomatic congestive heart failure
Discontinue trastuzumab emtansine.
Asymptomatic LVEF decrease
LVEF 45%
Continue trastuzumab emtansine at the same dose level.
LVEF 40% to 45% and decrease 
from baseline of 10% points
Withhold trastuzumab emtansine.  Repeat LVEF assessment within 3 weeks.  If LVEF decrease from 
baseline of 10% points is confirmed, discontinue trastuzumab emtansine.
LVEF 40% to 45% and decrease 
from baseline of 10% points
Continue trastuzumab emtansine at the same dose level.  Repeat LVEF assessment within 3 weeks.
LVEF 40%
Withhold trastuzumab emtansine.  Repeat LVEF assessment within 3 weeks.  If LVEF 40% is confirmed, 
discontinue trastuzumab emtansine.
Infusion-related reaction (caused by cytokine release) or hypersensitivity (allergic) reaction
Grade 2 reaction
Decrease trastuzumab emtansine infusion rate or interrupt infusion.  Administer supportive care with oxygen, 
-agonists, antihistamines, antipyretics, or corticosteroids, as appropriate, at the investigator’s discretion.  
Monitor patient until complete resolution of symptoms.  
May continue trastuzumab emtansine at the same dose level at the investigator’s discretion.   In the event of 
a true hypersensitivity reaction (in which severity of reaction increases with subsequent infusions), 
discontinue trastuzumab emtansine.
Premedication for infusion reactions (e.g., antihistamines such as diphenhydramine or corticosteroids) may be 
given at the investigator’s discretion.
Grade 3 reaction
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s discretion.  Monitor patient until complete 
resolution of symptoms.  
May continue trastuzumab emtansine at the same dose level at the investigator’s discretion.  In the event of a 
true hypersensitivity reaction (in which severity of reaction increases with subsequent infusions), discontinue 
trastuzumab emtansine.
Premedication for infusion reactions (e.g., antihistamines such as diphenhydramine or corticosteroids) may 


Appendix 10:  Management of Trastuzumab Emtansine-Specific Adverse Events (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
173/Protocol CO41863, Version 2 (VHP)
Event
Action to Be Taken
be given at the investigator’s discretion.
Grade 4 reaction
Stop trastuzumab emtansine infusion.  Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s discretion.  Monitor patient until complete 
resolution of symptoms.
Discontinue trastuzumab emtansine.
Neurotoxicity
Grade 3 peripheral neuropathy
Withhold trastuzumab emtansine until recovery to Grade 2.  
Following recovery, resume trastuzumab emtansine at the same dose level or with one dose level reduction, 
at the investigator's discretion.  
Discontinue trastuzumab emtansine if the event has not resolved to Grade 2 within 42 days after the last 
dose received.
Interstitial Lung Disease and Pneumonitis
Grades 14
Discontinue trastuzumab emtansine treatment.  
NRH
If there are signs of portal hypertension (e.g., ascites and/or varices) and/or a cirrhosis-like pattern is seen on 
a CT scan of the liver, the possibility of NRH should be considered.  
Discontinue trastuzumab emtansine treatment and have the patient evaluated by a hepatologist.
LVEF left ventricular ejection fraction, LVSD left ventricular systolic dysfunction; NRH Nodular Regenerative Hyperplasia. 


Venetoclax—F. Hoffmann-La Roche Ltd
174/Protocol CO41863, Version 2 (VHP)
Appendix 11
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.


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DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
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 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 


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METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 


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


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but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple 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").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked).


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


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


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there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 1
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and during the study only two lesions were assessed, but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 


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progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.  


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Appendix 12
National Cancer Institute Common Terminology Criteria
In the present study, toxicities will be graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 
A pdf of the NCI CTCAE v5.0 can be downloaded from the following website:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Investigators who do not have access to Internet can contact the Data Center to receive 
a hard copy of this document by mail.


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Appendix 13
Guidelines for Liver Biopsy
Because nodular regenerative hyperplasia (NRH) can be a very subtle diagnosis to 
make on liver biopsy, every attempt should be made to maximize the amount of tissue 
obtained.  
The needle used should be at least 18 gauge, and percutaneous biopsies of length at 
least 1.5 cm are recommended, if clinically appropriate.  In order to diagnose NRH, 
reticulin and trichrome stains are necessary.
Smaller biopsies obtained via a transjugular approach and smaller biopsy gun needle 
biopsies are discouraged.  Small wedge biopsies should also be discouraged.