Multicenter, Phase 3 Study of Venetoclax and Azacitidine as Maintenance Therapy for Patients With Acute Myeloid Leukemia in First Remission After Conventional Chemotherapy
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML)
Sponsor: AbbVie



 
 
 
    
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TABLE OF CONTENTS 
1 
SYNOPSIS 
5 
2 
INTRODUCTION 
8 
2.1 
BACKGROUND AND RATIONALE 
8 
2.2 
BENEFITS AND RISKS TO SUBJECTS 
9 
3 
OBJECTIVES AND ENDPOINTS 
10 
3.1 
PRIMARY ENDPOINT 
11 
3.2 
SECONDARY ENDPOINTS 
11 
3.3 
ADDITIONAL ENDPOINTS 
11 
3.4 
SAFETY ENDPOINTS 
12 
3.5 
PHARMACOKINETIC ENDPOINTS 
12 
3.6 
BIOMARKER RESEARCH ENDPOINTS 
12 
4 
INVESTIGATIONAL PLAN 
12 
4.1 
OVERALL STUDY DESIGN AND PLAN 
12 
4.2 
DISCUSSION OF STUDY DESIGN 
16 
5 
STUDY ACTIVITIES 
18 
5.1 
ELIGIBILITY CRITERIA 
18 
5.2 
CONTRACEPTION RECOMMENDATIONS 
21 
5.3 
PROHIBITED MEDICATIONS AND THERAPY 
23 
5.4 
PRIOR AND CONCOMITANT THERAPY 
24 
5.5 
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY 
26 
5.6 
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY 
27 
5.7 
STUDY DRUG 
28 
5.8 
DRUG ASSIGNMENT 
29 
5.9 
PROTOCOL DEVIATIONS 
30 
5.10 PUBLICATION POLICY 
30 
6 
SAFETY CONSIDERATIONS 
30 
6.1 
COMPLAINTS AND ADVERSE EVENTS 
30 
6.2 
TOXICITY MANAGEMENT 
34 
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6.3 
DOSE-LIMITING TOXICITY CRITERIA 
39 
7 
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE 
40 
7.1 
STATISTICAL AND ANALYTICAL PLANS 
40 
7.2 
DEFINITION FOR ANALYSIS POPULATIONS 
40 
7.3 
STATISTICAL ANALYSES FOR EFFICACY 
40 
7.4 
STATISTICAL ANALYSES FOR SAFETY 
41 
7.5 
MULTIPLICITY ADJUSTMENT AND OVERALL TYPE I ERROR CONTROL 
41 
7.6 
SAMPLE SIZE DETERMINATION 
42 
8 
ETHICS 
42 
8.1 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
42 
8.2 
ETHICAL CONDUCT OF THE STUDY 
43 
8.3 
SUBJECT CONFIDENTIALITY 
43 
9 
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION 
43 
10 DATA QUALITY ASSURANCE 
44 
11 START AND COMPLETION OF THE STUDY 
44 
12 REFERENCES 
44 
LIST OF TABLES 
TABLE 1. 
DOSE LEVELS FOR VENETOCLAX + AZACITIDINE FOR SUBJECTS IN PART 1 
14 
TABLE 2. 
VENETOCLAX AND ORAL AZA DOSE LEVELS 
15 
TABLE 3. 
DOSE-ESCALATION DECISION RULE 
16 
TABLE 4. 
VENETOCLAX DOSE MODIFICATION WHEN CO-ADMINISTERED WITH STRONG OR MODERATE 
CYP3A INHIBITORS 
25 
TABLE 5. 
STUDY DRUG INFORMATION 
29 
TABLE 6. 
REDUCED DURATION OF THE VENETOCLAX DOSING SCHEDULE FOR SUBJECTS (PART 1 ONLY) 
37 
TABLE 7. 
DOSE REDUCTION FOR VENETOCLAX + AZACITIDINE FOR SUBJECTS (PART 1 ONLY) 
38 
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TABLE 8. 
DOSE REDUCTION FOR VENETOCLAX + ORAL AZA FOR SUBJECTS – PART 3: DOSE FINDING 
39 
TABLE 9. 
PROBABILITY OF OBSERVING AT LEAST ONE ADVERSE EVENT IN A COHORT OF 20 SUBJECTS FOR 
VARIOUS TRUE ADVERSE EVENT RATES 
42 
TABLE 10. 
PROBABILITY OF OBSERVING AT LEAST 1 ADVERSE EVENT IN A COHORT OF 24 SUBJECTS FOR 
VARIOUS TRUE ADVERSE EVENT RATES 
42 
LIST OF FIGURES 
FIGURE 1. 
STUDY SCHEMATIC 
13 
LIST OF APPENDICES 
APPENDIX A. 
STUDY SPECIFIC ABBREVIATIONS AND TERMS 
49 
APPENDIX B. 
RESPONSIBILITIES OF THE INVESTIGATOR 
53 
APPENDIX C. 
LIST OF PROTOCOL SIGNATORIES 
54 
APPENDIX D. 
RECOMMENDED DOSE REDUCTIONS RELATED TO DRUG TOXICITIES 
55 
APPENDIX E. 
NCCN RISK CATEGORIZATION:  GUIDELINES FOR AML, VERSION 2, 2016 
57 
APPENDIX F. 
RECOMMENDATIONS FOR MANAGEMENT OF TREATMENT-INDUCED DIARRHEA 
58 
APPENDIX G. 
RECOMMENDATIONS FOR MANAGEMENT OF TREATMENT-INDUCED NAUSEA AND 
GASTROINTESTINAL EVENTS 
59 
APPENDIX H. 
ACTIVITY SCHEDULE 
61 
APPENDIX I. 
PROTOCOL SUMMARY OF CHANGES 
70 
APPENDIX J. 
OPERATIONS MANUAL 
72 
 
 
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2 INTRODUCTION 
2.1 Background and Rationale 
Why Is This Study Being Conducted 
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy typically defined by the World 
Health Organization (WHO) as a myeloid neoplasm with 20% or more blasts in the peripheral blood or 
bone marrow.1  In AML, the clonal expansion of myeloid blasts in bone marrow, peripheral blood, and 
occasionally extramedullary tissues leads to disruption of normal hematopoiesis.2-4  It is the most 
common form of acute leukemia in adults, with an estimated 19,520 new cases and 10,670 deaths in the 
United States (US) in 2018.3  Of all types of leukemia, AML has the lowest survival rate and accounts for 
the largest number of deaths. 
AbbVie and Genentech/Roche (sponsors) are jointly developing venetoclax for the treatment of subjects 
with hematological malignancies.  Venetoclax is a selective, potent, orally bioavailable, small molecule 
inhibitor of B-cell lymphoma (BCL)-2 that restores programmed cell death in cancer cells.  Venetoclax 
binds with high affinity (inhibition rate constant [Ki] < 0.010 nM) to anti-apoptotic protein BCL-2 and 
with lower affinity to other anti-apoptotic BCL-2 family proteins, like B-cell lymphoma  extra large 
(BCL-XL) and B-cell lymphoma - Walter and Eliza Hall Institute (BCL-w) (> 4,000-fold and > 2,000- to 
> 20,000-fold lower affinity than to BCL-2, respectively). 
Venetoclax was evaluated as a single agent (Study M14-212) in subjects with relapsed or refractory (R/R) 
AML or newly diagnosed subjects with AML who were unfit to receive intensive chemotherapy achieving 
a 19% objective response rate (ORR) with venetoclax monotherapy.5  Furthermore, studies in subjects 
with treatment-naïve AML who were ineligible for intensive chemotherapy reported complete remission 
(CR) + complete remission with incomplete blood count recovery (CRi) rates of 61% in combination with 
hypomethylating drugs (HMAs; Study M14-358)6 and 54% in combination with low-dose cytarabine 
(LDAC; Study M14-387).7  In a Phase 3, randomized, double-blind, placebo-controlled study (Viale A:  
Study M15-656), newly diagnosed subjects with AML who were unfit to receive intensive chemotherapy 
were treated with venetoclax in combination with azacitidine (AZA) or placebo in combination with AZA.  
As of 04 January 2020, the median overall survival (OS) was 14.7 months [95% confidence interval 
(CI):  11.9, 18.7] in the venetoclax + AZA arm versus 9.6 months [95% CI:  7.4, 12.7] in the placebo + AZA 
arm (hazard ratio 0.66 [95% CI:  0.52, 0.85]; p < 0.001).  The CR + CRi rate was 66.4% [95% CI:  60.6, 71.9] 
in the venetoclax + AZA arm versus 28.3% [95% CI:  21.1, 36.3] in the placebo + AZA arm (p < 0.001).8  
The safety profile of subjects treated with venetoclax in combination with AZA was consistent with the 
known side-effect profiles of both agents alone, and adverse events (AEs) were consistent with 
expectations for an older AML population.  The most common AEs in both treatment arms were GI and 
hematologic events with a higher frequency of neutropenia and febrile neutropenia in the venetoclax + 
AZA arm;8 these findings are consistent with those in previous studies.9 
For AML patients who are eligible, intensive chemotherapy during induction and consolidation is a 
standard-of-care treatment.5-7,10,11  Patients who are fit enough to receive intensive therapy will often 
achieve remission; however, the majority of these patients will ultimately relapse.  The prevention of 
relapse is a major therapeutic challenge in the treatment of AML.12-14  No post-consolidation treatment 
for prevention of relapse was previously established except for the use of allogeneic hematopoietic 
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stem cell transplant for a select group of relatively fit patients.15-17  Although there has been a long-
standing interest in maintenance therapies such as interleukin-2,18-20 LDAC,21 HMAs,22-30 and 
gemtuzumab ozogamicin26 after intensive induction treatment, the clinical benefits of such maintenance 
therapies have remained unclear.19  In 2020, ONUREG® (CC-486; orally [PO] administered AZA) was 
approved for continued treatment of patients with AML who achieved first CR or CRi following intensive 
induction chemotherapy and were not able to complete intensive curative therapy.  Data from the 
QUAZAR AML maintenance trial (CC-486-AML-001), a randomized, double-blind, placebo-controlled 
study, showed that the median OS in subjects receiving ONUREG was superior (median OS:  
24.7 months) to subjects who received placebo (median OS:  14.8 months) and the subgroup analysis 
showed consistency in the OS benefit for subjects who achieved either CR or CRi.  Adverse reactions in 
≥ 10% subjects receiving ONUREG were nausea, vomiting, diarrhea, fatigue/asthenia, constipation, 
pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in 
extremity.31 
The BCL-2 family of proteins is overexpressed in leukemic stem cells.  Leukemia stem cells drive the 
initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often 
persist after conventional chemotherapy resulting in relapse.  In recent literature, analysis of leukemic 
stem cells from subjects undergoing treatment with venetoclax in combination with azacitidine 
(VIDAZA®) showed disruption of the tricarboxylic acid cycle manifested by decreased α-ketoglutarate 
and increased succinate levels suggesting inhibition of electron transport chain complex II.  This leads to 
suppression of oxidative phosphorylation, which efficiently and selectively targets leukemic stem cells.  
These findings suggest that a therapeutic intervention can eradicate leukemic stem cells in patients with 
AML by disrupting the metabolic machinery, resulting in promising clinical activity in a patient 
population with historically poor outcomes.32 
This study will determine the recommended Phase 3 dose (RPTD) of venetoclax in combination with AZA 
(subcutaneous [SC] or intravenous [IV] administration) as maintenance therapy in subjects with AML 
who have achieved CR or CRi with conventional chemotherapy.  This study will also determine the dose 
of venetoclax in combination with oral AZA that can be safely administered (RPTD) as maintenance 
therapy, and evaluate the safety and efficacy of venetoclax in combination with oral AZA in subjects with 
AML who have achieved CR or CRi after conventional chemotherapy. 
2.2 Benefits and Risks to Subjects 
Most patients with AML will achieve remission with induction chemotherapy.  The majority of these 
patients will then go on to relapse.  Maintenance therapy to prolong remission and increase cure is an 
approved approach in acute promyelocytic leukemia (APL).  Maintenance strategies for non-APL AML 
are currently being tested.33,34  No standard-of-care exists for maintenance therapy in non-APL AML. 
It is hypothesized that a reservoir of leukemia stem cells that persist after primary therapy ultimately 
expand and drive relapse in AML.  Curative therapy in AML must incorporate agents with activity against 
these cells either during induction and consolidation or during maintenance.  Combined therapy with 
venetoclax + AZA has been shown to eradicate leukemia stem cells through disruption of oxidative 
phosphorylation and energy metabolism in preclinical models of AML.32  These data support the conduct 
of a maintenance study incorporating both these agents. 
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Venetoclax in combination with AZA was highly active for newly diagnosed patients with AML who are 
unfit to receive intensive chemotherapy.  Responses were deep and durable, and outcomes were 
superior compared with historical controls (Study M14-358).  The reported CR or CRi rate was 71.4%.  
Median duration of response was 21.2 months.  The most common treatment-emergent AEs were 
nausea (54%), febrile neutropenia (41%), diarrhea (44%), decreased appetite (33%), and peripheral 
edema (31%).  No dose-limiting toxicities (DLTs) were reported.  The most frequent serious AE (SAE) was 
febrile neutropenia (28%).  These AEs were experienced by subjects treated with venetoclax in 
combination with an HMA; however, subjects who are already in morphologic remission may experience 
a lower frequency rate of AEs than newly diagnosed subjects with AML who were unfit to receive 
intensive chemotherapy. 
CC-486 is an oral formulation of AZA with clinical activity in subjects with AML in Phase 1 studies.  The 
Phase 3, randomized, double-blind, placebo-controlled QUAZAR AML maintenance trial 
(CC-486-AML-001) examines CC-486 maintenance therapy (300 mg/day for 14 days of 28-day treatment 
cycles) in subjects aged ≥ 55 years with AML in first CR.  This trial investigated whether CC-486 
maintenance can prolong remission and improve survival for older subjects with AML.  CC-486 was the 
first maintenance therapy to provide statistically significant and clinically meaningful improvements in 
OS and RFS relative to placebo in a broad range of subjects with AML in remission following intensive 
induction chemotherapy.  The median OS and RFS were prolonged by 9.9 months and 5.3 months, 
respectively.  The safety and tolerability of oral AZA were manageable with no unexpected AEs.33,35 
For further details, please see findings from completed and ongoing studies, including safety data in the 
current venetoclax Investigator's Brochure,36 both the AZA and oral AZA Summaries of Product 
Characteristics (SmPC)37,38, package inserts, prescribing information, and/or their equivalents. 
Given the coronavirus disease  2019 (COVID-19) pandemic and based on the information to date, 
subjects receiving venetoclax in combination with AZA or oral AZA may be at an increased risk for 
COVID-19 or experience serious illness if infected.  Management of these AEs will be made on a case-by-
case basis with consideration of benefit/risk. 
3 OBJECTIVES AND ENDPOINTS 
Part 1 Objectives (Dose Confirmation) 
Primary 
• 
To determine the RPTD of venetoclax in combination with AZA as maintenance therapy in 
subjects with AML who have achieved CR or CRi with conventional induction and consolidation 
chemotherapy. 
 
Part 2 Objectives (Randomization) 
Not applicable; Part 2 was removed from Version 5.0 of this protocol. 
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Part 3 Objectives (Dose Finding) 
Primary 
• 
To determine the RPTD of venetoclax in combination with oral AZA as maintenance therapy in 
subjects with AML who have achieved CR or CRi with conventional induction and consolidation 
chemotherapy. 
 
Secondary 
• 
To characterize the safety, efficacy, pharmacokinetic (PK), and toxicity profiles of venetoclax in 
combination with oral AZA as maintenance therapy in subjects with AML who have achieved CR 
or CRi with conventional induction and consolidation chemotherapy. 
 
Part 3 Objectives (Randomization) 
Not applicable; Part 3 (Randomization) was removed from Version 6.0 of this protocol. 
3.1 Primary Endpoint 
Part 1 (Dose Confirmation) 
The primary endpoint is DLTs of venetoclax in combination with AZA. 
Part 3 (Dose Finding) 
The primary endpoint is DLTs of venetoclax in combination with oral AZA. 
Part 3 (Randomization) 
Not applicable; Part 3 (Randomization) was removed from Version 6.0 of this protocol. 
3.2 Secondary Endpoints 
Part 3 (Randomization) 
Not applicable; Part 3 (Randomization) was removed from Version 6.0 of this protocol. 
3.3 Additional Endpoints 
Part 3 (Dose Finding) 
• 
Relapse free survival 
• 
Overall survival 
• 
Minimal residual disease conversion  
• 
Time to deterioration GHS/QoL scale from the EORTC QLQ-C30 
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• 
Change in global fatigue score from baseline to post-baseline using the PROMIS Fatigue SF-7a 
global fatigue score 
• 
Change from baseline to post-baseline in subscales and items from EORTC QLQ-C30 and 
EQ-5D-5L 
 
3.4 Safety Endpoints 
Safety evaluations include AE monitoring, physical examinations, vital sign measurements, and clinical 
laboratory testing (hematology and chemistry) as measures of safety and tolerability for the entire study 
treatment duration through 30 days after last dose of study drug.  
3.5 Pharmacokinetic Endpoints 
Sparse PK samples will be collected and analyzed for plasma concentrations of venetoclax and 
azacitidine (active ingredient of AZA and oral AZA) in Part 1 and Part 3.  An analysis of venetoclax plasma 
concentrations may be performed using a nonlinear mixed-effect population PK modeling approach. 
For the intensive PK sampling days in Part 3 (Dose Finding), values for the PK parameters of venetoclax 
and azacitidine including the maximum observed plasma concentration (Cmax), the time to Cmax (Tmax), the 
area under the plasma concentration versus time curve (AUC) from time 0 to the time of the last 
measurable concentration (AUCt) for azacitidine, and AUC from time 0 to 24 hours postdose (AUC0-24) for 
venetoclax will be determined using noncompartmental methods. 
3.6 Biomarker Research Endpoints 
Biospecimens (e.g., blood, plasma, serum, and bone marrow aspirate) will be collected at specified time 
points (Appendix H) throughout the study to evaluate known and/or novel disease-related or drug-
related biomarkers.  Some of these samples may be optional.  Types of biomarkers may include nucleic 
acids, proteins, lipids, and/or metabolites, either free or in association with particular cell types.  The 
analyses may include but are not limited to prognostic, predictive, pharmacodynamic, or surrogate 
biomarker signatures.  This research may be exploratory in nature and the results may not be included 
in the clinical study report.  Further details regarding the biomarker research rationale and collection 
time points are located in the Operations Manual Section 3.15 and Appendix J. 
4 INVESTIGATIONAL PLAN 
4.1 Overall Study Design and Plan 
This is a Phase 3 multicenter, open-label study of venetoclax in combination with oral AZA administered 
PO to establish the RPTD and safety of the combination with a dose escalation phase (Part 3 [Dose 
Finding]) followed by a safety expansion component in subjects with AML after first remission resulting 
from conventional (including both induction and consolidation) chemotherapy.  
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This study will also have an open-label, dose-confirmation component to establish the recommended 
dose of venetoclax in combination with AZA (SC or IV) (Part 1 [Dose Confirmation]) in subjects with AML 
after first remission resulting from conventional (including both induction and consolidation) 
chemotherapy. 
Best supportive care (BSC) and expectant AML management for this patient population according to 
institutional standards, excluding any AML-directed therapy, is allowed throughout the study in Part 1 
and Part 3 (Dose Finding).  BSC will be determined for each subject by the investigator. 
As of 26 August 2021, 66 subjects were enrolled in Part 1 (Dose Confirmation); as of 08 September 2022, 
46 subjects were enrolled in Part 3 (Dose Finding).  
Note:  Part 2 (open-label, randomized, 2-arm portion of the study with venetoclax + AZA + BSC versus 
BSC) was removed from Version 5.0 of this protocol.  Part 3 (Randomization) was removed from Version 
6.0 of this protocol. 
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix J). 
Figure 1. 
Study Schematic 
 
IV = intravenous(ly); PO = oral; RPTD = recommended Phase 3 dose; SC = subcutaneous(ly) 
 
Screening 
Consent will be obtained at the initial screening visit. 
Unless otherwise specified, all other screening procedures must be performed within 28 days prior to 
start of study drug.  Once screening procedures are complete and eligibility is confirmed, subjects will be 
enrolled into the study.  Rescreening may be considered only once upon investigator discussion with the 
AbbVie Therapeutic Area Medical Director (TA MD) and subsequent agreement.  Subjects who do not 
meet severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection eligibility criteria must be 
screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance 
criteria: 
• 
At least 10 days since first positive test result have passed in asymptomatic patients or at least 
10 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms. 
 
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Subjects who rescreen must meet all eligibility criteria at the time of rescreen.  See Section 5 for 
information regarding eligibility criteria. 
Part 1:  Dose Confirmation 
For Part 1, the dose-confirmation cohort will enroll at least 20 subjects to receive venetoclax + AZA at 
the following dose levels:  venetoclax 400 mg once daily (QD; Days 1  28) for each 28-day cycle up to 
24 cycles and AZA 50 mg/m2 SC or IV, QD for 5 days beginning on Cycle 1, Day 1 (Days 1  5) of each 
28 day cycle up to 6 cycles. 
When at least 20 subjects have been treated for at least 28 days, an aggregate review of the toxicity 
data will be made by the sponsor.  If fewer than 20% of the subjects experience DLTs during Cycle 1, the 
RPTD will have been established.  However, if 20% or more have DLTs during Cycle 1, an additional 
cohort of approximately 20 subjects will be treated with a reduced dose of AZA (36 mg/m2, QD for 
5 days) without dose modification of venetoclax (400 mg, QD) for 28 days.  If 20% or more of these 
additional subjects experience DLTs during Cycle 1, a subsequent cohort of approximately 20 subjects 
may be treated with a reduced dose of AZA and/or reduced dosing duration per cycle of venetoclax.  
The recommended dose of venetoclax in combination with AZA will be such that fewer than 20% of 
subjects experienced a DLT during Cycle 1 in Part 1 (refer to Table 1). 
Table 1. 
Dose Levels for Venetoclax + Azacitidine for Subjects in Part 1 
Dose Level 
Venetoclax Dose 
Azacitidine Dose 
1 
400 mg × 28 days 
50 mg/m2 × 5 days 
–1 
400 mg × 28 days 
36 mg/m2 × 5 days 
–2 
400 mg × 21 days 
36 mg/m2 × 5 days 
–3 
400 mg × 21 days 
20 mg/m2 × 5 days 
 
Subjects are considered to have completed the study treatment once they complete 24 treatment 
cycles.  Subjects with controlled disease, who have not experienced a DLT, and who have tolerable side 
effects may continue to receive study drug for up to 48 cycles or until relapse, unacceptable toxicity 
occurs, or until the study closes.  The investigator may discontinue a subject from the study as deemed 
appropriate. 
As of 26 August 2021, 66 subjects were enrolled in Part 1 (Dose Confirmation). 
Part 3:  Dose Finding  
Part 3 (Dose Finding) will follow a Bayesian optimal interval (BOIN) design to guide dose-escalation and 
de-escalation decisions based on the cumulative number of subjects experiencing a DLT at the current 
dose level.  Table 2 gives the dose levels of venetoclax in combination with oral AZA to be explored.  
Venetoclax and oral AZA may be administered for up to 24 cycles. 
In the dose-escalation portion, each dose level will initially enroll at least 6 DLT-evaluable subjects.  The 
first cohort of subjects will be assigned to receive dose Level 1 (venetoclax [400 mg] QD on Days 1 to 21 
in combination with oral AZA [200 mg] QD on Days 1 to 14 of each 28-day cycle) with dose escalation or 
de-escalation for the subsequent cohort of subjects guided by a BOIN design.  Table 3 gives the BOIN 
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dose-escalation decision rule for a target toxicity rate of 20% and optimal interval of (16.9%, 25.1%).  
Approximately 12 subjects will be assigned to receive the preliminary RPTD identified during dose 
escalation. 
The safety expansion portion will enroll at least 12 additional subjects to receive venetoclax in 
combination with oral AZA at the preliminary RPTD identified from dose-escalation portion of Part 3. 
Subjects will be assessed for potential evidence of AML relapse through medical history, physical 
examination, and hematological laboratory review as detailed in the Operations Manual Section 3.14. 
Subjects with controlled disease who have not experienced a DLT and who have tolerable side effects 
may continue to receive study drugs for 24 cycles or until relapse or unacceptable toxicity occurs.  The 
investigator may discontinue a subject from the study as deemed appropriate.   
Subjects who discontinue study drug but have not had an event of documented relapse will return for 
post-treatment follow-up visits.  Subjects in Part 3 (Dose Finding) will return for post-treatment 
follow‑up visits every 3 months (± 28 days) for 1 year and then every 6 months (± 28 days) thereafter 
starting from study drug discontinuation until documented relapse or the study ends, whichever occurs 
first.  After relapse, survival information will be collected (e.g., via telephone calls and/or clinical visits) 
every 3 months (± 28 days) or more frequently at the sponsor's discretion for up to 2 years after relapse 
or until the sponsor's decision to stop follow-up. 
Table 2. 
Venetoclax and Oral AZA Dose Levels 
Dose Level 
Venetoclax Dose 
Oral AZA Dose 
–1a 
400 mg × 14 days 
200 mg × 14 days 
1b 
400 mg × 21 days 
200 mg × 14 days 
2 
400 mg × 21 days 
300 mg × 14 days 
3 
400 mg × 28 days 
300 mg × 14 days 
a. 
Dose level -1 may be explored if the starting dose is not tolerated. 
b. 
Starting dose level. 
 
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Table 3. 
Dose-Escalation Decision Rule 
Action 
Number of DLT-Evaluable Subjects at Current Dose Level 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Escalate if # subjects with DLT ≤ 
1 
1 
1 
1 
1 
1 
2 
2 
2 
Stay at current dose if # subjects with 
DLT =  
- 
- 
2 
2 
2 
2 
3 
3 
3 
De-escalate if # subjects with DLT ≥ 
2 
2 
3 
3 
3 
3 
4 
4 
4 
Eliminatea if # subjects with DLT ≥ 
3 
4 
4 
4 
5 
5 
5 
5 
6 
DLT = dose-limiting toxicity 
a. 
Eliminate current and higher dose levels (i.e., venetoclax dose level and oral AZA dose level ≥ current dose). 
 
As of 08 September 2022, 46 subjects were enrolled in Part 3 (Dose Finding). 
Part 3:  Randomization 
Part 3 (Randomization) was removed from Version 6.0 of this protocol. 
4.2 Discussion of Study Design 
Appropriateness of Measurements 
Standard clinical and laboratory procedures will be utilized in this study.  All efficacy measurements in 
this study are standard for assessing disease activity in subjects with AML.  All clinical and laboratory 
procedures in this study are standard and generally accepted. 
The PRO measures chosen for this study have been validated in cancer patients and include a generic 
health-related QoL measure (EQ-5D-5L), a cancer-specific health-related QoL measure that includes 
functional and symptom scales as well as a GHS scale (EORTC QLQ-C30), and a symptom-based measure 
to assess fatigue (PROMIS Fatigue SF 7a).  The specific symptoms and functional aspects assessed by 
these measures are considered to be among the most impactful to AML patients.4,39 
Suitability of Subject Population 
Subjects with AML have poor survival and high relapse rates.  The majority of patients with AML who 
achieve remission with induction chemotherapy will then go on to relapse.  The prevention of relapse is 
a major therapeutic challenge in the treatment of AML.  No post-consolidation treatment for prevention 
of relapse was previously established except for the use of allogeneic stem cell transplant for a select 
group of relatively fit patients and, more recently (2020), ONUREG (oral AZA) for patients with AML who 
achieved first CR or CRi following intensive induction chemotherapy and were not able to complete 
intensive curative therapy.31 
It is hypothesized that a reservoir of leukemia stem cells that persist after primary therapy ultimately 
expand and drive relapse in AML.  Combined therapy with venetoclax + AZA has been shown to 
eradicate leukemia stem cells through disruption of the metabolic machinery in AML.  These data 
support the conduct of a maintenance study incorporating both these agents. 
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Preliminary studies have demonstrated that both venetoclax and AZA can induce responses for subjects 
with AML and be dosed safely.  Therefore, given the high relapse rates and current limited effective 
options, and the safety of venetoclax and AZA to date, the subject population (subjects with AML in 
first remission after conventional chemotherapy) is suitable for treatment with venetoclax + AZA as 
maintenance therapy. 
Oral AZA was the first maintenance therapy to provide statistically significant and clinically meaningful 
improvements in survival relative to placebo in a similar patient population as this study with subjects 
who have AML in remission following intensive chemotherapy.31  Therefore, given the safety and 
efficacy of venetoclax and oral AZA to date, the subject population (subjects with AML in first remission 
after conventional chemotherapy) is suitable for treatment with venetoclax + oral AZA as maintenance 
therapy. 
Selection of Doses in the Study 
The maximum-tolerated dose (MTD) for venetoclax monotherapy has not been reached; however, 
1200 mg QD was safely dosed in Study M14-212 "A Phase 2 Study of ABT-199 in Subjects with Acute 
Myelogenous Leukemia (AML)."  In Study M14-212, subjects who did not respond at the 800-mg dose 
were allowed to dose escalate to 1200 mg.  None of the subjects who dose escalated to 1200 mg in 
Study M14-212 achieved a response upon escalation. 
Part 1 of this study consists of a dose confirmation cohort which will confirm the dose selection.  The 
target venetoclax dose for the initial cohort is 400 mg, a third of the dose safely administered to subjects 
with R/R AML as monotherapy in Study M14-212.  A dose of 400 mg was selected as the target dose as 
this is the approved dose in chronic lymphocytic leukemia (CLL) as monotherapy and the US Food and 
Drug Administration (FDA)-approved dose used in combination with AZA in AML (newly diagnosed 
subjects who are ineligible for intensive chemotherapy).  In the Phase 1b AML study, Study M14-358, 
subjects were safely administered 400 mg, 800 mg, and 1200 mg of venetoclax in combination with AZA. 
Although venetoclax 400 mg in combination with AZA treatment (75 mg/m2) in Study M14-358 was 
proven to be safe and is currently being administered in Study M15-656 "A Randomized, Double-Blind, 
Placebo Controlled Phase 3 Study of Venetoclax in Combination with Azacitidine Versus Azacitidine in 
Treatment Naïve Subjects with Acute Myeloid Leukemia Who Are Ineligible for Standard Induction 
Therapy" to subjects with active disease, subjects already in remission may benefit even greater from a 
regimen that is well tolerated.  Therefore, to reduce the rates of AEs and because this dose or lower has 
been proven to be pharmacodynamically active, AZA will be administered at 50 mg/m2 for 5 days 
(Days 1 - 5) for each 28-day cycle.40  The lead-in phase to confirm the dose for venetoclax + AZA (Part 1) 
will ensure that the thresholds of safety will be met.  In summary, venetoclax 400 mg QD in combination 
with AZA 50 mg/m2 QD is expected to be efficacious with an acceptable safety profile. 
Part 3 of this study consists of a dose-finding portion which will confirm the dose selection of venetoclax 
in combination with oral AZA.  The target venetoclax dose for the initial cohort is 400 mg, QD for 21 days 
for each 28-day cycle.  The target dose for the initial cohort for oral AZA is 200 mg (Days 1 to 14 for each 
28-day cycle).  Oral AZA has demonstrated a prolonged therapeutic activity over a 28-day cycle at this 
dose level when administered as a monotherapy.41 
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5 STUDY ACTIVITIES 
5.1 Eligibility Criteria 
A subject will be eligible for study participation if he/she meets the following criteria within 28 days 
prior to the first day of study drug administration. 
Consent 
 1. Subjects or their legally authorized representative (if permitted per local regulations) must be 
capable of understanding and complying with parameters as outlined in the protocol and must 
voluntarily sign and date an informed consent, approved by an independent ethics committee 
(IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific 
procedures. 
 
Demographic and Laboratory Assessments 
 2. Adult individuals ≥ 18 years old. 
 3. Subject must meet the following laboratory parameters, per laboratory reference range 
within the screening period prior to study drug administration: 
• 
creatinine clearance ≥ 30 mL/minute; calculated by the Cockcroft Gault formula or 
measured by 24-hour urine collection; 
• 
bilirubin < 3.0 × upper limit of normal (ULN) (adequate liver function) for Part 1, or 
bilirubin < 2.0 × ULN for Part 3; 
• 
absolute neutrophil count (ANC) ≥ 1,500/µL; 
• 
platelets ≥ 100,000/µL. 
 4. Subject is willing and able to comply with procedures required in this protocol. 
 
Disease Activity 
 5. Diagnosis of newly diagnosed AML. 
 6. Subject meets the following disease activity criteria: 
• 
confirmation of AML by the WHO criteria (2016)  
• 
confirmation of CR or CRi following completion of intensive Induction and Consolidation 
chemotherapies (note:  additional consolidation therapy on-study will be considered a 
protocol violation)  
• 
subject should be within one of the following time windows: 
• 
achieved first CR or CRi (after induction) within 120 days of the first dose of study drug 
(Cycle 1 Day 1), or 
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• 
be no more than 75 days since last dose of intensive conventional (including both 
induction and consolidation) chemotherapies until enrollment (Cycle 1 Day 1) 
• 
AML has intermediate or poor risk cytogenetics per National Comprehensive Cancer 
Network (NCCN) 2016 criteria (Appendix E)42 
 7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
 
Subject History 
 8. No history of APL. 
 9. No history of active central nervous system involvement with AML. 
 10. Subjects with human immunodeficiency virus (HIV) will be permitted provided that subjects 
have stable disease and are on antiretroviral medication (highly active antiretroviral therapy 
[HAART]) that are not strong or moderate cytochrome P450 (CYP)3A inducers.  Appropriate dose 
adjustments for venetoclax will be made for HAART therapy implicated in drug-drug 
interactions. 
 11. No subjects with active hepatitis B virus (HBV) and/or hepatitis C virus (HCV) with high viral 
titers.  Subjects with HBV inactive carrier status and/or HCV with low viral titers on antivirals 
(nonexclusionary medications) are eligible. 
 12. No known active SARS-CoV-2 infection.  If a subject has signs/symptoms suggestive of SARS-
CoV-2 infection, they should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2.  
Note:  SARS-CoV-2 diagnostic tests should be applied following local 
requirements/recommendations.  Subjects who do not meet SARS-CoV-2 infection eligibility 
criteria must be screen failed and may only rescreen once (Section 4.1). 
 13. No cardiovascular disability status of New York Heart Association Class > 2.  Class 2 is defined 
as cardiac disease which subjects are comfortable at rest but ordinary physical activity results in 
fatigue, palpitations, dyspnea, or angina pain. 
 14. No chronic respiratory disease that requires continuous oxygen or significant history of 
renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular 
disease, any other medical condition that, in the opinion of the investigator, would adversely 
affect his/her participating in this study. 
 15. No malabsorption syndrome or other condition that precludes enteral route of 
administration. 
 16. No evidence of other clinically significant uncontrolled systemic infection requiring therapy 
(viral, bacterial, or fungal). 
 17. No psychiatric illness/social situation that would limit compliance with the study. 
 18. No history of any malignancy with the exception of: 
• 
Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; 
• 
Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; 
• 
Previous malignancy confined and surgically resected (or treated with other modalities) with 
curative intent; 
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• 
Prior history of malignancy which is considered to be cured by the investigator. 
 19. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug. 
 20. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class. 
 21. Subject must not have been treated with a medical product without any global regulatory 
approvals within 30 days or 5 half-lives of the drug (whichever is shorter) prior to Cycle 1 Day 1. 
 22. Subject must not be currently receiving AML treatment in any other clinical study. 
 23. No history of allogeneic stem cell transplantation and subject is not a candidate for 
allogeneic stem cell transplantation and will not proceed with transplantation as a decision has 
been made on the recommendation of the treating physician or subject's preference, or a 
suitable donor source cannot be identified. 
 24. No history of autologous stem cell transplantation for AML. 
 
Contraception 
 25. For all females of childbearing potential; a negative serum pregnancy test at the screening 
visit and a negative urine pregnancy test at baseline prior to enrollment. 
 26. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 through at least 6 months after the last dose 
of AZA or oral AZA and 30 days after the last dose of venetoclax. 
 27. Female who is not pregnant, breastfeeding, or considering becoming pregnant from Study 
Day 1 through at least 6 months after the last dose of AZA or oral AZA and 30 days after the last 
dose of venetoclax. 
 28. If male, and is sexually active with female partner(s) of childbearing potential, he must 
agree, from Study Day 1 through 3 months after the last dose of AZA or oral AZA and 30 days 
after the last dose of venetoclax, to practice the protocol-specified contraception. 
 29. Male who is not considering fathering a child or donating sperm from Study Day 1 through 
at least 3 months after the last dose of AZA or oral AZA and 30 days after the last dose of 
venetoclax. 
 
Concomitant Medications 
 30. Subject must not have received any live vaccine within 4 weeks prior to enrollment or not 
be expected to need or to receive a live vaccination during study participation including within 
3 months of last dose of an oncologic therapy or within 6 months of receiving any anti-B-cell 
antibodies or within 12 months after remission. 
 31. Subject must not have received a known strong or moderate inducer of CYP3A 7 days 
before study drug administration.  Subject must not have known medical conditions requiring 
chronic therapy of moderate CYP3A inducers. 
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 32. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges), or star fruit within 3 days before study drug 
administration. 
 
5.2 Contraception Recommendations 
Contraception Requirements for Females 
Subjects receiving study drug must follow the following contraceptive guidelines as specified: 
• 
Females, Nonchildbearing Potential 
Females do not need to use birth control during or following study drug treatment if considered 
of nonchildbearing potential due to meeting any of the following criteria: 
• 
Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause. 
• 
Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone level > 40 IU/L. 
• 
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy). 
• 
Females who have not experienced menarche (at least 1 menstrual period). 
• 
Females, Childbearing Potential 
If a female does not meet the definition of a female of non-childbearing potential above, she 
would be considered to be a female of childbearing potential. 
• 
Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 6 months after the last dose of AZA or oral AZA and at least 30 days after the last 
dose of venetoclax, when the last dose of AZA or oral AZA was at least 6 months prior. 
• 
Females of childbearing potential must use a contraceptive method listed below that is 
highly effective (with a failure rate of < 1% per year, when used consistently and correctly): 
 
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days prior to study 
baseline (Day 1).  Also, subjects must use a barrier method during this study from initial study drug 
administration to at least 30 days after the last dose of venetoclax and at least 6 months after the last 
dose of AZA or oral AZA. 
• 
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study baseline (Day 1).  Also, subjects 
must use a barrier method during this study from initial study drug administration to at least 30 
days after the last dose of venetoclax and at least 6 months after the last dose of AZA or oral 
AZA. 
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• 
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure). 
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Vasectomized partner (provided the partner has received medical confirmation of the surgical 
success of the vasectomy and is the sole sexual partner of the trial subject). 
• 
Practice true abstinence, defined as:  Refraining from heterosexual intercourse when this is in 
line with the preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable). 
 
If required per local practices, one of the following should be used in addition to one of the birth control 
methods listed above (excluding true abstinence): 
• 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, initiated at least 30 days prior to Study Day 1; 
• 
male or female condom with or without spermicide; 
• 
cap, diaphragm, or sponge with spermicide; or 
• 
a combination of male condom with cap, diaphragm, or sponge with spermicide (double barrier 
method). 
Contraception recommendations related to use of concomitant therapies prescribed should be 
based on the local label. 
 
Contraception Requirements for Males 
Male subjects are eligible to participate if they agree to the following from Study Day 1 and for at least 
3 months after the last dose of AZA or oral AZA and 30 days after the last dose of venetoclax: 
• 
Refrain from donating sperm 
PLUS, either: 
• 
Practice true abstinence, defined as: Refraining from heterosexual intercourse when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable. 
OR 
• 
Use a male condom (even with a successful vasectomy) with female partner use of an additional 
highly effective contraceptive method with a failure rate of < 1% (when used consistently and 
correctly) per year 
AND 
• 
Advise of the benefit for a female partner to use a highly effective method of contraception (as 
a condom may break or leak) if having sexual intercourse with a woman of childbearing 
potential who is not currently pregnant 
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Highly effective methods of birth control (with a failure rate of < 1%, when used consistently and 
correctly) are the following: 
• 
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days 
prior to study baseline (Day 1). 
• 
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study baseline (Day 1). 
• 
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure). 
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject). 
 
5.3 Prohibited Medications and Therapy 
In addition to the medications and therapy listed in the eligibility criteria (Concomitant Medications, 
Section 5.1), the following are not allowed during the study (refer to the Operations Manual Appendix J): 
• 
strong CYP3A inducers (consider alternative treatments with less CYP3A induction) 
• 
grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) 
and star fruit 
• 
adjuvant therapies, concomitant medications, or herbal substances that exert 
immunomodulating or antitumor activity 
 
For subjects receiving Dose Level 1 or Dose Level 2 in the dose-escalation portion of Part 3 (Dose 
Finding), the following concomitant medications are also not allowed from Cycle 1 Day 7 through Cycle 1 
Day 22: 
• 
moderate CYP3A inducers 
• 
strong or moderate CYP3A inhibitors 
• 
P-glycoprotein (P-gp) inhibitors 
 
For all subjects, the following are not allowed during the study (after enrollment on Cycle 1 Day 1): 
• 
additional consolidation chemotherapy 
• 
cytotoxic chemotherapy agents or experimental agents 
• 
targeted therapy (e.g., FLT3 inhibitors) (note: subjects who received targeted therapies during 
Induction and/or Consolidation are allowed in the study) 
 
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Subjects must be consented for the study prior to discontinuing any prohibited medications for the 
purpose of meeting study eligibility. 
5.4 Prior and Concomitant Therapy 
If a subject reports taking any over-the-counter or prescription medications, vitamins, and/or herbal 
supplements or if administration of any medication becomes necessary, beginning with the screening 
visit through the end of the study, the name of the medication, dosage information including dose, 
route and frequency, date(s) of administration including start and end dates, and reason for use must be 
recorded.  The investigator should review all concomitant medications for any potential drug-drug 
interactions. 
The following concomitant medications/therapy are permitted as needed and per institutional 
guidelines: 
• 
supportive care medication; 
• 
anti-infectives, antiemetics, antidiarrhea, and other standard supportive care medication; 
• 
transfusion of blood and blood products; and 
• 
granulocyte-colony stimulating factor (G-CSF; may be administered when Grades 3 to 4 
neutropenia occurs per clinical practice). 
 
In addition, the following apply (except for subjects receiving Dose Level 1 or Dose Level 2 in the 
dose-escalation portion of Part 3 [Dose Finding], from Cycle 1 Day 7 through Cycle 1 Day 22 which 
prohibit the following): 
• 
Concomitant use of a moderate CYP3A inducer should be avoided.  Alternative treatments with 
less CYP3A induction should be considered. 
• 
Herbal supplements should be discouraged unless known not to be CYP3A active (inducers or 
inhibitors). 
• 
If a P-gp inhibitor must be used, monitor closely for signs of toxicities or follow local label as 
applicable. 
• 
Concomitant use of narrow therapeutic index P-gp substrates should be avoided.  If a narrow 
therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before 
venetoclax. 
 
CYP3A inhibitors and inducers should only be used when no appropriate therapeutic alternative exists.  
Co-administration of a strong or moderate CYP3A inhibitor requires a specified venetoclax dose 
reduction as presented in Table 4.  The venetoclax dose that was used prior to concomitant use of a 
strong or moderate CYP3A inhibitor should be resumed 2 to 3 days after discontinuation of the inhibitor. 
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Table 4. 
Venetoclax Dose Modification when Co-Administered with Strong or Moderate 
CYP3A Inhibitors 
Assigned Venetoclax Dose 
Venetoclax Dose if Co-
Administered with a Moderate 
CYP3A Inhibitor 
Venetoclax Dose if Co-Administered 
with a Strong CYP3A Inhibitor 
400 mg 
200 mg 
70 mga or 100 mgb,c 
CYP = cytochrome P450 
a. 
United States, China, Israel, Taiwan, and Russia will dose reduce to venetoclax 70 mg when co-administered with 
Posaconazole. 
b. 
All other countries will dose reduce to venetoclax 100 mg when co-administered with Posaconazole. 
c. 
All countries will dose reduce to venetoclax 100 mg when co-administered with other strong CYP3A inhibitors. 
 
Subjects who are taking a strong or moderate CYP3A inhibitor before Cycle 1 Day 1 would start 
venetoclax at a reduced dose on Cycle 1 Day 1 according to Table 4 and may receive venetoclax 400 mg 
2 to 3 days after discontinuation of the CYP3A inhibitor. 
Breast cancer resistance protein (BCRP) inhibitors are not expected to result in clinically relevant effects 
on venetoclax exposure.43  When coadministered with a BCRP inhibitor, no dose adjustment for 
venetoclax will be necessary or follow local label as applicable. 
Organic anion-transporting polypeptide (OATP) inhibitors are not expected to result in clinically relevant 
effects on venetoclax exposure.43  When coadministered with an OATP inhibitor, no dose adjustment for 
venetoclax will be necessary. 
In vitro, venetoclax is a BCRP inhibitor and a weak OATP1B1 inhibitor.  When a BCRP or OATP substrate 
is coadministered with venetoclax, follow the local label as applicable. 
Subjects should not receive live vaccines within 3 months of last dose of an oncologic therapy and within 
6 months of receiving any anti-B-cell antibodies.  Additionally, live vaccines should not be given within 
12 months remission and lymphocyte count must be > 1,500/μL. 
Any questions regarding concomitant or prior therapy should be raised to the AbbVie TA MD.  
Information regarding potential drug interactions with venetoclax, AZA, or oral AZA can be located in the 
venetoclax Investigator's Brochure,36 the AZA SmPC,37 the oral AZA SmPC38, package inserts, prescribing 
information, and/or their equivalents. 
COVID 19 Pandemic Related Vaccination Guidance 
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., messenger RNA [mRNA], 
non-replicating viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered 
during screening, the treatment period, or follow-up, as long as components of the vaccine are not 
contraindicated. 
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject. 
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The potential impact of venetoclax on SARS-CoV-2 vaccination is unknown.  Therefore, study drug 
should be administered as follows: 
• 
The first dose of study drug(s), when possible, is preferred to be given at least ± 7 days from the 
SARS-CoV-2 vaccine administration. 
 
Note:  The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
vaccination course. 
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines in subjects with AML and as more data are collected in real-world scenarios and 
clinical trials. 
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual for instructions on reporting any AEs associated with COVID-19 vaccine. 
5.5 Withdrawal of Subjects and Discontinuation of Study 
Withdrawal from Study Treatment 
A subject may voluntarily withdraw or be withdrawn from the study treatment at any time. These 
subjects will be included in the efficacy and safety analyses.  Reasons for withdrawal from study 
treatment include, but are not limited to, the following: 
• 
The investigator believes discontinuation is in the best interest of the subject. 
• 
The subject requests withdrawal from the study or study treatment. 
• 
Eligibility criteria violation was noted after the subject started the study and continuation on the 
study would place the subject at risk as determined by the investigator or the AbbVie TA MD. 
• 
The introduction of prohibited medication putting the subject at undue risk that may lead to 
withdrawal from the study as determined by the investigator or the AbbVie TA MD. 
• 
Clinically significant abnormal laboratory results or AEs which rule out continuation of the study 
drug with reductions in the lowest available dose, as determined by the investigator or the 
AbbVie TA MD. 
• 
The subject becomes pregnant while on study drug. 
• 
The investigator determines the subject is significantly noncompliant with study procedures. 
• 
Disease relapse:  reappearance of ≥ 5% blasts after CR or CRi in peripheral blood or bone 
marrow or development of extramedullary disease. 
 
All subjects will complete the procedures outlined for the final visit, within 2 weeks of the last dose of 
study drug, and a 30-day follow-up visit, also calculated from the last dose of study drug. 
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation. 
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Discontinuation of Study 
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at their site if they have safety concerns.  If AbbVie terminates the study for safety 
reasons, AbbVie will promptly notify the investigator. 
COVID 19 Pandemic Related Acceptable Protocol Modification 
During the COVID-19 pandemic, it may be necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix J. 
The investigator should contact the TA MD before discontinuing a subject from the study for a reason 
other than "planned per protocol," to ensure all acceptable mitigation steps have been explored. 
Refer to the Operations Manual in Appendix J for details on how to handle study activities/procedures. 
Interruption/Discontinuation of Study Drug Due to COVID 19 Infection 
During the study drug dosing period, a subject with confirmed (viral test positive) or suspected 
COVID-19 infection can only be dosed with study drug if the following COVID-19 viral clearance criteria 
are met: 
• 
At least 10 days since first positive test result have passed in asymptomatic subjects or at least 
10 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms. 
 
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie TA MD, along with the possibility of premature discontinuation from the study drug 
dosing period.  Follow guidelines in Section 5.6 for subjects who discontinue study drug. 
5.6 Follow-Up for Subject Withdrawal from Study 
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue the 
study drug should continue to be followed for all regularly scheduled visits unless subjects have decided 
to discontinue the study participation entirely (withdrawal of informed consent).  Subjects should be 
advised on the continued scientific importance of their data even if they discontinue treatment with 
study drug early. 
Part 3 subjects who discontinue study drug prior to Cycle 24 or who have completed 24 cycles but have 
not had an event of documented relapse will return for post-treatment follow-up visits every 3 months 
(± 28 days) for 1 year and then every 6 months (± 28 days) thereafter starting from study drug 
discontinuation until documented relapse or the study ends, whichever occurs first.  After relapse, 
survival information will be collected (e.g., via telephone calls and/or clinical visits) every 3 months 
(± 28 days) or more frequently at the sponsor's discretion for up to 2 years after relapse or until the 
sponsor's decision to stop follow-up. 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
If a Part 3 subject withdraws from study follow-up or withdraws permission for the collection of their 
personal data, the study staff may still use available public records to obtain information about survival 
status only, as appropriate per local regulations. 
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed that the patient 
has withdrawn consent and no longer wishes biomarker research to continue, samples will not be 
analyzed, no new biomarker analysis data will be collected for the withdrawn subject or added to the 
existing data or database(s).  A subject may withdraw consent for optional biomarker research at any 
time and remain in the clinical study.  Data generated from clinical study and/or optional biomarker 
research, before subject withdrawal of consent, will remain part of the study results. 
5.7 Study Drug 
Study drugs refer to drugs that are used (or can be used) in this study to assess the safety and the 
efficacy of the Investigational Product.  Investigators will assess the relationship of AEs to the use of 
study drugs (see Table 5 for the list of study drugs). 
Venetoclax manufactured by AbbVie will be administered orally, QD for each 28-day cycle beginning on 
Day 1 for subjects in Part 1 (Dose Confirmation) and Part 3 (Dose Finding). 
If vomiting occurs after taking venetoclax, another dose should not be taken that day.  In cases where a 
dose of venetoclax is missed or forgotten, the subject should take the forgotten dose as soon as 
possible, provided that the dose is taken within 8 hours of the missed dose and is taken with food and 
water.  Otherwise, the missed dose should not be taken and the subject should take the next dose at the 
next scheduled dosing time. 
AZA will be administered SC or IV, QD on Days 1 to 5 of each 28-day cycle, for up to 6 cycles (refer to 
Operations Manual Section 6.1) for subjects in Part 1.  AZA must be prepared and administered by the 
route indicated in the package insert, prescribing information, local SmPC, or equivalent. 
Oral AZA will be administered QD on Days 1 to 14 of each 28-day cycle for up to 24 cycles for subjects in 
Part 3. Subjects will be trained to self-administer oral AZA (refer to Operations Manual Section 6.1). 
If vomiting occurs after taking oral AZA, a second dose should not be taken that day as subjects must not 
take 2 doses on the same day. 
In cases where a dose of oral AZA is missed or forgotten, the subject should take the forgotten dose as 
soon as possible and resume the normal schedule in the following day. 
The investigational medicinal products for this study are venetoclax, AZA, and oral AZA.  AbbVie will 
supply venetoclax, AZA, and oral AZA.  AbbVie-provided study drug should not be substituted or 
alternately sourced unless otherwise directed by AbbVie.  AbbVie will not supply drugs other than 
venetoclax, AZA, and CC486.  Non-investigational medicinal product (i.e., BSC) must be obtained 
commercially.  AbbVie will not provide or reimburse for treatments administered for BSC. 
If a subject is unable to come to the study site to pick up their study drug due to COVID-19, a direct-to-
patient (DTP) study drug shipment can be made from the study site to the subject if allowed by local 
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regulations.  AbbVie will submit any required notifications to the regulatory authority as applicable.  
Refer to the Operations Manual in Appendix J for details on DTP shipment of study drug. 
Subjects will record venetoclax dosing in a subject dosing diary.  Subjects who are treated with oral AZA 
will also record oral AZA dosing in a subject dosing diary (refer to Operations Manual Section 3.17). 
The subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit.  The study site personnel will document compliance. 
Study drug information is presented in Table 5. 
Table 5. 
Study Drug Information 
Investigational 
Product 
Manufacturer 
Mode of 
Administration 
Dosage 
Form 
Strength 
Venetoclax 
AbbVie 
Oral 
Film-coated 
tablet 
100 mg, 50 mg, 10 mg 
Azacitidine 
Celgene or generic 
Subcutaneous 
or intravenous 
Powder for 
suspension 
or solution 
100 mg (25 mg/mL or 
10 mg/mL after 
reconstitution) 
Azacitidine 
BMS / Celgene / Fisher or 
generic 
Oral 
Film-coated 
tablet 
200 mg, 300 mg 
Note: 
Venetoclax, azacitidine, and oral AZA will be provided as open-label supplies for Part 1 and Part 3 (Dose Finding).   
 
Venetoclax will be packaged in bottles with quantities sufficient to accommodate study design.  AZA 
(IV/SC) will be in single-use vials packaged in cartons to accommodate the study design.  Each vial must 
be reconstituted and administered by the route as per the local AZA label.  Oral AZA will be packaged in 
blister cards with quantities sufficient to accommodate study design.  Each kit will be labeled per local 
requirements and this label must remain affixed to the kit.  Upon receipt, study drug should be stored as 
specified on the label and kept temperature monitored in a secure location.  Each kit will contain a 
unique kit number.  This kit number is assigned to a subject via interactive response technology (IRT) 
and encodes the appropriate study drug to be dispensed at the subject's corresponding study visit.  Site 
staff will complete all blank spaces on the label before dispensing to subjects.  Study drugs will only be 
used for the conduct of this study. 
Upon completion of or discontinuation from study treatment, all original study drug units (containing 
unused study drugs) will be returned to the sponsor (or designee) or destroyed on site.  All return or 
destruction procedures will be according to instructions from the sponsor and according to local 
regulations following completion of drug accountability procedures. 
5.8 Drug Assignment 
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  All subsequent drug assignments and changes in subject status (e.g., study completion) will be 
registered in the IRT. 
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5.9 Protocol Deviations 
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified), the investigator is responsible for notifying independent 
ethics committee (IEC)/independent review board (IRB), regulatory authorities (as applicable), and 
AbbVie. 
5.10 Publication Policy 
AbbVie as the sponsor has proprietary interest in this study.  Authorship and manuscript composition 
will reflect joint cooperation between multiple investigators and sites and sponsor personnel.  
Authorship will be established prior to the writing of the manuscript.  As this study involves multiple 
centers, no individual publications will be allowed prior to completion of the final clinical study report of 
the multicenter study except as agreed with the sponsor. 
The sponsor will comply with the requirements for publication of study results.  In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. 
Investigators are NOT employed by the organization sponsoring the study.  There is an agreement 
between investigators and the sponsor (or its agents) that restricts the investigator's rights to discuss or 
publish study results after the study is completed. 
AbbVie requests that any investigator or institution that plans on presenting/publishing results, provide 
written notification of their request 60 days prior to their presentation/publication.  AbbVie requests 
that no presentation/publication will be instituted until 12 months after a study is completed or after 
the first presentation/publication, whichever occurs first.  A delay may be proposed for a 
presentation/publication if AbbVie needs to secure patent or proprietary protection. 
6 SAFETY CONSIDERATIONS 
6.1 Complaints and Adverse Events 
Complaints 
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie. 
Product Complaint 
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s). 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues. 
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.   
Reporting will be done via electronic data capture (EDC).  The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie.  A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue.  If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie. 
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.  Product 
complaints occurring during the study will be followed up to a satisfactory conclusion. 
Medical Complaints/Adverse Events and Serious Adverse Events 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not the event is considered causally related to the use of the 
product. 
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations," such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, meets protocol-specific criteria (see 
Section 6.2 regarding toxicity management), and/or if the investigator considers them to be AEs. 
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion. 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
preplanned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE. 
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If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance as an SAE within 24 hours of the site being made aware of 
the SAE (refer the Operations Manual Section 4.3 for reporting details and contact information): 
Death of Subject 
An event that results in the death of a subject. 
Life-Threatening 
An event that, in the opinion of the investigator, would have resulted 
in immediate fatality if medical intervention had not been taken.  This 
does not include an event that would have been fatal if it had 
occurred in a more severe form. 
Hospitalization or 
Prolongation of 
Hospitalization 
An event that results in an admission to the hospital for any length of 
time or prolongs the subject's hospital stay.  This does not include an 
emergency room visit or admission to an outpatient facility. 
Congenital Anomaly 
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss. 
Persistent or Significant 
Disability/Incapacity 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle). 
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome 
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes listed 
above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important medical 
event along with any suspected transmission of an infectious agent 
via a medicinal product if no other serious criterion is applicable.  
Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug 
abuse. 
 
All serious and nonserious AEs reported from the time of study drug administration until 30 days after 
discontinuation of study drug administration will be collected whether solicited or spontaneously 
reported by the subject.  After 30 days following the last dose of study drug or completion of study 
treatment only spontaneously reported SAEs will be collected (nonserious AEs will not be collected).  In 
addition, study procedure-related SAEs and nonserious AEs will be collected from the time the subject 
signs the study-specific informed consent. 
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The following definitions will be used for a Serious Adverse Reaction (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR): 
SAR 
Defined as all noxious and unintended responses to an Investigational Medicinal 
Product (IMP) related to any dose administered that result in an SAE as defined 
above. 
SUSAR 
A suspected SAR:  refers to individual SAE case reports from clinical trials where 
a causal relationship between the SAE and the IMP was suspected by either the 
sponsor or the investigator, is not listed in the applicable Reference Safety 
Information, and meets one of the above serious criteria.  All individually 
reported SARs are considered suspected. 
 
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements, including reporting to Eudravigilance database in accordance with EU Clinical Trial 
Regulation. 
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects. 
Adverse Events of Special Interest 
The following AE of special interest will be monitored during the study: 
• 
tumor lysis syndrome (TLS) 
 
Adverse Event Severity and Relationship to Study Drug 
The investigators will rate the severity of each AE according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.  If a reported AE increases in 
severity, the initial AE should be given an outcome date and a new AE must be reported on a different 
onset date than the end date of the previous AE to reflect the change in severity.  The dates on the AEs 
cannot overlap.  For all reported SAEs that increase in severity, the supplemental electronic case report 
forms (eCRFs) also need to be updated to reflect any changes due to the increase in severity. 
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For AEs not captured by the NCI CTCAE, the following should be used: 
Grade 1 
The AE is transient and easily tolerated by the subject (mild). 
Grade 2 
The AE causes the subject discomfort and interrupts the subject's usual activities 
(moderate). 
Grade 3 
The AE causes considerable interference with the subject's usual activities and may 
be incapacitating (moderate to severe). 
Grade 4 
The AE is life-threatening and requires urgent intervention (severe). 
Grade 5 
The AE resulted in death of the subject (severe). 
 
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug: 
Reasonable 
Possibility 
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship. 
No Reasonable 
Possibility 
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship. 
 
Pregnancy 
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.5).  If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected. 
In the event of pregnancy occurring in a subject's partner during the study, written informed consent 
from the partner must be obtained prior to collection of any such information.  AbbVie will provide a 
separate consent form for this purpose.  Pregnancy in a subject's partners will be collected from the 
date of the first dose through 3 months after the last dose of AZA or oral AZA and 30 days after the last 
dose of venetoclax. 
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event. 
6.2 Toxicity Management 
The management of specific AEs and laboratory parameters is described below.  This includes AEs of 
neutropenia for venetoclax and known potential risks associated with AZA or oral AZA.  Subjects will be 
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monitored for these events throughout the study and treatment may be discontinued or adjusted as 
appropriate. 
Tumor Lysis Syndrome 
Subjects in this study will have AML after first remission (CR or CRi) resulting from conventional 
chemotherapy.  Therefore, although TLS is an identified risk with venetoclax treatment, TLS is highly 
unlikely to occur during this study because subjects will have relatively low levels of leukemic cells at the 
onset of venetoclax administration. 
Management of Treatment Related Neutropenia 
Venetoclax, AZA, and oral AZA may cause neutropenia.  Subjects with a history of neutropenia who have 
received multiple prior therapies may be at a particularly high risk.  Grade 3 or 4 neutropenia has been 
reported in subjects treated with venetoclax, AZA, and oral AZA.  Subjects will be managed for 
neutropenia as detailed below. 
Complete blood counts should be monitored throughout the treatment period.  Supportive measures 
including anti-infectives for prophylaxis or any signs of infection and prophylactic use of growth factors 
(e.g., G-CSF) should be considered. 
Management of Treatment Related Hematologic Toxicities 
Treatment may be withheld for any therapy-related Grade 4 hematologic toxicity if subject had 
≤ Grade 2 toxicity at baseline.  Treatment may be restarted after the toxicity has resolved to Grade 1 or 
75% of the baseline level (recovery) (Appendix D).  If the toxicity recurs, the dose reduction guidelines 
outlined in Table 6, Table 7, and Table 8 should be followed when resuming study drug following 
resolution.  Additional dose reductions may occur at the discretion of the investigator in consultation 
with the AbbVie TA MD. 
Management of Treatment Related Nonhematologic Adverse Events 
Treatment may be withheld for any clinically relevant ≥ Grade 3 nonhematologic AE.  Once the AE has 
resolved to Grade 1 or baseline grade level (recovery), treatment may be restarted.  If the toxicity 
recurs, the dose reduction guidelines outlined in Table 6, Table 7, and Table 8 should be followed when 
resuming study drug following resolution.  Additional dose reductions may occur at the discretion of the 
investigator. 
Management of Infection 
Anti-infective prophylaxis for bacterial, viral, and fungal infections is recommended for all subjects with 
ANC of < 500/μL at any time point.  Institutional infectious organisms and their drug resistance patterns 
should primarily be considered, and the choice of these agents should be based on regional guidelines 
or institutional standards.  The investigator should confirm that a concomitant medication/supplement 
can be safely administered with study drugs.  Some medications may require dose adjustments due to 
the potential for drug-drug interactions (Table 4). 
All subjects should be monitored for new onset hematologic toxicity, with dose delay or reduction as 
appropriate. 
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Management of Decrease in Spermatogenesis 
Venetoclax may cause a decrease in spermatogenesis.  Male subjects considering preservation of 
fertility should bank sperm before initiating treatment with venetoclax. 
Management of Diarrhea Grade ≥ 3 (Part 3 only) 
It is recommended that subjects experiencing diarrhea be managed according to the guidelines provided 
in Appendix F.  Antidiarrheal medication may be administered as prophylaxis against diarrhea and for 
treatment of any AEs of diarrhea.  In subjects not having problems during the first 2 cycles, the treating 
physician may discontinue use of antidiarrheal medications. 
Management of Nausea and Vomiting Grade ≥ 3 (Part 3 only) 
A serotonin (5-HT3) receptor antagonist (e.g., ondansetron) or other comparable medication should be 
administered as an antiemetic approximately 30 minutes prior to administration of study drug.  
Antiemetic medication(s) should be administered for treatment of any AEs of nausea and/or vomiting.  If 
there has been no nausea and/or vomiting during the first 2 cycles, the investigator may choose to omit 
antiemetic as required provided this is clearly documented in the eCRF. 
Refer to Appendix G for recommendations for management of treatment-induced nausea and GI events. 
Dose Modifications Based on Toxicities 
Subjects who interrupt study drug for drug-related toxicities should resume treatment when the toxicity 
has resolved.  Toxicity management guidelines and dose reductions will differ for subjects taking 
combination therapy (Table 7 and Table 8) compared to patients taking venetoclax monotherapy 
(Table 6). 
Dose Modifications for Venetoclax Monotherapy 
See Appendix D and Table 7 and Table 8 for dose interruptions and reductions for toxicities related to 
venetoclax + AZA or oral AZA and Table 6 for recommendations for reinitiating venetoclax treatment 
after interruption. 
If ANC drops below 500/µL, venetoclax may be interrupted for ANC recovery until ANC ≥ 500/µL or up 
until 14 days.  For subjects who have not recovered (ANC ≥ 500/µL) within or beyond 14 days of 
interruption, per investigator discretion, a bone marrow sample may be collected and analyzed to 
exclude relapse before proceeding.  If relapse is confirmed, subjects should be withdrawn from the 
study treatment for alternative therapy.  If relapse is excluded, per investigator discretion, growth factor 
support may be used to stimulate count recovery.  If a subject presents with new onset Grade 4 
neutropenia for more than 1 week during subsequent cycles, unless it is thought to be due to the 
underlying disease, venetoclax dosing may be interrupted until ANC recovery (≥ 500/µL) per investigator 
discretion and in consultation with the AbbVie TA MD.  Venetoclax may be reinitiated at a lower dose 
based on Table 6.  For subjects who require interruption or delay of study drug administration for 
cytopenia, venetoclax may be administered for 21 days out of 28 days during each of the subsequent 
cycles.  If a subject continues to have persistent cytopenia (i.e., ANC < 1,000/µL and/or platelets 
< 50,000/µL) venetoclax may be administered for 14 days out of 28 days during each of the subsequent 
cycles.  Subjects who develop cytopenias during subsequent cycles will have reduction in the duration of 
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venetoclax dosing as described in Table 6 beginning from whichever cycle cytopenias were first 
observed. 
Venetoclax dose modifications for possible drug-drug interactions are provided in the Section 5.4. 
Table 6. 
Reduced Duration of the Venetoclax Dosing Schedule for Subjects (Part 1 Only) 
Reduced Duration of 
Venetoclaxa 
Absolute 
Neutrophils/Platelets 
Venetoclax Dosing Schema 
First reduction 
< 500/µL/< 25,000/µL 
Venetoclax 400 mg Days 1 through 21  
for each 28-day cycle 
Second reduction 
< 1,000/µL/< 50,000/µL 
Venetoclax 400 mg Days 1 through 14  
for each 28-day cycle 
Subsequent reduction 
< 1,000/µL/< 50,000/µL 
Venetoclax 400 mg Days 1 through 10  
for each 28-day cycle 
a. 
Reduction in duration of venetoclax dosing should be followed sequentially in the order shown in the table above for 
subjects who require reductions in later treatment cycles. 
 
Dose Modifications for Venetoclax + Azacitidine (Part 1 Only) 
The use of venetoclax + AZA may exacerbate complications of myelosuppression which include 
infections and bleeding.  Venetoclax + AZA treatment may be interrupted, delayed, or reduced (refer to 
Table 7 and Appendix D) at the discretion of the investigator if the subject experiences 
myelosuppression-associated complications, such as those described below: 
• 
febrile neutropenia (temperature ≥ 38.5°C and ANC < 1,000/µL) 
• 
active viral, bacterial, or fungal infection (i.e., requiring IV antiinfectives or extensive supportive 
care) 
• 
hemorrhage (GI, genito-urinary, pulmonary with platelets < 25,000/µL, or any central nervous 
system hemorrhage) 
 
Treatment with venetoclax + AZA may be resumed once the above conditions have improved or have 
been stabilized with adequate treatment (i.e., anti-infective therapy, transfusions, or growth factors) 
and the toxicity has resolved to ≤ Grade 1 or has returned to baseline level.  Myelosuppression caused 
by venetoclax + AZA is reversible.  Complete blood and platelet counts should be performed regularly, as 
clinically indicated, and prior to each treatment cycle.  Subjects should not receive less than 400 mg for 
7 days and 20 mg/m2 for 5 days of venetoclax and AZA, respectively (Table 7). 
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Table 7. 
Dose Reduction for Venetoclax + Azacitidine for Subjects (Part 1 Only) 
If Current Dose Level 
Then Dose Reduction Level 
Venetoclax Dose 
Azacitidine Dose 
Venetoclax Dose 
Azacitidine Dose 
400 mg × 28 days 
50 mg/m2 × 5 days 
400 mg × 28 days 
36 mg/m2 × 5 days 
400 mg × 28 days 
36 mg/m2 × 5 days 
400 mg × 21 days 
36 mg/m2 × 5 days 
400 mg × 21 days 
36 mg/m2 × 5 days 
400 mg × 21 days 
20 mg/m2 × 5 days 
400 mg × 21 days 
20 mg/m2 × 5 days 
400 mg × 14 days 
20 mg/m2 × 5 days 
400 mg × 14 days 
20 mg/m2 × 5 days 
400 mg × 7 days 
20 mg/m2 × 5 days 
No further dose reductions 
 
Dose Modifications for Venetoclax + Oral AZA (Part 3 Only) 
The use of venetoclax + oral AZA may exacerbate complications of myelosuppression which include 
infections and bleeding.  Venetoclax + oral AZA treatment may be interrupted, delayed, or reduced 
(refer to Table 8 and Appendix D) at the discretion of the investigator if the subject experiences 
myelosuppression-associated complications such as those described below: 
• 
febrile neutropenia (temperature ≥ 38.5°C and ANC < 1,000/µL) 
• 
active viral, bacterial, or fungal infection (i.e., requiring IV antiinfectives or extensive supportive 
care) 
• 
hemorrhage (GI, genito-urinary, pulmonary with platelets < 25,000/µL, or any central nervous 
system hemorrhage) 
 
Dose interruptions greater than 21 days in duration must be discussed with the AbbVie TA MD to 
determine if the subject may continue on study treatment. 
Treatment with venetoclax + oral AZA may be resumed once the above conditions have improved or 
have been stabilized with adequate treatment (i.e., anti-infective therapy, transfusions, or growth 
factors) and toxicity has resolved to ≤ Grade 1 or has returned to baseline level.  Study treatment should 
not be resumed for at least 3 days following resolution of fever.  Complete blood and platelet counts 
should be performed regularly, as clinically indicated, and prior to each treatment cycle. 
In the event of toxicity, a maximum of 1 dose reduction to a daily dose of 400 mg for 14 days is 
permitted for venetoclax.  If toxicity persists in the subsequent cycle, a maximum of 1 dose reduction to 
a daily dose of 200 mg for 7 days is permitted for oral AZA.  The decision to modify a subject's treatment 
schedule of venetoclax from 21 to 14 days and oral AZA from 14 to 7 days should first be discussed with 
the TA MD.  Subjects should not receive less than 400 mg for 14 days and 200 mg for 7 days of 
venetoclax and oral AZA, respectively (Table 8).   
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Table 8. 
Dose Reduction for Venetoclax + Oral AZA for Subjects – Part 3: Dose Finding 
If Current Dose Level 
Then Dose Reduction Level 
Venetoclax Dose 
Oral AZA Dose 
Venetoclax Dose 
Oral AZA Dose 
400 mg × 21 days 
300 mg × 14 days 
400 mg × 21 days 
200 mg × 14 days 
400 mg × 21 days 
200 mg × 14 days 
400 mg × 14 days 
200 mg × 14 days 
400 mg × 14 days 
200 mg × 14 days 
400 mg × 14 days 
200 mg × 7 days 
No further dose reductions 
 
Any time during the study, if the subject must undergo emergency surgery, the study drug(s) should be 
interrupted at the time of the surgery.  After emergency surgery, allow reintroduction of study drug(s) 
once the physician has examined the surgical site and determined that it has healed and there is no sign 
of infection. 
6.3 Dose-Limiting Toxicity Criteria 
Part 1 (Dose Confirmation) and Part 3 (Dose Finding) 
Any of the following events during Cycle 1, which are considered possibly or probably related to the 
administration of venetoclax, will be considered a DLT: 
• 
Hematologic toxicities 
• 
any Grade ≥ 3 neutropenia lasting more than 7 days 
• 
any Grade ≥ 3 thrombocytopenia lasting more than 7 days 
• 
Nonhematologic toxicities 
• 
any Grade 3 AE lasting ≥ 72 hours except for Grade 3 hypersensitivity reactions or Grade 3 
localized injection-site toxicities 
• 
Grade ≥ 3 nausea, diarrhea, or vomiting despite adequate/maximal medical intervention 
lasting more than 7 days (Part 3 only) 
• 
any Grade ≥ 4 AE 
• 
any Hy's law cases defined as elevated aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) ≥ 3 × ULN with concurrent elevated total bilirubin ≥ 2 × ULN in the 
absence of elevated alkaline phosphatase or other conditions that could cause these 
laboratory abnormalities 
 
In addition, AEs not meeting above criteria but lead to omitting > 20% of the scheduled dose within the 
cycle should be considered as a DLT unless clearly related to underlying disease. 
Treatment delay due to toxicity lasting greater than 14 days since the last dose of venetoclax will also be 
considered DLT. 
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Any DLT will require an interruption and possible discontinuation of venetoclax or AZA.  Venetoclax may 
be reintroduced at a reduced dose if the toxicity grade returns to ≤ Grade 1 or to baseline if Grade 2 at 
study entry.  If the subject is considered to be acceptable for resumption of venetoclax dosing at the 
same dose or reduced dose on Day 7 of the dose interruption, the event should not be designated as a 
DLT. 
To be considered DLT-evaluable in Part 3, subjects must complete at least 80% of assigned venetoclax 
dosing and oral AZA dosing in Cycle 1 or experience a DLT in Cycle 1. 
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE 
7.1 Statistical and Analytical Plans 
The statistical methods provided in this protocol will be focused on primary and key secondary analyses.  
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the database lock. 
7.2 Definition for Analysis Populations 
The treated population includes all enrolled subjects who received at least one dose of both venetoclax 
and AZA in Part 1, as well as all subjects who received at least one dose of both venetoclax and oral AZA 
in Part 3.  Unless otherwise noted, the treated population will be used for all safety, efficacy, and 
baseline analyses. 
7.3 Statistical Analyses for Efficacy 
Efficacy Analyses 
Relapse Free Survival 
RFS is the time from drug assignment to the date of relapse or the date of death from any cause, 
whichever comes first.  If a subject does not experience an RFS event, the subject's data will be censored 
at the date of the subject's last disease assessment date (e.g., last bone marrow or hematology 
laboratory date) or date of drug assignment if the subject does not have any postbaseline disease 
assessment.  The distribution of RFS will be estimated using Kaplan-Meier methodology.44  
Overall Survival 
OS is defined as time from drug assignment to death from any cause.  OS data from subjects who have 
not died will be censored at the last known alive date.  The distribution of OS will be estimated for each 
study arm using Kaplan-Meier methodology.44 
MRD Conversion Rate 
The MRD conversion rate is defined as the proportion of subjects deemed MRD-positive (≥ 10 3) at 
screening who convert to MRD < 10 3 after drug assignment.  Subjects who are MRD < 10 3 at screening 
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will be excluded from the analysis.  The MRD conversion rate (95% CI) will be estimated using binomial 
distribution (Clopper-Pearson exact method).45  
Time to Deterioration in GHS/QoL Score 
Time to deterioration in GHS/QoL score is defined as time from drug assignment to death from any 
cause, or the first-time decrease of ≥ 10 points from baseline, whichever occurs first.46  Subjects without 
any of the specified events will be censored at subject's last EORTC QLQ-C30 assessment.  The 
distribution of time to deterioration in GHS/QoL will be estimated using Kaplan-Meier methodology.44  
Change in Global Fatigue Score from Baseline to Post baseline 
Fatigue will be assessed using the global fatigue score as measured by PROMIS Fatigue SF 7a.  Scores will 
be computed according to the PROMIS fatigue scoring manual.  Descriptive summaries will be provided 
for the change in fatigue score from baseline to post-baseline visits.  Subjects without baseline score or 
any postbaseline score will be excluded from the analysis. 
Additional Efficacy Analyses 
Details on other efficacy analyses (i.e., analysis based on ELN47 criteria if data are available) are provided 
in the SAP. 
7.4 Statistical Analyses for Safety 
Safety analyses will only include subjects in the Safety Analysis Set as defined in Section 7.2. 
Analysis of Adverse Events 
Treatment-emergent AEs will be summarized by preferred terms within a System Organ Class according 
to the Medical Dictionary for Regulatory Activities (MedDRA).  In addition, the percentage of subjects 
experiencing an AE at a given NCI CTCAE (version 5.0) toxicity grade and relationship to study drug will 
be provided.  Treatment-emergent SAEs will be summarized similarly. 
Analysis of Laboratory Data 
Change from baseline will be analyzed for each scheduled postbaseline visit for blood chemistry and 
hematology parameters.  Subjects who do not have a baseline measurement or do not have any 
postbaseline measurement will not be included. 
Where it is applicable, blood chemistry and hematology laboratory determinations will be categorized 
according to the NCI CTCAE.  Grades and shifts from baseline NCI CTCAE grades to maximum 
postbaseline grades will be assessed. 
7.5 Multiplicity Adjustment and Overall Type I Error Control 
Not applicable for this study. 
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7.6 Sample Size Determination 
Part 1 
The sample size for Part 1 is intended to provide an adequate safety evaluation.  The probability of 
observing at least 1 AE in a cohort of 20 subjects for various true AE rates is provided in Table 9. 
Table 9. 
Probability of Observing at Least One Adverse Event in a Cohort of 20 Subjects 
for Various True Adverse Event Rates 
True AE Rate 
Probability to Observe at Least 1 AE 
0.05 
0.64 
0.10 
0.88 
0.15 
0.96 
0.20 
0.99 
AE = adverse event 
 
Part 3 (Dose Finding) 
The total sample size for Part 3 (Dose Finding) will depend on the DLTs observed during dose escalation 
in Cycle 1 and is intended to provide an adequate safety evaluation of the RPTD of venetoclax in 
combination with oral AZA.  Approximately 24 subjects will be assigned to receive the RPTD of 
venetoclax in combination with oral AZA.  The probability of observing at least 1 AE in a cohort of 24 
subjects for various true AE rates is provided in Table 10. 
Table 10. 
Probability of Observing at Least 1 Adverse Event in a Cohort of 24 Subjects for 
Various True Adverse Event Rates 
True AE Rate 
Probability to Observe at Least 1 AE 
0.05 
0.71 
0.10 
0.92 
0.15 
0.98 
0.20 
> 0.99 
AE = adverse event 
 
8 ETHICS 
8.1 Independent Ethics Committee/Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
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consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved. 
8.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, EU Clinical Trial Regulation, applicable regulations, and guidelines 
governing clinical study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the investigator are specified in Appendix B. 
Investigators should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard. 
8.3 Subject Confidentiality 
Before subject data are shared with AbbVie, the study investigator and staff will replace the subject's 
name, address, and contact information with a generic code which AbbVie cannot link to that subject's 
identity to protect the confidentiality of the data. 
For the personal data that AbbVie Deutschland GmbH & Co acting as sponsor of the submitted study 
("AbbVie") controls and maintains, AbbVie Deutschland has developed a robust security program 
focused on due diligence in design, managed change, and information security governance.  Information 
Security policies govern the Information Security functions including identity and access management, 
operations, infrastructure, application, and third-party security requirements.  The risk-based AbbVie 
Data Classification Tool dictates the level of scrutiny and control required for the relevant activities per 
AbbVie's Information Security policies taking into account the sensitivity of the data. 
AbbVie has a data protection impact assessment program to ensure and document the appropriate 
controls and safeguards stated above are in place for clinical trial data that it controls and maintains and 
these processing activities respect privacy of clinical trial subjects.  AbbVie also maintains robust security 
incident response policies and procedures, including requirements for the containment of any data 
related incidents, the mitigation measures where needed, and notification to authorities or affected 
individuals where required. 
AbbVie Deutschland as the sponsor shall document any personal data breaches for which it is a 
controller and notify where required the competent national supervisory authority without undue delay 
and at the latest within 72 hours after becoming aware of such an incident.  AbbVie Deutschland shall 
create and maintain appropriate records of such an incident. 
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
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accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s), including EU Clinical Trial Regulation.   
10  DATA QUALITY ASSURANCE 
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements, including EU Clinical Trial Regulation. 
11  START AND COMPLETION OF THE STUDY 
The start-of-study is defined as the date of the first site activated. 
The end-of-study is defined as the date of the last subject's last visit or date of the last follow-up 
contact, whichever is later, in the last country where the study was conducted. 
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33. Roboz GJ, Montesinos P, Selleslag D, et al. Design of the randomized, Phase III, QUAZAR AML 
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41. Wei AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III 
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lymphocytic leukemia and Non-Hodgkin's lymphoma patients: a pooled population pharmacokinetic 
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47. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017;129(4):424-47. 
48. Ravandi F, Roboz GJ, Wei AH, et al. Management of adverse events in patients with acute myeloid 
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-24 
AUC from time 0 to 24 hours postdose 
AUCt 
AUC from time 0 to the time of the last measurable concentration 
AZA 
azacitidine 
BCL 
B-cell lymphoma 
BCL-w 
B-cell lymphoma - Walter and Eliza Hall Institute 
BCL-XL 
B-cell lymphoma - extra large 
BCRP 
breast cancer resistance protein 
BOIN 
Bayesian optimal interval 
BSC 
best supportive care 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
coronavirus disease – 2019 
CR 
complete remission 
CRi 
complete remission with incomplete blood count recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DSUR 
Development Safety Update Report 
DTP 
direct-to-patient 
EC 
Ethics Committee 
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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELN 
European LeukemiaNet 
EORTC 
European Organisation for Research and Treatment of Cancer 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality-of-Life 
Questionnaire - Core 30-item 
EQ-5D-5L 
European Quality-of-Life-5 dimensions-5-level 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GHS 
Global Health Status 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HAART 
highly active antiretroviral therapy 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agent 
HR 
hazard ratio 
IA 
interim analysis 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IE 
intercurrent events 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous 
IVRS 
Interactive Voice Response System 
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IWG 
International Working Group 
IWRS 
Interactive Web Response System 
Ki 
inhibition rate constant 
LDAC 
low-dose cytarabine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
mRNA 
messenger RNA 
MTD 
maximum-tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
OATP 
organic anion-transporting polypeptide 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
oral(ly) 
PRO 
patient-reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
prothrombin time 
QD 
once daily 
QoL 
quality-of-life 
RFS 
relapse-free survival 
RNA 
ribonucleic acid 
RPTD 
recommended Phase 3 dose 
R/R 
relapsed/refractory 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous(ly) 
SF 
short form 
SmPC 
Summary of Product Characteristics 
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SOC 
standard of care 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TA MD 
Therapeutic Area Medical Director 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
Tmax 
time to Cmax 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
WHO 
World Health Organization 
 
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR 
Protocol M19-708:  Multicenter, Phase 3 Study of Venetoclax and Azacitidine as Maintenance Therapy for Patients with Acute 
Myeloid Leukemia in First Remission After Conventional Chemotherapy (VIALE-M) 
Protocol Date:  26 April 2024 
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation (ICH) Good Clinical 
Practices (GCP), as well as applicable laws, regulations, and guidelines. Certain laws, regulations, or guidelines may apply to 
conduct of the study at investigator's site even if such laws, regulations, or guidelines originate in a foreign jurisdiction. The 
investigator agrees and acknowledges that applicable laws or regulations may require AbbVie to submit inspection reports, 
instances of significant non-compliance with the study protocol, or other documents regarding conduct of the study at the 
investigator's site to regulatory authorities, and such documents may be publicly disclosed by such authorities. In signing the 
Investigator Agreement, the investigator is agreeing to the following: 
1. 
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current protocol and 
operations manual, and making changes to a protocol only after notifying AbbVie and the appropriate Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), except when necessary to protect the subject from 
immediate harm. 
2. 
Personally conducting or supervising the described investigation(s). 
3. 
Informing all subjects, or persons used as controls, that the drugs are being used for investigational purposes and 
complying with the requirements relating to informed consent and ethics committees (e.g., IEC or IRB) review and 
approval of the protocol and its amendments. 
4. 
Reporting complaints that occur in the course of the investigation(s) to AbbVie. 
5. 
Reading the information in the Investigator's Brochure/safety material provided, including the instructions for use 
and the potential risks and side effects of the investigational product(s). 
6. 
Informing all associates, colleagues, and employees assisting in the conduct of the study about their obligations in 
meeting the above commitments. 
7. 
Maintaining adequate and accurate records of the conduct of the study, making those records available for inspection 
by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all study-related documents 
until notification from AbbVie. 
8. 
Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical protocol and 
all of its amendments. 
9. 
Reporting the following to AbbVie within 1 calendar day of becoming aware:  
• 
Any unanticipated problems involving risks to human subjects  
• 
Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has affected or is likely 
to affect to a significant degree the following: 
• 
Rights, safety, physical or mental integrity of the subjects in the clinical trial 
• 
Scientific value of the clinical trial, reliability or robustness of data generated 
Where required by local regulation, inform relevant Ethics Committees / Institutional Review Boards and other 
appropriate individuals (e.g., Co-ordinating Investigator, Institution Director). 
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, and regulatory 
inspection(s). 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Name of Principal Investigator (printed or typed) 
 
 
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES 
Name 
Title 
Functional Area 
  
 
Clinical Development 
 
 
Statistics 
 
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APPENDIX D. RECOMMENDED DOSE REDUCTIONS RELATED 
TO DRUG TOXICITIES 
Recommended Venetoclax/Azacitidine and Venetoclax/Oral AZA Dose Modifications for 
Toxicities 
Event 
Occurrence 
Action 
Nonhematologic Adverse Eventsa 
≥ Grade 3 nonhematologic 
toxicities 
1st occurrence 
Interrupt venetoclax + AZA or venetoclax + oral AZA.  Once 
the toxicity has resolved to Grade 1 or baseline level, 
venetoclax + AZA or venetoclax + oral AZA may be resumed 
at the same dose.  No dose modification is required. 
2nd and 
subsequent 
occurrences 
Interrupt venetoclax + AZA or venetoclax + oral AZA.  Follow 
dose reduction guidelines in Section 6.2 when resuming 
treatment with venetoclax + AZA or venetoclax + oral AZA 
after resolution.  A greater dose reduction may occur at the 
discretion of the investigator after discussion with TA MD. 
≥ Grade 3 diarrhea (Part 3 
only) 
1st occurrence 
Interrupt venetoclax + oral AZA and provide adequate/ 
maximum medical intervention (refer to Appendix F). 
Resume venetoclax + oral AZA at same dose when toxicity 
resolves to ≤ Grade 1. 
2nd and 
subsequent 
occurrences 
Interrupt venetoclax + oral AZA.  Follow dose reduction 
guidelines in Section 6.2 when resuming venetoclax + oral 
AZA after resolution.  A greater dose reduction may occur at 
the discretion of the investigator after discussion with TA 
MD. 
≥ Grade 3 nausea and/or 
vomiting (Part 3 only) 
1st occurrence 
Interrupt venetoclax + oral AZA and provide 
adequate/maximal medical intervention. 
Resume venetoclax + oral AZA at same dose when toxicity 
resolves to ≤ Grade 1. 
2nd and 
subsequent 
occurrences 
Interrupt venetoclax + oral AZA.  Follow dose reduction 
guidelines in Section 6.2 when resuming venetoclax + oral 
AZA after resolution.  A greater dose reduction may occur at 
the discretion of the investigator after discussion with TA 
MD. 
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Event 
Occurrence 
Action 
Hematologic Toxicitiesa,b 
Grade 3 neutropenia and/or 
thrombocytopenia if lasts 
7 days or longer; 
or 
Grade 3 neutropenia with 
infection or fever; 
or 
Grade 3 thrombocytopenia 
with hemorrhage; 
or 
All Grade 4 hematologic 
toxicities (except 
lymphopenia) 
1st occurrence 
Interrupt venetoclax + AZA or venetoclax + oral AZA.  
Treatment may be resumed at the same dose once the 
condition(s) have improved or have been stabilized with 
adequate treatment (anti-infective therapy, transfusions, or 
growth factors) and toxicity has resolved to ≤ Grade 1 or has 
returned to 75% of the baseline level, as assessed by 
investigator.  Dose interruption in case of prolonged toxicity 
(≥ 14 days) should be discussed with the TA MD.  Any dose 
reduction should be discussed with the TA MD when 
resuming treatment with venetoclax + AZA or venetoclax + 
oral AZA after resolution. 
2nd and 
subsequent 
occurrence 
Interrupt venetoclax + AZA or venetoclax + oral AZA.  Follow 
dose reduction guidelines in Section 6.2 when resuming 
treatment with venetoclax + AZA or venetoclax + oral AZA 
after resolution (resolved to ≤ Grade 1 or returned to 75% of 
the baseline level as assessed by investigator).  Additional 
dose reductions may occur at the discretion of the physician 
and in consultation with the TA MD. 
Consider discontinuing venetoclax for subjects who require dose reductions to less than 100 mg for more than 
2 weeks. 
AZA = azacitidine; TA MD = Therapeutic Area Medical Director 
a. 
Once a dose has been reduced, the dose will not be increased again. 
b. 
There is no increase in oral AZA dose independent of percentage of blasts in the bone marrow. 
 
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APPENDIX E. NCCN RISK CATEGORIZATION:  GUIDELINES FOR 
AML, VERSION 2, 2016 
Risk Category 
Cytogenetic 
Favorable Risk 
Core binding factor:  inv(16) or t(16; 16) 
or t(8; 21) 
t(15; 17) 
Intermediate Risk 
Normal cytogenetics 
+8 alone 
t(9; 11) 
Other non-defined 
Poor Risk 
Complex (≥ 3 clonal chromosomal abnormalities) 
Monosomal karyotype 
–5,5q–, –7,7q– 
11q23-non t(9; 11) 
Inv(3), t(3;3) 
t(6; 9) 
t(9;22) 
AML = acute myeloid leukemia; NCCN = National Comprehensive Cancer Network 
 
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APPENDIX F. RECOMMENDATIONS FOR MANAGEMENT OF 
TREATMENT-INDUCED DIARRHEA 
The following published guidelines (Benson et al 2004) were modified to be consistent with the clinical 
study protocol. 
 
Benson AB, Ajani JA, Catalano RB, et.al.  Recommended guidelines for the treatment of cancer treatment-induced diarrhea.  
2004.  J Clin Oncol.  22(24):2918-26. 
 
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APPENDIX G. RECOMMENDATIONS FOR MANAGEMENT OF 
TREATMENT-INDUCED NAUSEA AND 
GASTROINTESTINAL EVENTS 
The following guidance is provided for management of GI AEs in AML patients receiving oral AZA.48 
1. Treatment of GI reflux with proton pump inhibitors or histamine H2-receptor antagonists 
(e.g., cimetidine, famotidine) may ameliorate dyspepsia, which can mimic nausea. 
2. Taking oral AZA with food may alleviate nausea and vomiting by diluting the drug in the upper GI 
tract, improving motility, and slowing the rate of absorption. 
3. Consensus clinical practice guidelines49-51 emphasize the use of 3 drug classes for optimal 
treatment of chemotherapy-induced nausea and vomiting: 5-HT3 receptor antagonists, 
corticosteroids, and neurokinin-1 receptor antagonists. 
4. Although higher-grade GI events are uncommon, oral AZA treatment should be interrupted for 
subjects who experience Grade 3 4 nausea, vomiting, or diarrhea, according to Appendix D. 
5. Nonpharmacologic approaches to reducing nausea and vomiting are shown in the table below. 
6. Note: When adding a new medication given concomitantly to venetoclax, make sure to check if 
venetoclax dose needs to be adjusted in case the new medication is a CYP3A inhibitor (as 
instructed in Table 4).  
 
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Practical tips for managing/preventing nausea and vomiting 
Keep dry crackers near the bed for morning nausea 
Try chamomile, peppermint, catnip, or ginger tea, and fresh, dried, or candied ginger 
Sniff a cut lemon 
Eat salty foods such as pretzels; carry a small packet of salt when leaving home 
Avoid trigger foods known to cause nausea 
Avoid strong odors 
Avoid stomach irritants (e.g., tobacco, aspirin) 
If there is a pattern to nausea, eat more during periods with less nausea 
Do not eat and drink at the same time; drink liquids an hour before or after eating 
Avoid lying down for at least an hour after eating; rest with your head higher than your feet 
Keep the room temperature cool 
Avoid eating in a room that is hot, stuffy, or filled with cooking odors 
Dietary measures for relieving nausea, vomiting, and diarrhea 
Drink clear beverages such as fruit juices, broth, ginger ale, energy drinks, or herbal teas 
Eat small amounts of food every few hours rather than 2-3 large meals per day 
Eat slowly and sip beverages slowly 
Suck on popsicles or frozen fruit juice 
Try the BRAT diet: bananas, white rice, applesauce, and white bread toast 
Eat bland, soft foods (e.g., pasta, mashed potatoes, jello) 
Eat dry foods such as unbuttered toast, saltine crackers, and dry cereal without milk 
Avoid greasy foods, fried foods, margarine, butter, and oils 
Avoid spicy foods 
Avoid dairy products 
Avoid caffeine (in coffee, tea, soft drinks, chocolate, some pain medications) 
Avoid alcoholic beverages 
Avoid acidic foods and juices (e.g., citrus fruits, tomatoes) 
Eat foods high in soluble fiber and avoid foods high in insoluble fiber (e.g., nuts) 
Adapted from Maceira E, Lesar TS, Smith HS. Medication related nausea and vomiting in palliative medicine. Ann 
Palliat Med. 2012;1(2):161-76. 
 
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APPENDIX H. ACTIVITY SCHEDULE 
The following table shows the required activities across the 24 to 48 cycles each subject encounters.  
The individual activities are described in detail in the Operations Manual.  Allowed modifications due to 
a COVID-19 state of emergency are detailed within the Operations Manual (Appendix J). 
 
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APPENDIX I. PROTOCOL SUMMARY OF CHANGES 
Previous Protocol Versions 
Protocol 
Date 
Version 1.0 
20 August 2019 
Version 1.1 (VHP Countries Only) 
31 October 2019 
Version 1.1.1 (VHP Countries Only) 
26 November 2019 
Version 2.0 
18 December 2019 
Version 2.1 (Canada Only) 
17 February 2020 
Version 3.0 
01 December 2020 
Version 4.0 
29 December 2020 
Version 5.0 
18 August 2021 
Version 6.0 
05 June 2023 
Version 7.0 
01 August 2023 
 
The purpose of this amendment is to correct minor clerical errors for consistency and other 
administrative changes throughout the protocol and the following: 
• 
Rationale:  To update EudraCT number with EU CT number. 
• 
Updated throughout 
• 
Rationale:  To update the sponsor/emergency medical contact. 
• 
Updated throughout 
• 
Rationale:  The study title was updated to reflect that the Part 3 randomization portion from the 
study had been previously removed and to reflect both IV/SC AZA and oral AZA are being 
studied.  
• 
Updated throughout 
• 
Rationale:  CC-486 was changed to oral AZA. 
• 
Updated throughout 
• 
Rationale:  To remove Austria, Poland, Israel, and Portugal from the country site list. 
• 
Updated Protocol SYNOPSIS 
• 
Rationale:  To update references for prescribing information of drugs used in the study. 
• 
Updated Section 2.2 and Section 5.4 
• 
Rationale:  To clarify that that completion of the study treatment for Part 1 subjects is 
considered to be 24 cycles of venetoclax although subjects can go up to 48 cycles. 
• 
Updated Section 4.1 and throughout the Operations Manual 
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• 
Rationale:  To streamline Study Design and Plan wording.  
• 
Updated Section 4.1  
• 
Rationale:  To clarify that contraceptive recommendations apply to both AZA and oral AZA.  
• 
Updated Section 5.2  
• 
Rationale:  There are procedures that need to be done in-person for the 30-day follow-up visit. 
• 
Updated Section 5.5 
• 
Rationale:  Edited follow-up visit timing for Part 3 subjects that have discontinued study drug 
prior to Cycle 24 or who have completed 24 cycles for consistency with the rest of the protocol.  
• 
Updated Section 5.6 
• 
Rationale:  Updated to align with current AbbVie template 
• 
Updated Section 5.9, Section 5.10, Section 8.2, Section 8.3, Section 9, Section 10, and the 
Operations Manual 
• 
Rationale:  Bone Marrow Aspirate/Biopsy samples are not required for Part 1 and Part 3 Final 
Visits if the sample had been collected within 4 weeks prior to the Final Visit.   
• 
Updated Appendix H and the Operations Manual 
• 
Operations Manual. 
• 
Rationale:  Clarified that survival follow up includes follow-up on post-treatment cancer 
therapies as specified in Section 3.18 in the Operations Manual.   
• 
Updated Appendix H and the Operations Manual. 
• 
Rationale:  Clarify that Bone Marrow Aspirate/Biopsy samples and clinical chemistry and 
hematology labs will be collected as standard of care or as clinically indicated during Post 
Treatment Follow-up Visits for Part 3 subjects.    
• 
Updated Appendix H and the Operations Manual 
• 
Rationale:  Peripheral Blood samples and a bone marrow biopsy are not required to be drawn 
same day same time at the Part 3 Post Treatment Visit.   
• 
Edited sentence to read "A peripheral blood smear should also be evaluated from the same 
day and same time that the bone marrow aspirate and/or bone marrow biopsy is collected 
for disease assessment." from the Operations Manual 
• 
Rationale:  To clarify whether subjects have prematurely discontinued from the study.   
• 
Added Section 8 and Section 8.1 to the Operations Manual and added references to 
Section 8.1 in Operations Manual Section 2.2, Section 2.4, and Section 3.18. 
 
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