Conditions: Estrogen Receptor-positive (ER+)/Human Epidermal Growth Factor Receptor (HER2)-Negative Locally Advanced or Metastatic Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
This is a Phase II, multicenter, open-label, randomized study to compare the efficacy of venetoclax in combination with fulvestrant compared with fulvestrant alone in women with ER+, HER2-negative, locally advanced or Metastatic Breast Cancer (MBC) who experienced disease recurrence or progression during or after treatment with CDK4/6i therapy for at least 8 weeks. As of 9th October 2020, participants in the Venetoclax + Fulvestrant arm, have all discontinued Venetoclax treatment and have continued on Fulvestrant treatment alone.

Detailed description:

Arms:
arm 1: Participants were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days). arm 2: Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).

Interventions: intervention 1: Venetoclax intervention 2: Fulvestrant
Intervention descriptions: intervention 1: Venetoclax was administered orally, 800-mg tablet beginning on Cycle 1 Day 1 until the 9th October 2020. intervention 2: Fulvestrant was administered orally, 500 mg administered as two 250-mg IM injections on Cycle 1 Days 1 and 15 and on Day 1 of each subsequent 28-day cycle

Protocol document:
Prot_SAP_001.pdf: 
 
Official Title: 
 
A Phase II, Multicenter, Randomized Study To Compare The Efficacy 
Of Venetoclax Plus Fulvestrant Versus Fulvestrant In Women With 
Estrogen Receptor-Positive, Her2-Negative Locally Advanced Or 
Metastatic Breast Cancer Who Experienced Disease Recurrence Or 
Progression During Or After CDK4/6 Inhibitor Therapy 
NCT Number: NCT03584009 
Document Date: Protocol Version 4: 16-Oct-2020 
 
 


PROTOCOL AMENDMENT 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especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) 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 WO40181, Version 4
PROTOCOL
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED STUDY TO 
COMPARE THE EFFICACY OF VENETOCLAX PLUS 
FULVESTRANT VERSUS FULVESTRANT IN WOMEN WITH 
ESTROGEN RECEPTORPOSITIVE, HER2NEGATIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER WHO 
EXPERIENCED DISEASE RECURRENCE OR PROGRESSION 
DURING OR AFTER CDK4/6 INHIBITOR THERAPY
PROTOCOL NUMBER:
WO40181
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-005118-74
IND NUMBER:
137088
TEST PRODUCT:
Venetoclax (RO5537382)
NCT NUMBER
NCT03584009
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
DATES AMENDED:
Version 1:  26 January 2018
Version 2 (United Kingdom):  21 May 2018
Version 3: 19 September 2018
Version 4:  See electronic date stamp below.
 
16-Oct-2020 14:36:47
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Venetoclax—F. Hoffmann-La Roche Ltd
2/Protocol WO40181, Version 4
PROTOCOL AMENDMENT, VERSION 4 
RATIONALE
Protocol WO40181 has been amended to address recent data available from the 
primary analysis.  At the primary analysis of this study (clinical cut-off date of 5 August 
2020), a higher proportion of deaths was observed in the venetoclax plus fulvestrant arm 
compared with the fulvestrant arm. Additionally, the venetoclax plus fulvestrant arm did 
not demonstrate a numerical improvement in the primary endpoint of clinical benefit rate 
(CBR) or the secondary endpoint of progression-free survival (PFS) compared with the 
fulvestrant arm.  Changes to the protocol, along with a rationale for each change, are 
summarized below:

The study rationale and benefit-risk assessment has been updated to indicate that, 
based on the results of the primary analysis, it is no longer considered appropriate 
for patients in this study to receive venetoclax.  As of 8 October 2020, all active 
patients in the venetoclax plus fulvestrant arm of the study will be requested to
discontinue the venetoclax treatment immediately, and will be given the option to 
continue fulvestrant treatment alone (Section 1.4).

Language regarding the study design, study treatment, and treatment interruption 
has been updated to reflect the immediate discontinuation of venetoclax treatment
(Sections 3.1, 4.3.2.1, 5.1.3.2, Appendix 1).  

The frequency of survival follow-up has been increased from approximately every 
6 months to approximately every 3 months or more frequently after treatment 
discontinuation, to enhance safety data collection (Sections 3.1, 4.6.1, Appendix 1).  
Furthermore, language has been added to clarify that new anti-cancer therapy after 
study drug discontinuation should be reported once known (Appendix 1).
Additional changes made to the protocol are as follows:

On the basis of the updated fulvestrant Summary of Product Characteristics, 
language pertaining to the use of contraception has been updated to indicate that 
contraception should be used for up to 2 years after the last dose of study drug, or
based on local prescribing information for fulvestrant (Sections 4.1.1, 5.1.1.5).

Adverse events of special interest for the study have been modified to remove 
hepatitis B reactivation (Section 5.2.3)

The Medical Monitor has been changed and emergency medical contact information 
updated accordingly (Section 5.4.1).

The reference safety information document for venetoclax has been updated to 
Venetoclax Investigator’s Brochure for solid tumour studies (Section 5.7).

Language regarding the statistical considerations for primary and secondary efficacy 
endpoints has been amended to specify the calculation of the 95% confidence 
interval (CI) for CBR estimate, and 95% CI for the Cox proportional hazards model 
for PFS, following reporting conventions (Sections 6.4.1, 6.4.2.1).  


Venetoclax—F. Hoffmann-La Roche Ltd
3/Protocol WO40181, Version 4

The patient-reported outcome analysis has been updated and clarified the definition 
of clinically meaningful changes in European Organisation for Research and 
Treatment of Cancer QLQ-C30 scores (Section 6.7.1). 

Language has been added to indicate that the study will comply with applicable 
local, regional, and national laws (Section 8.1).

A new section has been added to describe the implementation of a system to 
manage the quality of the study (Section 9.3), and subsequent sections were 
renumbered accordingly.

Language has been revised to clarify that data posting will be available in clinical 
trial registries and to clarify that redacted Clinical Study Reports will be available 
upon request (Section 9.6).
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Venetoclax—F. Hoffmann-La Roche Ltd
4/Protocol WO40181, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 24
1.1
Background on Estrogen Receptor-Positive 
HER2-Negative Advanced or Metastatic Breast 
Cancer................................................................................... 24
1.2
BCL-2 Signaling Pathway and Cancer .................................. 25
1.3
Background on Venetoclax.................................................... 26
1.4
Study Rationale and Benefit-Risk Assessment...................... 28
2.
OBJECTIVES AND ENDPOINTS ............................................................... 29
3.
STUDY DESIGN......................................................................................... 31
3.1
Description of the Study......................................................... 31
3.2
Internal Monitoring Committee............................................... 34
3.3
End of Study and Length of Study......................................... 34
3.4
Rationale for Study Design.................................................... 35
3.4.1
Rationale for Venetoclax Dose and Schedule ....................... 35
3.4.2
Rationale for Patient Population ............................................ 35
3.4.3
Rationale for Control Treatment ............................................ 36
3.4.4
Rationale for Biomarker Assessments................................... 36
3.4.5
Rationale for Stratification by B-Cell Lymphoma-2 
Status .................................................................................... 37
3.4.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 38
4.
MATERIALS AND METHODS .................................................................... 38
4.1
Patients.................................................................................. 38
4.1.1
Inclusion Criteria.................................................................... 38
4.1.2
Exclusion Criteria................................................................... 41
4.2
Method of Treatment Assignment.......................................... 44
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 44


Venetoclax—F. Hoffmann-La Roche Ltd
5/Protocol WO40181, Version 4
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 44
4.3.1.1
Venetoclax............................................................................. 44
4.3.1.2
Fulvestrant............................................................................. 44
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 44
4.3.2.1
Venetoclax............................................................................. 45
4.3.2.2
Fulvestrant............................................................................. 45
4.3.3
Investigational Medicinal Product Accountability ................... 46
4.3.4
Continued Access to Venetoclax........................................... 46
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 47
4.4.1
Permitted Therapy................................................................. 47
4.4.2
Prohibited and Cautionary Therapy....................................... 47
4.4.2.1
Patients Randomized to Receive 
Venetoclax Fulvestrant ....................................................... 48
4.4.2.2
Herbal Therapies................................................................... 48
4.4.3
Prohibited Food ..................................................................... 48
4.5
Study Assessments ............................................................... 49
4.5.1
Informed Consent Forms and Screening Log........................ 49
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 49
4.5.3
Physical Examinations........................................................... 50
4.5.4
Vital Signs.............................................................................. 50
4.5.5
Tumor and Response Evaluations......................................... 50
4.5.5.1
Bone Lesions Assessments................................................... 51
4.5.5.2
Tumor Scans ......................................................................... 52
4.5.6
Other Disease-Specific Assessments.................................... 52
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 53
4.5.8
Electrocardiograms................................................................ 55
4.5.9
Patient-Reported Outcomes .................................................. 56
4.5.9.1
EORTC QLQ-C30 Background.............................................. 56
4.5.9.2
EORTC QLQ-C30 Procedures .............................................. 57
4.5.10
Optional Tumor Biopsies ....................................................... 57


Venetoclax—F. Hoffmann-La Roche Ltd
6/Protocol WO40181, Version 4
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 57
4.6.1
Study Treatment Discontinuation........................................... 57
4.6.2
Patient Discontinuation from Study........................................ 58
4.6.3
Study Discontinuation............................................................ 59
4.6.4
Site Discontinuation............................................................... 59
5.
ASSESSMENT OF SAFETY....................................................................... 59
5.1
Safety Plan ............................................................................ 59
5.1.1
Risks Associated with Venetoclax ......................................... 60
5.1.1.1
Tumor Lysis Syndrome.......................................................... 60
5.1.1.2
Neutropenia........................................................................... 61
5.1.1.3
Infections ............................................................................... 61
5.1.1.4
Other Hematological Effects.................................................. 61
5.1.1.5
Reproductive System Effects and Pregnancy........................ 62
5.1.1.6
Treatment-Emergent Malignancies (Second 
Primary Malignancies) ........................................................... 62
5.1.1.7
Food Effect ............................................................................ 62
5.1.1.8
Concomitant Use with Other Medications.............................. 62
5.1.2
Safety Plan for Fulvestrant .................................................... 63
5.1.3
Management of Patients Who Experience 
Specific Adverse Events........................................................ 63
5.1.3.1
Dose Modifications ................................................................ 63
5.1.3.2
Treatment Interruption ........................................................... 63
5.1.3.3
Management Guidelines........................................................ 64
5.2
Safety Parameters and Definitions ........................................ 66
5.2.1
Adverse Events ..................................................................... 66
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 67
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 68
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 68
5.3.1
Adverse Event Reporting Period ........................................... 68
5.3.2
Eliciting Adverse Event Information....................................... 69


Venetoclax—F. Hoffmann-La Roche Ltd
7/Protocol WO40181, Version 4
5.3.3
Assessment of Severity of Adverse Events ........................... 69
5.3.4
Assessment of Causality of Adverse Events ......................... 70
5.3.5
Procedures for Recording Adverse Events............................ 71
5.3.5.1
Injection-Site Reactions......................................................... 71
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 71
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 72
5.3.5.4
Persistent or Recurrent Adverse Events................................ 72
5.3.5.5
Abnormal Laboratory Values ................................................. 73
5.3.5.6
Abnormal Vital Sign Values ................................................... 73
5.3.5.7
Abnormal Liver Function Tests.............................................. 74
5.3.5.8
Deaths ................................................................................... 74
5.3.5.9
Preexisting Medical Conditions.............................................. 75
5.3.5.10
Lack of Efficacy or Worsening of Metastatic 
Breast Cancer........................................................................ 75
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 75
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 76
5.3.5.13
Patient-Reported Outcome Data ........................................... 76
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 76
5.4.1
Emergency Medical Contacts................................................ 77
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 77
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 77
5.4.2.2
Events That Occur after Study Drug Initiation........................ 77
5.4.3
Reporting Requirements for Pregnancies.............................. 78
5.4.3.1
Pregnancies in Female Patients............................................ 78
5.4.3.2
Abortions ............................................................................... 78
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 79
5.5
Follow-Up of Patients after Adverse Events .......................... 79
5.5.1
Investigator Follow-Up........................................................... 79
5.5.2
Sponsor Follow-Up ................................................................ 79
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 79


Venetoclax—F. Hoffmann-La Roche Ltd
8/Protocol WO40181, Version 4
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 80
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 80
6.1
Determination of Sample Size ............................................... 80
6.2
Summaries of Conduct of Study............................................ 81
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 81
6.4
Efficacy Analyses .................................................................. 81
6.4.1
Primary Efficacy Endpoint...................................................... 81
6.4.2
Secondary Efficacy Endpoints............................................... 82
6.4.2.1
Progression-Free Survival ..................................................... 82
6.4.2.2
Objective Response .............................................................. 82
6.4.2.3
Duration of Objective Response............................................ 82
6.4.2.4
Overall Survival ..................................................................... 82
6.5
Safety Analyses..................................................................... 83
6.6
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 83
6.7
Exploratory Objectives........................................................... 83
6.7.1
Patient-Reported Outcome Analyses .................................... 83
6.8
Biomarker Analyses............................................................... 84
6.9
Optional Interim Analyses...................................................... 84
7.
DATA COLLECTION AND MANAGEMENT ............................................... 84
7.1
Data Quality Assurance......................................................... 84
7.2
Electronic Case Report Forms............................................... 85
7.3
Patient-Reported Outcome Data ........................................... 85
7.4
Source Data Documentation.................................................. 85
7.5
Use of Computerized Systems .............................................. 86
7.6
Retention of Records............................................................. 86
8.
ETHICAL CONSIDERATIONS.................................................................... 87
8.1
Compliance with Laws and Regulations ................................ 87
8.2
Informed Consent.................................................................. 87
8.3
Institutional Review Board or Ethics Committee.................... 88


Venetoclax—F. Hoffmann-La Roche Ltd
9/Protocol WO40181, Version 4
8.4
Confidentiality........................................................................ 88
8.5
Financial Disclosure .............................................................. 89
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 89
9.1
Study Documentation ............................................................ 89
9.2
Protocol Deviations................................................................ 89
9.3
Management of Study Quality ............................................. 90
9.4
Site Inspections ..................................................................... 90
9.5
Administrative Structure......................................................... 90
9.6
Publication of Data and Protection of Trade 
Secrets .................................................................................. 90
9.7
Protocol Amendments ........................................................... 91
10. REFERENCES ........................................................................................... 92
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 30
Table 2
Biomarkers for Exploratory Research ......................................... 31
Table 3
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 65
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 70
Table 5
Causal Attribution Guidance ....................................................... 71
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 34
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 96
Appendix 2
Schedule of Pharmacokinetic Samples in the Venetoclax 
Arm ........................................................................................... 101
Appendix 3
Sample List of Medications to Avoid or Use with Caution......... 102
Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1).. 103


Venetoclax—F. Hoffmann-La Roche Ltd
10/Protocol WO40181, Version 4
Appendix 5
European Organisation for Research and Treatment of 
Cancer Core Quality of Life Questionnaire-Core 30 (EORTC 
QLQ-C30), Version 3 ................................................................ 114
Appendix 6
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale.............................................................................. 116
Appendix 7
Suggested Guidance for Atypical Infection Prophylaxis Due 
to Lymphopenia ........................................................................ 117
Appendix 8
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome............. 118
Appendix 9
Guidelines for Defining Tumor Lysis Syndrome........................ 119
Appendix 10
Venetoclax Dose Modifications with Concomitant Moderate 
and Strong CYP3A Inhibitors .................................................... 121


Venetoclax—F. Hoffmann-La Roche Ltd
11/Protocol WO40181, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED STUDY 
TO COMPARE THE EFFICACY OF VENETOCLAX 
PLUS FULVESTRANT VERSUS FULVESTRANT IN 
WOMEN WITH ESTROGEN RECEPTORPOSITIVE, 
HER2NEGATIVE LOCALLY ADVANCED OR 
METASTATIC BREAST CANCER WHO 
EXPERIENCED DISEASE RECURRENCE OR 
PROGRESSION DURING OR AFTER CDK4/6 
INHIBITOR THERAPY
PROTOCOL NUMBER:
WO40181
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-005118-74
IND NUMBER:
137088
NCT NUMBER
NCT03584009
TEST PRODUCT:
Venetoclax (RO5537382)
MEDICAL MONITOR:
, M.D., Ph.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 the contract research organization (CRO).


Venetoclax—F. Hoffmann-La Roche Ltd
12/Protocol WO40181, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED STUDY TO 
COMPARE THE EFFICACY OF VENETOCLAX PLUS 
FULVESTRANT VERSUS FULVESTRANT IN WOMEN WITH 
ESTROGEN RECEPTORPOSITIVE, HER2NEGATIVE 
LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
WHO EXPERIENCED DISEASE RECURRENCE OR 
PROGRESSION DURING OR AFTER CDK4/6 INHIBITOR 
THERAPY
PROTOCOL NUMBER:
WO40181
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-005118-74
IND NUMBER:
137088
NCT NUMBER
NCT03584009
TEST PRODUCT:
Venetoclax (RO5537382)
PHASE:
Phase II
INDICATION:
Estrogen receptor-positive (ER+)/human epidermal growth factor 
receptor (HER2)-negative locally advanced or metastatic breast 
cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy of venetoclax (GDC-0199; ABT199) in combination with 
fulvestrant compared with fulvestrant alone in women with estrogen receptor-positive (ER+), 
human epidermal growth factor receptor (HER2)-negative, locally advanced breast cancer not 
amenable to surgical or local therapy with curative intent or with metastatic breast cancer (MBC) 
who experienced disease recurrence or progression during or after being treated with 
cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy for at least 8 weeks prior to 
progression.  Specific objectives and corresponding endpoints for the study are outlined below.






Venetoclax—F. Hoffmann-La Roche Ltd
15/Protocol WO40181, Version 4

Control arm: fulvestrant 500 mg administered as two 250-mg IM injections on Cycle 1 
Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle.  No crossover to the 
venetoclax arm is permitted.  .
Tumor assessments will be conducted for all patients at screening and at every 8 weeks 
(5 days) from the date of randomization until Week 24 (5 days) and every 12 weeks 
(5 days) thereafter.  Tumor assessments will be conducted regardless of dose delays or early 
discontinuation until investigator-assessed disease progression (as specified below), the
predefined end of the study, or until death, whichever occurs first.
Study treatment for each patient will continue until disease progression, unacceptable toxicity, 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.
Diagnosis of disease progression should be supported by radiology assessments as per 
RECIST v1.1. All patients who are discontinued from all study treatment will return for a study 
drug discontinuation visit 28 days (+3 days) after the last dose of study treatment.
Patients who are discontinued from study treatment for reasons other than disease progression 
and have started follow-on treatment will be followed for survival approximately every 3 months,
or more frequently, 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 other than disease progression 
and have not started follow-on treatment 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, death, loss to follow-up, withdrawal of consent, 
or study termination by the Sponsor, whichever occurs first.
After disease progression, patients will be followed for survival and subsequent anti-cancer 
therapies approximately every 3 months, or more frequently, until death, loss to follow-up, 
withdrawal of consent, or study termination by the Sponsor, whichever occurs first.
Safety will be evaluated by monitoring the overall safety events, including all adverse events 
identified through physical examinations, and assessments of vital signs and laboratory test 
results.  Such events will be graded by the investigators with the use of the National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).  
Safety assessments from laboratory test results will include monitoring of hematology and blood 
chemistry.
As of 8 October 2020, all active patients in the venetoclax plus fulvestrant arm of the study 
will be requested to discontinue the venetoclax treatment immediately, and will be given the 
option to continue fulvestrant treatment alone.
Number of Patients
Approximately 100 patients from approximately 40 centers globally will be enrolled.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Female and 18 years of age at time of signing Informed Consent Form

Signed Informed Consent Form

Histological or cytological confirmation of ER+ invasive carcinoma of the breast with the 
following tumor molecular characteristics:

Documented ER+ defined by using IHC per ASCO/CAP criteria

Documented HER2-negative per ASCO/CAP criteria.  Patients who were originally 
diagnosed with HER2-positive breast cancer that converted to HER2-negative MBC are 
NOT eligible to take part in this study.

Evaluable sample for BCL-2 IHC value at the time of screening

Evidence of metastatic or locally advanced disease not amenable to surgical or local 
therapy with curative intent

Be either:
Postmenopausal, defined as:


Venetoclax—F. Hoffmann-La Roche Ltd
16/Protocol WO40181, Version 4

Age 60 years OR, 

Age 60 years AND have undergone bilateral oophorectomy, medically confirmed 
ovarian failure OR, 

Age 60 years AND have had cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause and have serum levels of 
estradiol and follicle-stimulating hormone within the laboratory’s reference range for 
postmenopausal females
Or pre- or perimenopausal and amenable to being treated with the luteinizing 
hormone-releasing hormone (LHRH) agonist goserelin
Patients must have commenced treatment with goserelin or an alternative LHRH 
agonist at least 28 days prior to first dose of treatment.  If patients have received an 
alternative LHRH agonist prior to study entry, they must switch to goserelin for the 
duration of the trial.

Patients must not have received more than two prior lines of hormonal therapy in the locally 
advanced or metastatic setting.  In addition, at least one line of treatment must be a 
CDK4/6i AND patients must have experienced disease recurrence or progression during or 
after CDK4/6i therapy, which must have been administered for a minimum of 8 weeks prior 
to progression.

Patients for whom endocrine therapy (e.g., fulvestrant) is recommended and treatment with 
cytotoxic chemotherapy is not indicated at the time of entry into the study, as per national or 
local treatment guidelines

Women of childbearing potential (i.e., not postmenopausal for at least 12 months or 
surgically sterile) must have a negative serum pregnancy test result at screening, within 
14 days prior to the first study drug administration

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods with a failure rate of 
1% per year during the treatment period and for up to 2 years after the last dose of study 
drug (or based on the local prescribing information for fulvestrant).  Women must refrain 
from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, and copper intrauterine devices.
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.

Willing to provide tumor biopsy sample
A tumor biopsy sample (either archival or fresh) must be collected from all patients from 
either the primary tumor or a metastatic site (if clinically feasible) for determination of 
expression of BCL-2 by central laboratory testing for patient eligibility purposes and for 
exploratory research on biomarkers.  The tumor specimen must contain adequate 
evaluable tumor cells (20% tumor cells) to enable BCL-2 IHC and other relevant 
biomarker analysis.  Samples can be in a tissue block (preferred) or prepared as 
20 unstained serial slides, and should be accompanied by an associated pathology 
report.  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.

Have at least one measurable lesion via RECIST v1.1. 


Venetoclax—F. Hoffmann-La Roche Ltd
17/Protocol WO40181, Version 4

Bone lesions that have been irradiated are not evaluable.  Previously irradiated lesions 
can be considered as measurable disease only if progressive disease has been 
unequivocally documented at that site since radiation.

Have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 01

Have adequate organ and marrow function as defined below:

Hemoglobin 9 g/dL

Absolute neutrophil count 1.5 109/L

Platelet count 100 109/L

ALT and AST 2.5 upper limit of normal (ULN), with the following exception:
o Patients with documented liver metastases:  AST and/or ALT 5.0 ULN 

Total serum bilirubin 1.5 ULN, with the following exception:
o Patients with previously documented Gilbert syndrome who may have a bilirubin 
5 ULN

Creatinine clearance 50 mL/min calculated with the use of the 24-hour creatinine 
clearance or modified Cockcroft-Gault equation (i.e., estimation of creatinine clearance 
rate [eCCr]) with the use of ideal body mass (IBM) instead of mass:
eCCr (140 Age) IBM (kg) [0.85 for female]
72 serum creatinine (mg/dL)
Or, if serum creatinine is in mol/L:
eCCr (140 Age) IBM (kg) [1.04 for female]
serum creatinine (mol/L)

Meet the following coagulation requirements: 

For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5 ULN within 
14 days prior to initiation of study treatment

For patients receiving therapeutic anticoagulation:  
o INR or aPTT within therapeutic limits for at least 1 week immediately prior to initiation 
of study treatment
o Stable anticoagulant regimen and stable INR during the 14 days immediately 
preceding initiation of study treatment

Have a life expectancy 3 months
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), 
venetoclax, or any investigational agent whose mechanism of action is to inhibit BCL-2

Pregnant, lactating, or intending to become pregnant during the study

Known untreated or active CNS metastases (progressing or requiring anticonvulsants or 
corticosteroids for symptomatic control)
Patients who have had previous treatment of brain metastases with surgery or radiotherapy 
may be eligible provided they meet all of the following criteria:

Evaluable or measurable disease per inclusion criteria outside the CNS is present

Radiographic demonstration of improvement upon the completion of CNS-directed 
therapy and no evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study

No history of intracranial or spinal cord hemorrhage

Administration of treatment 4 weeks prior to Cycle 1 Day 1 of the study

Asymptomatic from CNS metastases


Venetoclax—F. Hoffmann-La Roche Ltd
18/Protocol WO40181, Version 4

Recovered from significant (Grade 3) acute toxicity with no ongoing requirement for 
10 mg of prednisone per day or an equivalent dose of other corticosteroids and no 
change in dose of corticosteroid for at least 2 weeks prior to Cycle 1 Day 1 of treatment

Prior chemotherapy in the locally advanced or metastatic setting regardless of the duration 
of the treatment

Any anti-cancer therapy received within 21 days of the first dose of study drug, including 
chemotherapy, radiotherapy, hormonal therapy, immunotherapy, antineoplastic vaccines, or 
other investigational therapy, with the following exception: 

Radiotherapy with palliative intent to non-target sites is allowed

Concurrent radiotherapy to any site or prior radiotherapy within 21 days of Cycle 1 Day 1 or 
previous radiotherapy to the target lesion sites (the sites that are to be followed for 
determination of a response) or prior radiotherapy to 25% of bone marrow
Prior radiation therapy is allowed if it was completed 21 days before the Cycle 1 Day 1 
treatment AND the patient has recovered from all toxicities to CTCAE Grade 1 AND 
disease evaluable for response outside of the radiation fields or evidence of post-
radiation progression of previously irradiated sites of disease.

Current severe, uncontrolled, systemic disease (e.g., clinically significant cardiovascular, 
pulmonary, metabolic or infectious disease)

Any major surgery within 28 days of the first dose of study drug or anticipation of the need 
for major surgery during the course of study treatment

Administration of the following agents within 7 days prior to the first dose of study drug:

Steroid therapy for anti-neoplastic intent (stable steroid medication not more than 10 mg 
prednisolone per day or an equivalent dose of other corticosteroids for controlling CNS 
metastases is acceptable)

Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A 
inhibitors (e.g., fluconazole, ciprofloxacin, verapamil)

Strong CYP3A inducers (e.g., carbamazepine, phenytoin) or moderate CYP3A inducers 
(e.g., efavirenz, modafinil)

Consumption of one or more of the following within 3 days prior to the first dose of study 
drug:

Grapefruit or grapefruit products

Seville oranges including marmalade containing Seville oranges

Star fruit (carambola)

Need for current chronic corticosteroid therapy (10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids) 

Known infection with HIV or human T-cell leukemia virus 1 

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 

Positive test results for hepatitis B core antibody (HBcAb) or hepatitis C virus (HCV)
antibody at screening
Patients who are positive for HCV antibody must be negative for HCV by polymerase 
chain reaction (PCR) to be eligible for study participation.
Patients with a past or resolved hepatitis B virus (HBV) infection (defined as having a 
positive total HBcAb and negative hepatitis B surface antigen [HbsAg]) may be included 
if HBV DNA is undetectable.  These patients must be willing to undergo monthly DNA 
testing.

Active HCV infection, defined as having a positive HCV antibody test at screening
Patients who have a positive HCV antibody test are eligible for the study if a PCR assay 
is negative for HCV RNA.


Venetoclax—F. Hoffmann-La Roche Ltd
19/Protocol WO40181, Version 4

History of other malignancies within the past 5 years except for treated skin basal cell 
carcinoma, squamous cell carcinoma, non-malignant melanoma 1.0 mm without 
ulceration, localized thyroid cancer, or cervical carcinoma in-situ

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 
Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist) 
within 4 weeks prior to randomization, during treatment, or within 28 days following the 
last dose of venetoclax.

Cardiopulmonary dysfunction as defined by any of the following prior to randomization:

History of NCI CTCAE v5.0 Grade 3 symptomatic congestive heart failure or New York 
Heart Association criteria Class II

Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease

High-risk uncontrolled arrhythmias (i.e., atrial 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])

Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia

Myocardial infarction within 12 months prior to randomization

Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic blood 
pressure 100 mmHg)

Evidence of transmural infarction on ECG

Requirement for oxygen therapy

Other medical or psychiatric conditions that, in the opinion of the investigatory, may 
interfere with the patient’s participation in the study

Inability or unwillingness to swallow pills or receive IM injections 

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption

History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or active 
bowel inflammation (e.g., diverticulitis)

Concurrent hormone replacement therapy

Inability to comply with study and follow-up procedures

Known hypersensitivity to any of the study medications (fulvestrant, venetoclax) or to any of 
the excipients
End of Study
The study duration will be the time from screening of the first patient through 2 years after the 
last patient is enrolled, or all patients in the study have withdrawn consent or died, or if the study 
is prematurely terminated by the Sponsor, whichever occurs first.  
Length of Study
With enrollment anticipated to last approximately 18 months, the total length of the study is 
expected to be approximately 43 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) used in this study are venetoclax and fulvestrant.
Test Product (Investigational Drug)
Venetoclax:  Study patients will self-administer venetoclax tablets by mouth daily.  Venetoclax is 
formulated as 100-mg tablets, so patients will take eight 100-mg tablets daily to receive an 


Venetoclax—F. Hoffmann-La Roche Ltd
20/Protocol WO40181, Version 4
800-mg dose.  Each dose of venetoclax will be taken with approximately 240 mL of water within 
30 minutes after the patient’s first meal of the day (e.g., breakfast).
Comparator
Fulvestrant: Fulvestrant 500 mg will be administered in the clinic as two 250-mg IM injections 
on Cycle 1 Days 1 and 15 and then on Day 1 of each subsequent 28-day cycle.
Non-Investigational Medicinal Products
Necessary supportive measures for optimal medical care will be given throughout the study 
according to institutional standards, including the use of growth factors (e.g., erythropoietin) if 
clinically indicated.  Granulocyte stimulating factor (G-CSF) will be administered for neutropenia 
as indicated.  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 the risk of tumor lysis syndrome 
(TLS) in order to reduce the uric acid level.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is clinical benefit, defined as complete response (CR), partial 
response (PR), or stable disease (SD) lasting 24 weeks from randomization in patients with 
measurable disease at baseline, as determined by the investigator according to RECIST v1.1.
Patients with no response assessments for any reason will be considered non-responders.
The clinical benefit rate (CBR) analysis will be conducted for the intent-to-treat (ITT) population, 
the BCL-2 high subgroup, and the BCL-2 low subgroup.  The confidence intervals for the 
difference in CBR between the two treatment arms will be determined using the normal 
approximation to the binomial distribution. An estimate of the CBR and its 95% CI will be 
calculated for each treatment arm.
Determination of Sample Size  
Approximately 100 patients need to be recruited and randomized in a 1:1 ratio to two treatment 
arms (venetoclax fulvestrant and fulvestrant).  The study will enroll both BCL-2 high (50% of 
tumor cells stained with an intensity of IHC 2or 3) and low (50% of tumor cells stained with 
an intensity of IHC 0 or 1and 50% IHC 2or 3) patients, and it is planned to enroll 
approximately 50 BCL-2-high patients.
The sample size of 100 patients provides precision of 15% for 80% CI when calculating the 
absolute difference in the CBR between the two arms assuming the expected observed CBR in 
the control arm is 40% and in the venetoclax arm is 60% (i.e., the 80% CI for difference in CBR 
is from 5% to 35%).
Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct up to 
two interim efficacy analyses.  The decision to conduct an optional interim analysis and the 
timing of the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis.  The interim analysis will be performed and interpreted by members of the 
Sponsor study team and appropriate senior management personnel.


Venetoclax—F. Hoffmann-La Roche Ltd
21/Protocol WO40181, Version 4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AI
aromatase inhibitor
ALP
alkaline phosphatase 
AML
acute myeloid leukemia
ASCO
American Society of Clinical Oncology
AV
atrioventricular
BCL-2
B-cell lymphoma 2
BCRP
breast cancer resistance protein
BG
O6-benzylguanine
BR
bendamustinerituximab
BSA
body surface area
CAP
College of American Pathologists
CBR
clinical benefit rate
CDK4
cyclin-dependent kinase 4
CDK6
cyclin-dependent kinase 6
CLL
chronic lymphocytic leukemia
CR
complete response
CT
computed tomography
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DDI
drugdrug interaction
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
eCCr
estimation of creatinine clearance rate
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
ER+
estrogen receptor-positive
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
G-CHOP
obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and 
prednisone
G-CSF
granulocyte stimulating factor
GHS
global health status


Venetoclax—F. Hoffmann-La Roche Ltd
22/Protocol WO40181, Version 4
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 
HIPAA
Health Insurance Portability and Accountability Act
HR+
hormone receptor-positive
HRQoL
health-related quality of life
IBM
ideal body mass
ICH
International Council for Harmonisation
IHC
immunohistochemistry
IM
intramuscular
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ITT
intent-to-treat
IxRS
interactive voice or web-based response system
LHRH
luteinizing hormonereleasing hormone
MBC
metastatic breast cancer
MM
multiple myeloma
MRI
magnetic resonance imaging
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
NHL
non-Hodgkin lymphoma
NSG
NOD-SCID-ILR2c -/-
OATP1B1  
organic anion transporter protein 1B1
OR
objective response
ORR
objective response rate
OS
overall survival
P-gp
P-glycoprotein
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PO
orally 
PR
partial response


Venetoclax—F. Hoffmann-La Roche Ltd
23/Protocol WO40181, Version 4
PRO
patient-reported outcome
QD
once a day
QLQ-C30
Quality of Life QuestionnaireCore 30
QTc
QT interval corrected 
QTcF
QT interval corrected through use of Fridericia’s formula
R-CHOP
rituxan plus cyclophosphamide, doxorubicin, vincristine, and prednisone
RECIST
Response Evaluation Criteria in Solid Tumors
SC
subcutaneous
SD
stable disease
SERD
selective estrogen receptor degraders
SERMS
selective estrogen receptor modulators
SLL
small lymphocytic lymphoma
SOC
standard of care
TLS
tumor lysis syndrome
ULN
upper limit of normal
WTS
whole transcriptome sequencing


Venetoclax—F. Hoffmann-La Roche Ltd
24/Protocol WO40181, Version 4
1.
BACKGROUND
1.1
BACKGROUND ON ESTROGEN RECEPTOR-POSITIVE 
HER2-NEGATIVE ADVANCED OR METASTATIC BREAST
CANCER 
Breast cancer is the most frequent cancer diagnosed in women, with an estimated global 
incidence of 1.67 million new cases reported in 2012 (Ferlay et al. 2013). Breast cancer 
accounts for approximately 15% (approximately 522,000 cases) of all cancer deaths.
Breast cancer mortality rates differ by geographical region, with more favorable survival 
rates in more developed regions of the world (Ferlay et al. 2013).
Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 
(HER2)-negative breast cancer accounts for 60%70% of all breast cancers. The 
standard-of-care (SOC) treatment for patients with ER+ breast cancer takes several 
factors into consideration including the stage of disease and recurrence score
(Senkus et al. 2013; NCCN 2014). In the adjuvant treatment setting, endocrine therapy 
alone may be considered for patients with low volume disease (tumor size 0.5 cm, 
node-negative disease) and in patients with a low (18) recurrence score using a 
21-gene reverse transcriptase polymerase chain reaction (PCR) assay. Sequential 
treatment with chemotherapy followed by endocrine treatment should be considered for 
those patients with node-positive cancers or tumors 0.5 cm in size, and with 
intermediate (1830) to high (31) recurrence scores.
Administration of tamoxifen with consideration for ovarian ablation or suppression is 
recommended in premenopausal women (Senkus et al. 2013). The administration of 
aromatase inhibitors (AIs) as initial treatment or as a sequential treatment following 
tamoxifen has been recommended for postmenopausal women (Burstein et al. 2010;
Senkus et al. 2013).
Endocrine treatment options in the treatment of postmenopausal women whose cancer 
has recurred after adjuvant therapy include nonsteroidal AIs (anastrozole, letrozole), 
steroidal AIs (exemestane), ER down-regulators (fulvestrant), and ER modulators 
(tamoxifen, toremifene). Meta-analyses suggest that AIs may be superior to tamoxifen 
in prolonging the time to disease progression in this treatment setting (Bonneterre et al. 
2000; Nabholtz et al. 2000; Paridaens et al. 2008; Gibson et al. 2009). Treatment with 
fulvestrant may offer a survival advantage over anastrozole (Gibson et al. 2009). Very 
little evidence is available to support an optimal endocrine therapy sequence in the 
metastatic setting (NCCN 2014). The choice of agent, sequence of agents, and duration 
of treatment should be guided by practical considerations, such as prior endocrine 
treatment response and each agent’s safety profile.
More recently, inhibitors specific for cyclin-dependent kinase 4 (CDK4) and 
cyclin-dependent kinase 6 (CDK6) have entered clinical practice for patients with ER+
breast cancer. Three selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are now 


Venetoclax—F. Hoffmann-La Roche Ltd
25/Protocol WO40181, Version 4
approved: palbociclib, ribociclib, and abemaciclib. Positive results from several Phase II 
and III studies (PALOMA 1, 2, and 3 studies) have resulted in the U.S. Food and Drug 
Administration (FDA) and European Union approval of palbociclib, as first- or 
second-line treatment of hormone receptor-positive (HR+) breast cancer in combination 
with endocrine therapy.  In the first-line setting of metastatic HR+ breast cancer, the 
combination of palbociclib with letrozole increased the median progression-free survival 
(PFS) and objective response rate (ORR) of letrozole therapy alone (PFS: 20.2 months 
vs. 10.3 months; ORR:  55.4% vs. 39.4%), providing a significant improvement in 
therapy options for patients with HR+ breast cancer. Based on the results of these trials, 
the 2016 American Society of Clinical Oncology (ASCO) and European Society for 
Medical Oncology guidelines state that palbociclib in combination with endocrine therapy 
can be considered for treatment of HR+ metastatic breast cancer (MBC) in the first- or 
second-line setting (Rugo et al. 2016; Cardoso et al. 2017). Other CDK4/6i, such as 
ribociclib and abemaciclib, are approved by the FDA for the initial treatment of HR+ 
advanced or MBC, in combination with an AI for ribociclib and in combination with 
fulvestrant and in monotherapy for abemaciclib. However, despite these promising 
results, mechanisms of acquired resistance to CDK4/6i, as well as anecdotal evidence,
suggest poor patient outcomes following CDK4/6i treatments and highlight the unmet 
medical need for identifying new therapeutic regimens for these patients.
Although endocrine therapy can provide prolonged disease control, recurrence and
therapeutic resistance remains a significant problem for patients with HR+ advanced 
breast cancer. Patients who experience disease progression on endocrine therapies 
could range from patients with bone-only metastasis to those who have visceral crisis 
with multiple organ involvement. Our understanding of the mechanisms of resistance to 
endocrine therapy has improved in recent years. Mechanisms that can lead to primary 
and/or secondary hormonal resistance in ER+ breast cancer include a decrease or loss 
of ER expression or an upregulation of growth factor signalling pathways, such as the 
epidermal growth factor receptor or HER2.  Recently, mutations in the gene that 
encodes ER (ESR1) have been identified in metastatic ER+ tumors and are associated 
with resistance to anti-estrogen therapies (Robinson et al. 2013; Toy et al. 2013; 
Jeselsohn et al. 2014). In addition to the enhanced understanding of endocrine 
resistance in ER+ breast cancer, significant efforts are underway to address the 
treatments for patients who develop this resistance.  However, despite the development 
of new therapies, treatment of endocrine-resistant, HR+ breast cancer remains an area 
of high unmet need. Therefore, other markers, such as B-cell lymphoma 2 (BCL-2), are 
being investigated in order to develop treatments to fill this area of unmet medical need.
1.2
BCL-2 SIGNALING PATHWAY AND 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 
BCL-2 regulated mitochondrial pathway and the extrinsic death receptor pathway 


Venetoclax—F. Hoffmann-La Roche Ltd
26/Protocol WO40181, Version 4
(Strasser et al. 2011). BCL-2 is overexpressed in approximately 75% of breast cancer 
and has emerged as a prognostic marker (Dawson et al. 2010). This is demonstrated by 
the presence of BCL-2 protein as a component of Oncotype DX® a 21-gene recurrence 
score used to predict the risk of breast cancer recurrence in ER+, node-negative early 
stage disease (Paik et al. 2004).
BCL-2 has emerged as a promising therapeutic target in hematopoietic and possibly 
solid tumors. Patient derived xenograft tumor models of luminal B breast cancer 
demonstrated significantly improved tumor response and overall survival (OS) when 
treated with the BCL-2 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 inhibitor venetoclax, suggesting that BCL-2 is a crucial target. To date, 
venetoclax has been studied in multiple early phase clinical trials in relapsed/refractory 
hematopoietic malignancies and recently in combination with tamoxifen for patients with 
ER+, BCL-2 positive MBC (Registration ACTRN12615000702516).  This trial is still 
recruiting patients. An interim report of the dose-escalation phase of this trial was 
presented at ASCO in June 2016 and demonstrated the safety and efficacy for the 
combination of tamoxifen and venetoclax in ER+ MBC (Lindeman et al. 2017). 
1.3
BACKGROUND ON VENETOCLAX
Venetoclax (also referred to as GDC-0199, RO5537382, ABT-199, A-1195425.0, 
Venclexta®, and Venclyxto®) is a novel, orally bioavailable, small-molecule BCL-2 family 
inhibitor in the biaryl acylsulfonamide chemical class.
Venetoclax has been extensively studied in oncology, particularly in hematological 
malignancies.  Since 2011, multiple ongoing Phase I/II AbbVie and Phase I/II/III 
Genentech/Roche clinical studies are evaluating the safety, tolerability, 
pharmacokinetics, and efficacy of venetoclax as monotherapy or in combination with 
other therapies (e.g., rituximab, obinutuzumab, bendamustinerituximab [BR], 
O6-benzylguanine [BG], 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 chronic lymphocytic leukemia [CLL]/small lymphocytic 
lymphoma [SLL], non-Hodgkin lymphoma [NHL], multiple myeloma [MM], and acute 
myeloid leukemia [AML]). Data are available from drug-drug interaction (DDI) studies of 
venetoclax interaction with ketoconazole, with rifampin, and with warfarin. Additionally, 
two Phase III studies are ongoing: one study in relapsed/refractory CLL exploring the 
combination of venetoclax and rituximab against BR, and one Phase III study in first-line 
CLL exploring the combination of venetoclax and obinutuzumab against obinutuzumab 
plus chlorambucil.
Refer to the Venetoclax Investigator's Brochure for details on nonclinical and clinical 
studies.


Venetoclax—F. Hoffmann-La Roche Ltd
27/Protocol WO40181, Version 4
The two-drug combination (i.e., venetoclax plus fulvestrant) proposed for the treatment 
of ER+ MBC has been evaluated in a nonclinical model for pharmacologic proof of 
concept.  In addition, the data on the individual agents have been reviewed for potential 
DDI or overlapping toxicities.  The results of this nonclinical study and data analysis are 
summarized as follows:  

In the 315T ER+ human breast cancer xenografts grown in NOD-SCID-ILR2γc-/-
(NSG) mice, fulvestrant, administered subcutaneous (SC) once weekly, in 
combination with venetoclax, administered orally once a day (QD) for 5 days per 
week, for 3 weeks, enhanced tumor growth inhibition and significantly increased 
survival when compared with fulvestrant monotherapy.  All drugs and the 
combination were tolerated based on no signs of moribundity during the treatment 
period.

The combination of venetoclax and fulvestrant significantly increased survival in 
NSG mice bearing 315T xenografts when compared with fulvestrant alone (38 days 
vs. 25 days; p 0.005).  

The nonclinical data demonstrate that the combination of venetoclax with fulvestrant 
is more efficacious than either agent alone in an ER+ patient-derived xenograft in 
vivo model and has low risk for off-target safety pharmacology effects.

As venetoclax produced no CNS/neurological effects in non-clinical studies the risk 
for any significant overlapping CNS/neurological or cardiovascular effects is 
considered minimal.

Based on the known safety profiles and pharmacokinetics, the potential for DDI with 
the venetoclax and fulvestrant combination is considered to be low.

Both venetoclax and fulvestrant have the potential to cause reproductive organ and 
embryo-fetal developmental toxicities as single agents so there is the potential for 
this combination to cause overlapping or more/additional reproductive and 
embryo-fetal toxicities than the individual molecules.  No other potential overlapping 
toxicities were identified from nonclinical studies.

For this drug combination, the doses are based on human clinical trial data from the 
two approved drugs.  The recommended human dose of venetoclax of 800 mg QD
continuously is based on a Phase Ib clinical trial of venetoclax in combination with 
tamoxifen (Lindeman et al. 2017; venetoclaxtamoxifen in MBC) using that dose 
and schedule without employing a ramp-up. A dose of 800 mg venetoclax is 
currently being explored as a combination partner in the treatment of NHL and MM.  
In contrast to what has been observed in hematological cancers treated with 
venetoclax, tumor lysis syndrome (TLS) was not seen in the Phase Ib study, and a 
dose ramp-up phase is not being recommended.

Fulvestrant is recommended to be administered using the approved human dose 
and schedule:  500 mg administered in the clinic (before administration of 
venetoclax) as two intramuscular (IM) injections of 250 mg each on Cycle 1 Days 1 
and 15 and on Day 1 of each subsequent 28-day cycle.  Based on the mechanism 
of action and the nonclinical and clinical data available to date, the safety profile of 
venetoclax is well described and the potential overlapping toxicities between 


Venetoclax—F. Hoffmann-La Roche Ltd
28/Protocol WO40181, Version 4
venetoclax and fulvestrant are thought to be of minor clinical significance and 
manageable.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This study will enroll patients with ER+, HER2-negative, inoperable, locally advanced or 
MBC who had disease progression following treatment for first- or second-line metastatic 
disease with endocrine therapy that contains CDK4/6i, such as palbociclib, but does not 
include fulvestrant.  Although CDK4/6 inhibitors in combination with endocrine therapy 
have demonstrated an improvement in PFS in first- or second-line settings, the acquired 
resistance to CDK4/6 inhibitors, as well as anecdotal evidence, suggest poor patient 
outcomes following CDK4/6i therapy, highlighting the need for identifying new 
therapeutic regimens for these patients.
Given this unmet clinical need for patients with endocrine-resistant disease and 
observed emergence of acquired resistance to CDK4/6i (O’Leary et al. 2016), this 
population is considered appropriate for trials of novel therapeutic candidates to identify 
effective post-CDK4/6i treatment regimens, including BCL-2 inhibitors.
At the primary analysis (clinical cut-off date of 5 August 2020, data read-out available 
on 29 September 2020), the efficacy and safety data from 103 patients enrolled in this 
study (intent-to-treat [ITT] population) was reported.  A summary of findings from the 
primary analysis is provided below:
The study did not demonstrate a numerical improvement in the primary endpoint of 
clinical benefit rate (CBR) or the secondary endpoint of PFS in the venetoclax plus 
fulvestrant arm compared with the fulvestrant arm.  The secondary endpoint of OS was 
not mature (27.2% event/patient ratio) with a median duration of survival follow-up of 
9.89 months.  The stratified hazard ratio was 2.56 (95% CI: 1.11 to 5.89).  
Safety of the venetoclax plus fulvestrant was consistent with the known safety profile of 
the individual medicines.  No new safety signals were identified.  However, a higher 
proportion of deaths was observed in the venetoclax plus fulvestrant arm compared with
the fulvestrant arm.  In the ITT population, a total of 19 deaths (37.3%) was reported 
in the venetoclax plus fulvestrant arm compared with 9 deaths (17.3%) in the 
fulvestrant arm.
Deaths that occurred 28 days after the last dose of study drug were reported in 
2 patients in the venetoclax plus fulvestrant arm (primary cause of death included 1 
case due to adverse event and 1 case due to disease progression), compared with none in 
the fulvestrant arm.  Deaths that occurred 28 days after the last dose of study drug 
were reported in 17 patients in the venetoclax plus fulvestrant arm (primary cause of 
death included 16 cases due to progressive disease, and 1 case related to other causes 
which was reported post-study), compared with 9 patients in the fulvestrant arm 
(primary cause of death included 8 cases due to progressive disease and 1 case due to 
pneumonia).


Venetoclax—F. Hoffmann-La Roche Ltd
29/Protocol WO40181, Version 4
Overall, the results from the primary analysis do not support a positive benefit/risk 
profile for the treatment of venetoclax plus fulvestrant in patients with ER+, HER2-
negative locally advanced or MBC who experienced disease recurrence or progression 
during or after CDK4/6 inhibitor therapy. While the Sponsor is carrying out 
additional analyses to further understand these results, it is no longer considered 
appropriate for patients in this study to receive venetoclax.  
Investigators were informed on 8 October 2020, and as of this date, all active patients 
in the venetoclax plus fulvestrant arm of the study will be requested to discontinue the 
venetoclax treatment immediately, and will be given the option to continue fulvestrant 
treatment alone.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy of venetoclax (GDC-0199; ABT199) in combination 
with fulvestrant compared with fulvestrant alone in women with ER+, HER2-negative,
locally advanced breast cancer not amenable to surgical or local therapy with curative 
intent or with MBC who experienced disease recurrence or progression during or after 
being treated with CDK4/6i therapy for at least 8 weeks prior to progression.  Specific 
objectives and corresponding endpoints for the study are outlined in Table 1.






Venetoclax—F. Hoffmann-La Roche Ltd
32/Protocol WO40181, Version 4
least 8 weeks.  Approximately 100 patients from approximately 40 centers globally will 
be enrolled.  Fresh tumor tissue (or archival tissue) will be collected during screening 
from all patients to confirm and determine HER2, ER, and BCL-2 status.  ER status will 
be defined by using immunohistochemistry (IHC) per the ASCO/College of American 
Pathologists (CAP) criteria (Hammond et al. 2010), and HER2 negativity will be defined 
per the ASCO/CAP criteria (Wolff et al. 2013).  BCL-2 expression will be assessed by a 
central laboratory using the Ventana BCL-2 IHC assay.  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 
50% stained with an intensity of IHC 0 or 1and 50% stained an intensity of IHC 2or 
3.
Patients who do not initially meet all eligibility criteria may be rescreened once within 
2 weeks, given that the reason for screening failure was not ER or HER-2 status (see 
Section 4.5.1 for further information).
Central laboratory assessments will occur prior to randomization.  Patients must have 
measurable disease (per Response Evaluation Criteria in Solid Tumors, Version 1.1 
[RECIST v1.1]) locally advanced or metastatic disease with at least one evaluable 
lesion.  Detailed information is listed in the inclusion and exclusion criteria in Section 4.1
and Appendix 4.  Locally advanced disease must not be amenable to resection or other 
local therapy with curative intent.
Patients will be randomized in a 1:1 ratio to receive venetoclax in combination with
fulvestrant or fulvestrant alone.  Randomization will be stratified between the two arms 
on the basis of BCL-2 status and one versus two lines of prior therapy in the locally 
advanced/metastatic setting.

Venetoclax arm:  venetoclax 800-mg tablet (8100-mg tablet formulation) taken 
orally (PO) QD beginning on Cycle 1 Day 1 and fulvestrant 500 mg administered as 
two 250-mg IM injections on Cycle 1 Days 1 and 15, and then on Day 1 of each 
subsequent 28-day cycle.

Control arm: fulvestrant 500 mg administered as two 250-mg IM injections on 
Cycle 1 Days 1 and 15, and then on Day 1 of each subsequent 28-day cycle.  No 
crossover to the venetoclax arm is permitted.  
Tumor assessments will be conducted for all patients at screening and at every 8 weeks 
(5 days) from the date of randomization until Week 24 (5 days) and every 12 weeks 
(5 days) thereafter.  Tumor assessments will be conducted regardless of dose delays 
or early discontinuation, until investigator-assessed disease progression (as specified
below), the predefined end of the study (Section 3.3), or until death, whichever occurs 
first.
Study treatment for each patient will continue until disease progression, unacceptable 
toxicity, withdrawal of consent, death, or study termination by the Sponsor, whichever 
occurs first.


Venetoclax—F. Hoffmann-La Roche Ltd
33/Protocol WO40181, Version 4
Diagnosis of disease progression should be supported by radiology assessments as per 
RECIST v1.1. All patients who are discontinued from all study treatment will return for a 
study drug discontinuation visit 28 days (+3 days) after the last dose of study treatment.
Patients who are discontinued from study treatment for reasons other than disease 
progression and have started follow-on treatment will be followed for survival
approximately every 3 months, or more frequently, 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 other than disease 
progression and have not started follow-on treatment 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, death, loss to 
follow-up, withdrawal of consent, or study termination by the Sponsor, whichever occurs 
first.
After disease progression, patients will be followed for survival and subsequent 
anti-cancer therapies approximately every 3 months, or more frequently, until death, 
loss to follow-up, withdrawal of consent, or study termination by the Sponsor, whichever 
occurs first.
Safety will be evaluated by monitoring the overall safety events, including all adverse 
events identified through physical examinations, and assessments of vital signs and 
laboratory test results.  Such events will be graded by the investigators with the use of 
the National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 (NCI CTCAE v5.0).  Safety assessments from laboratory test results will 
include monitoring of hematology and blood chemistry.
As of 8 October 2020, all active patients in the venetoclax plus fulvestrant arm of the 
study will be requested to discontinue the venetoclax treatment immediately, and will 
be given the option to continue fulvestrant treatment alone.
The study schema is presented in Figure 1.  A schedule of activities is provided in 
Appendix 1.


Venetoclax—F. Hoffmann-La Roche Ltd
34/Protocol WO40181, Version 4
Figure 1
Study Schema
2Lsecond line; 3Lthird line; BCbreast cancer; BCL-2B-cell lymphoma 2; 
CDK4/6icyclin-dependent kinase 4/6 inhibitor; ERestrogen receptorpositive;  
HER2human epidermal growth factor receptornegative; Rrandomization.
Note: Stratification is by one vs. two lines of prior therapy in the locally advanced/metastatic 
setting and BCL-2 High vs. Low (see Section 4.2).
3.2
INTERNAL MONITORING COMMITTEE
An Internal Monitoring Committee (IMC) will monitor the totality of the safety data 
collected during the clinical trial.  The IMC will convene to review initial safety data after 
5 patients in each arm (10 patients) have been randomized and treated for at least one 
cycle or 3 months after the first patient has been enrolled, whichever comes first.  
Thereafter, the IMC will convene approximately every 6 months, or more frequently as 
needed, to review cumulative safety data, including data regarding serious adverse 
events, death, events Grade 3, clinically significant laboratory abnormalities, and
adverse events of special interest.
The IMC will include at a minimum the study Medical Monitor, a safety scientist, 
biostatistician, and a designated Sponsor medical oncologist who is not the Medical 
Monitor and is not associated with the study.  Representatives from other Sponsor 
function areas may be included as ad hoc members.  The IMC will operate according to 
a pre-specified charter that will outline the IMC members, roles, responsibilities, and 
communication processes, and this charter will be made available upon request to the 
appropriate regulatory agencies.
3.3
END OF STUDY AND LENGTH OF STUDY
The study duration will be the time from screening of the first patient through 2 years 
after the last patient is enrolled, or all patients in the study have withdrawn consent or
died, or if the study is prematurely terminated by the Sponsor, whichever occurs first.  
With enrollment anticipated to last approximately 18 months, the total length of the study 
is expected to be approximately 43 months.


Venetoclax—F. Hoffmann-La Roche Ltd
35/Protocol WO40181, Version 4
3.4
RATIONALE FOR STUDY DESIGN
3.4.1
Rationale for Venetoclax Dose and Schedule
Venetoclax has been investigated in multiple trials of hematopoietic malignancies at 
doses ranging from 200 mg to 1200 mg, as monotherapy and in combination with other 
agents including dexamethasone, rituximab, obinutuzumab, bortezomib, and 
chemotherapy. The safety, tolerability, and efficacy of venetoclax have been confirmed.
Venetoclax was granted approval in the United States (see VenclextaU.S. Prescribing 
Information 2016) and conditional market approval by the European Medicines Agency 
(EMA) (Venclyxto® EMA Summary of Product Characteristics 2016) as monotherapy for 
the treatment of patients with CLL who have 17p deletion at the dose of 400 mg QD.  
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 tamoxifen in patients with ER+, 
BCL-2positive MBC.  Although dose-limiting toxicity (DLT) was not reached, venetoclax 
at the dose of 800 mg QD orally was demonstrated to be safe and tolerable in 
combination with tamoxifen.  The nature and frequencies of these 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 (Lindeman et al. 2017).  Therefore, the 800-mg dose was 
selected for the expansion phase of the study (venetoclax+tamoxifen), which is ongoing 
and planned to enroll approximately 30 patients with ER+ metastatic breast cancer.  
Additionally, as the overlapping toxicities and potential for DDI between venetoclax and 
fulvestrant are thought to be of minimum significance, there is no dose adjustment 
considered for the combination of these two products.
3.4.2
Rationale for Patient Population
HR+ breast cancer accounts for over 70% of breast cancer subtypes.  Until the recent 
emergence of selective CDK4/6 inhibitors, endocrine therapy remained the SOC
treatment for metastatic disease through multiple lines of therapy followed by 
chemotherapy in the late metastatic, endocrine therapy-resistant setting.  Recent data 
from the PALOMA 3 trial has demonstrated the efficacy of combined palbociclib and 
fulvestrant in premenopausal patients who were treated with goserelin as well as those 
with postmenopausal status (Loibl et al. 2017).  However, despite recent PFS 
improvements with CDK4/6i, the emergence of acquired resistance to CDK4/6i highlights 
the continued unmet need to identify new treatment regimens for patients with 
second-line metastatic ER+ breast cancer following such treatment (O’Leary et al. 2016).  
Despite the benefits from current endocrine therapies and chemotherapies, HR+ MBC
remains an incurable disease and the majority of patients will eventually progress and 
subsequently die from the disease. BCL-2 is expressed in approximately 75% of breast 
cancer (Callagy et al. 2006; Dawson et al. 2010) and is an established therapeutic target 
in CLL. Early phase clinical trials have demonstrated efficacy using the BCL-2 inhibitor 
venetoclax in combination with tamoxifen for patients with ER+ positive, BCL-2 positive 


Venetoclax—F. Hoffmann-La Roche Ltd
36/Protocol WO40181, Version 4
MBC, providing a rationale for investigating BCL-2 inhibitor treatment regimens in this 
patient population.
3.4.3
Rationale for Control Treatment
Treatment for HR+, HER2-negative breast cancer usually consists of multiple rounds of 
endocrine therapy with or without selective CDK4/6 inhibitors followed by cytotoxic 
chemotherapy once all endocrine therapy options have been exhausted or symptomatic 
or rapid disease progression warrants the use of cytotoxic chemotherapy. Fulvestrant 
has been approved by the FDA and EMA for the treatment of HR+ or ER+, locally 
advanced or MBC in postmenopausal women with disease progression following prior 
anti-estrogen therapy (Howell et al. 2002; Osborne et al. 2002; Di Leo et al. 2010) and 
postmenopausal women not previously treated with endocrine therapy. Fulvestrant is 
not indicated for use in the adjuvant setting, whereas AIs are currently approved for use 
and are considered the SOC (in the United States and European Union) in this setting. 
Therefore, given the unique mechanism of action and the current treatment paradigm 
that indicates the sequential use of endocrine therapies for patients without visceral 
crisis (Senkus et al. 2013) for treatment of locally recurrent or MBC, fulvestrant 
represents an appropriate treatment option for patients whose disease failed to respond 
to prior AI therapy.
3.4.4
Rationale for Biomarker Assessments
Breast cancer is a heterogeneous disease that can be divided into at least four distinct
molecular subtypes defined as basal/triple-negative, HER2-enriched, and luminal 
subtypes A and B.  Luminal breast cancers are characterized by elevated hormone 
receptor expression (Perou et al. 2000), and BCL-2 expression is enriched in these ER+
luminal subgroups (Vaillant et al. 2013).  ER, progesterone receptor, and HER2 
expression measures are used clinically to both establish prognosis as well as identify 
targeted treatment options.
While nonclinical studies have not shown single-agent activity by BCL-2 inhibitors in 
breast cancer, it has been demonstrated that ER inhibitors, such as tamoxifen, are more 
effective when used in combination with BCL-2 inhibitors (Vaillant et al. 2013).  This 
observation suggests the potential for enhancement of anti-estrogen therapy in 
combination with anti-BCL-2 therapy.  Molecules have been designed with different 
mechanisms to block activity driven by the ER, such as selective ER modulators 
(SERMS), steroidal and non-steroidal AIs, and estrogen-targeting therapies, such as 
fulvestrant (a selective ER degrader [SERD]), that compromise ER-driven signaling by 
degrading the receptor. SERDs are often applied when SERMs or AIs are no longer 
effective and are used in the MBC setting.  Activity of SERDs, such as fulvestrant, may 
be enhanced by BCL-2 inhibition as, in addition to the fulvestrant-dependent reduction of 
ER driven BCL-2 expression; BCL-2 inhibitors, such as venetoclax, may block any 
residual BCL-2 activity that contributes to pathogenesis.  As nonclinical studies have 
shown that BCL-2 protein levels may be predictive of response to venetoclax in 


Venetoclax—F. Hoffmann-La Roche Ltd
37/Protocol WO40181, Version 4
hematologic malignancies (Souers et al. 2013), there is potential for biological 
target-based (both ER and BCL-2) inhibition in MBC.  
Even within luminal, ER+ breast cancer patients in whom BCL-2 expression is elevated 
relative to the other molecular subtypes, BCL-2 levels can vary.  Currently, there are
limited data about the correlation of response to BCL-2 inhibition in breast cancer and 
BCL-2 expression levels.  BCL-2 levels are elevated in estrogen-positive subgroups 
relative to the other molecular subgroups that comprise breast cancer.  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 might 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, 
whole transcriptome sequencing (WTS), 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 mutations 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.
3.4.5
Rationale for Stratification by B-Cell Lymphoma-2 Status
BCL-2 levels are elevated in estrogen positive tumors; however, currently there is little 
data demonstrating a pathogenic role for BCL-2 in breast cancer.  Venetoclax 
specifically inhibits BCL-2 activity, and there is potential that BCL-2 target-expression 
levels may correlate with activity.  The role of BCL-2 in pathogenesis is confounded by 
the prognostic profile associated with the estrogen-positive subtype.  In order to 
distinguish the potential for predictive value of BCL-2 expression levels with targeted 
BCL-2 inhibition, patients will not only be randomized into fulvestrant and venetoclax 
versus fulvestrant alone arms to distinguish prognostic effects but also stratified into 
BCL-2 high (50% of tumor cells stained with an intensity of IHC 2or 3) and BCL-2 low 
(50% stained with an intensity of IHC 0 or 1and 50% stained an intensity of IHC 2
or 3) populations.  In nonclinical analyses, elevated BCL-2 expression levels in NHL cell
lines correlate with venetoclax activity using this high versus low cutoff.  Stratification will 
enable evaluation of the correlation between BCL-2 expression and venetoclax activity in 
breast cancer.  Responses will be evaluated by comparing the two stratified subgroups.  


Venetoclax—F. Hoffmann-La Roche Ltd
38/Protocol WO40181, Version 4
Since a cutoff for BCL-2 levels in breast cancer has not been established, retrospective 
analyses may also be performed to evaluate alternative cutoffs.
3.4.6
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. 
2012). Disease symptoms are dependent on sites of metastases (Irvin et al. 2011), and 
patients can have bone involvement. Examining and measuring patients’ pain, their 
global health status (GHS)/overall health-related quality of life (HRQoL), as well as their 
treatment-related symptoms and their interference with daily life is important and will be 
assessed using validated PRO assessments.  
The European Organisation for Research and Treatment of Cancer Core Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) will be administered to patients to assess 
disease/treatment-related symptoms, functioning, and HRQoL (see Section 4.5.9 and 
Appendix 5).
In addition, for patients with metastatic disease, pain can be a serious 
symptom. Therefore, measuring pain and the progression of pain and its impact on 
patients are important; thus, this symptom will be assessed using the pain scale from the 
EORTC QLQ-C30.
The EORTC QLQ-C30 will be assessed at baseline (Cycle 1, Day 1), at Day 1 of each 
subsequent cycle, and at the treatment discontinuation visit (see Appendix 1). The PRO 
data will be collected using paper questionnaires completed at the clinic site visit.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 100 patients with ER+, HER2-negative locally advanced or MBC will be 
enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Female and 18 years of age at time of signing Informed Consent Form

Signed Informed Consent Form

Histological or cytological confirmation of ER+ invasive carcinoma of the breast with 
the following tumor molecular characteristics:

Documented ER+ defined by using IHC per ASCO/CAP criteria 
(Hammond et al. 2010)

Documented HER2-negative per ASCO/CAP criteria (Wolff et al. 2013).  Patients 
who were originally diagnosed with HER2-positive breast cancer that converted 
to HER2-negative MBC are NOT eligible to take part in this study.


Venetoclax—F. Hoffmann-La Roche Ltd
39/Protocol WO40181, Version 4

Evaluable sample for BCL-2 IHC value at the time of screening

Evidence of metastatic or locally advanced disease not amenable to surgical or local 
therapy with curative intent

Be either:
Postmenopausal, defined as:

Age 60 years OR, 

Age 60 years AND have undergone bilateral oophorectomy, medically 
confirmed ovarian failure OR, 

Age 60 years AND have had cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause 
and have serum levels of estradiol and follicle-stimulating hormone within the 
laboratory’s reference range for postmenopausal females
Or pre- or perimenopausal and amenable to being treated with the luteinizing 
hormone-releasing hormone (LHRH) agonist goserelin
Patients must have commenced treatment with goserelin or an alternative LHRH 
agonist at least 28 days prior to first dose of treatment.  If patients have 
received an alternative LHRH agonist prior to study entry, they must switch to 
goserelin for the duration of the trial.

Patients must not have received more than two prior lines of hormonal therapy in 
the locally advanced or metastatic setting.  In addition, at least one line of treatment 
must be a CDK4/6i AND patients must have experienced disease recurrence or 
progression during or after CDK4/6i therapy, which must have been administered for 
a minimum of 8weeks prior to progression.  

Patients for whom endocrine therapy (e.g., fulvestrant) is recommended and 
treatment with cytotoxic chemotherapy is not indicated at the time of entry into the 
study, as per national or local treatment guidelines.

Women of childbearing potential (i.e., not postmenopausal for at least 12 months or 
surgically sterile) must have a negative serum pregnancy test result at screening,
within 14 days prior to the first study drug administration

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use non-hormonal contraceptive methods with a failure 
rate of 1% per year during the treatment period and for up to 2 years after the last 
dose of study drug (or based on the local prescribing information for fulvestrant).  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 
1% per year include bilateral tubal ligation, male sterilization, and copper 
intrauterine devices.


Venetoclax—F. Hoffmann-La Roche Ltd
40/Protocol WO40181, Version 4
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.

Willing to provide tumor biopsy sample
A tumor biopsy sample (either archival or fresh) must be collected from all 
patients from either the primary tumor or a metastatic site (if clinically feasible) 
for determination of expression of BCL-2 by central laboratory testing for patient 
eligibility purposes and for exploratory research on biomarkers.  The tumor 
specimen must contain adequate evaluable tumor cells (20% tumor cells) to 
enable BCL-2 IHC and other relevant biomarker analysis.  Samples can be in a 
tissue block (preferred) or prepared as 20 unstained serial slides, and should 
be accompanied by an associated pathology report.  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. 

Have at least one measurable lesion via RECIST v1.1.

Bone lesions that have been irradiated are not evaluable. Previously irradiated 
lesions can be considered as measurable disease only if progressive disease 
has been unequivocally documented at that site since radiation.

Have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 01

Have adequate organ and marrow function as defined below:

Hemoglobin 9 g/dL

Absolute neutrophil count 1.5109/L

Platelet count 100109/L

ALT and AST 2.5upper limit of normal (ULN), with the following exception: 
o
Patients with documented liver metastases:  AST and/or ALT 5.0ULN 

Total serum bilirubin 1.5ULN, with the following exception:
o
Patients with previously documented Gilbert syndrome who may have a 
bilirubin 5ULN

Creatinine clearance 50 mL/min calculated with the use of the 24-hour 
creatinine clearance or modified Cockcroft-Gault equation (i.e., estimation of 
creatinine clearance rate [eCCr]) with the use of ideal body mass (IBM) instead 
of mass):
eCCr(140Age)IBM (kg)[0.85 for female]
72serum creatinine (mg/dL)
Or, if serum creatinine is in mol/L:
eCCr(140Age)IBM (kg)[1.04 for female]
serum creatinine (mol/L)


Venetoclax—F. Hoffmann-La Roche Ltd
41/Protocol WO40181, Version 4

Meet the following coagulation requirements: 

For patients not receiving therapeutic anticoagulation:  INR or aPTT 1.5ULN 
within 14 days prior to initiation of study treatment

For patients receiving therapeutic anticoagulation:  
o
INR or aPTT within therapeutic limits for at least 1 week immediately prior to 
initiation of study treatment
o
Stable anticoagulant regimen and stable INR during the 14 days immediately 
preceding initiation of study treatment

Have a life expectancy3 months
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior treatment with fulvestrant or other SERDs, venetoclax, or any investigational 
agent whose mechanism of action is to inhibit BCL-2

Pregnant, lactating, or intending to become pregnant during the study

Known untreated or active CNS metastases (progressing or requiring 
anticonvulsants or corticosteroids for symptomatic control)
Patients who have had previous treatment of brain metastases with surgery or 
radiotherapy may be eligible provided they meet all of the following criteria:

Evaluable or measurable disease per inclusion criteria outside the CNS is 
present

Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic study

No history of intracranial or spinal cord hemorrhage 

Administration of treatment 4 weeks prior to Cycle 1 Day 1 of the study

Asymptomatic from CNS metastases

Recovered from significant (Grade 3) acute toxicity with no ongoing 
requirement for 10 mg of prednisone per day or an equivalent dose of other 
corticosteroids and no change in dose of corticosteroid for at least 2 weeks prior 
to Cycle 1 Day 1 of treatment

Prior chemotherapy in the locally advanced or metastatic setting regardless of the 
duration of the treatment

Any anti-cancer therapy received within 21 days of the first dose of study drug, 
including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, 
antineoplastic vaccines, or other investigational therapy, with the following 
exception: 

Radiotherapy with palliative intent to non-target sites is allowed


Venetoclax—F. Hoffmann-La Roche Ltd
42/Protocol WO40181, Version 4

Concurrent radiotherapy to any site or prior radiotherapy within 21 days of Cycle 1 
Day 1 or previous radiotherapy to the target lesion sites (the sites that are to be 
followed for determination of a response) or prior radiotherapy to 25% of bone 
marrow
Prior radiation therapy is allowed if it was completed 21 days before the Cycle 1 
Day 1 treatment AND the patient has recovered from all toxicities to CTCAE 
Grade 1 AND disease evaluable for response outside of the radiation fields or 
evidence of post-radiation progression of previously irradiated sites of disease.

Current severe, uncontrolled, systemic disease (e.g., clinically significant 
cardiovascular, pulmonary, metabolic or infectious disease)

Any major surgery within 28 days of the first dose of study drug or anticipation of the 
need for major surgery during the course of study treatment

Administration of the following agents within 7 days prior to the first dose of study 
drug:

Steroid therapy for anti-neoplastic intent (stable steroid medication not more than 
10 mg prednisolone per day or an equivalent dose of other corticosteroids for 
controlling CNS metastases is acceptable)

Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A 
inhibitors (e.g., fluconazole, ciprofloxacin, verapamil) (see Appendix 3)

Strong CYP3A inducers (e.g., carbamazepine, phenytoin) or moderate CYP3A 
inducers (e.g., efavirenz, modafinil) (see Appendix 3)

Consumption of one or more of the following within 3 days prior to the first dose of 
study drug:

Grapefruit or grapefruit products

Seville oranges including marmalade containing Seville oranges

Star fruit (carambola)

Need for current chronic corticosteroid therapy (10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids) 

Known infection with HIV or human T-cell leukemia virus 1 

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 

Positive test results for hepatitis B core antibody (HBcAb) or hepatitis C virus (HCV) 
antibody at screening
Patients who are positive for HCV antibody must be negative for HCV by PCR to 
be eligible for study participation.
Patients with a past or resolved hepatitis B virus (HBV) infection (defined as
having a positive total HBcAb and negative hepatitis B surface antigen [HbsAg]) 


Venetoclax—F. Hoffmann-La Roche Ltd
43/Protocol WO40181, Version 4
may be included if HBV DNA is undetectable.  These patients must be willing to 
undergo monthly DNA testing.

Active HCV infection, defined as having a positive HCV antibody test at screening
Patients who have a positive HCV antibody test are eligible for the study if a PCR 
assay is negative for HCV RNA.

History of other malignancies within the past 5 years except for treated skin basal 
cell carcinoma, squamous cell carcinoma, non-malignant melanoma 1.0 mm 
without ulceration, localized thyroid cancer, or cervical carcinoma in-situ

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
Patients must agree not to receive live, attenuated influenza vaccine 
(e.g., FluMist®) within 4 weeks prior to randomization, during treatment, or within 
28 days following the last dose of venetoclax.

Cardiopulmonary dysfunction as defined by any of the following prior to
randomization:

History of NCI CTCAE v5.0 Grade 3 symptomatic congestive heart failure or
New York Heart Association criteria Class II

Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease

High-risk uncontrolled arrhythmias (i.e., atrial 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])

Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac
arrhythmia, or cardiac ischemia

Myocardial infarction within 12 months prior to randomization

Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic 
blood pressure 100 mmHg)

Evidence of transmural infarction on ECG

Requirement for oxygen therapy

Other medical or psychiatric conditions that, in the opinion of the investigatory, may 
interfere with the patient’s participation in the study

Inability or unwillingness to swallow pills or receive IM injections 

History of malabsorption syndrome or other condition that would interfere with 
enteral absorption

History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or 
active bowel inflammation (e.g., diverticulitis)

Concurrent hormone replacement therapy


Venetoclax—F. Hoffmann-La Roche Ltd
44/Protocol WO40181, Version 4

Inability to comply with study and follow-up procedures 

Known hypersensitivity to any of the study medications (fulvestrant, venetoclax) or 
to any of the excipients
4.2
METHOD OF TREATMENT ASSIGNMENT
After written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established, the study site 
will enter demographic and baseline characteristics in the interactive voice or web-based 
response system (IxRS).  For those patients who are eligible for enrollment, the study 
site will obtain the patient’s identification number and treatment assignment from the 
IxRS.
Randomization will be conducted using a permuted block randomization method through 
the IxRS. Patients will be randomized into one of the two treatment arms in a 1:1 ratio 
based on the following stratification factors:

BCL-2 status: high (50% IHC 2+ or 3+) versus low (50% IHC 0 or 1+ and 50% 
IHC 2or 3).  It is planned to enroll approximately 50 BCL-2high patients.

Number of prior therapy in the locally advanced/metastatic setting:  one versus two
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) used in this study are venetoclax and 
fulvestrant.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Venetoclax
Venetoclax will be supplied by the Sponsor. For information on the formulation, 
packaging, and handling of venetoclax, please see the Venetoclax Investigator’s
Brochure.  
4.3.1.2
Fulvestrant
Fulvestrant will be supplied by the Sponsor in all participating countries, except the 
countries where procurement will be reimbursed. For countries in which the Sponsor is 
supplying fulvestrant, it will be supplied in sterile, single-patient, prefilled syringes 
containing 50 mg/mL fulvestrant as a 5-mL injection.  For information on the formulation 
and handling of fulvestrant, please see the package insert.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any overdose or incorrect administration of venetoclax or fulvestrant should be noted on 
the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 


Venetoclax—F. Hoffmann-La Roche Ltd
45/Protocol WO40181, Version 4
should be recorded on the Adverse Event eCRF.  Section 5.3.5.12 summarizes available 
safety data related to overdosing of venetoclax.
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
Study patients will self-administer venetoclax tablets by mouth daily.  Venetoclax is 
formulated as 100-mg tablets, so patients will take eight 100-mg tablets QD to receive 
an 800-mg dose.  Each dose of venetoclax will be taken with approximately 240 mL of 
water within 30 minutes after the patient’s first meal of the day (e.g., breakfast).
On days that predose pharmacokinetic (PK) sampling is required, the patient’s first meal 
of the day (e.g., breakfast) will be provided in the morning at the clinic, and venetoclax 
dosing will occur in the clinic after completion of the meal to facilitate PK sampling.
On days when both venetoclax and fulvestrant are given, the order of study treatment 
administration will be venetoclax followed by fulvestrant (there is no minimum time 
required between the administration of venetoclax and the start of fulvestrant 
administration). If vomiting occurs within 15 minutes of taking venetoclax and all 
expelled tablets are still intact, another dose may be given and the second dose noted in 
the drug log.  Otherwise, no replacement dose is to be given.  In cases where a dose of 
venetoclax is missed or forgotten, the patient should take the dose as soon as possible, 
ensuring that the dose is taken within 8 hours of the missed dose with food.  Otherwise, 
the dose should not be taken.  On days when patients are scheduled to have blood 
samples collected for PK assessments, the time of each dose of venetoclax will be 
recorded to the nearest minute.  Venetoclax must be stored according to labeled storage 
conditions.  There is to be no break between cycles.
As of 8 October 2020, all active patients in the venetoclax plus fulvestrant arm of the 
study will be requested to discontinue the venetoclax treatment immediately, and will 
be given the option to continue fulvestrant treatment alone.
4.3.2.2
Fulvestrant
Fulvestrant 500 mg will be administered in the clinic as two 250-mg IM injections on 
Cycle 1 Days 1 and 15 and then on Day 1 of each subsequent 28-day cycle. For details 
regarding the dosing instructions and safety profile of fulvestrant, refer to the local 
fulvestrant package insert or Summary of Product Characteristics.
The fulvestrant dose level cannot be modified. In general, the investigator may consider 
continuing fulvestrant if the adverse event observed is not thought to be 
fulvestrant-related. See Section 5.1.3 for guidelines for treatment interruption or 
discontinuation of fulvestrant.


Venetoclax—F. Hoffmann-La Roche Ltd
46/Protocol WO40181, Version 4
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (venetoclax and fulvestrant) will be 
provided by the Sponsor where required by local health authority regulations.  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 (if supplied by 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.
4.3.4
Continued Access to Venetoclax
The Sponsor will offer continued access to Roche IMP (venetoclax) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (venetoclax) 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 IMP (venetoclax) 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 would not 
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 ER+, HER2-negative locally advanced or MBC

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
ER+, HER2-negative locally advanced or MBC.

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country


Venetoclax—F. Hoffmann-La Roche Ltd
47/Protocol WO40181, Version 4
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS
4.4.1
Permitted Therapy 
Concomitant therapy includes any prescription medication, over-the-counter 
preparations, herbal or homeopathic remedies, and nutritional supplements used by a 
patient from 28 days prior to the screening visit through to Study completion/early 
termination.  All concomitant medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF.
Patients who experience toxicities should be treated symptomatically as clinically 
indicated.  Patients treated with anti-seizure medications, for reasons other than CNS 
metastases, should have levels monitored regularly.  Patients who require maintenance 
therapy, as specified in the eligibility criteria (see Section 4.1.1 and Section 4.1.2), 
should continue to receive maintenance therapy.  
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drug.  At the discretion of the investigator, prophylactic 
anti-emetic and anti-diarrheal medication(s) may be used as per standard clinical 
practice before subsequent doses of study drug.  Anti-emetic therapy should be 
administered per institutional guidelines.
Pain medications administered per standard clinical practice are acceptable while the 
patient is enrolled in the study.
Bisphosphonate therapy or denosumab for bone metastases are permitted.
4.4.2
Prohibited and Cautionary Therapy
Patients who require the use of any of the excluded therapies listed below will be 
discontinued from study treatment.  Patients who are discontinued from study treatment 
will be followed for safety outcomes for 28 days following the patient’s last dose of study 
treatment. 
Use of the following therapies is prohibited 21 days prior to first dose of venetoclax or 
fulvestrant and during the study:

Radiotherapy (other than palliative radiotherapy to non-target sites)

Chemotherapy (prior chemotherapy in the locally advanced or metastatic setting is 
an exclusion criteria; see Section 4.1.2)

Immunotherapy


Venetoclax—F. Hoffmann-La Roche Ltd
48/Protocol WO40181, Version 4

Hormone therapy (other than LHRH agonists [e.g., goserelin injections] for ovarian 
suppression in premenopausal women)
Steroid therapy for anti-neoplastic intent, with the exception of inhaled steroids for 
asthma, topical steroids, or replacement/stress corticosteroids, are not permitted during 
the study at any time.
Other treatments not part of the protocol-specified anti-cancer therapy are not permitted.
Any exceptions must be discussed with the Medical Monitor prior to initiation.
4.4.2.1
Patients Randomized to Receive VenetoclaxFulvestrant
The following concomitant medications are not allowed within 7 days prior to the 
administration of the first dose of study drug and should be avoided during venetoclax 
administration:

Strong and moderate CYP3A inducers (see Appendix 3 for examples)

Strong and moderate CYP3A inhibitors (see Appendix 3 for examples)

If these medications cannot be avoided during the study, the Medical Monitor must 
be contacted.  Strong or moderate CYP3A inhibitor use would require venetoclax dose 
reduction under the guidance of the Medical Monitor (Appendix 10).
Warfarin may be co-administered with venetoclax with caution and with the guidance of 
the Medical Monitor (additional INR monitoring may also be required).
A sample list of cautionary and avoided medications that fall into the categories within 
this section can be found in Appendix 3.  It is not possible to produce a 100% exhaustive 
list of medications that fall into these categories; therefore, if in question, refer to the 
appropriate product label.
The administration of live, attenuated influenza vaccine (e.g., FluMist®) is prohibited 
during treatment and within 28 days following the last dose of venetoclax.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential DDIs are generally unknown.  
4.4.3
Prohibited Food
Use of the following foods by patients randomized to receive venetoclax + fulvestrant is 
prohibited for at least 3 days prior to initiation of venetoclax treatment, throughout 
venetoclax administration and for 28 days after last dose of study treatment.  


Venetoclax—F. Hoffmann-La Roche Ltd
49/Protocol WO40181, Version 4
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
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  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.
Patients who do not initially meet all eligibility criteria may be re-screened once, given 
that the reason for screening failure was not ER or HER-2 status.  Re-screening refers to 
repeating the entire screening process.  Re-screening must occur within 2 weeks of the 
initial screening, and each patient must be re-consented before re-screening occurs.  It 
will not be considered a re-screening if blood samples have to be redrawn because of 
sample handling problems, breakage, sample integrity, or laboratory error.  Discuss with 
the Medical Monitor for further guidance.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history,
will be recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 28 days prior to the screening visit will be 
recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.


Venetoclax—F. Hoffmann-La Roche Ltd
50/Protocol WO40181, Version 4
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.
An assessment of the patient’s ECOG Performance Status (see Appendix 6) will be 
completed at screening and as specified in the schedule of activities (see Appendix 1).
It is recommended, where possible, that a patient’s performance status be assessed by 
the same person throughout the study.
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.
Height, weight, and BSA will be measured at Screening; weight and BSA are to be 
measured as clinically indicated during the study based on findings of the limited, 
symptom-directed physical examinations.
As part of tumor assessments, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
4.5.4
Vital Signs
Vital signs will include measurements of body temperature, respiratory rate, pulse rate, 
and systolic and diastolic blood pressures while the patient is in a seated position.
4.5.5
Tumor and Response Evaluations
All known sites of disease must be assessed per RECIST v1.1 and documented at 
screening (within 28 days prior to Cycle 1 Day 1) and re-assessed at each subsequent 
tumor evaluation (every 8 weeks [5 days] from the date of randomization until Week 24 
[5 days] and every 12 weeks [5 days] thereafter).  Tumor assessments should be 
performed on this schedule regardless of dose delay until disease progression. In case 
of early discontinuation, only the patients who discontinue study treatment early without 
progression and who have not started follow-on treatment will remain on the study’s 
schedule of assessments for progression. Patients who progress or discontinue early 
without progression but who have initiated a new treatment will remain on the study for 
OS.  
Screening assessments must include computed tomography (CT)/magnetic resonance 
imaging (MRI) scans of the chest, abdomen, and pelvis; CT/MRI scans of the neck and 
brain imaging should be included if clinically indicated.  A documented SOC tumor 
assessment performed within 28 days prior to Cycle 1 Day 1 may be used for the 


Venetoclax—F. Hoffmann-La Roche Ltd
51/Protocol WO40181, Version 4
screening assessment provided it meets the above requirements.  CT scans should be 
performed with a contrast agent. For patients with known allergies to the contrast 
media, it is acceptable to perform a chest CT scan without contrast and an MRI scan for 
the abdomen (ideally at baseline and every tumor assessment thereafter).
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan.
Response assessment will be made by the investigator on the basis of physical 
examinations, CT scans, or MRI, and/or bone scans using criteria outlined in 
RECIST v1.1 (Appendix 4). The same radiographic procedure used to assess disease 
sites at screening should be used throughout the study (e.g., the same contrast protocol 
for CT scans). Assessments should be performed by the same evaluator to ensure 
internal consistency across visits.
CT scans throughout the study should include chest, abdomen, and pelvic scans. CT 
scans of the neck and brain imaging should be included if clinically indicated. At the 
investigator’s discretion, CT scans may be repeated at any time if progressive disease
(PD) is suspected.
4.5.5.1
Bone Lesions Assessments
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. The special 
considerations regarding the measurability of bone lesions are outlined in RECIST v1.1 
(see Appendix 4).
Bone scans should be performed within 28 days prior to Cycle 1 Day 1. Positive areas
on bone scans must be assessed by either CT scan with bone windows, MRI, or X-ray
prior to randomization.
Bone lesions identified at baseline by CT scan, MRI, or X-ray should be assessed using 
the same modality (CT scan, MRI, or X-ray) and following the same schedule for 
measurable lesions until disease progression, as described above. Additional bone 
scans should be performed if clinically indicated.  If a bone scan cannot be performed 
during the course of the study due to, for example, a Technetium-99m shortage, 
alternative imaging options should be discussed with the Sponsor (e.g., sodium fluoride).
Abnormalities found on subsequent bone scans must also be confirmed by CT scan, 
MRI, or X-ray assessment.
If the patient presents with both irradiated and non-irradiated bone lesions, only the 
non-irradiated lesions should be followed for tumor assessments unless progression is 


Venetoclax—F. Hoffmann-La Roche Ltd
52/Protocol WO40181, Version 4
documented after the radiation.  In patients without bone-only disease, bone scans 
should be repeated in the event of a clinical suspicion of progression of existing bone 
lesions, the development of new bone lesions, and in the assessment of a complete 
response (CR), if any disease was evident at screening.  Any changes in bone imaging 
should be evaluated radiographically by CT scan, MRI, or X-ray to ascertain the 
presence of bone destruction versus a healing reaction.  
In the event that it is not feasible to perform a bone scan or it is anticipated that it will not 
be feasible to perform bone scans throughout the study, 18F sodium fluoride (NaF) PET 
bone scans may be substituted, with the Sponsor’s approval.  The same modality used 
at screening should be used throughout the study.
Patients with symptoms of rapidly progressing disease without radiological (or 
photographical) evidence will not be considered to have progressed for efficacy 
analyses.  The evaluation of overall lesion response will be performed according to 
RECIST v1.1 as described in Appendix 4. 
4.5.5.2
Tumor Scans
To ensure a valid comparison of tumor data and uniformity in the assessment of tumor 
response during the study, the following procedures must be implemented at the study 
site:

All lesions identified at baseline (target and non-target) will be reassessed using the 
same method throughout the course of the study.

All CT scans and MRIs obtained for all patients enrolled at the center should be 
reviewed by the local radiologist who, together with the investigator, will determine 
the local assessment of response and progression.  All bone scans obtained from 
the patient with bone metastases at baseline also should be reviewed similarly.

For patients with measurable disease at baseline, tumor response and progression 
will be determined by the investigator according to RECIST v1.1 criteria and will be 
the basis for the efficacy analyses.
Only the patients who discontinue study treatment early without progression and who 
have not started follow-on treatment will continue to undergo tumor-response 
evaluations until PD.
4.5.6
Other Disease-Specific Assessments
Tumor samples from the primary tumor (or metastatic site, in the absence of primary 
site) are to be assessed for expression of BCL-2 and other markers of breast disease 
biology (i.e., ER, PR, HER2, Ki67, and other BCL-2 family members), mutations in 
cancer-related genes assessed by NGS of DNA and expression of cancer-related genes 
assessed by quantification of RNA. 

ER-positive status will be determined prior to study entry by local laboratory testing
using IHC per ASCO/CAP criteria (Hammond et al. 2010)


Venetoclax—F. Hoffmann-La Roche Ltd
53/Protocol WO40181, Version 4

HER2-negative disease status will be determined prior to study entry by local 
laboratory testing as per the ASCO/CAP criteria (Wolff et al. 2013).  Patients who 
were originally diagnosed with HER2-positive breast cancer that converted to 
HER2-negative MBC are NOT eligible to take part in this study.

BCL-2 expression status will be determined prior to study entry by central laboratory 
testing using the Ventana BCL-2 IHC assay.  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 
50% stained with an intensity of IHC 0 or 1, and 50% stained an intensity of IHC 
2or 3.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for hematology, blood chemistries, and urinalysis will be analyzed at the study 
site’s local laboratory. Samples for biologic markers and pharmacokinetics will be sent 
to one or more central laboratories or to the Sponsor or designee for analysis.  Samples 
will be collected as per the schedule of activities in Appendix 1.
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.
Laboratory assessments will include the following: 

Hematology: hemoglobin, hematocrit, RBC count, platelet count, WBC count, and 
WBC differential count (neutrophils, bands [optional], lymphocytes, eosinophils, 
basophils, monocytes), and absolute counts

Chemistry: sodium, potassium, chloride, random glucose, BUN, creatinine, ALT, 
AST, total bilirubin, amylase, lipase, total protein, albumin, calcium, phosphorus, 
LDH, CK, gamma-glutamyl transferase, alkaline phosphatase (ALP), and uric acid 
To evaluate any possible risk of TLS with venetoclax in patients with 
ER-positive breast cancer, the first 10 patients enrolled into each arm will have 
a sample collected for a serum chemistry panel 24 hours after the first dose of 
study drug.

Coagulation: INR or aPTT (or PTT) required for all patients within 14 days prior to 
Cycle 1 Day 1 and then as clinically indicated

Urinalysis: Specific gravity, pH, glucose, protein, ketones, and blood
Urinalysis is required for all patients within 28 days prior to Cycle 1 Day 1 and 
then as clinically indicated

Viral serology: hepatitis B (HBsAg) or hepatitis C (HCV antibody)
Patients who are positive for HCV antibody must be negative for HCV by PCR 
to be eligible for study participation. 
Patients with a past or resolved HBV infection (defined as having a positive 
total HBcAb and negative HBsAg) may be included if HBV DNA is 
undetectable. These patients must be willing to undergo monthly DNA testing.

Pregnancy test:  


Venetoclax—F. Hoffmann-La Roche Ltd
54/Protocol WO40181, Version 4
Women of childbearing potential (defined in Section 4.1.1) must have a 
negative serum pregnancy test result at screening within 14 days prior to the 
first study drug administration.
The urine pregnancy tests should be repeated during the treatment period
within 3 days prior to each cycle (every 28 days starting on Day 1 of Cycle 2), 
at the study discontinuation visit, and as clinically indicated.
–
Any positive urine pregnancy test must be confirmed with a serum β-hCG evaluation 
at the local laboratory.  Pregnancy test results must be available prior to the 
administration of fulvestrant.
For all other women, documentation must be present in the medical history 
confirming that the patient is not of childbearing potential.
The following samples will be sent to the Sponsor or a designee for analysis.  

Plasma PK assessments for venetoclax.  See the Schedule of Pharmacokinetic 
Samples provided in Appendix 2 for specific timepoints.  

Archival or newly collected tumor tissue sample obtained at baseline for 
determination of expression of BCL-2 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.
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 ctDNA
(i.e., mutation profiles associated with palbociclib, that is, cyclin 4/6, ER, or BCL-2 
family), and genes or gene signatures associated with apoptosis (i.e., BCL-2 family or 
immunobiology), and may involve extraction of DNA, ctDNA, or RNA, analysis of somatic 


Venetoclax—F. Hoffmann-La Roche Ltd
55/Protocol WO40181, Version 4
mutations, and use of WTS, or NGS.  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 can obtain results from these analyses in the form of 
an NGS report, which is available upon request directly from Foundation 
Medicine.  If allowed by local laws, the investigator may share and discuss the 
results with the patient, unless the patient chooses otherwise.  The Foundation 
Medicine NGS assay has not been cleared or approved by health authorities.  
The NGS report is generated for research purposes and is not provided for the 
purpose of guiding future treatment decisions.  Results may not be available for 
samples that do not meet testing criteria.
For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions:

Plasma samples collected for PK analysis may be needed for additional PK assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Plasma and tumor tissue samples collected for biomarker research will be destroyed
no later than 5 years after the final Clinical Study Report has been completed.

For enrolled patients, remaining archival tissue blocks will be returned to the site
upon request or 18 months after 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 
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.
4.5.8
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), 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.  


Venetoclax—F. Hoffmann-La Roche Ltd
56/Protocol WO40181, Version 4
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at 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.  SOC 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 drug 
discontinuation should be made, as described in Section 5.1.3.2.  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 Outcomes
4.5.9.1
EORTC QLQ-C30 Background
The EORTC QLQ-C30 (see Appendix 5) is a validated and reliable self-reported 
measure (Aaronson et al. 1993; Sprangers et al. 1996; Fitzsimmons et al. 1999)
consisting of 30 questions that assess 5 aspects of patient functioning (physical, 
emotional, role, cognitive, and social), 8 symptoms (fatigue, nausea and vomiting, pain, 
dyspnea, insomnia, appetite loss, constipation, and diarrhea), financial difficulties, and 
GHS/HRQoL with a recall period of the previous week. The EORTC QLQ-C30 data will 
be scored according to the EORTC scoring manual (Fayers et al. 2002).  Scale scores 
will be obtained for each of the multi-item and single-items scales by using a linear 
transformation for standardization of the calculated raw score. The EORTC QLQ-C30 
takes approximately 10 minutes to complete.
To fully characterize venetoclax with fulvestrant compared with single-agent fulvestrant 
as a second-line treatment in patients with MBC, PRO data will be collected using the 
EORTC QLQ-C30.  Specifically, the GHS/overall HRQoL scale score (Questions 29 and 
30) will be used to assess patients’ overall HRQoL and the pain (Questions 9 and 19) 


Venetoclax—F. Hoffmann-La Roche Ltd
57/Protocol WO40181, Version 4
scale of the EORTC QLQ-C30 will be used evaluate the proportion of patients with 
disease-related pain of venetoclaxfulvestrant compared with fulvestrant alone.  
The EORTC QLQ-C30 will be administered to patients to assess pain, 
disease/treatment-related symptoms, functioning, and HRQoL (see Section 4.5.9.2 and
Appendix 5).
4.5.9.2
EORTC QLQ-C30 Procedures
The EORTC-QLQ-C30 must be administered at the pre-specified clinic visits, and the 
questionnaire must be completed by the patient at the investigational site at the start of 
the clinic visit prior to receiving information on disease status, prior to any other study 
assessments, and before administration of study treatment.  Patients will complete paper 
versions of the questionnaire, which will be provided by site staff.  Interviewer 
assessment is allowed but can only be conducted by a member of the clinic staff for 
patients who are unable to complete the measures on their own.  Study personnel 
should review all questionnaires for completeness before the patient leaves the 
investigational site.  Appropriate translated versions of the local language of the PRO 
measures will be available at the site.
4.5.10
Optional Tumor Biopsies
Consenting patients will undergo optional tumor biopsies at Cycle 3 Day 1 (3 days)
after treatment initiation and at disease progression 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.  (Note:  biopsies collected via fine-needle aspirations are not acceptable.)  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
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.
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


Venetoclax—F. Hoffmann-La Roche Ltd
58/Protocol WO40181, Version 4

Investigator or Sponsor determines it is in the best interest of the patient (including 
high-grade toxicities when continuing treatment is deemed detrimental)

Pregnancy

Use of an anti-cancer therapy not required per protocol

Disease progression
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for a treatment completion or treatment discontinuation 
visit 28 days (+3 days) after the last dose of study drug (see Appendix 1 for additional
details).
After treatment discontinuation due to disease progression, information on survival 
follow-up and new anti-cancer therapy will be collected via telephone calls, patient 
medical records, and/or clinic visits approximately every 3 months, or more frequently,
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 other than disease 
progression and have started follow-on treatment/s will be followed for survival
approximately every 3 months, or more frequently, until death, lost to follow-up, 
withdrawal of consent, or study termination by the Sponsor, whichever occurs first.
Patients who are discontinued from study treatment/s 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 for additional details).
4.6.2
Patient Discontinuation from 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 withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

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 information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 


Venetoclax—F. Hoffmann-La Roche Ltd
59/Protocol WO40181, Version 4
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.
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 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Venetoclax was granted approval in the United States (see Venclexta® U.S. Prescribing 
Information 2016) and conditional market approval by the EMA (see Venclyxto® EMA 
Summary of Product Characteristics 2016) as monotherapy for the treatment of patients 
with CLL who have 17p deletion.
Venetoclax, however, is not approved for the treatment of breast cancer, 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 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 


Venetoclax—F. Hoffmann-La Roche Ltd
60/Protocol WO40181, Version 4
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.
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 
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
The available data suggest that in patients with non-CLL, with the exception of those 
with mantle cell lymphoma, the risk of TLS is low.  Due to different biology between ER+
breast cancer and hematological malignancies, the risk of TLS is considered to be very 
low in patients with ER+ breast cancer.  Therefore, TLS prophylaxis is not recommended 
by any of the international guidelines for patients with ER+ breast cancer, 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 and therefore TLS risk is negligible.  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 the risk of TLS in order to reduce the uric acid level.  Laboratory values 
obtained before the dose of venetoclax are to be used to determine whether a patient 
developed a change related to TLS. Laboratory results of the 24-hour postdose 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 9.
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 tumor lysis syndrome are provided in Appendix 8.  In some cases, dialysis 
may be indicated.  Guidelines for defining TLS are provided in Appendix 9.
To evaluate any possible risk of TLS with venetoclax in patients with ER+ breast cancer, 
the first 10 patients enrolled into each arm of the study will each have a sample collected 
for a serum chemistry panel 24 hours after the first dose of study drug.  The IMC will 
convene after 5 patients are enrolled in each arm to review the chemistry panel results 
and establish a management plan for TLS if an increased risk is identified, if needed.  


Venetoclax—F. Hoffmann-La Roche Ltd
61/Protocol WO40181, Version 4
5.1.1.2
Neutropenia
Neutropenia is an important identified risk for venetoclax. Clinical data from the 
oncology studies suggest that the neutropenia adverse events are observed among 
subjects 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 3. 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
Infections
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.
Patients in this study will be closely monitored for infections and prompt therapy will be 
instituted as necessary as per local SOC.
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 
implemented (if applicable) as per local institutional practice, although some guidance is 
provided in Appendix 7.


Venetoclax—F. Hoffmann-La Roche Ltd
62/Protocol WO40181, Version 4
5.1.1.5
Reproductive System Effects and Pregnancy
This study enrolls only 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.
Two human pregnancies have been reported in the clinical program with venetoclax so 
far, including one pregnancy of a partner; in both cases, a live infant with no neonatal 
complication, congenital anomalies, or birth defects was delivered.
In nonclinical studies, both venetoclax and fulvestrant 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 than the individual molecules.  Consequently, both venetoclax 
and fulvestrant should not be administered to pregnant women, and they must be 
discontinued if a patient becomes pregnant.  Additionally, patients are advised to remain 
abstinent (i.e., refrain from heterosexual intercourse) or use non-hormonal contraceptive 
methods with a failure rate of 1% per year during the treatment period and for up to 
2 years after the last dose of study drug (or based on the local prescribing information 
for fulvestrant).  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)
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. The 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.
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 


Venetoclax—F. Hoffmann-La Roche Ltd
63/Protocol WO40181, Version 4
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
Safety Plan for Fulvestrant
Fulvestrant is an ER antagonist indicated for the treatment of HR+ MBC in 
postmenopausal women with disease progression following anti-estrogen therapy.
In a study with postmenopausal women with advanced breast cancer who had disease 
recurrence on or after adjuvant endocrine therapy or progression following endocrine 
therapy for advanced disease, the most frequently reported adverse events were 
injection-site pain (11.6% of patients), nausea (9.7%), and bone pain (9.4%).  Because 
fulvestrant is administered intramuscularly, it should be used with caution in patients with 
bleeding diatheses, thrombocytopenia, or anticoagulant use.  For details regarding the 
safety profile of fulvestrant, refer to the local prescribing information.
There are no expected clinically significant overlapping toxicities between venetoclax 
and fulvestrant.  Routine safety monitoring and periodic laboratory tests for the 
fulvestrant and venetoclax combination will occur throughout the study.
Fulvestrant should not be administered to pregnant women and it must be discontinued 
if a female patient becomes pregnant.  Please refer to Section 4.1.1 and Section 4.1.2
for further details on study eligibility and contraceptive requirements for patients.
5.1.3
Management of Patients Who Experience Specific Adverse 
Events
5.1.3.1
Dose Modifications
The fulvestrant dose level cannot be modified. In general, the investigator may consider 
continuing fulvestrant if the observed adverse event is not thought to be 
fulvestrant-related.
See Section 5.1.3.3 for dose delay or modification guidelines of venetoclax.
5.1.3.2
Treatment Interruption
Patients who interrupt all study treatments secondary to treatment-related adverse 
events for longer than 28 days should discontinue all study drugs, although they are to 
continue being followed for disease progression as described in Appendix 1.  However, 
patients who are deriving benefit from the treatment may continue treatment at the 
investigator’s discretion based upon the risk/benefit balance.


Venetoclax—F. Hoffmann-La Roche Ltd
64/Protocol WO40181, Version 4
As of 8 October 2020, venetoclax will no longer be administered to patients in the 
study.
Patients who discontinue fulvestrant should also discontinue venetoclax, although they 
are to continue evaluation per protocol.
5.1.3.3
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 3.  
Recommendations for the initial management of electrolyte imbalances and prevention 
of TLS are provided in Appendix 8. Additional guidelines are provided in the subsections 
below.


Venetoclax—F. Hoffmann-La Roche Ltd
65/Protocol WO40181, Version 4
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events
Event
Action to Be Taken
Grade 3 or 4 (NCI grading 
scale) neutropenia with or 
without fever and infection
Withhold venetoclax for at least 7 days.
Administer treatment including G-CSF or growth factors for 
neutropenia as indicated.
When counts recover to ANC 1109/L resume venetoclax at 
one dose-level reduction.
Grade 3 thrombocytopenia 
with symptomatic bleeding 
or Grade 4 
thrombocytopenia
Withhold venetoclax for Grade 4 thrombocytopenia or Grade 3 in 
presence of symptomatic bleeding until resolution of bleeding.
Platelets may be transfused at the discretion of the investigator.
When platelet level rises to 75,000/L without transfusional 
support, restart venetoclax at previous dose.
For a second episode of severe thrombocytopenia and/or 
symptomatic bleeding, withhold venetoclax.
When platelet level rises to 75,000/L without transfusional 
support, restart venetoclax at one dose-level reduction.
For subsequent episodes of severe thrombocytopenia, withhold 
venetoclax.
When platelet level rises to 75,000/L without transfusional 
support, restart venetoclax at one dose-level reduction.
For recurrent severe thrombocytopenia in spite of dose reduction
and/or symptomatic bleeding, consult the Medical Monitor 
regarding continuation on the protocol.
Non-hematologic toxicity
Grade 3 or 4 
non-hematologic events 
not specifically described 
above
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.


Venetoclax—F. Hoffmann-La Roche Ltd
66/Protocol WO40181, Version 4
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Grade 2 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
There is no dose reduction or delay.
CTCAECommon Terminology Criteria for Adverse Events; G-CSFgranulocyte stimulating factor; 
NCINational Cancer Institute.
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. Each dose reduction of venetoclax will occur by 
200 mg (e.g., the starting dose of 800 mg will be reduced to 600 mg, then to 400 mg.  If 
a third dose reduction is necessary (from 400 mg to 200 mg) this should be discussed 
with the Medical Monitor. Patients who require venetoclax dose reduction below 200 mg 
should discontinue venetoclax.  Such patients may continue to receive fulvestrant at the 
discretion of the investigators.  Patients requiring clarification regarding management of 
adverse events and dosing and all patients requiring more than two 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.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 


Venetoclax—F. Hoffmann-La Roche Ltd
67/Protocol WO40181, Version 4
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the
character, frequency, or severity of a known condition) (see Section 5.3.5.9 and 
Section 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
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 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
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.


Venetoclax—F. Hoffmann-La Roche Ltd
68/Protocol WO40181, Version 4
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 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

TLS
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, Section 5.5, and 
Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).


Venetoclax—F. Hoffmann-La Roche Ltd
69/Protocol WO40181, Version 4
After initiation of study drug, all adverse events will be reported through 28 days after the 
last dose of study drug (venetoclax or fulvestrant, whichever is later).  After this period, 
investigators should report any deaths, serious adverse events, or other adverse events 
of concern that are believed to be related to prior study drug treatment as prescribed in 
Section 5.6.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation 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?" 
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 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


Venetoclax—F. Hoffmann-La Roche Ltd
70/Protocol WO40181, Version 4
Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
https://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 (see also
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event


Venetoclax—F. Hoffmann-La Roche Ltd
71/Protocol WO40181, Version 4
Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection-Site Reactions
Adverse events that occur during or within 24 hours after study drug administration and
are judged to be related to study drug injection should be captured as a diagnosis 
(e.g., "injection-site 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 Injection-Site Reaction eCRF.  If a patient experiences both a local and 
systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Injection-Site Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection-site reactions (see Section 5.3.5.1), 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 


Venetoclax—F. Hoffmann-La Roche Ltd
72/Protocol WO40181, Version 4
signs and symptoms should be nullified and replaced by one adverse event report based 
on the single diagnosis, with a starting date that corresponds to the starting date of the 
first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult,
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported
separately on the eCRF.
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.


Venetoclax—F. Hoffmann-La Roche Ltd
73/Protocol WO40181, Version 4
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


Venetoclax—F. Hoffmann-La Roche Ltd
74/Protocol WO40181, Version 4
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
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 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).
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").


Venetoclax—F. Hoffmann-La Roche Ltd
75/Protocol WO40181, Version 4
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of 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.  The expected pattern of progression will be 
supported by radiology assessments as per RECIST v1.1.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., to provide TLS prophylaxis or 
monitoring without significant clinical sequelae, or to perform an efficacy 
measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


Venetoclax—F. Hoffmann-La Roche Ltd
76/Protocol WO40181, Version 4
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event. All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded 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).
No safety data related to overdosing of venetoclax are available.  Refer to the local 
fulvestrant package insert for safety information related to fulvestrant.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for an adverse event.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3, see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events 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


Venetoclax—F. Hoffmann-La Roche Ltd
77/Protocol WO40181, Version 4

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 Institutional Review Board (IRB)/Ethics 
Committee (EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor/Roche Medical Responsible:
, M.D., Ph.D. (Primary)
Mobile Telephone No.:
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 non-serious adverse events of 
special interest will be reported through 28 days after the last dose of study drug.
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 


Venetoclax—F. Hoffmann-La Roche Ltd
78/Protocol WO40181, Version 4
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 adverse events that occur more than 30 days after the last 
dose of venetoclax or fulvestrant 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 28 days after the last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator must 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
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 


Venetoclax—F. Hoffmann-La Roche Ltd
79/Protocol WO40181, Version 4
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
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
At the time of study treatment completion or study treatment discontinuation, the 
investigator should instruct each patient to report to the investigator any subsequent 
adverse events that the patient’s personal physician believes could be related to prior 
study drug treatment or study procedures.  
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as
28 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.


Venetoclax—F. Hoffmann-La Roche Ltd
80/Protocol WO40181, Version 4
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 using the following reference documents:
Drug
Document
Fulvestrant 
Fulvestrant Summary of Product Characteristics 
Venetoclax plus 
fulvestrant combination
Venetoclax Investigator’s Brochure for solid tumour 
studies 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Analysis populations are defined as follows:

The ITT population is defined as all randomized patients whether or not they were 
assigned to the arm where the study treatment was administered.

The BCL-2 high population (patients within ITT and with50% of tumor cells stained 
with an intensity of IHC 2or 3) or BCL-2 low population (patients within ITT and 
with BCL-2 50% stained with an intensity of IHC 0 or 1and 50% stained 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 the study.
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 100 patients need to be recruited and randomized in a 1:1 ratio to 
two treatment arms (venetoclax fulvestrant and fulvestrant).  The study will enroll both 
BCL-2 high (50% of tumor cells stained with an intensity of IHC 2or 3) and low 


Venetoclax—F. Hoffmann-La Roche Ltd
81/Protocol WO40181, Version 4
(50% of tumor cells stained with an intensity of IHC 0 or 1and 50% IHC 2or 3) 
patients, and it is planned to enroll approximately 50 BCL-2-high patients.
The sample size of 100 patients provides precision of 15% for 80% CI when calculating 
the absolute difference in the CBR between the two arms assuming the expected 
observed CBR in the control arm is 40% (Cristofanilli et al. 2016) and in the 
venetoclax arm is 60% (i.e., the 80% CI for difference in CBR is from 5% to 35%).
6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment, duration of follow-up, and discontinuation from the study and reasons 
for discontinuation will be summarized by treatment arm for all randomized patients. In 
addition, major protocol violations will be summarized by treatment arm.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race, lines of prior 
therapy in the locally advanced/metastatic setting, BCL-2 status, sites of disease [bone 
vs. nodal vs. visceral], previous endocrine therapy type [AI vs. tamoxifen vs.
combination], menopausal status [pre-/perimenopausal vs. postmenopausal]), will be 
summarized using means, 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
Patients will be analyzed in accordance with the treatment arm to which they were 
randomized.  
The primary analysis will be conducted when all patients have discontinued from study 
treatment, or 6 months after last patient in, whichever occurs first.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is clinical benefit, defined as CR, partial response (PR) or 
SD lasting 24 weeks from randomization in patients with measurable disease at 
baseline, as determined by the investigator according to RECIST v1.1. Patients with no 
response assessments for any reason will be considered non-responders.
The CBR analysis will be conducted for the ITT population, the BCL-2 high subgroup,
and the BCL-2 low subgroup.  The CIs for the difference in CBR between the two 
treatment arms will be determined using the normal approximation to the binomial 
distribution. An estimate of the CBR and its 95% CI will be calculated for each treatment
arm.


Venetoclax—F. Hoffmann-La Roche Ltd
82/Protocol WO40181, Version 4
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Progression-Free Survival
PFS is defined as the time from randomization to the first occurrence of disease 
progression (as determined by the investigator according to RECIST v1.1) or death from 
any cause, whichever occurs first. 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 the 
last tumor assessment (or at 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.  The Cox proportional hazards model and its 95% CI, stratified by lines of prior 
therapy (one vs. two) and BCL-2 status (high vs. low), will be used to estimate the 
hazard ratio between the two treatment arms.  The unstratified hazard ratio will also be 
provided.
6.4.2.2
Objective Response
The objective response (OR) is defined as PR or CR, which is determined by the 
investigator according to RECIST v1.1.  Patients without post-baseline information will 
be counted as non-responders.
The same analyses for CBR will be conducted on the objective response rate. 
6.4.2.3
Duration of Objective Response 
Duration of response (DOR) is defined as time from the first occurrence of a 
documented objective response to the time of the first documented disease progression 
(as determined by the investigator according to RECIST v1.1) or death from any cause, 
whichever occurs 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 the last tumor
assessment.
DOR will be estimated using the Kaplan-Meier methodology, with patients grouped
according to the treatment arm assigned at randomization. Only patients achieving a 
CR or PR will be included in the assessment of DOR.
6.4.2.4
Overall Survival 
OS is defined as the 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. 
The same analyses for PFS will be conducted for OS.


Venetoclax—F. Hoffmann-La Roche Ltd
83/Protocol WO40181, Version 4
6.5
SAFETY ANALYSES
The safety analyses will include all randomized patients who received at least one dose 
of venetoclax or fulvestrant (the safety population) with patients grouped according to 
the treatment actually received. 
Drug exposure will be summarized to include duration of treatment, number of doses, 
and intensity of dose.
All adverse events occurring during or after the first study drug dose will be summarized 
by treatment arm and NCI CTCAE grade. In addition, serious adverse events, adverse 
events of special interest, and adverse events leading to study drug discontinuation or 
interruption will be summarized accordingly. Multiple occurrences of the same event will 
be counted once at the maximum severity.
Deaths reported during the study treatment period and those reported during the safety 
follow-up period will be summarized by treatment arm.
6.6
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Sparse PK samples will be collected and analyzed for venetoclax and fulvestrant
concentrations in the venetoclax arm.  The PK data will be summarized after appropriate 
grouping.  Venetoclax and/or fulvestrant results may be incorporated into a nonlinear 
mixed-effect population PK model to estimate the PK parameters.  Pharmacodynamic 
modulation of BCL-2 and estrogen-responsive genes will be evaluated in optional 
on-treatment biopsies relative to pre-dose biopsies.
Additional PK analyses will be conducted as appropriate.
6.7
EXPLORATORY OBJECTIVES
6.7.1
Patient-Reported Outcome Analyses 
Summary statistics (i.e., mean, standard deviation, median, minimum, maximum, and 
range) of linear transformed scores will be reported for all scales (symptom, functional 
domains, and single items) of the EORTC QLQ-C30 according to the EORTC scoring 
manual guidelines (Fayers et al. 2002) for each assessment timepoint. Line charts 
depicting the mean changes standard deviations of items and scales over time will be 
provided for each treatment arm from the baseline assessment. 
Previously published minimally important differences will be used to identify meaningful 
change from baseline within each treatment group on the functional and 
disease/treatment related symptoms scales (Osoba et al. 1998).  In the event of 
incomplete data, for all questionnaire subscales, if more than 50% of the constituent 
items are completed, a prorated score will be computed consistent with the scoring 
manuals and validation papers.  For subscales with less than 50% of the items 
completed, the subscale will be considered as missing.


Venetoclax—F. Hoffmann-La Roche Ltd
84/Protocol WO40181, Version 4
To evaluate patient-reported HRQoL while on study treatment, descriptive analysis of 
the mean and mean change from patients’ baseline GHS/HRQoL scale score, which 
consists of Questions 29 and 30 of the EORTC QLQ-C30 (see Appendix 5), will be 
assessed by cycle and independently within each cohort. GHS/HRQoL will also be 
calculated as the number, proportion, and 95% CI of patients with a change in score
reflecting clinically meaningful deterioration, defined as a decrease of 10 points or more
(Osoba et al., 1998).
To evaluate patient-reported pain while on study treatment, descriptive analysis of the 
mean and mean change from patients’ baseline pain scale score, which consists of 
Questions 9 and 19 of the EORTC QLQ-C30 (see Appendix 5), will be assessed by 
cycle and independently within each cohort.  Additionally, the pain scale data will also be 
calculated as the number, proportion, and 95% CI of patients with clinically meaningful 
pain progression defined by an increase in score of 10 points or more (Osoba et al., 
1998).
6.8
BIOMARKER ANALYSES
Exploratory analyses of biomarkers related to tumor biology and the mechanisms of 
action of venetoclax will be conducted.  Analyses will assess prognostic and/or 
predictive value of candidate biomarkers.  The association between candidate biomarker
measures of efficacy, with treatment and independent of treatment, will be explored to 
assess potential predictive and prognostic value, respectively. The effects of baseline 
prognostic and potentially predictive characteristics, including BCL-2 expression, BCL-2 
family member transcript and/or gene signatures, as well as ctDNA profiles on efficacy 
outcomes, will be evaluated using univariate and/or multivariate statistical methods such 
as Cox regression and logistic regression.
6.9
OPTIONAL INTERIM ANALYSES
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two interim efficacy analyses.  The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor’s trial master 
file prior to the conduct of the interim analysis.  The interim analysis will be performed 
and interpreted by members of the Sponsor study team and appropriate senior 
management personnel.
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.


Venetoclax—F. Hoffmann-La Roche Ltd
85/Protocol WO40181, Version 4
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and any other 
externally generated electronic study 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 will be collected on paper questionnaires.  The data from the questionnaires 
will be 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 on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
PATIENT-REPORTED OUTCOME DATA
Patients will use paper forms to record PRO data.  PROs must be stored in the 
appropriate patient file as source data and maintained at the study site.
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.


Venetoclax—F. Hoffmann-La Roche Ltd
86/Protocol WO40181, Version 4
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 
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, 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 Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.


Venetoclax—F. Hoffmann-La Roche Ltd
87/Protocol WO40181, Version 4
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient 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.


Venetoclax—F. Hoffmann-La Roche Ltd
88/Protocol WO40181, Version 4
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  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 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
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.


Venetoclax—F. Hoffmann-La Roche Ltd
89/Protocol WO40181, Version 4
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
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 3.3).
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, PROs, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 


Venetoclax—F. Hoffmann-La Roche Ltd
90/Protocol WO40181, Version 4
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.  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.  Detection of deviations from quality tolerance limits will trigger an
evaluation to determine if action is needed.  Details on the establishment and 
monitoring of quality tolerance limits will be provided in a Quality Tolerance Limit 
Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 40 centers globally will participate to enroll approximately 100 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An IMC will be formed to monitor and evaluate patient safety throughout the study, as 
specified in Section 3.2.  
9.6
PUBLICATION 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 


Venetoclax—F. Hoffmann-La Roche Ltd
91/Protocol WO40181, Version 4
request. For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following web site:
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 
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).


Venetoclax—F. Hoffmann-La Roche Ltd
92/Protocol WO40181, Version 4
10.
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:36576.
Adams JM, Cory S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. 
Curr Opin Immunol 2007;19:48896.
Bonneterre J, Thürlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-
line therapy for advanced breast cancer in 668 postmenopausal women: results of 
the Tanoxifen or Arimidex Randomized Group Efficacy and Tolerability study. 
J Clin Oncol 2000;18:374857.
Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology 
clinical practice guideline: update on adjuvant endocrine therapy for women with 
hormone receptor-positive breast cancer. J Clin Oncol 2010;28:378496.
Callagy GM, Pharoah PD, Pinder SE, et al. Bcl-2 is a prognostic marker in breast cancer 
independently of the Nottingham Prognostic Index. Clin Cancer Res 
2006;12:246875.
Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus 
guidelines for Advanced Breast Cancer (ABC 3). Breast 2017;31:24459.
Cardoso F, Narbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol 2012;23(Suppl 7):vii119. 
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus 
fulvestrant plus placebo for treatment of hormone-receptor-positive, 
HER2-negative metastatic breast cancer that progressed on previous endocrine 
therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 
randomised controlled trial. Lancet Oncol 2016;30;17:42539. 
Dawson SJ, Makretsov N, Blow FM, et al. BCL2 in breast cancer: a favourable 
prognostic marker across molecular subtypes and independent of adjuvant therapy 
received. Br J Cancer 2010;103:66875.
Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial 
comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women 
with estrogen receptor-positive advanced breast cancer. J Clin Oncol 
2010;28:4594600.
Fayers P, Bottomley A, EORTC Quality of Life Group. Quality of life research within the 
EORTC—the EORTC QLQ-C30. Eur J Cancer 2002;38(Suppl 4):S12533. 
Ferlay J, Stellarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality 
patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 
2013;49:1374403.


Venetoclax—F. Hoffmann-La Roche Ltd
93/Protocol WO40181, Version 4
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality 
of life (QoL) questionnaire module to supplement the EORTC core cancer QoL 
questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study 
Group on Quality of Life. Eur J Cancer 1999;35:93941. 
Gibson L, Lawrence D, Dawson C, et al. Aromatase inhibitors for treatment of advanced 
breast cancer in postmenopausal women. Cochrane Database Syst Rev 2009;
CD003370.
Hammond ME, Hayes DF, Wolff AC, et al. American Society of Clinical 
Oncology/College of American Pathologists guideline recommendations for 
immunohistochemical testing for estrogen and progesterone receptors in breast 
cancer. J Clin Oncol 2010;28:278495.
Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is 
as effective as anastrozole in postmenopausal women with advanced breast 
cancer progressing after prior endocrine treatment. J Clin Oncol 
2002;20:3396403.
Irvin W Jr, Muss HB, Mayer DK. Symptom management in metastatic breast cancer. 
Oncologist 2011;16:120314.
Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active 
estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive 
breast cancer. Clin Cancer Res 2014;20:175767.
Lindeman GJ, Lok SW, Bergin AR, et al. Safety and efficacy of the BCL2 inhibitor 
venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: 
the mBEP study. J Clin Oncol 2017;35(Suppl 15):1044.
Loibl S, Turner NC, Ro J, et al. Palbociclib combined with fulvestrant in premenopausal 
women with advanced breast cancer and prior progression on endocrine therapy: 
PALOMA-3 results. Oncologist 2017;22:102838.
Nabholtz JM, Mouret-Reynier MA, Durando X, et al. Role of aromatase inhibitors in the 
upfront adjuvant hormonal therapy of postmenopausal patients with breast cancer. 
Indian J Surg Oncol 2010;1:1926.
[NCCN] National Comprehensive Cancer Network®. NCCN clinical practice guidelines in 
oncology (NCCN Guidelines®) [resource on the Internet]. 2014 [updated 20 March 
2013; cited November 2017]. Available from: 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
Oakes SR, Vaillant F, Lim E, et al. Sensitization of BCL-2-expressing breast tumors to 
chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci USA 
2012;109:276671.
O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat 
Rev Clin Oncol 2016;13:41730. 


Venetoclax—F. Hoffmann-La Roche Ltd
94/Protocol WO40181, Version 4
Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the 
efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal 
women with advanced breast cancer progressing on prior endocrine therapy: 
results of a North American trial. J Clin Oncol 2002;20:338695.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:13944.
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of 
tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:281726.
Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane with 
tamoxifen as first-line hormonal treatment of metastatic breast cancer in 
postmenopausal women: the European Organisation for Research and Treatment 
of Cancer Breast Cancer Cooperative Group. J Clin Oncol 2008;26:488390.
Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumors. Nature 
2000;406:74752. doi: 10.1038/35021093.
Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant 
metastatic breast cancer. Nat Genet 2013;45:144651.
Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive 
metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin 
Oncol 2016;34:3069103.
Senkus E, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO clinical 
practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;
24(Suppl 6):vi723.
Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 
inhibitor, achieves antitumor activity while sparing platelets. Nat Med 
2013;19:2028.
Sprangers MA, Groenvold M, Arraras JI, et al. The European Organization for Research 
and Treatment of Cancer breast cancer-specific quality-of-life questionnaire
module: first results from a three-country field study. J Clin Oncol 
1996;14:275668.
Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death to 
improve therapy of cancer and other diseases. EMBO J 2011;30:366783.
Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-
resistant breast cancer. Nat Genet 2013;45:143945.
Vaillant F, Merino D, Lee L, et al. Targeting BCL-2 with the BH3 mimetic ABT-199 in 
estrogen receptor-positive breast cancer. Cancer Cell 2013;24:1209.
Venclexta® (venetoclax) tablets for oral use, U.S. Prescribing Information, AbbVie, Inc.
Venclyxto® (venetoclax) film-coated tablets, EMA Summary of Product Characteristics, 
AbbVie Ltd.


Venetoclax—F. Hoffmann-La Roche Ltd
95/Protocol WO40181, Version 4
Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal 
growth factor receptor 2 testing in breast cancer. American Society of Clinical 
Oncology/College of American Pathologists clinical practice guideline update. 
J Clin Oncol 2013;31:39974013.


Venetoclax—F. Hoffmann-La Roche Ltd
96/Protocol WO40181, Version 4
Appendix 1
Schedule of Activities
Study Period Screening a
Treatment Period
Study Drug 
Discontinuatio
n Visit c
Off-Tx 
Follow-Up 
Visit d
Survival 
Follow-
Up 
Visit e
Cycle
(Every 28 days (3 days of scheduled 
treatment day)
Cycle 1
Cycl
e 2
Cycles 
34
Cycles 
56
Subsequent 
Cycles b
Day of Cycle
-28 to -1
1
2 f
15
1 (3)
1 (3)
1 (3)
1 (3)
Informed consent
x
Demographic data and menopausal status
x
General medical history and baseline 
conditions
x
ECOG Performance Status
x
x
x
x
x
x
x
x
Complete physical examination g
x
Limited, symptom-directed physical 
examination
x
x
x
x
x
x
x
x
Vital signs h
x
x
x
x
x
x
x
x
x
x
Height
x
Weight and BSA
x
As clinically indicated
Bone scan i
x
12-Lead ECG 
x
Tumor or response assessment j
x
Every 8 weeks (5 days) from the date of 
randomization until Week 24 (5 days) 
and every 12 weeks (5 days) thereafter
x
PRO assessments k
x
x
x
x
x
x
Drug administration l:
Venetoclax
x
Fulvestrant
x
x
x
x
x
x
Local laboratory assessments
Hematology m
x
x
x
x
x
x
x
x
x n


Appendix 1
Schedule of Activities (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
97/Protocol WO40181, Version 4
Study Period Screening a
Treatment Period
Study Drug 
Discontinuatio
n Visit c
Off-Tx 
Follow-Up 
Visit d
Survival 
Follow-
Up 
Visit e
Cycle
(Every 28 days (3 days of scheduled 
treatment day)
Cycle 1
Cycl
e 2
Cycles 
34
Cycles 
56
Subsequent 
Cycles b
Day of Cycle
-28 to -1
1
2 f
15
1 (3)
1 (3)
1 (3)
1 (3)
Chemistry o
x
x
x
x
x
x
x
x
x
x n
Coagulation
x
As clinically indicated
Urinalysis
x
As clinically indicated
Viral serology p
x
Serum pregnancy test q
x
Urine pregnancy test r
x
x
x
x
x
Central laboratory assessments:
Plasma sample for ctDNA s
x
x
x
x
Tumor sample for BCL-2 family 
expression, ER, and HER2 
determination and exploratory 
biomarkers 
x t
x u
x v
Plasma sample for PK w
x
x
x
x
Concomitant medications x
x
x
x
x
x
x
x
x
x
x y
Adverse events
x z
x
x
x
x
x
x
x
x
x y
x y
Survival follow-up and anti-cancer 
treatment
xaa
xaa
x
ALPalkaline phosphatase; -hCG -human chorionic gonadotropin; BCL-2B-cell lymphoma 2; BSAbody surface area; ctDNAcirculating 
tumor DNA; ECOGEastern Cooperative Oncology Group; EORTCEuropean Organisation for Research and Treatment of Cancer; 
ERestrogen receptor; GGTgamma-glutamyl transferase; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; 
HBVhepatitis B virus; HCVhepatitis C virus; HER2 human epidermal growth factor receptor; IMintramuscular; PCRpolymerase chain 
reaction; PKpharmacokinetic; PRO patient-reported outcomes; QLQ-C30Quality of Life QuestionnaireCore 30; TLStumor lysis syndrome; 
Txtreatment.


Appendix 1
Schedule of Activities (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
98/Protocol WO40181, Version 4
a Patients who do not initially meet all eligibility criteria may be re-screened once within 2 weeks, given that the reason for screening failure was 
not ER or HER-2 status (see Section 4.5.1).
b Patients will continue subsequent cycles every 28 days (3 days of scheduled treatment day) until disease progression, death, loss to follow 
up, withdrawal of consent, or study termination by the Sponsor (Section 3.3), whichever occurs first.
c All patients who discontinue study treatment will return for a study drug discontinuation visit 28 days after last dose (up to 3 days of delay [to 
Day 31] is acceptable)
d For patients who discontinue study treatment early for reasons other than disease progression and have not started follow-on treatment.  These 
patients will be followed 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 death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor, whichever occurs first.
e Follow-up of survival and anti-cancer treatment will be conducted approximately every 3 months, or more frequently, from disease progression 
for all patients until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor, whichever occurs first.  The same 
survival follow-up will be done for patients who discontinue study treatment early for reasons other than disease progression and have started
follow-on treatment.   
f
Cycle 1 Day 2 (i.e., 24-hour) visit is required only for the first 10 patients enrolled in each arm.  A chemistry panel to monitor for TLS (see Section 
5.1.1.1) will be collected and must include at least electrolytes, uric acid, phosphorous, calcium, and creatinine levels.
g
Complete physical examination includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. 
h Vital signs to include body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated 
position.  Height and BSA are only required at screening.  Subsequent BSA is required if there is a 10% change in weight.
i
A bone scan is to be performed within 28 days prior to Cycle 1 Day 1.  See Section 4.5.5.1 for further instructions.
j
See Section 4.5.5 for tumor and response evaluation instructions. 
k PRO assessments will comprise the EORTC QLQ-C30 (see Appendix 5).  PRO questionnaires will be self-administered at the start of each 
pre-specified clinic visit before the patient receives any information on disease status, prior to the administration of any study treatment, and/or 
prior to any other study assessments. 
l
Drug administration: Venetoclax will be administered on a once daily dosing schedule. On days when both venetoclax and fulvestrant are given, 
the order of study treatment administration will be venetoclax followed by fulvestrant (there is no minimum time required between the 
administration of venetoclax and the start of fulvestrant administration).  See Section 4.3.2.1 for more details.  As of 8 October 2020, all active 
patients in the venetoclax plus fulvestrant arm will be requested to discontinue the venetoclax treatment immediately (see Section 3.1). 
Fulvestrant 500 mg will be administered in the clinic as two 250-mg IM injections on Cycle 1 Days 1 and 15 and then on Day 1 of each 
subsequent 28-day cycle.


Appendix 1
Schedule of Activities (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
99/Protocol WO40181, Version 4
m Hematology includes hemoglobin, hematocrit, RBC count, platelet count, WBC count, and WBC differential count (neutrophils, bands [optional], 
lymphocytes, eosinophils, basophils, monocytes).  Reporting the differential as absolute counts is preferred, but percentages are accepted.  
Assessment must be performed within 3 days (with results available) prior to the administration of study medication.  If the screening 
assessments were done within 3 days prior to Cycle 1 Day 1 there is no need to repeat the hematology at Cycle 1 Day 1.
n To be collected if the investigator determines that the tests are clinically indicated.
o Chemistry includes sodium, potassium, chloride, random glucose, BUN, creatinine, ALT, AST, total bilirubin, amylase, lipase, total protein, 
albumin, calcium, phosphorus, LDH, CK, GGT, ALP, and uric acid. Assessment must be performed within 3 days (with results available) prior to 
the administration of study medication.  If the screening assessments were done within 3 days prior to Cycle 1 Day 1 there is no need to repeat 
the chemistry panel at Cycle 1 Day 1. 
p Viral serology includes HBsAg or HCV antibody. Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for 
study participation.  Patients with a past or resolved HBV infection (defined as having a positive total HBcAb and negative HBsAg) may be 
included if HBV DNA is undetectable.  These patients must be willing to undergo monthly DNA testing.
q Required for all women of reproductive potential (see inclusion criteria in Section 4.1.1).
r
For women of childbearing potential (defined in Section 4.1.1), a urine pregnancy test will be repeated during the treatment period within 3 days 
prior to each cycle (every 28 days starting on Day 1 of Cycle 2), at study discontinuation visit, and as clinically indicated.  Any positive urine 
pregnancy test must be confirmed with a serum -hCG evaluation at the local laboratory.  Pregnancy test results must be available prior to the 
administration of fulvestrant.  Women who have undergone surgical sterilization or are postmenopausal are exempt from pregnancy 
assessments.
s Samples should be collected predose for analysis of circulating tumor markers of response/resistance at baseline (predose) Cycle 1 Day 1, 
between Cycle 2 Day 15 and Cycle 3 Day 1, between Cycle 4 Day 15 and Cycle 5 Day 1, and at study drug discontinuation visit.
t
Sample must include a tumor paraffin tissue block or at least 20 unstained slides (sections obtained 3 months) from the tumor tissue block from 
either the primary tumor or a metastatic site obtained at the time of the most recent progression prior or during screening for this trial.  
A pathology report should accompany the tissue sample.
u Optional on-treatment tumor biopsy to be performed on Cycle 3 Day 1 (3 day) only.
v Optional tumor biopsy if disease progression is the reason for the patient discontinuing study treatment.
w Refer to Appendix 2 for the schedule of PK samples in the venetoclax arm. On days that predose pharmacokinetic sampling is required, the 
patient’s first meal of the day (e.g., breakfast) will be provided in the morning at the clinic and venetoclax dosing will occur in the clinic after 
completion of the meal.
x Concomitant therapy includes any prescription medication, over-the-counter preparations, herbal or homeopathic remedies, and nutritional 
supplements used by a patient from 28 days prior to the screening visit through to study completion/early termination.


Appendix 1
Schedule of Activities (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
100/Protocol WO40181, Version 4
y Adverse events possibly related to study drug are to be recorded as well as any concomitant medications used in association with the event.
z 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.  After initiation of study drug, all 
adverse events will be reported through 28 days after the last dose of venetoclax or fulvestrant, whichever is later.
aa New anti-cancer therapy after study drug discontinuation should be reported once known.


Venetoclax—F. Hoffmann-La Roche Ltd
101/Protocol WO40181, Version 4
Appendix 2
Schedule of Pharmacokinetic Samples in the Venetoclax Arm
Study Visit
Timepoint
Sample
(Plasma)
Draw 
Sequence
Cycle 1, Day 1
4 hours postdose (10 minutes)
venetoclax PK
1
Cycle 2, Day 1
Predose
(within 1 hour before dosing) a
venetoclax PK
1
fulvestrant PK
2
2 hours postdose (10 minutes)
venetoclax PK
1
4 hours postdose (10 minutes)
venetoclax PK
1
6 hours postdose (20 minutes)
venetoclax PK
1
8 hours postdose (30 minutes)
venetoclax PK
1
Cycle 6, Day 1
Predose
(within 1 hour before dosing) a
venetoclax PK
1
fulvestrant PK
2
Study drug 
discontinuation/
Early Terminationb
Anytime during clinic visit
venetoclax PK
1
fulvestrant PK
2
PKpharmacokinetic.
Note:  For the PK sample, the plasma samples including primary and back-up samples will be 
collected per procedures outlined in the separate laboratory manual.  Detailed instructions for PK 
plasma sample preparation and shipping will be provided to the study sites in a separate 
laboratory manual.  
Record exact date and time of all PK sample collections (relative to the administration of the 
study drug being measured).
a Record exact date and time of all study drug doses in the dosing diary.
b Obtain a PK blood sample if the patient discontinues study drug.


Venetoclax—F. Hoffmann-La Roche Ltd
102/Protocol WO40181, Version 4
Appendix 3
Sample List of Medications to Avoid or Use with Caution
Strong CYP3A inhibitors: boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and 
ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juice, idelalisib, indinavir and ritonavir,
itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir
and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, troleandomycin, voriconazole
Moderate CYP3A inhibitors: aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, 
cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil
Strong CYP3A inducers:  carbamazepine (Tegretol®), enzalutamine, mitotane, phenytoin,
rifampin (Rifadin®), St. John's wort
Moderate CYP3A inducers: bosentan, efavirenz, etravirine, modafinil
Cautionary a
Warfarin b
P-gp substrates: dabigatran, digoxin, fexofenadine
P-gp inhibitors: amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, 
lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, 
telaprevir, tipranavir and ritonavir, verapamil
BCRP substrates: rosuvastatin, sulfasalazine
BCRP inhibitors: curcumin, cyclosporine A, eltrombopag
OATP1B1/1B3 substrates: asunaprevir, atorvastatin, bosentan, cerivastatin, danoprevir, 
docetaxel, fexofenadine, glyburide, nateglinide, paclitaxel, pitavastatin, pravastatin, repaglinide,
rosuvastatin, simvastatin acid
BCRPbreast cancer resistance protein; CYPcytochrome P450; OATP1B1organic anion 
transporter protein 1B1; P-gpP-glycoprotein.
a If a patient requires use of these medications, use with caution and ask the Medical Monitor
for guidance.
b Closely monitor INR.
Note: This is not an exhaustive list.  For an updated list and detailed explanations, see the
following website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm
In addition to the medications listed in this table, patients receiving venetoclax should not 
consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville 
oranges), or starfruits.


Venetoclax—F. Hoffmann-La Roche Ltd
103/Protocol WO40181, Version 4
Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as follows.
a.
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum 
size of:

10 mm by computed tomography (CT) or magnetic resonance imagining (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
b.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:22847.
2
For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
104/Protocol WO40181, Version 4
c.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such 
as CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
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.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS
a.
Measurement of 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.
b.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
105/Protocol WO40181, Version 4
the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
IV contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (without IV contrast) will be used to evaluate the patient at 
baseline and during the study should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For patients who develop contraindications to 
contrast after baseline contrast CT is done, the decision as to whether non-contrast CT 
or MRI (enhanced or non-enhanced) will be performed should also be based on the 
tumor type and the anatomic location of the disease and should be optimized to allow for 
comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions on a different modality and interpretation of 
non-target disease or new lesions since the same lesion may appear to have a different 
size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
106/Protocol WO40181, Version 4
BASELINE DOCUMENTATION 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 in instances where patients have only one or two 
organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will be 
recorded as non-measurable lesions (even if the size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs but, additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis 
10 mm are considered non-pathological and should not be recorded or followed.
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
107/Protocol WO40181, Version 4
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
108/Protocol WO40181, Version 4
b.
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
10 mm.
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the 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 BML (below measurable limit) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such 
as in the retroperitoneum; however, if a lymph node is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well and BML should also be ticked.)
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
109/Protocol WO40181, Version 4
c.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although 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 protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level)
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
d.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease; that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from “trace” to 
“large” or an increase in lymphangitic disease from localized to widespread or may be 
described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  Although it would be ideal to have objective criteria to apply to non-measurable 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
110/Protocol WO40181, Version 4
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.
e.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
111/Protocol WO40181, Version 4
Table 1
Timepoint Response:  Patients with Target Lesions 
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
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.
b.
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 only a subset of lesion measurements are made at an 
assessment, 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 
lesion(s) 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.
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.
c.
Best Overall Response:  All Timepoints
The best overall response is determined once all data for the patient is known, and is 
interpreted as in Table 2.  Complete or partial responses may be claimed if the criteria 
for each are met at a subsequent timepoint 4 weeks later.  


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
112/Protocol WO40181, Version 4
Table 2
Best Overall Response When Confirmation Is Required
Overall Response 
at First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
PR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
d.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
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 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
(cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
113/Protocol WO40181, Version 4
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1 and Table 2.
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.
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.


Venetoclax—F. Hoffmann-La Roche Ltd
114/Protocol WO40181, Version 4
Appendix 5
European Organisation for Research and Treatment of Cancer 
Core Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), 
Version 3


Appendix 5
European Organisation for Research and Treatment of Cancer 
Core Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), 
Version 3 (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
115/Protocol WO40181, Version 4


Venetoclax—F. Hoffmann-La Roche Ltd
116/Protocol WO40181, Version 4
Appendix 6
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale
Table 1
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work or office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
ECOGEastern Cooperative Oncology Group.


Venetoclax—F. Hoffmann-La Roche Ltd
117/Protocol WO40181, Version 4
Appendix 7
Suggested Guidance for Atypical Infection Prophylaxis Due to 
Lymphopenia
In patients who develop Grade 3 and 4 lymphopenia, the following recommendations, as 
well as those in Table 1, are to be followed, but they may be tailored to the patient and 
her lymphocyte counts:

Pneumocystis jiroveci pneumonia prophylaxis in the form of combination 
sulfamethoxazole-trimethoprim (Bactrim DS; 800 mg/160 mg) ii tablets Monday, 
Wednesday, and Friday

Varicella zoster virus prophylaxis in the form of valaciclovir 500 mg daily
Table 1
Management of Grade 3 and 4 Lymphopenia
Lymphocyte count
Grade 
(CTCAE 5.0)
Recommendation
LLN0.8 109/L
1
No prophylaxis
0.80.5 109/L
2 
Consider prophylaxis if patient will be exposed to 
further immune-suppressants (e.g., dexamethasone) 
and/or radiotherapy
0.50.2 109/L
3 
Consider PJP prophylaxis and VZV prophylaxis
0.2 109/L
4
PJP prophylaxis and VZV prophylaxis strongly 
recommended.
CTCAECommon Terminology Criteria for Adverse Events; LLNlower limit of normal; 
PJPPneumocystis jiroveci pneumonia; VZVvaricella zoster virus.
When the lymphocyte count is 0.5109/L, the prophylaxis may be stopped, at the 
investigator’s discretion.  At study completion, cessation of prophylaxis can occur when 
lymphocyte counts normalize.


Venetoclax—F. Hoffmann-La Roche Ltd
118/Protocol WO40181, Version 4
Appendix 8
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). 

Intravenous (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 (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 tumor lysis syndrome 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. 


Venetoclax—F. Hoffmann-La Roche Ltd
119/Protocol WO40181, Version 4
Appendix 9
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 9
Guidelines for Defining Tumor Lysis Syndrome (cont.)
Venetoclax—F. Hoffmann-La Roche Ltd
120/Protocol WO40181, Version 4
Table 2
Howard Definition of Clinical Tumor Lysis Syndrome
The presence of laboratory tumor lysis syndrome and one or more of the following criteria:
Creatininea:  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, laryngospasm or 
bronchospasm), hypotension, or heart failure probably or definitely caused by hypocalcemia b
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 mol/L) or a period of oliguria lasting 6 hours.  By definition, if acute kidney injury is 
present, the patient has clinical tumor lysis syndrome.
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
121/Protocol WO40181, Version 4
Appendix 10 Venetoclax Dose Modifications with Concomitant 
Moderate and Strong CYP3A Inhibitors
Dose Level
Venetoclax Dose 
(mg)
with No Moderate 
or Strong CYP3A 
Inhibitor
Venetoclax Dose (mg)
if Co-Administered 
with a Moderate 
CYP3A Inhibitor
Venetoclax Dose 
(mg)
if Co-Administered 
with a Strong CYP3A 
Inhibitor
Starting dose
800
400
200
Dose level –1
600
300
100
Dose level –2
400
200
100
Dose level –3
200
100
Interrupt venetoclax 
temporarily
CYPcytochrome P450.