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
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML)
Sponsor: AbbVie

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
1
1.0
Title Page
Clinical Study Protocol 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
Incorporating Amendments 1, 2, 2.01 (China Only), 3, 
4, 5, 6, 7, and 8
AbbVie Investigational
  Product:
Venetoclax (ABT-199/GDC-0199)
Date:
01 July 2020
Development Phase:
3
Study Design:
This is a randomized, double-blind, placebo controlled, multicenter trial 
evaluating efficacy and safety of venetoclax in combination with azacitidine 
versus placebo in combination with azacitidine in treatment naïve subjects 
with AML who are ≥ 18 years of age and not eligible for standard induction 
therapy due to age or co-morbidities.  
EudraCT Number:
2016-001466-28
Investigator:
Investigator information on file at AbbVie
Sponsor:
AbbVie Inc.
Sponsor/Emergency 
  Contact:
 MD, FACP
Senior Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Cell:
Fax:
Email:
Emergency 24 Hour Number: +1 973-784-6402
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
 
NCT02993523

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
25 October 2016
Amendment 1
21 December 2016
Amendment 2
20 February 2017
Amendment 2.01 (China Only)
29 March 2017
Amendment 3
10 May 2017
Amendment 4
01 March 2018
Amendment 5
08 August 2018
Amendment 6
15 May 2019
Amendment 7
21 August 2019
The purpose of this amendment is to:
●
Section 1.2 Synopsis and Section 5.1 Overall Study Design and Plan, update 
number of subjects enrolled to 443.
Rationale:  To update the actual number of subjects enrolled on the study.
●
Update Section 1.2, Synopsis and Section 5.1.3, Treatment Period, text 
updated  to clarify that subjects will continue to receive assigned study drug 
without cross over until discontinuation and to clarify that disease assessment 
will no longer be reviewed by IRC following the 75% OS interim analysis.
Rationale:  The study has met its primary endpoints of overall survival based 
on the 75% OS interim analysis and response rates based on the previously 
performed interim analysis for CR/CRi.
●
Updates made throughout the protocol and Appendix C to incorporate 
necessary protocol modifications due to the COVID-19 pandemic.
Rationale:  To allow flexibility for subject treatment during the COVID-19 
pandemic
●
Update Section 5.1.4 Post Treatment Follow-Up, update to survival and post 
treatment follow up language.
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Rationale:  To allow for more frequent assessment of subjects's survival status 
and post treatment follow up and clarify the Survival and Post Treatment 
Follow-up period.
●
Update Section 5.3.1.1 Study Procedures, sub-section Bone Marrow Aspirate 
and Biopsy for Disease Assessment update text to indicate that the IRC would 
no longer be completing disease assessments.
Rationale: To clarify that disease assessments would not be completed by the 
IRC following the 75% OS interim analysis.
●
Update Section 5.5.5.1 Blinding of Investigational Product, update to clarify 
unblinded team members.
Rationale:  To clarify that limited AbbVie personnel have been unblinded to 
support data interpretation and that subjects currently on treatment who are 
unblinded by the investigator will be discontinued from study treatment.
●
Update Section 6.1.7 Toxicity Management and Appendix L, Venetoclax and 
Azacitidine Dose Modifications, update to guidance regarding delay of 
treatment cycle by adding clarity to the criteria defining count recovery.
Rationale:  To further clarify count recovery to include 'and' in the guidance 
criteria specific to delay of treatment cycle "and/or platelet count 
≥50 × 103/μL."
●
Update Section 7.0 Protocol Deviations, update study contact.
Rationale:  Update to current alternate contact for protocol deviations.
●
Update Section 10.2 Case Report Forms, to update vendor information.
Rationale:  Updated to current name of ePRO vendor.
●
Update Appendix B List of Protocol Signatories, to update and add signatories.
Rationale:  To add additional signatories.
●
Update Appendix C, Multiple footnote section language updates.
Rationale:  To clarify survival visits and post treatment follow up visits and 
update language for corresponding pathology reports.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix M.
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
4
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-656
Name of Study Drug:  Venetoclax 
(ABT-199/GDC-0199)
Phase of Development:  3
Name of Active Ingredient:
ABT-199 (GDC-0199)
Date of Protocol Synopsis:  01 July 2020
Protocol Title:  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
Objectives:  
Primary Objectives:

To evaluate if venetoclax in combination with azacitidine will improve overall survival (OS) 
and composite complete remission rate (complete remission + complete remission with 
incomplete marrow recovery; CR + CRi) versus placebo in combination with azacitidine, in 
treatment naïve subjects with acute myeloid leukemia (AML).
Secondary Objectives:

To evaluate if venetoclax in combination with azacitidine will improve the rate of CR.

To evaluate if venetoclax in combination with azacitidine will improve the rate of CR and 
complete remission with partial hematologic recovery rate (CRh).

To evaluate if venetoclax in combination with azacitidine will improve the proportion of 
subjects achieving composite complete remission (CR or CRi) by initiation of Cycle 2.

To evaluate if venetoclax in combination with azacitidine will improve the transfusion 
independence rate.

To evaluate if venetoclax in combination with azacitidine will improve the MRD response rate 

To evaluate if venetoclax in combination with azacitidine will improve the response rates and 
overall survival in molecular subgroups.

To evaluate if venetoclax in combination with azacitidine reduces fatigue and improves global 
health status/quality of life (GHS/QoL) based on patient reported outcome (PRO) assessments 
(Patient Reported Outcomes Measurement Information System [PROMIS], Cancer Fatigue 
Short Form [SF] 7a and European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire Core [EORTC QLQ-C30]).

To evaluate if venetoclax in combination with azacitidine will improve, event-free survival 
(EFS).
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Objectives (Continued):  
Exploratory Objectives:

Exploration of biomarkers predictive of venetoclax activity and duration of response may be 
performed.  These analyses maybe part of a multi-study assessment to compare responses to the 
therapies and/or disease state.  Potential analyses may include, but will not be limited to:
o
To evaluate BCL2 expression and outcome measures of overall survival and complete 
remission rate

To evaluate the impact of venetoclax on remaining subscales/items from the EORTC QLQ-C30 
and EQ-5D-5L.
Investigators:  Investigator information on file at AbbVie
Study Sites:  Approximately 180 sites
Study Population:  Adult male and female subjects, with confirmed AML, who are treatment naïve for 
AML, with a projected life expectancy of at least 12 weeks and be ineligible for treatment with a 
standard cytarabine and anthracycline induction regimen due to age or co-morbidities.
Number of Subjects to be Enrolled:  Approximately 400 to 412 subjects (Enrollment completed with 
443 subjects)
Methodology:  
This is a randomized, double-blind, placebo controlled, multicenter trial evaluating efficacy of 
venetoclax in combination with azacitidine versus placebo in combination with azacitidine in treatment 
naïve subjects with AML who are ≥ 18 years of age and not eligible for standard induction therapy due 
to age or co-morbidities.  If a subject enrolled on any arm achieves complete remission with incomplete 
marrow recovery (CRi) or has a morphologic leukemia free bone marrow after completion of Cycle 1, 
venetoclax/placebo may be interrupted from Day 29 for up to 14 days or until recovery of ANC 
≥500/μL.  If venetoclax/placebo is interrupted, then Cycle 2 administration of azacitidine will also be 
delayed.  Cycle 2 treatment with venetoclax/placebo and azacitidine will resume on the same day after 
the interruption.  Subjects with resistant disease after end of Cycle 1 will need a bone marrow aspirate to 
evaluate response after completion of Cycle 2 or 3 if hematologic improvement is seen.  A bone 
marrow aspirate and biopsy will be done at the end of Cycle 4 and every 3 cycles after for subjects 
with resistant disease until two successive samples indicate CR or CRi.  For subjects with a response 
of CRi a repeat bone marrow aspirate must be performed to confirm a CR once peripheral blood count 
recovery is noted.  For subjects who have not recovered ANC ≥500/μL within 14 days of drug 
interruption or require longer duration of interruption between treatment cycles, bone marrow aspirate 
may be performed per investigator discretion to assess disease status before resuming treatment with 
next Cycle.  Blood and bone marrow samples will be collected for biomarker analysis and exploratory 
research at designated timepoints throughout the study.
Screening
Unless otherwise specified, screening procedures must be performed within 21 days prior to 
randomization.  Once screening procedures are complete and eligibility is confirmed, subjects will be 
randomized using a 2:1 ratio to one of the following two arms:

Arm A:  Venetoclax plus Azacitidine

Arm B:  Placebo plus Azacitidine 
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Methodology (Continued):  
Study Treatment 
All subjects will receive venetoclax or placebo orally once daily (QD) plus Azacitidine QD beginning on 
Cycle 1 Day 1.  Venetoclax or placebo should be taken within 30 minutes of food intake.  Subjects will 
receive Azacitidine for 7 days from Day 1 of each cycle beginning with Cycle 1.
Cycle Length – 28 Days

Venetoclax 400 milligram (mg) or Placebo Daily on Days 1 – 28

Azacitidine 75 mg/m2 Subcutaneous (SC) or IV Daily for 7 days
Subjects will continue their treatment assignment until documented disease progression per Investigator 
assessment, unacceptable toxicity, withdrawal of consent, or the subject meets other protocol criteria for 
discontinuation (whichever occurs first).  Subjects will continue to receive the assigned study treatment 
without cross over until treatment discontinuation.  All subjects will have a final visit performed when 
treatment is discontinued unless the subject has withdrawn consent to participate in the study.  Baseline 
laboratory assessments will be obtained at Cycle 1 Day 1 prior to first dose of study treatment.  Patient-
reported outcome (PRO) measures should be completed after a blood sample is taken to confirm the 
subject is able to receive study treatment at the study visit, but prior to the performance of all other non-
PRO assessments and the administration of study treatment.  Disease assessments by IWG criteria will 
be performed at end of Cycle 1 (± 3 days) and every 3 cycles starting on Cycle 4 Day 1 and continuing 
until disease progression per the modified IWG criteria, or the subject withdraws consent.  In addition to 
being reviewed by the Investigator and local hematopathologists, all disease assessment information will 
be sent to an Independent Review Committee (IRC) to provide response assessment.  Interpretations 
from the IRC will not be shared with sites.  Upon unblinding at the 75% Overall Survival Interim 
Analysis, disease assessments will no longer be performed by the IRC.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
A subject will be eligible for study participation if he/she meets the following criteria within 21 days 
prior to randomization.
1.
Subject must have confirmation of AML by WHO criteria, previously untreated and be ineligible for 
treatment with a standard cytarabine and anthracycline induction regimen due to age or co-
morbidities. 
2.
Subject must be ≥ 18 years of age.
3.
Subject must have a projected life expectancy of at least 12 weeks.
4.
Subject must be considered ineligible for induction therapy defined by the following: 

≥ 75 years of age;
OR

≥ 18 to 74 years of age with at least one of the following co-morbidities:
o
ECOG Performance Status of 2 or 3;
o
Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or chronic stable 
angina;
o
DLCO ≤ 65% or FEV1 ≤ 65%;
o
Creatinine clearance ≥ 30 mL/min to < 45 ml/min 
o
Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
o
Any other comorbidity that the physician judges to be incompatible with intensive 
chemotherapy must be reviewed and approved by the AbbVie Therapeutic Area Medical 
Director (TA MD) during screening and before study enrollment
5.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status:

of 0 to 2 for subjects ≥ 75 years of age.
OR
of 0 to 3 for subjects ≥ 18 to 74 years of age.
6.
Subject must have adequate renal function as demonstrated by a creatinine clearance ≥30 mL/min; 
calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
7.
Subject must have adequate liver function as demonstrated by:

aspartate aminotransferase (AST) ≤ 3.0 × ULN*

alanine aminotransferase (ALT) ≤ 3.0 × ULN*

bilirubin ≤ 1.5 × ULN*
*
Unless considered to be due to leukemic organ involvement
o
Subjects who are < 75 years of age may have a bilirubin of ≤ 3.0 × ULN
8.
Female subjects must be either postmenopausal defined as:

Age > 55 years with no menses for 12 or more months without an alternative medical cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND an FSH level > 40 IU/L.
OR

Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR
Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method of 
birth control, starting at Study Day 1 through at least 90 days after the last dose of study drug.
9.
Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after 
the last dose of study drug, to practice the protocol specified contraception.  Male subjects must 
agree to refrain from sperm donation from initial study drug administration through at least 90 days 
after the last dose of study drug.
10. Female subjects of childbearing potential must have negative results for pregnancy test performed:

At Screening with a serum sample obtained within 14 days prior to the first study drug 
administration, and

Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since 
obtaining the serum pregnancy test results.
11. Subject must voluntarily sign and date an informed consent form, approved by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or 
study-specific procedures.
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:  
1.
Subject has received treatment with the following:

A hypomethylating agent, venetoclax and/or any chemo-therapeutic agent for Myelodysplastic 
syndrome (MDS).

CAR-T cell therapy.

Experimental therapies for MDS or AML.

Current participation in another research or observational study
2.
Subject has history of myeloproliferative neoplasm [MPN] including myelofibrosis, essential 
thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 
translocation and AML with BCR-ABL1 translocation.
3.
Subject has:

Favorable risk cytogenetics such as t(8;21), inv(16), t(16;16) or t(15;17) as per the NCCN 
Guidelines Version 2, 2016 for Acute Myeloid Leukemia.
4.
Subject has acute promyelocytic leukemia 
5.
Subject has known active CNS involvement with AML.
6.
Subject has known HIV infection (due to potential drug-drug interactions between antiretroviral 
medications and venetoclax) HIV testing will be performed at Screening, only if required per local 
guidelines or institutional standards.
7.
Subject is known to be positive for hepatitis B or C infection [HCV Ab indicative of a previous or 
current infection; and/or positive HBs Ag or detected sensitivity on HBV-DNA PCR test for HBc 
Ab and/or HBs Ab positivity] with the exception of those with an undetectable viral load within 
3 months of screening.  (Hepatitis B or C testing is not required).  Subjects with serologic evidence 
of prior vaccination to HBV [i.e., HBs Ag-, and anti-HBs+] may participate.
8.
Subject has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of 
study treatment.

Chinese AML subjects participating in the safety cohort per Appendix K are also excluded from 
receiving strong and/or moderate CYP3A inhibitors from 7 days prior to the initiation of study 
treatment through the entire dose limiting toxicity (DLT)/safety evaluation period.
9.
Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
10. Subject has a cardiovascular disability status of New York Heart Association Class > 2.  Class 2 is 
defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity 
results in fatigue, palpitations, dyspnea, or anginal pain.
11. Subject has chronic respiratory disease that requires continuous oxygen, or significant history of 
renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular 
disease, any other medical condition or known hypersensitivity to any of the study medications 
including excipients of azacitidine that in the opinion of the investigator would adversely affect 
his/her participating in this study.
12. Subject has a malabsorption syndrome or other condition that precludes enteral route of 
administration.
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
13. Subject exhibits evidence of other clinically significant uncontrolled systemic infection requiring 
therapy (viral, bacterial or fungal).
14. Subject has a history of other malignancies within 2 years prior to study entry, 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:  requires discussion with TA MD.
15. Subject has a white blood cell count > 25 × 109/L.  (Hydroxyurea or leukapheresis are permitted to 
meet this criterion.)
Investigational Product:
Venetoclax, 100 mg, 50 mg and 10 mg tablet
Dose:
Cycle 1:  Day 1:  100 mg, Day 2:  200 mg, Day 3:  400 mg, 
Day 4 – Day 28:  400 mg
Subsequent cycles:  Day 1 – Day 28:  400 mg QD
Mode of Administration:
Oral
Reference Therapy:
Placebo (to match venetoclax 100 mg, 50 mg, and 10 mg tablet)
Dose:
Not Applicable
Mode of Administration:
Oral
Reference Therapy:
Azacitidine
Dose:
75 mg/m2; Daily for 7 Days of all cycles, Cycle = 28 days QD
Mode of Administration:
Subcutaneous (SC) or IV as indicated in local label
Duration of Treatment:  
Subjects will receive venetoclax/placebo/azacitidine until documented disease progression, unacceptable 
toxicity or intolerance, withdrawal of consent, or the subject meets other criteria for discontinuation per 
study protocol (whichever occurs first).
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Criteria for Evaluation:
Efficacy:
Bone marrow biopsies and aspirates must be performed at screening for all subjects.  Cytogenetic and 
molecular profiling will be done at a local lab during screening.  Samples for molecular markers and 
baseline disease assessment for MRD evaluation must be collected at screening for confirmation at 
central lab.  Bone marrow aspirate and biopsy must be performed at the end of Cycle 1.  For subjects 
with resistant disease at the end of Cycle 1 a repeat bone marrow aspirate and biopsy must be performed 
at the end of Cycle 2 or Cycle 3 based on the hematologic recovery to assess response.  For all subjects a 
bone marrow aspirate and biopsy must be performed at end of Cycle 4 and every 3 cycles thereafter 
(± 1 week).  Bone marrow will be performed until two successive samples indicate CR or CRi.  For 
subjects with a response of CRi on two successive bone marrow samples an additional bone marrow 
aspirate and biopsy must be performed to confirm a CR once peripheral blood count recovery is noted.  
Subsequently, disease assessments are based on laboratory results and physical examination.  A bone 
marrow aspiration and biopsy is required if relapse is suspected or at the Final Visit.  All subjects will 
have response assessment according to the modified IWG criteria for AML.  Progressive disease is 
defined per European LeukemiaNet recommendations.  If additional treatments are needed to optimize 
subjects' medical care, they can be performed following institutional standards and procedures.  Subject's 
disease assessment is based on the most recent physical examination, bone marrow results and recent 
hematology values.  For subjects who require a delay in next cycle of study treatment for blood count 
recovery after a bone marrow evaluation, hematology values for up to 2 weeks or pre-dose labs from 
Day 1 of the next cycle can be used to determine the IWG response.
All subjects who completed at least one cycle of study treatment will be assessed by the investigators 
using the modified IWG criteria for AML as described below.  Subjects who have discontinued study 
treatment prior to completion of Cycle 1 will be deemed non-evaluable for response assessment.
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Criteria for Evaluation (Continued):
Efficacy (Continued):
CR:
Absolute neutrophil count > 103/µL, platelets > 105/µL, red cell transfusion 
independence, and bone marrow with < 5% blasts.  Absence of circulating 
blasts and blasts with Auer rods; absence of extramedullary disease.
CRi:
All of the criteria for CR except for residual neutropenia ≤ 103/µL (1000/µL) 
or thrombocytopenia ≤ 105/µL (100,000/µL).  Red blood cell transfusion 
(RBC) dependence is also defined as CRi.
PR:
All of the hematologic values for a CR but with a decrease of at least 50% in 
the percentage of blasts to 5% to 25% in the bone marrow aspirate.
MLFS:
Less than 5% blasts in an aspirate sample with marrow spicules and with a 
count of at least 200 nucleated cells, absence of circulating blasts and 
extramedullary disease without peripheral blood count recovery that meet the 
thresholds for either CR or CRi.
RD:
Failure to achieve CR, CRi, PR or MLFS; only for subjects surviving at least 
7 days following completion of Cycle 1 treatment, with evidence of persistent 
leukemia by blood and/or bone marrow examination.
MR:
Reappearance of ≥ 5% blasts after CR/CRi in peripheral blood or bone 
marrow or development of extramedullary disease.
PD:*  

50% increase in marrow blasts over baseline (a minimum 15% point 
increase is required in cases with < 30% blasts at baseline; or persistent 
marrow blast percentage of > 70% over at least 3 months; without at least 
a 100% improvement in ANC to an absolute level (> 0.5 × 109/L 
[500/µL], and/or platelet count to > 50 × 109/L [50 000/µL] 
non-transfused); or

50% increase in peripheral blasts (WBC × % blasts) to > 25 × 109/L 
(> 25 000/µL); or

New extramedullary disease
CR = complete remission; CRi = CR with incomplete blood count recovery; PR = partial remission; 
MLFS = morphologic leukemia free state; RD = resistant disease; MR = morphologic relapse
*
PD = Progressive disease as defined by ELN criteria.
In addition to the response assessment using the above response criteria, each subject will also be 
evaluated for complete remission with partial hematologic recovery rate (CRh) based on the bone 
marrow and hematologic parameters.
Pharmacokinetic:
Sparse pharmacokinetic (PK) samples will be collected and analyzed for venetoclax and azacitidine.  
Venetoclax results may be incorporated into a population PK analysis to estimate parameters such as 
clearance.
 

Venetoclax
M15-656 Protocol Amendment 8
EudraCT 2016-001466-28
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Criteria for Evaluation (Continued):
Safety:
Adverse event (AE) monitoring, vital signs, physical examination, and laboratory values.  If any 
additional diagnostic testing performed as clinically indicated will be assessed.  Note:  All subjects will 
be hospitalized for the first 4 days of dosing during Cycle 1 and longer as needed per standard of care for 
peripheral blood count recovery and management of disease related complications during the escalation 
of venetoclax dose from 100 to 400 mg.
Patient-Reported Outcomes:
PROs will be evaluated using the following measures at specific time points throughout the study:  
PROMIS Cancer Fatigue SF 7a, GHS/QoL as assessed by EORTC QLQ-C30, and EQ-5D-5L.
Statistical Methods:  
Efficacy:
Primary and Secondary Efficacy Endpoints:
Overall Survival (OS):
Overall survival will be defined as the number of days from the date of randomization to the date of 
death.  Subjects that have not died will be censored at the last known date to be alive.
Composite Complete Remission Rate:  
The proportion of subjects with complete remission or complete remission with incomplete marrow 
recovery (CR + CRi) will be calculated based on current IWG criteria for AML.  Subjects who are 
randomized but have no IWG disease assessment will be considered as non-responders for CR + CRi 
rate.
Complete Remission (CR) Rate: 
The proportion of subjects with complete remission (CR) will be calculated based on current IWG 
criteria for AML.  Subjects who are randomized but have no IWG disease assessment will be considered 
as non-responders for CR rate.
CR + CRh rate
The proportion of subjects with complete remission or complete remission with incomplete marrow 
recovery (CR + CRh) will be calculated.  Subjects who are randomized but have no post-baseline disease 
assessment will be considered as non-responders for CR + CRh rate.
Composite Complete Remission Rate by the Initiation of Cycle 2:
The proportion of subjects with complete remission or complete remission with incomplete marrow 
recovery (CR + CRi) by the initiation of Cycle 2 will be calculated based on the modified IWG criteria 
for AML.  Subjects who are randomized but have no IWG disease assessment by the initiation of 
Cycle 2 will be considered as non-responders.
Post Baseline RBC Transfusion Independence Rate
Post baseline RBC transfusion independence rate will be calculated as the portion of subjects who 
achieved RBC transfusion independence post baseline.  The RBC Transfusion independence is defined 
as a period of at least 56 days with no RBC transfusion between the first dose of study drug and the last 
dose of study drug + 30 days.  All randomized subjects will be included to estimate the post-baseline 
transfusion independence rates.
 

Venetoclax
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Statistical Methods (Continued):
The Rate of Conversion (RBC)
The rate of conversion will be calculated as proportion of subjects being post-baseline transfusion 
independent from baseline RBC transfusion dependence.  
The Rate of Conversion (Platelets)
The rate of conversion will be calculated as proportion of subjects being post-baseline Platelets 
transfusion independent from baseline platelets transfusion dependence.  
MRD Response Rate
MRD response will be defined using a threshold of less than 0.1% of residual blasts per leukocytes as 
measured in bone marrow.  Additional thresholds may also be explored and correlated with efficacy 
outcomes.  Subjects who are randomized but have no MRD assessment will be considered as non-
responders for the calculation of MRD response rate.  The proportion of subjects (CR + CRi, or CR + 
CRh) achieving an MRD response will be calculated.
Event-Free Survival (EFS):
EFS will be defined as the number of days from randomization to the date of progressive disease, relapse 
from CR or CRi, treatment failure or death from any cause.  If a specified event does not occur, subjects 
will be censored at the date of last disease assessment.  Data for subjects without any disease 
assessments performed after randomization will be censored at the date of randomization.
Pharmacokinetic:
An analysis of venetoclax plasma concentrations may be performed using a nonlinear mixed effect 
population PK modeling approach.
Pharmacodynamic and Predictive Biomarker Analysis (Not Applicable for China):
Exploratory research may be conducted to find biomarkers predictive of venetoclax activity.  Peripheral 
blood and bone marrow samples will be obtained at study specified time points.  Biomarkers 
(e.g., cytogenetics, molecular markers, characterization of Bcl-2 family members and minimal residual 
disease status MRD) may be assessed to compare patient responses in the two arms in order to identify 
markers that may be predictive of venetoclax activity.
Safety:
A safety analysis will be performed for all dosed subjects unless otherwise indicated.  For the study as a 
whole, AEs will be evaluated and summarized.  Laboratory test results and vital signs will be explored 
for trends and summarized as appropriate.
Patient-Reported Outcomes:
Fatigue as assessed by the PROMIS Cancer Fatigue SF 7a and GHS/QoL as assessed by the EORTC 
QLQ-C30 will be evaluated using a linear mixed effects regression model to test for differences between 
the two treatment arms.  Exploratory research will also be conducted on the subscales and items from the 
PROMIS Cancer Fatigue SF 7a, EORTC QLQ-C30, and EQ-5D-5L.
 

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Statistical Methods (Continued):
Sample Size:
For US and countries using the US as the reference country, the study includes single primary endpoint 
of overall survival.  For Japan, EU and countries using EU as reference for obtaining approval, the study 
includes dual-primary endpoints of overall survival (OS) and CR + CRi rate.  The sample size 
calculation is based on the following assumptions:

The significance level (two-sided 0.05) will be split to give a 0.01 significance level to the CR 
+ CRi rate analysis and an overall 0.04 significance level to the OS analysis.

Median OS of 10.4 months for placebo plus azacitidine arm

Median OS of 14.9 months for venetoclax plus azacitidine arm (hazard ratio of 0.7)

Interim analysis of OS at 75% of death events with O'Brien-Fleming boundary

2:1 randomization ratio to venetoclax plus azacitidine, and placebo plus azacitidine arm, 
stratified by age (18 – < 75, ≥ 75), cytogenetics (intermediate risk, poor risk) and region (US, 
EU, China, Japan, Rest of world)
With the above assumptions, a total of 360 death events will provide 86.7% power to detect statistically 
significant difference in OS between treatment arms at alpha level of 0.04.  A total of approximately 
400 subjects (267 in venetoclax in combination with azacitidine arm, and 133 in placebo with azacitidine 
arm) will be randomized into the study to obtain the 360 death events.  A total of approximately 
412 subjects including the open label Chinese safety cohort may be enrolled.
 

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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase (also called SGPT)
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASD
Amorphous solid dispersion
AST
Aspartate aminotransferase (also called SGOT)
AZA
Azacitidine
Bcl 
B-Cell Lymphoma
BCRP
Breast Cancer Resistant Protein
BM
Bone Marrow
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CD-ROM
Compact Disc – Read Only Memory 
CHF
Congestive Heart Failure
CI
Confidence Interval
CLL
Chronic Lymphocytic Leukemia
CMH
Cochran Mantel Haenszel
CNS
Central Nervous System
CR
Complete Remission
CRF
Case Report Form
CRh
Complete Remission with partial hematologic recovery
CRi
Complete Remission with Incomplete Blood Count Recovery
CRp
Complete Remission with Incomplete Platelet Recovery
CS
Clinically Significant
CTCAE
Common Terminology Criteria for Adverse Events
CYP1A2
Cytochrome P450 1A2
CYP2B6
Cytochrome P450 2B6
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
CYP2C19
Cytochrome P450 2C19
 

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CYP2D6
Cytochrome P450 2D6
CYP3A4
Cytochrome P450 3A4
DLCO
Diffusing Capacity of the Lung for Carbon Monoxide
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFS
Event-Free Survival
ELN
European LeukemiaNet
EMEA
European Agency for the Evaluation of Medicinal Products
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
EQ-5D-5L
EuroQol EQ-5D-5L
EU
European Union
FDA
Food and Drug Administration 
FEV1
Forced Expiratory Volume in 1 Second
FFPE
Formalin-Fixed Paraffin-Embedded
FSH
Follicle-Stimulating Hormone
GHS/QOL
Global Health Status/Quality Of Life
GCP
Good Clinical Practice
HBV
Hepatitis B Virus
HDPE
High Density Polyethylene
HIV
Human Immuno-Deficiency Virus
HMA
Hypomethylating agent
HNSTD
Highest Non-severely Toxic Dose
HR
Hematologic Response
hr
Hour
HSCT
Hematopoietic Stem Cell Transplantation
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
 

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IEC
Independent Ethics Committee
IMP
Investigational Medical Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
IWG
International Working Group
JP
Japan
kg
Kilogram
L
Liter
LDH
Lactate Dehydrogenase
LTLS
Laboratory Tumor Lysis Syndrome
MTD
Maximum Tolerated Dose
MCL
Mantle Cell Lymphoma
MD
Medical Director
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple Myeloma
MR
Morphologic Relapse
µg
Microgram
mg
Milligram
mL
Milliliter
µM
Micromolar
MLFS
Morphologic leukemia free state by bone marrow
MPN
Myeloproliferative Neoplasm
MRD
Minimal Residual Disease
MUGA
Multiple Gated Acquisition Scan
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
NCS
Not clinically significant
NHL
Non-Hodgkin's Lymphoma
nM
Nanomolar
 

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ORR
Overall Response Rate
OS
Overall Survival
PFS
Progression Free Survival
PK
Pharmacokinetic
PR
Partial Remission
PRO
Patient Reported Outcome
PROMIS
Patient Reported Outcome Measurement Information System
PT
Prothrombin Time
PD
Progressive Disease
QD
Once Daily
QTcF
QT interval measurement corrected by Fridericia's formula
RBC
Red Blood Cell
RD
Resistant Disease
RNA
Ribonucleic Acid
RPTD
Recommended Phase 2 Dose
R/R
Relapse/Refractory
SAE
Serious Adverse Event
SC
Subcutaneous
SF
Short Form
SGOT
Serum Glutamic-oxaloacetic Transaminase (also called AST)
SGPT
Serum Glutamic-pyruvic Transaminase (also called ALT)
SLL
Small Lymphocytic Lymphoma
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
STD
Severely Toxic Dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA
Therapeutic Area
TLS
Tumor Lysis Syndrome
TTP
Time to Progression
ULN
Upper Limit of Normal
US
United States
WBC
White Blood Cell
WHO
World Health Organization
 

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Pharmacokinetic and Statistical Abbreviations
AUC
Area under the plasma concentration-time curve
AUC0-24
Area under the plasma concentration-time curve from time zero to Hour 24
AUC∞
Area under the plasma concentration-time curve from time zero to infinity
CL/F
Apparent oral clearance
Cmax
Maximum observed plasma concentration
Cmin
Minimum observed plasma concentration
IC50
Half maximal inhibitory concentration
t1/2
Terminal phase elimination half-life
Tmax
Time to maximum observed plasma concentration
V/F
Apparent volume of distribution
 

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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................15
2.0
Table of Contents...................................................................20
3.0
Introduction ...........................................................................25
3.1
Differences Statement..............................................................................36
3.2
Benefits and Risks....................................................................................37
4.0
Study Objectives....................................................................38
4.1
Primary Objective ....................................................................................38
4.2
Secondary Objectives...............................................................................38
4.3
Exploratory Objectives ............................................................................39
5.0
Investigational Plan...............................................................39
5.1
Overall Study Design and Plan:  Description ..........................................39
5.1.1
Screening..................................................................................................40
5.1.2
Rescreening..............................................................................................40
5.1.3
Treatment Period......................................................................................41
5.1.4
Post Treatment Follow-Up.......................................................................43
5.2
Selection of Study Population..................................................................44
5.2.1
Inclusion Criteria .....................................................................................44
5.2.2
Exclusion Criteria ....................................................................................47
5.2.3
Prior and Concomitant Therapy...............................................................49
5.2.4
Contraception Recommendations ............................................................52
5.3
Pharmacokinetic, Biomarker, Exploratory Research, Safety and 
Efficacy, Assessments/Variables .............................................................53
5.3.1
Safety and Efficacy Measurements Assessed and Flow Chart ................53
5.3.1.1
Study Procedures .....................................................................................53
5.3.1.2
Collection and Handling of Biomarker and Exploratory Research 
Samples (Not Applicable for China)........................................................69
5.3.1.3
Samples for Optional Pharmacogenetic Exploratory Research 
(Not Applicable for China) ......................................................................71
 

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5.3.1.4
Meals and Dietary Requirements.............................................................71
5.3.2
Drug Concentration Measurements .........................................................72
5.3.2.1
Collection of Samples for Analysis .........................................................72
5.3.2.2
Handling/Processing of Samples .............................................................72
5.3.2.3
Disposition of Samples ............................................................................72
5.3.2.4
Measurement Methods.............................................................................73
5.3.3
Efficacy Variables....................................................................................73
5.3.4
Safety Variables.......................................................................................75
5.3.5
Pharmacokinetic Variables ......................................................................75
5.3.6
Biomarker and Optional Exploratory Research Variables (Not 
Applicable for China) ..............................................................................75
5.4
Removal of Subjects from Therapy or Assessment.................................76
5.4.1
Discontinuation of Individual Subjects from Treatment..........................76
5.4.2
Discontinuation of Entire Study...............................................................78
5.5
Treatments................................................................................................79
5.5.1
Treatments Administered.........................................................................79
5.5.2
Identity of Investigational Products.........................................................79
5.5.2.1
Storage and Disposition of Study Drug(s) ...............................................80
5.5.3
Method of Assigning Subjects to Treatment Groups...............................81
5.5.4
Selection and Timing of Dose for Each Subject......................................81
5.5.5
Blinding....................................................................................................81
5.5.5.1
Blinding of Investigational Product.........................................................81
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ....................................................................................................82
5.5.6
Treatment Compliance.............................................................................82
5.5.7
Drug Accountability.................................................................................84
5.6
Discussion and Justification of Study Design..........................................84
5.6.1
Discussion of Study Design and Choice of Control Groups....................84
5.6.2
Appropriateness of Measurements...........................................................85
5.6.3
Suitability of Subject Population .............................................................85
5.6.4
Selection of Doses in the Study ...............................................................85
5.6.4.1
Dose Adjustments for Venetoclax Upon Co-Administration with 
Anti-Fungal Agents..................................................................................86
 

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6.0
Complaints .............................................................................87
6.1
Medical Complaints.................................................................................88
6.1.1
Definitions................................................................................................88
6.1.1.1
Adverse Events ........................................................................................88
6.1.1.2
Serious Adverse Events ...........................................................................89
6.1.1.3
Adverse Events Commonly Associated with AML Study 
Population and/or Progression of AML...................................................91
6.1.1.4
Adverse Events Expected due to Study Related Endpoints.....................92
6.1.1.4.1
Deaths ......................................................................................................92
6.1.2
Adverse Event Severity............................................................................92
6.1.3
Relationship to Study Drug......................................................................93
6.1.4
Adverse Event Collection Period.............................................................93
6.1.5
Adverse Event Reporting.........................................................................94
6.1.6
Pregnancy.................................................................................................96
6.1.7
Toxicity Management ..............................................................................97
6.1.7.1
Prophylaxis and Management of Tumor Lysis Syndrome (TLS)............99
6.2
Product Complaint .................................................................................100
6.2.1
Definition ...............................................................................................100
6.2.2
Reporting................................................................................................100
7.0
Protocol Deviations..............................................................101
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................102
8.1
Statistical and Analytical Plans..............................................................102
8.1.1
Definition for Analysis Populations.......................................................102
8.1.2
Baseline Characteristics.........................................................................103
8.1.3
Pharmacokinetics ...................................................................................103
8.1.4
Efficacy Endpoints.................................................................................103
8.1.4.1
Primary Efficacy Endpoint ....................................................................103
8.1.4.1.1
Primary Efficacy Endpoint in US and US Reference Countries............103
8.1.4.1.2
Primary Efficacy Endpoints in EU and EU Reference Countries..........104
8.1.4.2
Secondary Efficacy Endpoints...............................................................104
8.1.4.3
Exploratory Efficacy Endpoint ..............................................................107
8.1.5
Efficacy Endpoints per Independent Review Committee......................108
 

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8.1.6
Timing of Efficacy Analyses .................................................................108
8.1.7
Safety .....................................................................................................109
8.1.7.1
Study Drug Exposure.............................................................................109
8.1.7.2
Adverse Events ......................................................................................109
8.1.7.3
Serious Adverse Events .........................................................................109
8.1.7.4
Deaths ....................................................................................................110
8.1.7.5
Laboratory Tests and Vital Signs...........................................................110
8.1.7.6
Special Safety Evaluation of Venetoclax Among Chinese Subjects .....110
8.2
Determination of Sample Size ...............................................................111
9.0
Ethics.....................................................................................112
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................112
9.2
Ethical Conduct of the Study.................................................................112
9.3
Subject Information and Consent...........................................................113
9.3.1
Informed Consent Form and Explanatory Material ...............................114
9.3.2
Revision of the Consent Form and Explanatory Material .....................114
10.0
Source Documents and Case Report Form 
Completion ...........................................................................115
10.1
Source Documents .................................................................................115
10.2
Case Report Forms.................................................................................115
11.0
Data Quality Assurance ......................................................117
12.0
Use of Information...............................................................118
13.0
Completion of the Study .....................................................119
14.0
Investigator's Agreement....................................................121
15.0
Reference List ......................................................................122
List of Tables
Table 1.
Excluded Food/Medications ....................................................................50
Table 2.
Dose Modifications for Venetoclax:  Moderate and Strong 
CYP3A Inhibitor Use...............................................................................51
Table 3.
Patient-Reported Outcome Assessments .................................................58
Table 4.
Clinical Laboratory Tests.........................................................................64
 

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Table 5.
Identity of Investigational Product and Non-Investigational 
Products....................................................................................................79
Table 6.
Predicted Geometric Mean (and 90% CI) AUC24 Exposures of 
Venetoclax When Administered Alone and in Presence of Strong 
CYP3A Inhibitor......................................................................................87
Table 7.
Azacitidine Dose Modification................................................................98
List of Figures
Figure 1.
(Dosing Schematic)..................................................................................41
Figure 2.
Adverse Event Collection ........................................................................94
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................128
Appendix B.
List of Protocol Signatories....................................................................130
Appendix C.
Study Activities......................................................................................131
Appendix D.
Schedule of Biomarker/Pharmacodynamic/Pharmacogenetic 
Sample Collection (Not Applicable for China) .....................................135
Appendix E.
Schedule of Blood Collection for Venetoclax and Azacitidine 
Assay (Pharmacokinetic Sampling).......................................................136
Appendix F.
NCCN Risk Categorization:  Guidelines for AML Version 2.2016......137
Appendix G.
Tumor Lysis Syndrome Classification...................................................138
Appendix H.
Sample List of Excluded and Cautionary Medication ...........................139
Appendix I.
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (TLS) ..............141
Appendix J.
Japan Specific Information ....................................................................144
Appendix K.
Safety Cohort for Evaluation of Venetoclax in AML Chinese 
Subjects..................................................................................................146
Appendix L.
Venetoclax and Azacitidine Dose Modifications...................................150
Appendix M.
Protocol Amendment:  List of Changes.................................................152
 

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3.0
Introduction
Venetoclax Activity and Preclinical Pharmacokinetic Profile
Hematologic malignancies are highly dependent upon the anti-apoptotic protein BCL-2 
for survival.  Over-expression of BCL-2 is associated with tumor initiation, disease 
progression, and drug resistance, and is thus a compelling target for anti-tumor therapy.  
Venetoclax is a potent, selective and orally bioavailable small molecule inhibitor of 
BCL-2 that binds with > 1,000-fold higher affinity for BCL-2 (Ki < 0.010 nM) than for 
BCL-XL (Ki = 48 nm) or MCL-1 (Ki > 444 nM).1  In vitro, venetoclax has demonstrated 
cell killing activity against patient-derived chronic lymphocytic leukemia (CLL) cells and 
a variety of lymphoma and leukemia cell lines, including acute myeloid leukemia 
(AML).1  Venetoclax was especially potent against non-Hodgkin's lymphoma (NHL) cell 
lines expressing high levels of BCL-2 protein due to the t(14;18) chromosome 
translocation, amplification of the BCL-2 gene locus, or aberrantly activated signaling 
mechanisms.
BCL-2 over-expression has also been implicated in the maintenance and survival of AML 
cells and has been associated with resistance to chemotherapeutics.  In addition, high 
levels of BCL-2 were associated with poor survival in a subset of patients with this 
disease.2,3  The BCL-2/BCL-XL inhibitor ABT-737 has been shown to kill AML cells, 
including leukemic stem/progenitor cells, as both a single agent and in combination with 
cytarabine2 or 5-azacitidine.3  To further define the role of BCL-2 in this disease, panels 
of AML cell lines and primary patient samples were cultured in the presence of 
venetoclax.  Twelve of 24 AML cell lines tested were sensitive to venetoclax, with cell 
killing IC50 values of < 1.0 µM.  The sensitivity of primary AML subject samples was 
comparable to that observed for primary CLL samples, with a median IC50 = 0.010 µM 
(n = 57) for AML4 versus a median IC50 = 0.003 µM (n = 35) for CLL (AbbVie 
R&D/10/1025, AbbVie R&D/12/538).  Venetoclax has also demonstrated killing of AML 
leukemic stem/progenitor cells ex vivo and antitumor efficacy in vivo, inhibiting the 
growth of AML cell lines or AML patient-derived primary cells systemically engrafted 
into immunocompromised mice.4  Single agent venetoclax is currently being studied in 
 

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relapsed/refractory (R/R) AML and was found to induce rapid reduction in blast counts in 
some patients indicating activity in subject with this disease.  However, not all AML cell 
lines, primary patient samples, or subjects treated with single agent venetoclax were found 
to be sensitive, and there is biologic rationale for combining venetoclax with certain 
chemotherapeutic agents in the treatment of AML.  The MCL-1 protein can act as a 
resistance factor for Bcl-2 family inhibitors5,6 including in AML.2  Therapeutic agents 
such as the DNA methyltransferase inhibitor azacitidine,3 the DNA synthesis inhibitor 
cytarabine7 and the anthracycline doxorubicin8 have shown an ability to down-regulate 
MCL-1, indicating that they might combine well with BCL-2 inhibitors.  In support of 
this, ABT-737 has demonstrated synergistic killing of AML cell lines when combined 
with cytarabine or doxorubicin.2  Likewise, the combination of ABT-737 and azacitidine 
demonstrated synergistic killing of 7 of 8 primary AML patient samples and completely 
inhibited the engraftment of human CD45 + AML cells into immunocompromised mice.3  
Combinations of venetoclax and chemotherapeutic agents commonly used in the 
treatment of AML were recently tested against a panel of 20 AML cell lines.  While most 
combinations resulted in additive cell killing, venetoclax combined with cytarabine or 
azacitidine showed synergistic effects on several AML cell lines.  These data suggest that 
BCL-2 inhibition alone may be sufficient for the synergistic effects that have been 
observed between ABT-737 and cytarabine or azacitidine, and thus provides a rationale 
for testing these combinations with venetoclax in subjects with AML.  In mouse, rat, 
monkey, and dog, the venetoclax pharmacokinetic profile was characterized by low
plasma clearance (CLp = 0.02 to 0.27 L/hr•kg) and low volumes of distribution (Vss = 0.3 
to 1.1 L/kg).  Half-lives ranged from 2.2 hours in monkey to 12.0 hours in dog.  
Formulation-dependent oral bioavailability was noted in all species.  Studies in both rat 
and dog have defined the behavior of the amorphous solid dispersion (ASD) for both 
toxicology and first-in-human evaluation.  Plasma concentrations obtained from fed dogs 
were 30% to 50% higher than those obtained from fasted animals.
Venetoclax and M27 metabolite are predominantly metabolized by cytochrome P450 
(CYP) 3A4 (CYP3A4) in vitro; UDP-glucuronosyltransferases (UGTs) are not involved 
in the metabolism of venetoclax.  Venetoclax is also substrate for P-glycoprotein (P-gp) 
 

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and breast cancer resistance protein (BCRP) transporters.  No active uptake of venetoclax 
was observed in cells overexpressing organic anion transporting polypeptide 1B1 
(OATP1B1) or OATP1B3.  Based on in vitro results, venetoclax was a P-gp, BCRP, and 
OATP1B1 inhibitor.  It was not a potent in vitro inhibitor of CYP3A4, CYP1A2, 
CYP2B6, or CYP2D6 (IC50 > 30 µM); and it did not induce CYP3A4 or CYP1A2 at 
concentrations up to 10 µM.  Venetoclax is also not predicted to cause inhibition of 
CYP2C19, CYP2C8, CYP2C9, and UGT1A1 at clinically relevant concentrations.  It is 
not an inhibitor of UGT1A4, UGT1A6, UGT1A9 and UGT2B7.
Venetoclax Preclinical Toxicology
Toxicology studies completed with venetoclax are general toxicology studies with periods 
of once-daily oral dosing ranging from 2 weeks to 6 months in mice, from 2 weeks to 
13 weeks in rats, and from 1 week to 9 months in dogs, in vitro and in vivo genetic 
toxicology, dose range-finding in mice and rats to support dose selection for possible 
carcinogenicity assessments, embryo-fetal development in mice and rabbits, fertility and 
early embryonic development in male and female mice, dose range-finding in juvenile 
mice, and phototoxicity in mice.  Other studies were in vitro genetic toxicity testing of the 
M27 major human metabolite and in vitro and in vivo impurity qualification.  
Reversibility of venetoclax-related changes was assessed in the 4-week study in mice and 
in the 2- and 4-week studies in dogs.
The primary toxicities associated with repeat-dose administration of venetoclax are effects 
on the hematologic system (decreased lymphocytes and red blood cell mass in mice, rats 
and dogs), the male reproductive system (testicular germ cell depletion in dogs), and 
embryo-fetal toxicity in mice.  Other noteworthy findings are epithelial single cell 
necrosis in multiple tissues and hair coat color change, both in dogs.  Maximum 
venetoclax plasma exposures (mean AUC0-24h, combined male and female values) 
achieved in the 4-week studies were 92 µg•hr/mL (at 600 mg/kg/day) in mice and 
572 µg•hr/mL (at 150 mg/kg/day) in dogs.  In the 6-month mouse and 9-month dog 
chronic toxicity studies, AUCs reached 34.1 µg•h/mL (at 300 mg/kg/day) in mice and 
85.6 µg•h/mL (at 20 mg/kg/day) in dogs.  In rats, exposures were higher in females than 
 

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in males; at dosages of 150 and 400 mg/kg/day in the 13-week maximum tolerated dose 
study, exposures ranged up to 83.1 to 127.8 µg•h/mL in females and up to 26.4 to 
44.3 µg•h/mL in males.
Venetoclax produced generally dose-related decreases in lymphocytes in the peripheral 
blood (up to –75% in mice, –64% in rats, and –81% in dogs) and in lymphoid tissues.  
These findings are consistent with the expected pharmacology of venetoclax (a selective 
Bcl-2 inhibitor).9
Following a 4-week recovery period, lymphocyte counts remained minimally decreased 
by –21% to –26% in mice, indicating that reversibility was occurring but was not 
complete.  In dogs, the recovery of decreases in peripheral blood total lymphocytes and 
lymphocyte subsets (CD4+ T-cells and CD8+ T-cells and [CD21+] mature B cells) was 
prolonged, requiring up to 18 weeks after a single dose or after completion of 2 weeks of 
dosing.  B-cells were the most sensitive lymphocyte subtype based on the magnitude of 
decrease (> –90%) and/or the length of time required for recovery.  Lymphocyte 
decreases in lymphoid tissues were reversible in mice and dogs, but as with peripheral 
blood lymphocytes, required up to 18 weeks in dogs.  Decreases in lymphocyte counts can 
be readily monitored in clinical trial subjects.
In the 4-week mouse and dog studies, dose-related reversible decreases in red blood cell 
(RBC) mass were observed. Effects on RBC mass were typified by hemoglobin 
decreases.  At the highest dosages administered, decreases in hemoglobin reached –21% 
in mice at 600 mg/kg/day and –23% in dogs at 150 mg/kg/day, and were considered to be 
adverse based on a criterion of –20% decrease.  In rats, decreases in hemoglobin were 
more severe than in mice and dogs at comparable exposures and reached 30% to 49% at 
≥150 mg/kg/day in female rats.  Hematologic parameters are readily monitored in clinical 
trial subjects.
No effects of venetoclax have been identified on the female reproductive tract of mice, 
rats, and dogs.  However, in dogs venetoclax produced adverse, non-dose-related 
microscopic findings of testicular germ cell loss at all dosages tested (2 to 
 

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150 mg/kg/day).  In the 4-week study, testicular spermatogonia were decreased at the end 
of the dosing period, and their loss was consistent with the observed depletion of all germ 
cell types at the end of the 4-week recovery period.  There were no testicular effects in 
mice or rats; in these animal species, exposures overlapped those in dogs.  
Venetoclax-induced testicular changes may be related to venetoclax pharmacology, as one 
or more members of the Bcl-2 family of proteins play a role in spermatogenesis.10-12  
There are currently no data assessing the effect of venetoclax on human spermatogenesis, 
and the actual risk to humans for testicular findings similar to those observed in dogs 
remains unknown.  In view of the potential treatment benefits of venetoclax, this finding 
is anticipated not to impact the treatment of subjects with advanced hematologic 
malignancies.
In the mouse embryo fetal development study, increased post-implantation loss and 
decreased fetal body weights occurred at the highest dosage administered 
(150 mg/kg/day); the NOAEL was defined at the mid dosage of 50 mg/kg/day.  No fetal 
toxicity was observed in rabbits, but exposures were approximately one-tenth those in 
mice.  Venetoclax was not teratogenic in mice or rabbits, and there were no other effects 
on development or fertility.
Additional effects of venetoclax were white hair coat discoloration in dogs at 
≥6 mg/kg/day and single-cell necrosis in multiple epithelial tissues at ≥ 2 mg/kg/day in 
dogs.
Hair coat discoloration (increased amount of hair that was white) was observed in the dog 
after approximately 3 months of dosing in the 9-month chronic toxicity study.  This 
change was consistent with loss of pigment in the hair and correlated histopathologically 
with decreased pigment in hair follicle bulbs.  A change to gray coat color was also seen 
in NZBWF1 mice treated daily with 33 or 100 mg/kg venetoclax, but not at lower 
dosages.  Evidence from Bcl-2 knockout mouse (Bcl-2 -/-) studies indicates that hair
hypopigmentation occurs due to loss of hair follicle melanocytes dependent on Bcl-2 for 
survival.13 In the dog, pigmentation of the skin and in the eye (particularly in the 
pigmented iris and fundus) appeared unaffected; this was confirmed by the absence of 
 

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associated histopathologic findings in skin (other than in hair follicles) and in the eye.  
The risk of hair graying in clinical trial subjects treated with venetoclax is unknown.  
Single cell necrosis occurred in the gallbladder, exocrine pancreas, epididymides, 
prostate, and stomach of dogs.  These changes were minimal except for non-dose-
dependent minimal to mild single cell necrosis in the pylorus of the stomach at 
≥2 mg/kg/day in the 9-month study.  After 4 weeks of dosing and a 4-week recovery 
period, reversibility was observed in the gallbladder and exocrine pancreas, but minimal 
single cell necrosis was still present in the epididymides and prostate (potentially related 
to the testicular effects) and in the stomach.  Single cell necrosis was considered not to be 
adverse due to its minimal to mild magnitude and because no loss of mucosal integrity 
was observed microscopically.  Single cell necrosis was not found in the mouse or rat; 
maximum achieved exposures were comparable to or greater than the lowest exposures at 
which this finding occurred in dogs.
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax, nor was there 
evidence of phototoxicity (tested in vivo in hairless mice).  Venetoclax administration in 
dogs in the 4-week study was associated with dose related, transient post-dose emesis, 
increased salivation, and fecal alterations (unformed or watery feces) at dosages of 
≥5 mg/kg/day.  These clinical signs were present throughout the dosing phase, but were 
not dose-limiting and were not observed in the recovery phase.  In the 9-month dog study, 
non-adverse decreases in mean body weight and body weight gain, associated with 
decreases in food consumption, were present at ≥ 2 mg/kg/day.
Dogs at the high dosage of 150 mg/kg/day in the 4-week study had clinical signs of 
swelling of the skin on the ears, head (cranial area), and forepaws and/or hindpaws.  Most 
but not all animals (8 of 10 dogs) were affected, and in three dogs the swelling reaction 
was observed after the first dose.  The clinical signs were limited to the 
150 mg/kg/dosage, were transient and sporadic in occurrence, and were absent during the 
recovery period.  A mechanistic basis for the swelling reactions was not established, but 
the clinical signs were mild to moderate in severity and reversible, and there were no 
signs of anaphylaxis.
 

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M27 is a major human metabolite observed at steady state in chronic lymphocytic 
leukemia (CLL) or non-Hodgkin's lymphoma (NHL) patient plasma samples.  It is present 
at significantly lower exposure levels (0.04- and 0.06-fold, respectively) in the mouse and 
dog, and therefore is a disproportionate metabolite.  M27 was negative in Ames and 
chromosome aberration in vitro assays, has at least 58-fold less in vitro potency than 
venetoclax, and demonstrates low off-target toxicity potential based on in vitro secondary 
pharmacology assays.  Taken together, these nonclinical results suggest that M27 does not 
represent a significant safety risk, and does not change the benefit/risk ratio for clinical 
trial subjects with advanced hematologic malignancies treated with venetoclax.
Venetoclax was tested in a battery of safety pharmacology assays, and produced no 
effects in the central nervous system (CNS)/neurobehavioral or respiratory studies in mice 
at oral doses up to and including the highest oral dose of 600 mg/kg.  No effects on QTc 
were observed up to a maximum plasma concentration of 46 μg/mL in dogs.  In conscious 
dogs, venetoclax did not produce any cardiovascular effects up to and including the 
highest oral dose of 150 mg/kg (Cmax = 16 μg/mL).  In the anesthetized dog at higher 
plasma concentrations, venetoclax produced mild reductions in myocardial contractility 
(–6% to –13%) and cardiac output (–11% to –19%) at plasma concentrations of 
≥16 μg/mL and ≥ 32 μg/mL, respectively.  These concentrations are greater than the 
plasma concentration of venetoclax in humans (average Cmax = 6.09 μg/mL at the 
1200 mg/day dose).
On the basis of nonclinical toxicology and safety pharmacology evaluations of 
venetoclax, and on the basis of nonclinical and human studies of related anti-apoptotic 
Bcl-2 family protein inhibitors, potential mechanism-based toxicities may include 
lymphopenia and neutropenia,14 signs of tumor lysis, reduction in red cell mass, decreased 
spermatogenesis, skin swelling, and hair hypopigmentation.  Although no effects of 
venetoclax on female reproductive tissues have been observed in general repeat-dose 
toxicology studies, embryo-fetal toxicity studies in animals have identified a fetal toxicity 
risk.  Thrombocytopenia has not been a significant finding in toxicology studies in mice 
 

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and dogs.  These findings are consistent with venetoclax as a Bcl-2 specific (Bcl-XL
sparing) inhibitor.  Consequently, thrombocytopenia is not expected to be dose limiting.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the current Investigator's Brochure.14
Acute Myeloid Leukemia
Acute myeloid leukemia is the most common form of acute leukemia in adults and is 
characterized by the clonal expansion of myeloid blasts in the bone marrow, peripheral 
blood and extra medullary tissues.  It is a heterogeneous disease, encompassing a large 
number of distinctly different subtypes that may have different clinical presentations and 
differing responses to treatment.  AML is defined by World Health Organization (WHO) 
as a myeloid neoplasm with 20% or more blasts in the peripheral blood or bone marrow.17  
The estimated number of new cases is 19,950 and 10,430 deaths in 2016 in the United 
States.18  The incidence is approximately 36,000 cases worldwide.  The median age of 
diagnosis is 67 years, with 55% of the patients diagnosed at 65 years or older, and
approximately a third of them are diagnosed over the age of 75.  Standard treatment for 
newly diagnosed AML for patients who are medically fit consists of remission induction 
therapy with cytarabine as the backbone combined with an anthracycline, usually 
daunorubicin or idarubicin (7 + 3) followed by consolidation therapy.  Elderly AML is a 
biologically and clinically distinct disease with a diminished response to chemotherapy 
with low remission rates and short disease-free and overall survival.  Higher proportion of 
unfavorable cytogenetics, higher frequency of antecedent hematologic disorders or prior 
therapy for previous malignancies, and more frequent expression of the multidrug 
resistance phenotype accounts for the poor outcomes associated with current therapy.  
Additionally, the presence and severity of comorbid conditions, compromised end organ 
function that enhance the toxicity of induction chemotherapy, and functional incapacity 
all decrease the ability for the elderly patient to tolerate induction chemotherapy and 
survive life-threatening infections often associated with AML therapy.19  While some 
elderly patients are able to receive standard induction or intensive chemotherapy, the 
majority are treated with less intensive therapies such as hypomethylating agents, low 
 

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dose cytarabine or best supportive care.  Similarly, younger patients with significant 
cardiac, pulmonary or other comorbidities may not be eligible to receive standard 
induction therapy.  Several studies have also demonstrated the benefits of induction 
therapy over supportive care only, with respect to survival and quality of life, suggesting 
that treatment should be offered to all patients diagnosed with AML.20
Venetoclax Clinical Data
As of 28 November 2015, based on the data available in the AbbVie and 
Genentech/Roche clinical databases, a total of 1509 subjects have been exposed to at least 
1 dose of venetoclax in the oncology development program.  Of these, data are available 
for 1498 subjects; 102 had AML, 935 subjects had CLL/SLL, 346 subjects had NHL, and 
115 subjects had MM.  An additional 66 subjects were healthy volunteers who 
participated in the DDI studies.  Based on the available data, a total of 564 oncology 
subjects received the drug as monotherapy and 933 subjects received the drug in 
combination with other therapies.
Based on the mechanism of action and nonclinical and clinical data available to date, the 
safety profile of venetoclax is well described.  The most common adverse drug reactions 
across all indications are nausea, diarrhea, hematological effects, and serious and/or 
opportunistic infections.  Hematologic effects include neutropenia/febrile neutropenia, 
thrombocytopenia, anemia, and lymphopenia.  Upper respiratory tract infections are 
among the most common infections.  TLS is an important identified risk and is 
predominantly seen in the CLL population with high tumor burden.  Based on pre-clinical 
data, decreased spermatogenesis has been identified as a potential risk for venetoclax.
Clinical Data in AML
As of 09 March 2016 a total of 102 subjects with AML have been treated in the 
venetoclax oncology clinical program:  32 subjects with R/R and in unfit AML received 
venetoclax as a single agent (Study M14-212) and 70 subjects received venetoclax in 
combination with other therapeutic agents including 45 subjects with HMAs 
(Study M14-358) and 25 subjects with low-dose cytarabine (LDC) (Study M14-387).  To 
 

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date, the adverse events observed occurred at an incidence that appeared to be consistent 
with what would be expected in the AML patients both in monotherapy and combination 
studies.  Neutropenia is being closely monitored.
Overview of Phase 2 Study M14-212:  Venetoclax Monotherapy in AML
This is a completed study with single agent venetoclax in subjects with R/R AML and 
those unfit for intensive therapy.  A total of 32 subjects were dosed.  Exposure, safety, and 
efficacy data are available for this study.21  The most common adverse events observed in 
≥ 30% of the subjects in Study M14-212 were nausea (59.4%); diarrhea (56.3%); 
hypokalemia, vomiting (40.6% each); fatigue, headache (34.4% each); hypomagnesemia 
(37.5%); febrile neutropenia (31.3%); abdominal pain, cough, hypophosphatemia (28.1% 
each); epistaxis, hyperphosphatemia, hypocalcemia, malignant neoplasm progression 
(25.0% each); dyspnea, hypotension, peripheral edema, pyrexia, and pneumonia (21.9% 
each).  Serious adverse events were reported in 27 subjects (84.4%), the most common 
being febrile neutropenia (28.1%), malignant neoplasm progression (25.0%), and 
pneumonia (15.6%).  Three serious adverse events were considered to have a reasonable 
possibility of being related to venetoclax (i.e., 1 event each of diarrhea, febrile 
neutropenia, and pseudomonal bacteremia).  No cases of TLS occurred during venetoclax 
treatment.
Efficacy data for Study M14-212 are available for all 32 subjects, the majority (30, 94%) 
of the subjects had R/R AML and a few (2, 6%) were deemed unfit for intensive therapy.  
The ORR was 19% (6 of 32 subjects), with complete remission (CR) in 2 (6%) and 
complete remission with incomplete marrow recovery (CRi) in 4 (13%) subjects.  
Anti-leukemic activity was observed in an additional 7 (22%) subjects, with ≥ 50% bone 
marrow reduction with hematologic recovery in 4 of these subjects.  Increase activity was 
observed in patients with a high percentage of BCL2 expressing cells and low percentage 
of BCLxL expressing cells by flow cytometry.
 

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Overview of Ongoing Phase 1b Study (M14-358):  Venetoclax in Combination with 
HMA in Treatment Naïve AML
As of 09 March 2016, a total of 45 subjects ≥ 65 years of age with treatment naïve AML 
ineligible to receive standard induction therapy were enrolled into the escalation stage at 
3 dose levels of venetoclax at 400 mg, 800 mg, and 1200 mg.  Venetoclax was 
administered daily during the 28-day cycles in combination with decitabine (20 mg/m2
intravenously on Days 1 – 5 once every 28 days) or azacitidine (75 mg/m2 intravenously 
or subcutaneously on Days 1 – 7 once every 28 days).  Preliminary safety and efficacy 
data are available from the ongoing dose escalation stage of this trial.22
The most common adverse events for all subjects in Study M14-358 were nausea (53.3%), 
diarrhea (44.4%), febrile neutropenia (40.0%), neutrophil count decreased (31.1%), 
platelet count decreased, cough, and fatigue (28.9% each), edema peripheral and 
hypokalemia (26.7% each).  Events grade 3 and above were reported for the majority 
(91.1%) of subjects; the most common event was febrile neutropenia (40.0%).  Serious 
adverse events were reported for 27 (60.0%) subjects, including febrile neutropenia 
(11 subjects), malignant neoplasm progression (3 subjects) atrial fibrillation, abdominal 
pain, non-cardiac chest pain, pyrexia, pneumonia, sepsis, bone pain (2 subjects each).  All 
other events occurred in 1 subject each.  The combination of venetoclax with decitabine 
and azacitidine demonstrates a tolerable safety profile.  
As of 09 March 2016, the ORR, as assessed by the investigators for the subjects enrolled 
into the 3 dose levels, was 62.2% (28 of 45), with CR in 12 (26.7%), CRi in 15 (33.3%), 
and PR in 1 (2.2%).  Four subjects (8.9%) were reported to have morphologic leukemia-
free state (less than 5% blasts in bone marrow aspirate sample with at least 200 nucleated 
cells) after completion of Cycle 1.  Eight patients (17.8%) had resistant disease.  
However, all of the patients with resistant disease had evidence of blast reduction at 
completion of Cycle 1.  The patients enrolled into the 1200 mg dose level had a shorter 
follow-up at the time of this analysis.  
 

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The maximum tolerated dose has not been reached in either arm and dose escalation stage 
has completed enrollment.  Enrollment into safety expansion at 400 mg and 800 mg dose 
of venetoclax in combination with both HMAs is ongoing.  
Overview of Ongoing Phase 1/2 Study M14-387:  Venetoclax in Combination with 
low Dose Cytarabine in Treatment Naïve AML
As of 28 November 2015, a total of 25 subjects ≥ 65 years of age with treatment naïve 
AML ineligible to receive standard induction therapy were enrolled; 18 subjects were 
enrolled into the Phase 1 portion of the study and a RPTD of 600 mg has been identified.  
Enrollment into the subsequent Phase 2 portion with approximately 50 subjects is ongoing 
to evaluate the RPTD for efficacy and safety.  Preliminary efficacy data for 
Study M14-387 are available for 18 subjects with AML as of 28 November 2015.  The 
ORR was 44.4% including 4 (22.2%) subjects achieving CR and 4 (22.2%) subjects 
achieving CRi.
Of the 25 subjects enrolled in study the most common adverse events were nausea 
(68.0%), anemia (52.0%), and febrile neutropenia (36.0%).  Events grade 3 and above 
were reported for all but one subject (96.0%) of subjects; the most common event was 
anemia (48.0%).  Serious adverse events were reported for 19 (76.0%) subjects, including 
febrile neutropenia (7 subjects), pyrexia, hyponatremia, and malignant neoplasm 
progression (2 subjects each).  All other events occurred in 1 subject each.  Fatal adverse 
events occurred in 5 (20.0%) subjects:  2 events of malignant neoplasm progression and 
1 event each of acute hepatic failure, Candida pneumonia, and lung infection.  
Additional safety and efficacy data are described in more detail in the current version of 
the Investigator's Brochure.14
3.1
Differences Statement
This is the first randomized study comparing venetoclax in combination with azacitidine 
versus placebo in combination with azacitidine in subjects with AML who are treatment 
naïve and are considered ineligible for standard induction therapy.
 

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3.2
Benefits and Risks
Venetoclax was evaluated as a single agent (Study M14-212) in patients with R/R AML 
or frontline in patients with AML who are unfit to receive intensive chemotherapy 
demonstrating clinical activity.  Venetoclax in combination with hypomethylating agents 
(decitabine or azacitidine) in treatment naïve patients ≥ 65 years of age who were 
ineligible to receive standard induction therapy (Study M14-358) is an ongoing study 
again demonstrating an acceptable benefit risk profile.  Data from Study M14-358 
demonstrate favorable safety profile and promising clinical activity in subjects with 
untreated AML who are unfit to receive standard induction therapy.
Currently there are no approved therapies in the US for patients with AML who are not 
candidates for conventional induction treatment.  In Europe, decitabine and azacitidine are 
approved as single agents for patients with treatment naïve AML.  However, the reported 
overall response (CR + CRp) rate in a randomized trial was 17.8% and the median overall 
survival was 7.7 months with decitabine compared with 7.8% and 5.0 months in treatment 
choice arm consisting of either subcutaneous low dose cytarabine (88.5% of patients) or 
supportive care (11.5% of patients).23  The reported overall response (CR+CRi) rate and 
median overall survival were 27.8% and 10.4 months with azacitidine versus 25.1% and 
6.5 months, respectively, in the conventional care regimens arm consisting of best 
supportive care, low dose cytarabine or intensive chemotherapy.24  Both of these trials in 
AML patients are ≥ 65 years of age demonstrate lower response rates and survival than 
standard induction therapy.  These data highlight the need for novel approaches that offer 
greater improvements in survival for those patients who are not eligible for treatment with 
standard induction therapy.
Rapid cell death in patients with AML can result in tumor lysis syndrome (TLS) during 
initial dosing.  To mitigate the risk of TLS in AML patients the regimen is designed to 
escalate the dose of venetoclax rapidly and safely with standard doses and schedule of 
azacitidine to optimize the opportunity for achieving a response and enable close subject 
monitoring.  
 

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Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  No additional risk to study subjects is 
anticipated with the use of venetoclax/placebo in this population with limited treatment 
options for their underlying AML.
For additional safety and efficacy data please refer to the current Investigator Brochure.14
4.0
Study Objectives
4.1
Primary Objective
The primary objective is: 
●
To evaluate if venetoclax in combination with azacitidine will improve overall 
survival (OS) and composite complete remission rate (complete remission + 
complete remission with incomplete marrow recovery; CR + CRi) versus 
placebo in combination with azacitidine, in treatment naïve subjects with acute 
myeloid leukemia (AML).
4.2
Secondary Objectives
The secondary objectives are:
●
To evaluate if venetoclax in combination with azacitidine will improve the rate 
of CR.
●
To evaluate if venetoclax in combination with azacitidine will improve the rate 
of CR and complete remission with partial hematologic recovery rate (CRh).
●
To evaluate if venetoclax in combination with azacitidine will improve the 
proportion of subjects achieving composite complete remission (CR or CRi) 
by initiation of Cycle 2.
●
To evaluate if venetoclax in combination with azacitidine will improve the 
transfusion independence rate.
●
To evaluate if venetoclax in combination with azacitidine will improve the 
MRD response rate.
 

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●
To evaluate if venetoclax in combination with azacitidine will improve the 
response rates and overall survival in molecular subgroups.
●
To evaluate if venetoclax in combination with azacitidine reduces fatigue and 
improves global health status/quality of life (GHS/QoL) based on patient 
reported outcome (PRO) assessments (Patient Reported Outcomes 
Measurement Information System [PROMIS], Cancer Fatigue Short Form 
[SF] 7a and European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core [EORTC QLQ-C30]).
●
To evaluate if venetoclax in combination with azacitidine will improve, event-
free survival (EFS).
4.3
Exploratory Objectives
The exploratory objectives are: 
●
Exploration of biomarkers predictive of venetoclax activity and duration of 
response may be performed.  These analyses maybe part of a multi-study 
assessment to compare responses to the therapies and/or disease state.  
Potential analyses may include but not limited to:
○
To evaluate BCL2 expression and outcome measures of overall survival 
and complete remission rate
●
To evaluate the impact of venetoclax on the remaining subscales/items from 
the EORTC QLQ-C30 and EQ-5D-5L.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, randomized, double-blind, placebo controlled, multicenter trial 
evaluating efficacy and safety of venetoclax in combination with azacitidine versus 
placebo in combination with azacitidine in treatment naïve subjects with AML who are 
≥18 years of age and not eligible for standard induction therapy due to age or 
 

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comorbidities.  Subjects will be randomized to one of the two treatment Arms in a 
2:1 ratio, both of which will have treatment cycles of 28 days.
●
Arm A:  Venetoclax 400 mg orally QD on Days 1 – 28 plus Azacitidine 
75 mg/m2 SC or IV (per local label) Daily for 7 days
●
Arm B:  Placebo orally QD on Days 1 – 28 plus Azacitidine 75 mg/m2 SC or 
IV (per local label) Daily for 7 days
443 subjects were randomized to meet scientific and regulatory objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.
This study is sponsored by AbbVie in collaboration with Roche/Genentech.
5.1.1
Screening
At the Screening Visit, subjects who provide written (signed and dated) informed consent 
prior to any study specific procedures will receive a unique subject number via the 
Interactive Response Technology (IRT) system.  The investigator will evaluate whether 
the subject meets all of the eligibility criteria specified in Section 5.2.1 during the period 
from the Screening Visit up to dosing on Cycle 1 Day 1, and will record the results of this 
assessment and the details of the informed consent process in the subject's medical 
records.  
Eligible subjects have up to 21 days to complete screening procedures.  Once screening 
procedures are completed and eligibility is confirmed, subjects will be randomized.  After 
being randomized, subjects will have up to 5 days to initiate Cycle 1 Day 1 however this 
window cannot exceed the allotted 21 day Screening period.
5.1.2
Rescreening
Due to the acute nature of AML, subjects who have failed to meet the eligibility criteria 
during screening period will not be permitted to re-screen. 
 

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5.1.3
Treatment Period
After meeting the eligibility criteria, subjects will be enrolled via IRT into a treatment 
arm.  All subjects will begin study drugs (investigational product and reference therapy) 
on Cycle 1 Day 1.  Subjects in Arm A will receive venetoclax orally QD plus Azacitidine 
(SC or IV per local label instructions) QD beginning on Cycle 1 Day 1.  Venetoclax 
should be taken within 30 minutes after completion of a meal (preferably breakfast).  
Subjects in Arm B will receive placebo orally QD plus Azacitidine (SC or IV per local 
label instructions) QD beginning on Cycle 1 Day 1.  Placebo should be taken within 
30 minutes after completion of a meal (preferably breakfast).  Subjects will receive 
Azacitidine for 7 days of each cycle, beginning on Day 1 of each cycle.
Dosing Schedule Overview – For Venetoclax/Placebo
Venetoclax or placebo for venetoclax will be administered with a 3-day ramp up 
beginning with 100 mg dose on Day 1 to reach the final dose of 400 mg on Day 3 of 
Cycle 1.  Venetoclax or placebo for venetoclax will be continued at 400 mg daily 
thereafter.  
Figure 1.
(Dosing Schematic)
Subjects will be hospitalized during the venetoclax ramp-up period during Cycle 1 
(e.g., Days –1 through Day 4).
 
  
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

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Cycle Length – 28 Days
●
Venetoclax 400 mg or Placebo QD on Days 1 – 28
●
Azacitidine75 mg/m2 SC or IV (per local label) Daily for 7 Days
Subjects will continue their study treatment until documented disease progression per 
Investigator assessment, unacceptable toxicity, withdrawal of consent, or the subject 
meets other protocol criteria for discontinuation (whichever occurs first).  Subjects will 
continue to receive the assigned study treatment without cross over until treatment 
discontinuation.  Azacitidine administration starting with Cycle 5 and subsequent cycles 
may be administered in a non-hospital/clinic environment, as allowed per local 
regulations.  Baseline laboratory assessments will be obtained at Cycle 1 Day 1 prior to 
first dose of study treatment.  PRO measures scheduled for administration should be 
completed after a blood sample is taken to confirm the subject is able to receive study 
treatment at the study visit, but prior to the performance of all other non-PRO assessments 
and the administration of study treatment.  All subjects will have a Final Visit performed 
when treatment is discontinued unless subject has withdrawn consent to participate in the 
study.  All subjects will be followed for survival information (i.e., date and cause of 
death) unless the subject requests to be withdrawn specifically from this study survival 
follow-up; this request must be documented in the subject's medical record and signed by 
the Investigator.
Disease assessments by the modified IWG criteria15 will be performed at end of Cycle 1 
(± 3 days) and every 3 cycles starting on Cycle 4 Day 1 and continuing until disease 
progression as defined per ELN criteria16 or the subject withdraws consent.  In addition to 
being reviewed by the Investigator and local hematopathologists, all pertinent information 
for disease assessment will be reviewed by an Independent Review Committee (IRC) to 
provide response assessment.  Interpretations from the IRC will not be shared with sites.  
Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will 
no longer be performed by the IRC.  A charter will outline the review process for the 
IRC's determination of response.  An Independent Data Monitoring Committee (IDMC) 
 

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will periodically review safety and efficacy data per the IDMC Charter.  Details regarding 
the IDMC are provided in Section 5.5.5.2. 
5.1.4
Post Treatment Follow-Up
Survival information and post treatment follow up (i.e., the date and cause of death, all 
post treatment cancer therapies including stem cell transplantation, regimens, dates of 
initiation and completion, etc.) will be collected (e.g., via telephone calls and/or clinical 
visits) every 2 months after the last study visit or as needed to allow for more frequent 
survival analyses until end of study, defined as last subject last visit.
Post treatment follow up for subjects who discontinue study drugs for reasons other than 
disease progression, hematology and disease assessments data will be collected every 
2 months or as needed to allow for more frequent survival analyses until end of study, 
defined as last subject last visit.
All subjects will be followed for survival information (i.e., date and cause of death) unless 
the subject requests to be withdrawn specifically from this study survival follow-up; this 
request must be documented in the subject's medical record and signed by the 
Investigator.  In such instances, sites may enter confirmation of death using source 
documentation from publicly available records such as death certificates or funeral 
notices.
For subjects that are considered lost to follow-up but have not withdrawn consent, 
reasonable attempts must be made to obtain information on the survival status of the 
subject.  At a minimum, two phone calls must be made and one certified letter must be 
sent and documented in the subject's source documents.
30 Day Safety Follow-Up Visit
A Safety Follow-Up Visit should be performed for all subjects approximately 30 days 
following discontinuation of study drug and then as clinically appropriate for safety 
 

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assessment.  The subject will be followed until a satisfactory clinical resolution of the 
adverse event is achieved.
A Safety Follow-Up Visit does not need to be performed for subjects who had a Final 
Visit conducted > 30 days after discontinuation of study drug and did not require 
additional adverse event follow-up.  If the subject refuses or is unable to attend the Safety 
Follow-Up Visit, this should be noted in the subject's source documentation.
5.2
Selection of Study Population
The study population consists of treatment naïve subjects with AML who are considered 
ineligible for standard induction therapy.  Adult male and female subjects who meet the 
inclusion criteria and who do not meet any of the exclusion criteria will be eligible for 
enrollment into the study.
5.2.1
Inclusion Criteria
1.
Subject must have confirmation of AML by WHO criteria, previously untreated 
and be ineligible for treatment with a standard cytarabine and anthracycline 
induction regimen due age or comorbidities.
2.
Subject must be ≥ 18 years of age.
3.
Subject must have a projected life expectancy of at least 12 weeks.
4.
Subject must be considered ineligible for induction therapy defined by the 
following: 
●
≥ 75 years of age;
OR
●
≥ 18 to 74 years of age with at least one of the following co-morbidities:
○
ECOG Performance Status of 2 or 3;
○
Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or 
chronic stable angina;
○
DLCO ≤ 65% or FEV1 ≤ 65%;
 

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○
Creatinine clearance ≥ 30 mL/min to < 45 ml/min;
○
Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN;
○
Any other comorbidity that the physician judges to be incompatible with 
intensive chemotherapy must be reviewed and approved by the AbbVie TA 
MD during screening and before study enrollment.
5.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance 
status: 
●
0 to 2 for subjects ≥ 75 years of age.
OR 
●
0 to 3 for subjects ≥ 18 to 74 years of age.
6.
Subject must have adequate renal function as demonstrated by a creatinine 
clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 
24-hours urine collection.
eCCr =
(140 – Age) • (Weight in kg) • [0.85 if Female]
72 • Serum Creatinine (mg/dL)
Or, if serum creatinine is in µmol/L:
eCCr 
=
(140 – Age) • (Weight in kg) • [1.23 if Male, 1.04 if Female]
Serum Creatinine (µmol/L)
7.
Subject must have adequate liver function as demonstrated by:
●
aspartate aminotransferase (AST) ≤ 3.0 × ULN*
●
alanine aminotransferase (ALT) ≤ 3.0 × ULN*
●
bilirubin ≤ 1.5 × ULN*
*
Unless considered due to leukemic organ involvement.
○
Subjects who are < 75 years may have a bilirubin of ≤3.0 × ULN
 

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8.
Female subjects must be either postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
Women of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control, starting at Study Day 1 through at least 90 days 
after the last dose of study drug.
9.
Male subjects who are sexually active, must agree, from Study Day 1 through at 
least 90 days after the last dose of study drug, to practice the protocol specified 
contraception.  Male subjects must agree to refrain from sperm donation from 
initial study drug administration through at least 90 days after the last dose of study 
drug.
10.
Female subjects of childbearing potential must have negative results for pregnancy 
test performed:
●
At Screening with a serum sample obtained within 14 days prior to the 
first study drug administration, and
●
Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been 
> 7 days since obtaining the serum pregnancy test results.
11.
Subject must voluntarily sign and date an informed consent form, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures.
 

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Rationale for Inclusion Criteria
1 – 7
To select the appropriate subject population for the evaluation
8 – 10
The impact of venetoclax on pregnancy is unknown
11
In accordance with Harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Subject has received treatment with the following:
●
A hypomethylating agent, venetoclax and/or chemo therapeutic agent for 
Myelodysplastic syndrome (MDS).
●
CAR-T cell therapy.
●
Experimental therapies for MDS or AML.
●
Current participation in another research or observational study
2.
Subject has history of myeloproliferative neoplasm [MPN] including 
myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid 
leukemia (CML) with or without BCR-ABL1 translocation and AML with 
BCR-ABL1 translocation.
3.
Subject has the following:
●
Favorable risk cytogenetics such as t(8;21), inv(16), t(16;16) or t(15;17) as per 
the NCCN Guidelines Version 2, 2016 for Acute Myeloid Leukemia.
4.
Subject has acute promyelocytic leukemia.
5.
Subject has known active CNS involvement with AML.
6.
Subject has known HIV infection (due to potential drug-drug interactions between 
antiretroviral medications and venetoclax) HIV testing will be performed at 
Screening, only if required per local guidelines or institutional standards.
7.
Subject is known to be positive for hepatitis B or C infection [HCV Ab indicative 
of a previous or current infection; and/or positive HBs Ag or detected sensitivity on 
HBV-DNA PCR test for HBc Ab and/or HBs Ab positivity] with the exception of 
 

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those with an undetectable viral load within 3 months of screening.  (Hepatitis B or 
C testing is not required).  Subjects with serologic evidence of prior vaccination to 
HBV [i.e., HBs Ag-, and anti-HBs+] may participate.
8.
Subject has received strong and/or moderate CYP3A inducers within 7 days prior 
to the initiation of study treatment.
●
Chinese AML subjects participating in the safety cohort per Appendix K are 
also excluded from receiving strong and/or moderate CYP3A inhibitors from 
7 days prior to the initiation of study treatment through the entire dose limiting 
toxicity (DLT)/safety evaluation period.
9.
Subject has consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Starfruit within 3 days prior to the 
initiation of study treatment.
10.
Subject has a cardiovascular disability status of New York Heart Association 
Class > 2.  Class 2 is defined as cardiac disease in which patients are comfortable at 
rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or 
anginal pain.
11.
Subject has chronic respiratory disease that requires continuous oxygen, or 
significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, 
immunologic, hepatic, cardiovascular disease, any other medical condition or 
known hypersensitivity to any of the study medications including excipients of 
azacitidine that in the opinion of the investigator would adversely affect his/her 
participating in this study.
12.
Subject has a malabsorption syndrome or other condition that precludes enteral 
route of administration.
13.
Subject exhibits evidence of other clinically significant uncontrolled systemic 
infection requiring therapy (viral, bacterial or fungal).
14.
Subject has a history of other malignancies within 2 years prior to study entry, with 
the exception of:
 

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●
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; requires discussion with TA MD.
15.
Subject has a white blood cell count > 25 × 109/L.  (Hydroxyurea or leukapheresis 
are permitted to meet this criterion.)
Rationale for Exclusion Criteria
1 – 10
To select the appropriate subject population for the evaluation
11 – 15
For the safety of the subjects
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medications, 
vitamins and/or herbal supplements) that the subject is receiving at the time of enrollment, 
or receives during the study, must be documented in source documents and electronic case 
report forms (eCRFs) along with the reason for use, date(s) of administration including 
start and end dates, and dosage information including dose, route, and frequency.
The AbbVie TA MD or designee (refer to Section 6.1.5) should be contacted if there are 
any questions regarding prior and concomitant therapies.
General guidelines regarding excluded, cautionary and allowed medications are 
summarized in Table 1 and Appendix H.
 

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Table 1.
Excluded Food/Medications
Excluded Food (From 3 Days Prior to Study Administration Until Last Day of Treatment)

Grapefruit and grapefruit products

Seville Oranges (including marmalade containing Seville oranges)

Starfruit
Excluded Medications

Strong CYP3A Inducers – during ramp up and throughout the study
Cautionary, Additional Guidance Noted 

Strong and Moderate CYP3A inhibitors^ 
Consider alternative medications.  If subject requires use of these medications, use with caution 
and reduce the venetoclax dose by at least 2-fold for moderate inhibitors and at least 8-fold for 
strong inhibitors during co-administration (see Table 2).

Moderate CYP3A inducers^
Exclude during the ramp-up phase and consider alternative medications.  If subject requires use of 
these medications, use with caution and contact AbbVie TA MD or designee (refer to 
Section 6.1.5) for guidance.

P-gp inhibitors
Consider alternative medications.  If subject requires use of these medications, use with caution 
and reduce the venetoclax dose by at least 2-fold (see Table 2).
Cautionary

Warfarin*

Coumarin derivatives* e.g., phenprocoumon

P-gp substrates**

BCRP substrates

OATP1B1/1B3 substrates

BCRP inhibitors
^
Chinese AML subjects enrolled in the safety cohort are prohibited to take strong CYP3A inhibitors, moderate 
CYP3A inhibitors and inducers from the initiation of study treatment through the entire dose limiting toxicity 
(DLT)/safety evaluation period.
*
Closely monitor International Normalized Ratio (INR).
**
If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before venetoclax.
 

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Table 2.
Dose Modifications for Venetoclax:  Moderate and Strong CYP3A 
Inhibitor Use
Venetoclax Dose
Modified Venetoclax Dose if 
Co-Administered with a 
Moderate CYP3A or P-gp 
Inhibitor
Modified Venetoclax Dose if 
Co-Administered with a 
Strong CYP3A Inhibitor
100 mg (Cycle 1 Day 1 ONLY)
50 mg
10 mg
200 mg (Cycle 1 Day 2 ONLY)
100 mg
20 mg
400 mg
200 mg
50 mg
Note:
After discontinuation of the inhibitor, wait for 2 to 3 days before venetoclax dose is increased back to the 
previous dose level.  Ramp-up is not required upon discontinuation of the inhibitor.
A sample list of excluded medications and cautionary medications that fall into the 
categories within section can be found in Appendix H.  It is not possible to produce a 
100% exhaustive list of medications that fall into these categories, so if in question, please 
refer to the appropriate local product label and/or FDA website:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm080499.htm.
If the investigator determines that such a medication is medically necessary without an 
available alternative, the investigator will notify the AbbVie TA MD prior to 
administration and discuss the investigator's use of these medications and the 
investigator's plans to medically monitor the subject.  Commonly used anti-infective 
agents for prophylaxis have CYP3A inhibitory properties and dose reductions of 
venetoclax/placebo are required.  When feasible, administration of such a medication 
should be planned prior to beginning ramp up or beginning of a cycle to prevent dose 
reductions during a treatment cycle.
Steroid therapy during study participation should be limited to lower dose and short 
duration if medically indicated.  Exceptions can be inhalational steroids for the treatment 
of asthma or COPD, topical steroids and for prevention and/or treatment of transfusion 
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Intrathecal chemotherapy or radiation therapy for CNS prophylaxis is not permitted 
during study participation.
5.2.4
Contraception Recommendations
While participating in this research study, female subjects should not become pregnant or 
breastfeed a baby.  Male subjects should not father a baby.  
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Women of Childbearing Potential, 
practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 90 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to Study Day 1.  Also, subjects must use a 
barrier method during this study from initial study drug administration to 
90 days after the last dose of study drug as drug.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.  Also, subjects must use a barrier method during this study from initial 
study drug administration to 90 days after the last dose of study drug.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.  
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, vasectomy occurred 
more than 3 months prior to screening and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
 

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(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
Male subjects who are sexually active with a WOCBP, even if the male subject has 
undergone a successful vasectomy, must agree from Study Day 1 through at least 90 days 
after the last dose of study drug to use condoms and his female partner(s) must use at least 
one of the contraceptive measures (as defined in the protocol for female study subjects of 
childbearing potential).
Additionally, male subject agrees not to donate sperm from Study Day 1 through at least 
90 days after the last dose of study drug.
5.3
Pharmacokinetic, Biomarker, Exploratory Research, Safety 
and Efficacy, Assessments/Variables
5.3.1
Safety and Efficacy Measurements Assessed and Flow 
Chart
This study is designed to assess Pharmacokinetic, Biomarker, Exploratory Research, and 
Safety data.  Exploratory efficacy analyses will be performed on all subjects enrolled 
unless otherwise specified.  Study procedures described in this protocol are summarized in 
Appendix C.
5.3.1.1
Study Procedures
All study procedures outlined in Appendix C are discussed in detail in this section, with 
the exception of adverse event information (discussed in Section 6.0).  All study data will 
be recorded on eCRFs.
Study visits may be impacted by changes in local regulations due to the COVID-19 
pandemic.  Every effort should be made to ensure the safety of subjects, while 
 

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maintaining the integrity of the study.  If visits cannot be conducted onsite due to travel 
restrictions or other pandemic-related reasons, follow the details in this section and 
Appendix C on how to proceed.
Procedures performed at Screening will serve as baseline, unless repeated on Cycle 1 
Day 1 prior to dosing; in which case the latter will serve as baseline.  Any abnormal 
laboratory or vital sign assessment between screening and prior to administration of study 
drug will be recorded in the subject's medical history and will also serve as the subject's 
baseline.  Record highest grade of cytopenias in medical history, including any 
transfusion support, prophylaxis received regardless if screening value indicates a lesser 
grade.
A subject who has signed the informed consent, has had at least one study procedure 
conducted, and is determined to be a screen failure, will not proceed into the study.
Informed Consent
Signed informed consent form will be obtained from the subject or the subject's legally 
acceptable representative in order to participate in this study.  The IRB approved informed 
consent form must be signed and dated by each subject prior to undergoing any study 
procedures or before any prohibited medications are withheld from the subject in order to 
participate in this study.  Informed consent will also be required for the optional 
exploratory research sampling portion of the study.  Refer to Section 9.3 for details on 
obtaining and documenting informed consents.
Due to the COVID-19 pandemic, modifications to the protocol procedures may be 
necessary.  Subjects should be informed of the changes to the conduct of the study 
relevant to their participation (e.g., cancellation of visits, change in laboratory testing site, 
drug delivery method, etc.).  Documentation of this notification and verbal consent should 
be maintained at the site.  A signed and dated informed consent form should be obtained 
from the subject afterwards as soon as possible.
 

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Medical and Oncologic History
The following will be collected during the Screening Visit:
●
Complete medical history, including documentation of any clinically 
significant medical condition
●
History of tobacco and alcohol use
●
Detailed oncology history including:
○
Date of diagnosis of AML and subtype
○
Date of diagnosis of any previous malignancy and/or antecedent 
hematologic disorder
○
Histology
○
Any surgical procedures
○
Treatments administered (including dates and type of modality)
○
Transfusion of blood products within 8 weeks
●
Prior and concomitant medication usage including dates of usage and dosing 
information for all medications and supplements taken.
On Cycle 1 Day 1, any changes observed from the Screening assessments (prior to dosing 
and not related to study specific required procedures) will be recorded in the subject's 
medical history.  At each visit, including the Final Visit and the 30-Day Safety Follow-Up 
Visit, the subject's medical history will be reviewed and any clinically significant changes 
from baseline will be recorded on the adverse event eCRF.
Adverse Event and Prior/Concomitant Medication Assessment
All concomitant medications (prescription or over-the-counter, including vitamins and/or 
herbal supplements) and AE assessments will be performed per Appendix C.  On Cycle 1 
Day 1, any events observed from the time of signing of the informed consent but prior to 
initial study drug administration will be recorded as a serious or non-serious adverse 
event, if considered by the Investigator to be causally related to the study-required 
procedures.
 

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Cytogenetic Assessment
Cytogenetic (chromosomal) analysis must be performed locally from diagnostic bone 
marrow (preferred) or from peripheral blood if adequate number of circulating blasts 
(> 109/L) are present.  Fluorescence-in-situ hybridization (FISH) analysis can be 
performed to exclude favorable risk cytogenetic risk category (per NCCN Guidelines 
listed in Appendix F) where available during screening to avoid undue delay of 
enrollment, however, cytogenetic analysis must be completed for all subjects and the 
results must be available prior to randomization.  Historic cytogenetic data will be 
accepted if done within 1 month prior to screening.
Molecular Markers
Profiling of common genetic abnormalities in AML may be explored on a mandatory 
bone marrow sample at a central laboratory designated by AbbVie.  
Patient-Reported Outcome (PRO) Variables
PRO assessments include PROMIS Cancer Fatigue SF 7a, EORTC QLQ-C30, and EQ-
5D-5L.  These assessments will be collected on or within 3 days prior to Cycle 1 Day 1 
and then on Day 1 of every other cycle throughout the trial, per Appendix C, including 
Final Visit.  PRO assessments will be self-administered by subjects using the electronic 
tablets supplied by the sponsor and site personnel shall not provide interpretation or 
assistance to subjects other than encouragement to complete the tasks.  PRO assessments 
should generally be completed prior to any other procedures and clinical assessments and 
prior to dosing; however, they may be administered following confirmation that the 
subject is able to receive study treatment at the visit.
Due to the COVID-19 pandemic and any local restrictions, sites may administer PRO 
instruments over the phone as needed.  Delegated site staff may read the PRO questions 
and response options to the subject and record the subject's responses.  Sites may send the 
questionnaires (email or hard copy) to the subjects to allow them to read/understand the 
questions and responses when the subject is providing responses over the phone.  The date 
 

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and time of PRO data collection should be recorded along with who collected the 
information.  Subject responses will be entered into Trialmax, the Electronic Patient 
Reported Outcome (ePRO) system, instead of the electronic tablet, by the site staff.  
IRB/EC approval should be obtained prior to completing PROs by phone interview.
PROMIS Cancer Fatigue SF 7a
PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.25  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Cancer Fatigue SF that has been developed 
for use in oncology populations.26,27  PROMIS Cancer Fatigue SF 7a is a seven item 
questionnaire that assesses the impact and experience of fatigue over the past 7 days.  The 
recommended minimum important difference range is 3 – 5 points; the lower bound (3) is 
being used as the minimum important difference in this study.28  All questions employ the 
following five response options:  1 = Never, 2 = Rarely, 3 = Sometimes, 4 = Often, and 
5 = Always.
EORTC QLQ-C30
Health-related quality of life (HRQoL) and symptoms will be assessed with the EORTC-
QLQ-C30 version 3.29  The QLQ-C30 is a 30-item subject self-report questionnaire 
composed of both multi-item and single scales, including five functional scales (physical, 
role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and 
vomiting, and pain), a global health status/quality of life scale, and six single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).  
Subjects rate items on a four-point scale, with 1 as "not at all" and 4 as "very much."  The 
QLQ-C30 was developed and validated for use in a cancer patient population, and its 
reliability and validity is highly consistent across different language-cultural groups.  A 
change of 5 to 10 points is considered a small change, and the lower bound (5) is being 
used to define the minimum important difference.  A change of ≥ 10 to < 20 points is 
considered a moderate change.
 

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EQ-5D-5L
The EQ-5D-5L is a generic preference instrument that has been validated in numerous 
populations.30,31  The EQ-5D-5L has five dimensions:  mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression.  These dimensions are measured on a five level 
scale:  no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  The scores for the 5 dimensions are used to compute a single utility index 
score ranging from zero (0.0) to 1 (1.0) representing the general health status of the 
individual.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the 
subject's overall health.  The minimum important difference for the EQ-5D-5L utility 
index score in cancer patients is 0.08, and the minimum important difference for EQ-5D 
VAS is 7.32,33
Table 3.
Patient-Reported Outcome Assessments
Administration Order
Test
Administration Time
1
PROMIS Cancer Fatigue SF 7a
Approximately 5 minutes
2
EORTC QLQ-C30
Approximately 12 minutes
3
EQ-5D-5L
Approximately 5 minutes
Total Admin Time:  Approximately 22 minutes
Physical Examination
Physical examinations (full and targeted exams), including body weight, will be 
performed per Appendix C.  These will be measured at:
●
Screening
●
Day 1 of every cycle
●
Prior to discharge from hospital
●
Final Visit
●
30-Day Safety Follow-up
The targeted physical exam includes an assessment of heart, lung, and abdomen, and any 
body system, guided by the examiner's observations or subject complaints on new or
 

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changed conditions, symptoms, or concerns.  Targeted exams can be performed by the 
Principal Investigator (PI) or delegated to qualified medical staff (e.g., a sub-Investigator, 
nurse, etc.).
If the screening physical examination is performed within 7 days of Cycle 1 Day 1, it is 
not required to repeat the exam on Cycle 1 Day 1 unless clinically indicated.  Physical 
examinations after screening may be performed within 3 days before the scheduled visit.  
Clinically significant changes from baseline will be documented in the source 
documentation and eCRFs as adverse events.
Height will be measured at the Screening Visit only.  For height and weight, subject 
should not wear shoes and wear lightweight clothing.
Vital Signs
Body temperature, weight, sitting blood pressure, pulse, and respiratory rate will be 
measured at all visits prior to blood collections and prior to dosing with 
venetoclax/placebo and azacitidine per Appendix C.  These will be measured at:
●
Screening
●
Cycle 1 Day 1 and Day 1 of every cycle
●
Final Visit
●
30-Day Safety Follow-up
It is recommended that vital signs should be assessed after the subject has been seated 
quietly for at least 5 minutes.  
ECOG Performance Status
The ECOG performance status per Appendix C will be assessed at:
●
Screening
●
Cycle 1 Day 1 and Day 1 of every cycle
●
Final Visit
 

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●
30-Day Safety Follow-up
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self -care.  Totally confined to 
bed or chair.
12-Lead Electrocardiogram (ECG)
A single 12-lead resting ECG per Appendix C will be obtained at:
●
Screening
●
Final Visit (May be obtained within ± 2 days of the visit)
●
As clinically indicated 
Electrocardiograms will be recorded after the subject has been in the supine position for at 
least 5 minutes.  Subjects will be instructed to remain completely stationary for 
approximately 10 seconds during the ECG recording.  While ECGs are being acquired, 
subjects and staff are prohibited from having devices (e.g., cellular telephones, fans, 
heaters, etc.) that emit radiofrequency signals in the room.
Each ECG will be evaluated by an appropriately qualified physician at the study site (the 
"local reader") who will determine if any findings outside normal physiological variation 
are clinically significant.  The local reading of the ECG will be used by the investigator 
for subject safety assessments, including adverse event determination and management, 
and subject discontinuation from the study.
 

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The local reader will sign and date the safety ECG and provide a global interpretation 
using the following categories:
●
Normal ECG
●
Abnormal ECG – Not clinically significant (NCS)
●
Abnormal ECG – Clinically significant (CS)
●
Unable to evaluate
All local reader evaluations of ECGs will be entered into the electronic case report forms 
(eCRFs).  If the global interpretation is Abnormal (NCS or CS), the local reader will 
provide further information (e.g., sinus bradycardia, arrhythmia).  The QT interval 
corrected for heart rate using Fridericia's formula (QTcF) will be calculated for all ECGs 
and documented only if the QT interval is determined to be prolonged by the local reader.
All ECG source documentation will be retained at the study site.  The automatic 
cardiograph reading (i.e., cardiograph-generated measurements and interpretations) will 
not be collected for analysis.
Multiple Gated Acquisition Scan (MUGA)/2D Echocardiogram with Doppler
Assessment of ejection fraction will be made at Screening per Appendix C by either a 
MUGA (preferred method) or 2D echocardiogram with Doppler only if needed to 
determine eligibility for subjects ≥ 18 to 74 years of age with cardiac disease.  Findings 
will be documented on the appropriate eCRF.  Subsequent MUGAs/echocardiograms will 
be performed whenever clinically necessary.  It is preferred that the same method of 
assessment is used for a given subject. 
The original MUGA/echocardiogram report with physician assessment will be retained in 
the subject's records at the study site.  If necessary, AbbVie may request that copies of 
MUGA/echocardiogram reports be sent in for further analysis.
 

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Pulmonary Function Tests
Assessment of lung function by diffusion capacity of lung (DLCO) or forced expiratory 
volume during the first second (FEV1) will be made at Screening per Appendix C only if 
needed to determine eligibility for subjects ≥ 18 to 74 years of age with respiratory 
disease.
Bone Marrow Aspirate and Biopsy For Disease Assessment
Bone marrow aspirates and biopsies per Appendix C will be obtained for local assessment 
at the following time points until two successive samples indicate CR or CRi:
●
Screening
●
End of Cycle 1 (must be performed within ± 3 days of Cycle 1 Day 28 and 
resulted prior to the administration of treatment for Cycle 2)
●
For subjects with resistant disease at end of Cycle 1 a repeat bone marrow 
must be performed at the end of Cycle 2 or Cycle 3 based on the hematologic 
recovery to assess for a response of CR/CRi.
●
For subjects with a response of CRi on two successive bone marrow samples 
an additional bone marrow aspirate and biopsy must be performed to confirm a 
CR once peripheral blood count recovery is noted.
●
For all subjects a bone marrow aspirate and biopsy must be performed at end 
of Cycle 4 and every 3 cycles (± 1 week). 
●
Upon concern for relapse.
●
Final Visit (If no BM collected within last 6 – 8 weeks, or if relapse of disease 
has already been confirmed).
Historical bone marrow aspirates and biopsies assessed locally to confirm the diagnosis 
could be used as baseline assessment to satisfy eligibility criteria as long as the samples 
were taken 30 days prior to randomization.  A bone marrow aspirate and biopsy must be 
performed for all subjects during screening to collect mandatory samples for biomarker 
assessments (biomarker collections are not applicable to subjects enrolled in China).  
 

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Bone marrow aspirates and/or biopsies performed in addition to those required per 
protocol as standard of care throughout the study should also be captured on an eCRF.
A sufficient bone marrow aspirate and bone marrow core biopsy must be collected for all 
subjects at each of the disease assessments for local pathology assessment and mandatory 
biomarker assessments.  The bone marrow core biopsy sample collection is mandatory; it 
is considered an optional procedure only for subjects enrolled at sites in countries where 
an aspirate evaluation by morphologic assessment and flow cytometry is considered 
standard of care.  For these subjects if the marrow aspirate sample is inadequate or un-
evaluable for disease assessment, another bone marrow aspirate and biopsy sample must 
be performed within 7 days.  The corresponding local laboratory pathology/bone marrow 
report should be sent to the central laboratory for each local disease assessment.  The local 
laboratory's pathology/bone marrow report will be used by the IRC during their 
assessment of disease response.  Detailed collection instructions for the local laboratory 
pathology/bone marrow report which is to be utilized by the IRC will be provided by the 
Sponsor.  Upon unblinding at the 75% Overall Survival Interim Analysis, disease 
assessments will no longer be performed by the IRC.
Clinical Laboratory Tests
All subjects will undergo the laboratory assessments listed in Table 4 per the schedule in 
Appendix C.  Certified local laboratories will be utilized to process and provide results for 
all of the tests listed in Table 4.  These data will be used for all data analysis.  The 
appropriate certifications will be collected from the local laboratories.  
Due to travel restrictions and other changes in local regulations in light of the COVID-19 
pandemic, if possible, arrange for subjects to have laboratory work done at a local lab, 
hospital, or other facility.  Local lab results should be obtained along with reference 
ranges and kept within the subjects' source documentation.  Local lab results should be 
reviewed by the investigator as soon as possible for subject safety and to determine the 
next cycle of study treatment.
 

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If laboratory samples cannot be obtained, study drug administration cannot be continued 
unless the investigator has reviewed all prior laboratory results as close to the planned 
new cycle of study treatment, confirms and discusses with the subject that there is no 
safety concern for the subject to continue use of the study drug in the absence of current 
labs.  The subject should be scheduled for laboratory draws as soon as feasible within 
approximately 3 days from the scheduled visit.
Table 4.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not 
acceptable)
Blast count (if detected)
Blood urea nitrogen (BUN) or 
Urea
Creatinine
Calculated or Measured 
creatinine clearance
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid or Urate
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH)
Bicarbonate or 
Carbon dioxide 
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination (as 
clinically indicated)
Coagulation
Prothrombin time (PT) or 
International Normalized 
Ratio (INR) 
Activated partial thromboplastin 
time (aPTT)
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator may repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
 

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●
A laboratory test value that requires a subject to be discontinued from the 
study, requires a subject to receive treatment, meets protocol specific criteria 
(see Section 6.1.7 regarding toxicity management) and/or the investigator 
considers clinically significant will be recorded as an adverse event. 
Chemistry and Hematology
Chemistry and hematology per Appendix C will be performed at:
●
Screening
●
Cycle 1 Days 1, 2, 3, 4, 5,* 8, 15, 22
●
Day 1 of Cycle 2 and Day 1 of every cycle thereafter.  Starting with Cycle 3 
Day 1 may be performed within 3 days prior to the scheduled visit.**
●
Final Visit
●
30-Day Safety Follow-up
●
As needed throughout study
*
Additional laboratory assessments may be performed per investigator discretion, up to 
48 hours after reaching final dose if clinically indicated.
** For cycles with bone marrow assessments, hematology and chemistry labs should be 
performed on the same day as the bone marrow assessment.  If the disease assessment 
occurs outside of the visit window, then the hematology and chemistry labs should be 
repeated prior to dosing.
Additional hematology and chemistry laboratory assessments will be performed based on 
the clinical indications per institutional guidelines and regional standards between Cycle 1 
to the beginning of Cycle 2 Day 1 and after subsequent treatment cycles.
For chemistry labs performed for TLS prophylaxis and monitoring during dose ramp up 
period during Cycle 1, refer to Section 6.1.7.1, Management of Tumor Lysis Syndrome, 
and Appendix I, Recommendations for Initial Management of Electrolyte Abnormalities 
and Prevention of Tumor Lysis Syndrome (TLS), for specific requirements.
 

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Coagulation
Prothrombin time (PT) or International Normalized Ratio (INR) and activated partial 
thromboplastin time (aPTT) samples per Appendix C will be collected at: 
●
Screening 
●
Cycle 1 Day 1
●
Final Visit
Urinalysis
Urinalysis samples per Appendix C will be collected at:
●
Screening 
●
Cycle 1 Day 1
●
Final Visit
Documentation of Non-Childbearing Status and Pregnancy Testing
For each female subject, the Investigator will document non-childbearing status 
(surgically sterile or post-menopausal for at least 1 year) or potential childbearing status.
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined in Section 5.2.4) at Screening do not require pregnancy testing. 
For all female subjects of childbearing potential, pregnancy testing must be performed as 
follows:
●
Screening – with serum sample obtained within 14 days prior to the first study 
drug administration.
●
Cycle 1 Day 1 – if it has been > 7 days since obtaining the serum pregnancy 
results (performed by either urine or serum pregnancy testing),
●
Subjects with borderline pregnancy test at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result.
 

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●
Day 1 of each subsequent cycle, until all study drugs are permanently 
withdrawn (performed by either urine or serum pregnancy testing)
Subject Calendar/Diaries
Subject calendars/diaries will be provided at the time of discharge from the hospital.  
Subjects will be instructed to bring their calendars/diaries back to the site to be reviewed 
at each visit, including at any visit at which a dose level change may be required.
Subjects will be instructed to record the date and time each dose of study drug is taken, 
(indicating if any doses of study drug are missed) and whether or not doses were taken 
within 30 minutes after the completion of a meal.
Subjects will also be instructed to record adverse events and concomitant medications in 
the subject calendars/diaries.
The calendars/diaries are to be reviewed at each visit and relevant pages are to be 
photocopied by study staff.  By the end of the subject's participation in the study, the 
calendars/diaries are to be returned to the site and appropriately filed with the subject's 
source documents for this study.
Randomization and Subject (Screening) Number Assignment
Interactive Response Technology (IRT) will be utilized to register (screen and randomize) 
subjects on study.  The site will contact the IRT to obtain a screening (subject) number 
only after the subject has signed the informed consent and prior to any study-specific 
procedures being performed (e.g., labs are drawn).  Screening numbers will be a unique 
5 – digit number and will begin with 10001 with the first three digits representing the 
investigative site, and the last two digits representing the subjects at that site.  Subjects 
who meet all Inclusion Criteria and none of the Exclusion Criteria after Screening will 
proceed to being randomized.  The site will contact the IRT to complete the 
randomization process and obtain study drug assignment.  Subjects will be enrolled as 
described in Section 5.5.3 and will receive a separate unique 6-digit randomization 
 

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number that will be automatically recorded in the eCRF through the IRT system.  This 
randomization number will be used only by AbbVie for loading the treatment schedule 
into the database.  Study treatment should start within 5 days after randomization, 
however this window cannot exceed the allotted 21 day Screening period.  All subsequent 
drug assignments and changes in subject status (e.g., treatment completion) will be 
registered in the IRT.
Dispensing Venetoclax/Placebo
Randomized subjects will receive sufficient quantities of venetoclax/placebo for 28 days 
in each 28-day cycle during all cycles.  The IRT will assign kit of venetoclax/placebo to 
be dispensed to a subject.  Prior to each drug dispensation, site personnel must contact 
IRT for kit number assignment.  Venetoclax/placebo cannot be dispensed without 
contacting the IRT.  AbbVie or designee (refer to Section 7.0) will provide specific 
instructions on the use of IRT.
Subjects will be provided with venetoclax/placebo self-administration instructions.  
Subjects will be instructed to store venetoclax/placebo according to specific directions 
included in Section 5.5.2.1.  Subjects are required to return bottles of venetoclax/placebo 
(empty, partially filled, or full) to the study site prior to the start of the next cycle and at 
the Final Visit.
Dispensing Azacitidine
The IRT will assign every vial of azacitidine which was supplied by AbbVie to be 
dispensed for use by the site.  Prior to each drug dispensation, site personnel must contact 
IRT for vial number assignment.  AbbVie supplied Azacitidine cannot be dispensed 
without contacting the IRT.  AbbVie or designee (refer to Section 7.0) will provide 
specific instructions on the use of IRT.
Azacitidine which is to be supplied locally will be dispensed and tracked per the normal 
practices of those sites.
 

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5.3.1.2
Collection and Handling of Biomarker and Exploratory 
Research Samples (Not Applicable for China)
Whole blood, plasma, bone marrow aspirate, and bone marrow core biopsy tissue will be 
collected per Appendix D.  In addition to the mandatory biomarker research specimens, 
subjects will also have the option to provide samples for exploratory research.  Subjects 
may still participate in the main study even if they decide not to participate in the optional 
exploratory research.  Specimens collected for these purposes may be utilized to evaluate 
known and/or novel markers (nucleic acids, peptides/proteins and/or metabolites) of 
disease status, related conditions or to evaluate the association with pharmacokinetics, 
safety or efficacy.  All samples should be prepared, labeled, and shipped as outlined in the 
study-specific laboratory manual.  The biomarker rationale is discussed in the Biomarker 
Research Variables Section (Section 5.3.6).
AbbVie (or people or companies working with AbbVie) will store the mandatory and 
optional biomarker and exploratory research samples in a secure storage space with 
adequate measures to protect confidentiality.  The samples will be retained while research 
on venetoclax (or drugs of this class) or this disease and related conditions continues, but 
for no longer than 20 years after study completion.  The procedure for obtaining and 
documenting informed consent is discussed in Section 9.3.
Mandatory Samples for Biomarker Analysis
Blood Collections:
Whole blood will be collected into appropriately labeled tubes and processed as outlined 
in the most current version of Study M15-656 Laboratory Manual.
Blood Collection for Plasma:
Approximately 4 mL or 20 mL of blood will be collected prior to dose at:
●
Screening or prior to first dose of study drug (4 mL)
●
End of Cycle 1 (20 mL)
 

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●
Response assessments:  every 3 cycles after end of Cycle 1 assessment 
(20 mL)
●
Final Visit/Time of Relapse (20 mL)
Bone Marrow Aspirate and Biopsy Collections
Bone marrow aspirates should be drawn into appropriately labeled tubes in conjunction 
with the disease assessments.  A portion of the aspirate must be processed according to 
the institutional standard procedures for diagnostic evaluation (locally); however, 
approximately 6 to 7 mL of the bone marrow aspirate should be collected for biomarker 
assessments, which will be shipped to the central laboratory.  Detailed processing will be 
outlined in the most current version of the Study M15-656 Laboratory Manual for the 
following:
Bone Marrow Collection for Disease Assessment/MRD by Flow Cytometry
NOTE:  This should be the first tube drawn from the bone marrow aspirate collection.
Approximately 1 to 2 mL of bone marrow aspirate at:
●
Screening visit
●
End of Cycle 1
●
Response assessments:  every 3 cycles after end of Cycle 1 assessment
●
Final Visit/Time of Relapse
Bone Marrow Collection for AML Mutational Profiling
Approximately 1 mL of bone marrow aspirate at:
●
Screening visit 
●
Final Visit/Time of Relapse 
Bone Marrow Collection for Translational Research:
●
Screening visit (4 mL)
 

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●
End of Cycle 1 and every 3 cycles after end of Cycle 1 for response assessment 
(1 mL)
●
Final Visit/Time of Relapse (4 mL)
For subjects, where bone marrow aspirates are no longer required for response 
assessments, the biomarker samples will also not be collected.
Bone Marrow Biopsy for Bcl-2 Family Protein Analysis
Either an FFPE tissue block or approximately 6 to 10 slides from the bone marrow core 
biopsy should be collected at:
●
Screening visit
●
Final Visit/Time of Relapse
5.3.1.3
Samples for Optional Pharmacogenetic Exploratory 
Research (Not Applicable for China)
Optional whole blood samples for DNA and RNA isolation will be collected on Cycle 1 
Day 1 (pre-dose), Cycle 3 Day 1 and Final/Relapse Visit from each subject who consents 
to provide samples for exploratory research.  Pharmacogenetic samples should be 
prepared, labeled, and shipped as outlined in the most current Study M15-656 laboratory 
manual.
5.3.1.4
Meals and Dietary Requirements
Each dose of venetoclax/placebo will be taken orally once daily with approximately 
240 mL of water within approximately 30 minutes after the completion of a meal 
(preferably after breakfast).  Tablets must be swallowed whole and must not be broken, 
chewed, or crushed.
Subjects may not consume the following:  grapefruit or grapefruit products, Seville 
oranges (including marmalade containing Seville oranges) or star fruit within the 3-day 
period prior to the first study drug administration and until the last day of treatment is 
 

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completed due to possible CYP3A mediated metabolic interaction.  It is expected that 
sites record if excluded food products are consumed by the subject during the study.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assays of venetoclax, azacitidine and their possible 
metabolites will be collected by venipuncture at each study visit indicated in Appendix E.  
Blood samples must be protected from direct sunlight during collection, processing and 
storage.  A total of approximately 7 blood samples (3 ml) for venetoclax will be collected 
per subject.  A total of approximately 5 blood samples (6 mL) for azacitidine will be 
collected from approximately 75 subjects.  The total number of venetoclax 
pharmacokinetic samples planned is 2800 and at minimum 375 azacitidine 
pharmacokinetic samples for analysis.  Additionally, intensive pharmacokinetic samples 
will be obtained on Cycle 2 Day 4 for the Chinese AML safety cohort subjects from 
China mainland sites, as indicated in Appendix K.
5.3.2.2
Handling/Processing of Samples
Blood Samples for Venetoclax PK Assay
Detailed sample collection and processing instructions for the venetoclax PK will be 
provided in the current Study M15-656 laboratory manual.
Blood Samples for Azacitidine PK Assay (Only Australia, Canada, France, 
Germany, Japan and US)
Detailed sample collection and processing instructions for the azacitidine PK will be 
provided in the current Study M15-656 laboratory manual.  
5.3.2.3
Disposition of Samples
The frozen plasma pharmacokinetic samples for venetoclax and azacitidine assays will be 
packed in dry ice sufficient to last during transport and shipped from the study site to a 
central lab designated by AbbVie.  An inventory of the samples included will accompany 
 

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the package.  Please refer to current Study M15-656 laboratory manual for complete 
shipping instructions.
5.3.2.4
Measurement Methods
Plasma concentrations of venetoclax and azacitidine will be determined under the 
supervision of the Drug Analysis Department at AbbVie.  Plasma concentration of 
possible venetoclax metabolite(s) may be determined with validated or non-validated 
methods.
5.3.3
Efficacy Variables
Efficacy Assessments
Responses will be evaluated based on the revised guidelines by the International Working 
Group (IWG) for AML.  Progressive disease is defined per European LeukemiaNet 
recommendations.  Subject's response is based on most recent physical examination, bone 
marrow results and recent hematology values.  For subjects who require a delay in next 
cycle of study treatment for peripheral blood count recovery after a bone marrow 
evaluation, hematology values for up to 2 weeks from the bone marrow evaluation or pre-
dose labs from Day 1 of the next cycle can be used to determine the IWG response.  As a 
significant number of the subjects in this study might have antecedent hematologic 
illnesses, hematologic response including transfusion independence will also be evaluated.
Criteria for evaluation are as follows:
●
CR:  Absolute neutrophil count > 103/µL, platelets > 105/µL, red cell 
transfusion independence, and bone marrow with < 5% blasts, absence of 
circulating blasts and blasts with Auer rods; absence of extramedullary disease 
●
CRi:  All criteria as CR except for residual neutropenia ≤ 103/µL (1000/µL) or 
thrombocytopenia ≤ 105/µL (100,000/µL).  Red blood cell transfusion (RBC) 
dependence is also defined as CRi.
●
PR:  All of the hematologic values for a CR but with a decrease of at least 50% 
in the percentage of blasts to 5% to 25% in the bone marrow aspirate.
 

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●
MLFS:  Less than 5% blasts in an aspirate sample with marrow spicules and 
with a count of at least 200 nucleated cells, absence of circulating blasts and 
extramedullary disease without peripheral blood count recovery that meet the 
thresholds for either CR or CRi.
●
RD:  Failure to achieve CR, CRi, PR or MLFS; in subjects surviving at least 
7 days following completion of Cycle 1 treatment, with evidence of persistent 
leukemia by blood and/or bone marrow examination.
●
MR:  Bone Marrow blasts ≥ 5% after CR/CRi in peripheral blood or bone 
marrow or development of extramedullary disease.
*
In cases with bone marrow blast percentages of 5% – 10%, a repeat 
marrow should be performed 1 week later to distinguish relapse from bone 
marrow regeneration.
●
PD:
○
> 50% increase in marrow blasts over baseline (a minimum 15% point 
increase is required in cases with < 30% blasts at baseline; or persistent 
marrow blast percentage of > 70% over at least 3 months; without at least a 
100% improvement in ANC to an absolute level (> 0.5 × 109/L [500/µL], 
and/or platelet count to > 50 × 109/L [50 000/µL] non-transfused); or
○
50% increase in peripheral blasts (WBC × % blasts) to > 25 × 109/L 
(> 25 000/µL); or
○
New extramedullary disease
Reporting of Results
All dosed subjects will be assessed for response to treatment based on the published 
guidelines.  Assessments will be performed at the end of Cycle 1 and every 3 cycles 
thereafter for response assessment.  Subject will be assigned to one or more of the 
following categories by the investigators:
1.
complete remission;
2.
complete remission with incomplete blood count recovery;
3.
partial remission;
 

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4.
morphologic leukemia free state;
5.
resistant disease;
6.
progressive disease;
7.
indeterminate (not assessable, insufficient data);
8.
morphologic relapse;
MRD status if performed at investigator site for subjects who achieve CR or CRi:
1.
minimal residual disease negative;
2.
minimal residual disease positive.
5.3.4
Safety Variables
The safety of venetoclax or placebo plus azacitidine will be assessed by evaluating study 
drug exposure, adverse events, serious adverse events, deaths, and changes in laboratory 
determinations and vital sign parameters.
5.3.5
Pharmacokinetic Variables
Values for the PK parameters of venetoclax, including the apparent clearance (CL/F), may 
be determined using a population PK approach.  Additional parameters may be calculated 
if useful in the interpretation of the data.
5.3.6
Biomarker and Optional Exploratory Research Variables 
(Not Applicable for China)
Blood and bone marrow specimens will be collected to conduct exploratory biomarker 
analyses.  The types of biomarkers to be analyzed may include, but are not limited to, 
nucleic acids, proteins, lipids or metabolites.  Evaluations may include the identification 
of common molecular aberrations at baseline, the assessment of minimal residual disease 
levels present after therapy, and analyzing biomarkers related to the pathway(s) targeted 
 

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by the study drug or believed to be related to the disease or to drug response.  For 
example, inhibition of BCL-2 by Venetoclax induces apoptosis in AML cell lines and 
patient derived blasts suggesting that BCL-2 levels may be predictive of response.  
Therefore, we may evaluate the relationships between BCL-2 (protein, activity and/or 
gene expression) at baseline and patient responses to therapy (i.e., overall survival and 
complete response rates) for correlations with efficacy.  The information learned from 
analyzing these samples may be used to investigate factors impacting response to 
treatment, scientific questions related to AML or in the development of new therapies.  
The results of biomarker analysis are exploratory in nature, may not be conducted in GLP 
laboratories, and the results may not be included with the clinical study report.
Blood and bone marrow samples collected during the course of this study may be banked 
and used in the future to investigate new scientific questions related to this study.  The 
samples may also be used for diagnostic test development.  AbbVie (or a designated 
laboratory) will store the samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on venetoclax (or 
drugs of this class) continues but no longer than 20 years after study completion.
Overall, the goals of the biomarker analyses described in this section are to 1) determine 
the relationship between drug concentration and disease status (pharmacodynamics) and 
2) identify responsive patient populations (based on subject characteristics at baseline and 
relapse).
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects from Treatment
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator will discontinue a subject from the study treatment at any time if the 
investigator considers it necessary for any reason including:
●
The investigator believes it is in the best interest of the subject;
 

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●
The subject's response to therapy is unsatisfactory, as evidenced by 
progression of disease as defined per ELN criteria while on study drug;
●
Treatment failure, defined as failure to achieve CR, CRi, PR, or MLFS after at 
least 6 cycles of study treatment;
●
The subject experiences toxicities related to study drug that require more than 
a 4-week (1 cycle) dose interruption of venetoclax or azacitidine, in the 
absence of clinical benefit;
●
The subject requires any radiotherapy or chemotherapy agents during the study 
period (with the exception of hydroxyurea allowed during Cycle 1);
●
The occurrence of an adverse event that precludes further azacitidine drug 
administration;
●
Noncompliance with the protocol.
●
The subject becomes pregnant while on study drug.
The investigator or the study site personnel will inform AbbVie prior to discontinuing a 
subject from the study by contacting the AbbVie TA MD as identified in Section 7.0.  All 
subjects will be included for analysis of safety data.
In the event that a subject withdraws or is discontinued from the study, the reason(s) for 
the discontinuation from the study and the primary reason will be recorded and a Final 
Visit along with all necessary procedures per Appendix C (will be performed as soon as 
possible after discontinuation from the study).  The subject would then enter Post 
Treatment Follow Up as outlined in Section 5.1.4 and follow all necessary procedures per 
Appendix C.
Subjects with disease progression or relapse may continue to receive study treatment if the 
investigator considers it to be in the best interest of the subject.  Disease assessment will 
be captured in EDC per protocol criteria.  The subject will be monitored per study 
procedures described in Section 5.3.1.1 or more often if the investigator considers it 
necessary.
 

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Due to the COVID-19 pandemic, temporary study drug interruption may occur.  Refer to 
the Section 5.3.1.1, Study Procedures and Appendix C for details on how to handle study 
activities/procedures accordingly.  Study drug interruptions due to COVID-19 restrictions 
should be captured in EDC.
At the end of the subject's participation in the study, the calendars/diaries are to be 
returned to the site and appropriately filed with the subject's source documents for this 
study.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
If, in the judgment of the investigator and AbbVie, the continued exposure to the study 
drug represents a significant risk to subjects, the study will be stopped.  The following 
procedures for discontinuation will be followed:
●
If the sponsor has decided to prematurely discontinue the study, the sponsor 
will promptly notify in writing the investigator as well as regulatory authorities 
of the decision and give detailed reasons for the discontinuation.
●
The investigator must promptly notify the IEC/IRB and give detailed reasons 
for the discontinuation.
The investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of the 
treatment regimen, if applicable, by other appropriate regimens.
 

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5.5
Treatments
5.5.1
Treatments Administered
Subjects will take daily venetoclax 400 mg or placebo orally in the form of tablets.  
Venetoclax or placebo should always be given before azacitidine when administered for 
7 days of every cycle, starting on Day 1 of each cycle.  Subjects will self-administer 
Venetoclax or placebo by mouth QD.  Tablets must be swallowed whole and must not be 
broken, chewed, or crushed.  
Azacitidine must be prepared as per the applicable Summary of Product Characteristics 
(SmPC), and administered by the route indicated in the package insert or prescribing 
information.  Subjects should be pre-medicated with anti-emetics for nausea and 
vomiting.
5.5.2
Identity of Investigational Products
Table 5.
Identity of Investigational Product and Non-Investigational 
Products
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Venetoclax Film-Coated Tablet
N/A
100 mg 
Oral
AbbVie
Venetoclax Film-Coated Tablet
N/A
50 mg 
Oral
AbbVie
Venetoclax Film-Coated Tablet
N/A
10 mg 
Oral
AbbVie
Matching Placebo for Venetoclax 
100 mg Film-Coated Tablet
N/A
0 mg 
Oral
AbbVie
Matching Placebo for Venetoclax 
50 mg Film-Coated Tablet
N/A
0 mg 
Oral
AbbVie
Matching Placebo for Venetoclax 
10 mg Film-Coated Tablet
N/A
0 mg 
Oral
AbbVie
Azacitidine
Vidaza
100 mg powder 
for injection
SC or IV
Celgene or 
generic
AbbVie will provide venetoclax, and placebo for venetoclax for the study.  AbbVie will 
provide azacitidine for selected countries.
 

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Identity of Non-Investigational Product
Sites may be responsible for obtaining azacitidine in countries where it is approved for 
AML.  For operational or regulatory purposes, AbbVie may provide azacitidine 
depending on local requirements.  Azacitidine should be obtained from a licensed 
pharmacy or wholesaler.
Each site will be responsible for maintaining drug accountability records including 
product description, manufacturer, and/or lot numbers for all azacitidine dispensed by the 
site.
Packaging and Labeling
Venetoclax tablets or placebo for venetoclax tablets will be packaged in high density 
polyethylene (HDPE) plastic bottles.  The Venetoclax 100 mg or placebo bottle will 
contain 140 tablets, 50 mg or placebo bottle will contain 28 tablets, and 10 mg or placebo 
bottle will contain 5 tablets.  The bottles will be labeled as per local regulatory 
requirements.  
Azacitidine which is supplied by AbbVie will be provided as 100 mg lyophilized powder 
per single use vial.  Each vial and carton will be labeled per local regulatory requirements.  
Each vial must be reconstituted and administered by the route as per the local azacitidine 
label.
5.5.2.1
Storage and Disposition of Study Drug(s)
Venetoclax or placebo for venetoclax study drug must be stored at 15° to 25°C (59° to 
77°F).  Azacitidine must be stored between 15° to 25°C (59° to 77°F).  The 
investigational products are for investigational use only and are to be used only within the 
context of this study.  The study drug supplied for this study must be maintained under 
adequate security and stored under the conditions specified on the label until dispensed for 
subject use or returned to AbbVie.
 

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5.5.3
Method of Assigning Subjects to Treatment Groups
The IRT will randomize subjects into the 2 treatment arms in a 2:1 ratio (venetoclax + 
azacitidine or placebo + azacitidine).  A bottle (kit) number randomization schedule and a 
subject randomization schedule will be generated by the Clinical Statistics Department at 
AbbVie prior to the start of the study.  A copy of all randomization schedules will be kept 
by the Clinical Statistics Department at AbbVie and a copy will be forwarded to the IRT 
vendor.  Subject randomization will be stratified by age (18 – < 75, ≥ 75), cytogenetics 
(intermediate risk, poor risk) and region (US, EU, China, Japan, Rest of world).
5.5.4
Selection and Timing of Dose for Each Subject
Venetoclax/placebo will be administered orally once daily (QD) Days 1 through 28, of a 
28-day cycle, with a designated dose of 400 mg daily after ramp up in Cycle 1.  During 
Cycle 1 Days 1 – 3, the dose will ramp up from 100 mg on Day 1, 200 mg on Day 2, and 
400 mg on Day 3. 
Azacitidine (75 mg/m2) should be given QD following administration of venetoclax or 
placebo for 7 days of every cycle, starting on Day 1 of each cycle.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
The Investigator, the study site personnel, AbbVie site monitoring team and the subject 
will remain blinded to each subject's treatment with venetoclax/placebo throughout the 
course of the study.  Limited AbbVie personnel have been unblinded following the 
planned second interim analysis, including AbbVie Clinical Drug Supply Management 
and AbbVie Pharmacovigilance Team.
The Chinese subjects in mainland China who are participating in the AML safety cohort 
will receive open label venetoclax during the participation, as described in Appendix K. 
All subjects will be treated with open-label azacitidine.
 

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The IRT system can provide access to blinded subject treatment information during the 
study.  AbbVie must then be notified within 24 hours of the blind being broken.  The date 
and reason that the blind was broken must be recorded in the source documentation and 
eCRF, as applicable.
If the blind is broken for a subject currently on study treatment by the investigator, that 
subject would need to be discontinued from study treatment and post treatment or survival 
follow-up would commence.
5.5.5.2
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
An IDMC will review safety and efficacy data for this study in an un-blinded fashion and 
provide recommendations to AbbVie as per the IDMC charter.  Details of the IDMC, 
including IDMC membership, which will include individuals with experience in treatment 
of patients with AML, and member responsibilities, will be outlined in the IDMC Charter.  
Clinical safety data will be reviewed at pre-determined intervals throughout the course of 
the study.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will dispense study 
drug only to subjects enrolled in the study in accordance with the protocol.  The study 
drug must not be used for reasons other than that described in the protocol.
An interactive response system (IRT) will assign every bottle and/or kit of 
venetoclax/placebo and AbbVie supplied azacitidine to be dispensed to a subject during 
the study.  Prior to each scheduled visit, site personnel must contact IRT for the next 
bottle or kit number(s) assignment.  AbbVie or its designee will provide specific 
instructions on the use of IRT.
Depending on local regulations due to the COVID-19 pandemic, provision of study drug 
for direct-to-patient (DTP) and direct-frompatient (DFP) transfer will be available upon 
request.  AbbVie has contracted with a third party vendor, Marken, for sites to ship study 
 

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drug DTP and DFP.  Sites will be able to use Marken and/or another local courier for drug 
shipment, as needed.  If necessary, notify AbbVie if DTP and/or DFP shipping will be 
used.
Sites will be responsible to:
●
Meet IRB/IEC reporting requirements and submit the booking form (which 
will be provided) to the local IRB/IEC, as applicable.
●
Submit the booking form at least 72 business hours before the drug needs to be 
picked up.
●
Discuss the DTP and DFP process with the subject including:
○
Obtain consent to provide delivery information to Marken and/or local 
courier and document this in the source.
○
Obtain results of required safety procedures (e.g., urine pregnancy testing) 
before registering subject dispensation of study drug in IRT.
○
Confirm the subject will be available to accept delivery.
○
Confirm the subject will maintain the drug containers, as well as any 
unused drug for return to site.
●
Follow up with the subject after shipment is received.
●
Retain documentation of the shipment for IP accountability and monitoring.
To document compliance with the treatment regimen, subjects will be instructed to return 
all unused tablets and/or bottles (even if empty) and any other study-related items as 
necessary to the study coordinator at scheduled study visits.  Compliance will be 
monitored and documented by the designated study site personnel on the appropriate 
form.  The designated study site personnel will question the subject regarding adherence 
to the dosing regimen, record the number of tablets and/or bottles returned, the date 
returned and determine treatment compliance before dispensing new study drug to the 
subject.  Compliance below 80% may require counseling of the subject by study site 
personnel.
 

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5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt or similar document.  The investigator or his/her designated 
representatives will administer study drug only to subjects enrolled in the study.  A 
current (running) and accurate inventory of study drug will be kept by the investigator and 
will include shipping invoices and the date on which study drug is dispensed to the 
subject.  An overall accountability of the study drug will be performed and verified by the 
AbbVie monitor throughout the study and at the study site closeout visit. Upon 
completion or termination of the study, all original containers (containing partially used or 
unused venetoclax/placebo) will be returned to AbbVie according to instructions from 
AbbVie or the designated monitor(s).  If pre-arranged between AbbVie and the site, 
destruction of used and unused venetoclax or placebo bottles will be performed at the site.  
Empty containers will be destroyed at the site.  Labels must remain attached to the 
containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is a multicenter, randomized, double blind study to evaluate the efficacy and safety 
of venetoclax plus azacitidine compared to an active control of placebo plus azacitidine.  
The choice of the control group allows for a double blind assessment of the contribution 
of venetoclax to the safety and efficacy of the backbone regimen azacitidine.
Azacitidine is a low intensity therapy for AML and is currently approved in Europe as a 
single agent for patients with AML who are not candidates for standard induction 
chemotherapy or HSCT.  The response rate in patients who were treated with azacitidine 
as monotherapy are substantially lower than what is seen in Study M14-358 in 
combination with venetoclax, a novel agent with BCL-2 inhibition.  This combination 
would be a reasonable therapeutic regimen to be studied as an active comparator in a 
randomized, controlled study designed to evaluate the therapeutic value of a novel 
 

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investigational agent added to a hypomethylating agent that is currently used standard of 
care in this population. 
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical and laboratory procedures will be utilized in 
this study.  The efficacy measurements in this study are standard and validated.
The PRO measures chosen for this study have been validated in cancer patients.  The 
specific symptoms and functional aspects assessed by these measures are considered to be 
among the most impactful to AML patients.34,35
5.6.3
Suitability of Subject Population 
Subjects who have histological confirmation of acute myeloid leukemia who are treatment 
naïve, greater than or equal to 18 years of age, considered ineligible for treatment with a 
standard induction regimen due to age and comorbidity, and appropriate for azacitidine 
control arm may be enrolled.  Study M14-358, which provides the experimental arm 
projections, enrolled a similar patient population.
5.6.4
Selection of Doses in the Study
The selected dosage of venetoclax is based on the results from Study M14-358, an 
ongoing Phase 1b study of escalating doses of venetoclax in combination with 
hypomethylating agents (HMA) i.e., decitabine and azacitidine in treatment naïve AML 
subjects greater than or equal to 65 years of age, and ineligible for treatment with a 
standard cytarabine and anthracycline induction regimen.  The ORR of CR/CRi/PR was 
higher than the reported ORR from the Phase 3 monotherapy HMA trials in this 
population as reported in Section 3.0.  While the efficacy and safety data at both 400 mg 
and 800 mg dose of venetoclax in combination with HMAs was comparable, prolonged 
neutropenia is reported in subjects receiving 800 mg dose of venetoclax after achieving a 
CR/CRi compared to subjects receiving 400 mg dose.
 

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An exposure-response analysis of the efficacy from Study M14-358 indicated that the 
predicted probability of achieving CRi or better was approximately 70% at exposures 
associated with both the 400 mg and 800 mg daily dosage regimen of venetoclax in 
combination with the HMAs.  The Maximum Tolerated Dose (MTD) of venetoclax was
not reached in Study M14-358 at the highest tested dose of venetoclax (1200 mg daily).  
Only short-term safety and efficacy data are available at the 1200 mg dose.  The emerging 
safety data with doses at 1200 mg daily, demonstrated increase in gastrointestinal adverse 
events of nausea (≥ 80%) and diarrhea (≥ 50%) in both of the HMA combination arms.  
Both safety and efficacy were taken into consideration for the selection of a maximum 
400 mg daily dose of venetoclax to be used in combination with azacitidine for this study. 
The dosing regimen for azacitidine is the dose specified for treatment of adult patients 
with AML in the EU SmPC and for treatment of myelodysplastic syndrome in the US 
prescribing information.  Subjects will be treated for a minimum of 6 cycles.  Failure to 
achieve CR, CRi or MLFS after at least 6 cycles of study treatment is considered as 
treatment failure.  Treatment will be continued as long as the patient continues to derive 
clinical benefit or until documented disease progression or develops unacceptable toxicity.
5.6.4.1
Dose Adjustments for Venetoclax Upon Co-Administration 
with Anti-Fungal Agents
Patients with AML are at high risk for febrile neutropenia and life threatening fungal 
infections.  Azoles, all of which are CYP3A inhibitors, are widely used in these patients 
for prophylaxis and treatment of invasive fungal infections.36  As venetoclax is 
predominantly metabolized by CYP3A, co-administration with antifungal agents which 
are strong or moderate CYP3A inhibitors are expected to increase venetoclax exposures.
The effect of two strong CYP3A inhibitors (posaconazole and ketoconazole) on the 
pharmacokinetics of venetoclax was evaluated in two separate studies.  Study M13-364 
was conducted to evaluate the effect of ketoconazole given once daily on 
pharmacokinetics of a single dose of venetoclax in 12 subjects with NHL,37 and a cohort 
of 12 untreated elderly AML subjects in Study M14-358 was enrolled to assess the effect 
 

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of posaconazole given twice daily on exposures of venetoclax given once daily.38  
Furthermore, prior studies indicated venetoclax bioavailability to be dependent on both 
food and dose.  To account for the effect of covariates such as food and dose non-linearity 
on the bioavailability of venetoclax, a population PK model was used to simulate 
exposures of venetoclax in presence of strong CYP3A inhibitors. 
The ramp-up scheme for venetoclax when given alone is 100 mg on Day 1, 200 mg on 
Day 2 and 400 mg QD from Day 3 onwards.  To match the exposures (AUC) from these 
doses, venetoclax doses of 10 mg on Day 1, 20 mg on Day 2 and 50 mg QD from Day 3 
onwards were chosen when co-administered with strong CYP3A inhibitors to mitigate 
any possible risk for TLS and ensure safety.  Predicted venetoclax exposures when 
administered alone and in presence of strong CYP3A inhibitors at the recommended dose 
reductions are shown in Table 6.  
Table 6.
Predicted Geometric Mean (and 90% CI) AUC24 Exposures of 
Venetoclax When Administered Alone and in Presence of Strong 
CYP3A Inhibitor
PK 
Parameter
Venetoclax Alone
Venetoclax + Strong CYP3A Inhibitor
Ramp-Up
Steady-
State
Ramp-Up
Steady-
State
Day 1
100 mg
Day 2
200 mg
Day 3
400 mg
Day 28
400 mg
Day 1
10 mg
Day 2
20 mg
Day 3
50 mg
Day 28
50 mg
AUC24
(µg•hr/mL)
4.23
(3.65 –
4.84)
8.86
(7.69 –
10.1)
15.9
(13.8 –
18.3)
20.5
(17.24 –
24.29)
1.20
(1.04 –
1.38)
3.17
(2.77 –
3.62)
7.01
(6.12 –
7.97)
26.4
(22.3 –
31.3)
6.0
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 after it is released for 
distribution.  Complaints associated with any component of this investigational product 
must be reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to 
Sections 6.1 through 6.1.7.1.  For product complaints, please refer to Section 6.2.
 

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6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other cause of the event."  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event 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 accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
 

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medical intervention, meet protocol specific criteria (see Section 6.1.7) regarding toxicity 
management) or if the Investigator considers them to be adverse events.
Hospitalization of a subject to allow observation and management (e.g., for IV hydration) 
for the purpose of TLS prophylaxis will not be captured as a serious adverse event (SAE), 
unless there is an additional reason for hospitalization or an additional criterion for 
seriousness other than hospitalization.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned 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 adverse event.
A treatment-emergent adverse event is defined as any adverse event with onset or 
worsening reported by a subject from the time that the first dose of venetoclax/placebo or 
azacitidine is administered until 30 days have elapsed following discontinuation of 
venetoclax/placebo and Azacitidine administration.
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event within 24 hours of the site being made aware of the serious adverse 
event:
 

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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.  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.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.  Deaths related to disease progression will 
not be recorded as adverse events.
 

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6.1.1.3
Adverse Events Commonly Associated with AML Study 
Population and/or Progression of AML
Certain adverse events are anticipated to occur in the study population (AML) at some 
frequency independent of drug exposure.  These are discussed here as Adverse Events 
commonly associated with AML or progression of AML.  Such events include known 
consequences of the underlying disease under investigation (e.g., symptoms, disease 
progression) and events unlikely to be related to the underlying disease under 
investigation but common in the study population independent of drug therapy 
(e.g., cardiovascular events in an elderly population). 
These adverse events may occur alone or in various combinations and are considered 
expected for reporting purposes for this protocol.  An Independent Data Monitoring 
Committee will monitor the incidence of these expected events during the study.  An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to health authorities.
Cytopenias (anemia, neutropenia, or thrombocytopenia) are part of the natural history of 
AML.  Persistent cytopenias at the same CTCAE grade as at baseline are not to be 
reported as adverse events, unless they fulfill a seriousness criteria, result in permanent 
discontinuation of a study drug, or the investigator had an identifiable cause other than the 
underlying disease.  Record highest grade of cytopenias in medical history, including 
transfusion support and prophylaxis administered, regardless if screening value indicates a 
lesser CTCAE grade.  Any clinically relevant abnormal laboratory assessment between 
screening and prior to administration of Venetoclax will be recorded in the patient's 
medical history.
Although exempted from expedited reporting to Health Authorities and IRBs as 
individual cases, these Serious Adverse Event commonly associated with AML or 
progression of AML should be reported to AbbVie as a serious adverse event within 
24 hours of the site being made aware of the serious adverse event (as defined in this 
Section).
 

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6.1.1.4
Adverse Events Expected due to Study Related Endpoints
6.1.1.4.1
Deaths
For this protocol, overall survival is an efficacy endpoint.  Deaths that occur during the 
protocol specified adverse event collection period (Section 6.1.4) that are attributed by the 
investigator solely to progression of AML should be recorded only on the Death eCRF 
and the Study Completion Form eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and immediately 
reported to the Sponsor (Section 6.1.5). 
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.03).  When applicable, once the diagnosis is confirmed the medical term should 
be reported for an event rather than the abnormal lab result as identified in CTCAE.  If a 
reported adverse event increases in severity, the initial adverse event should be given final 
outcome date and a new adverse event must be reported to reflect the change in severity 
such that the dates on these AE's cannot overlap.  For all reported serious adverse events 
that increase in severity, the supplemental eCRFs also need to be updated to reflect any 
changes due to the increase in severity.
For adverse events not captured by the Common Terminology Criteria, the following 
should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (moderate to severe).
Grade 4
The adverse event is life-threatening requiring urgent intervention 
(severe).
 

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Grade 5
The adverse event resulted in death of the subject (severe).
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event 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
The Investigator will assess the relationship of each adverse event to venetoclax/placebo, 
and to azacitidine.  Some events may be reasonably related to more than one drug or to 
none.  For causality assessments, events assessed as having a reasonable possibility of 
being related to the study drug will be considered "associated."  Events assessed as having 
no reasonable possibility of being related to study drug will be considered "not 
associated."  In addition, when the Investigator has not reported causality or deemed it not 
assessable, AbbVie will consider the event associated to study drug.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an "Other" cause of event must be provided by the Investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
Serious and nonserious adverse events occurring after the study-specific informed consent 
is signed but prior to the initial dose of venetoclax/placebo, or azacitidine will be collected 
only if they are considered by the Investigator to be causally related to the study-required 
procedures.
 

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In addition, all serious and nonserious adverse events reported from the time of study drug 
administration until 30 days following discontinuation of study drug administration have 
elapsed will be collected, whether elicited or spontaneously reported by the subject.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
*
Only if considered by the Investigator to be causally related to study-required procedures.
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system or if RAVE is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of being made aware of the serious adverse event.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847)-938-0660
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines and Appendix A of the Investigator Brochure will serve as 
the Reference Safety Information (RSI).  The RSI in effect at the start of the DSUR 
reporting period serves as the RSI during the reporting period.  For follow up reports, 
the RSI in place at the time of occurrence of the 'suspected' Serious Adverse Reaction 
will be used to assess expectedness.
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
Due to the COVID-19 pandemic and evolving local regulations, urgent safety measures 
may need to be employed in order to protect participating subjects from any immediate 
hazard.  Such events and measures should be reported to the sponsor emergency medical 
contact listed above immediately.
6.1.6
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie 
within 1 working day of the site becoming aware of the pregnancy.  Subjects who become 
pregnant during the study must be discontinued (Section 5.4.1).  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.  A separate consent will be provided by AbbVie for this purpose.  Pregnancy 
in a subject's partner will be collected from the date of the first dose through 90 days 
following the last dose of study drug.
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 of the site 
becoming aware of the event.
 

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6.1.7
Toxicity Management
Management of Cytopenias and Infections
Myelosuppression and the related adverse events (thrombocytopenia, anemia, 
neutropenia, and febrile neutropenia) are common in subjects with AML.  Subjects with 
baseline neutropenia or those with secondary AML might be particularly at high risk.
Anti-infective prophylaxis for bacterial, viral and fungal infections are required for all 
subjects with ANC of < 500/μL.  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.  Potential for drug-drug 
interactions should be considered.  Please refer to Table 1, Table 2 and Appendix H for 
list of excluded and cautionary medications and implement dose reductions for 
venetoclax/placebo as necessary.
If a subject achieves CRi or has a morphologic leukemia free bone marrow (MLFS) 
(i.e., bone marrow blasts < 5%) after completion of Cycle 1, venetoclax/placebo should be 
interrupted to allow for ANC recovery from Day 29 until ANC ≥ 500/μL or up to 14 days.  
Cycle 2 administration of azacitidine will also be delayed until ANC ≥ 500/μL.  Both 
venetoclax/placebo and azacitidine will resume on the same day after the interruption.  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/placebo dosing should be interrupted until ANC is ≥ 500/μL.  After Cycle 3, 
for subjects in CR/CRi who required interruption or delay of study drug administration for 
cytopenias (neutropenia [≤ 500/μL] or thrombocytopenia [≤ 50 × 103/μL]) 
venetoclax/placebo should be administered for 21 days out of 28 days during each of the 
subsequent cycles.  Treatment cycle should also be delayed to allow for count recovery 
until ANC ≥ 500/μL and/or platelet count ≥ 50 × 103/μL or for up to 14 days whichever 
occurs earlier.
 

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Subjects with ANC of 1000/μL and platelet count > 100 × 103/μL at end of C1 may 
proceed to C2D1 study treatment before the results of the bone marrow aspirate and 
biopsy preformed at end of C1 become available.
Subjects with resistant disease after Cycle 1 should receive subsequent cycles of study 
treatment with no dose interruption/delay until a repeat bone marrow assessment 
demonstrates CRi or MLFS.  Once this response is achieved, dose interruptions and 
reduction in duration of venetoclax administration for neutropenia should be implemented 
as described above beginning from the cycle where a CRi or MLFS is demonstrated.  If 
hematologic recovery (ANC or platelets) is achieved within 14 days after completion of 
the cycle, the duration of venetoclax is reduced to 21 days of the subsequent 28-day cycle.  
During subsequent cycles, if hematologic recovery with more than 25% increase above 
the nadir is not seen by Day 28, reassess counts every 7 days.  If a 25% increase has not 
been achieved within 14 days after the completion of a cycle, based on the bone marrow 
biopsy cellularity azacitidine dose adjustment can be made as follows:
Table 7.
Azacitidine Dose Modification
Bone Marrow Cellularity
% Dose in the Next Cycle
if Recovery is Not Achieved Within 14 Days
Recovery ≤ 21 Days
Recovery > 21 Days
15 – 50%
100%
50%
< 15%
100%
33%
These are provided in Appendix L.  If additional dose reductions or modifications that are 
thought to be necessary by the investigator a discussion with the AbbVie medical monitor 
(TA MD) is required.  Subjects experiencing delays for a medical event unrelated to study 
treatment may delay study treatment up to 4 weeks.  Delays greater than 21 days must be 
discussed with the AbbVie TA MD or a designee.
 

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6.1.7.1
Prophylaxis and Management of Tumor Lysis Syndrome 
(TLS)
There is a potential risk for TLS in subjects with AML, especially in those with elevated 
leukocyte count, circulating blasts, elevated pretreatment LDH levels, renal dysfunction, 
and dehydration.39,40  In addition, on-target effect of venetoclax could lead to rapid cell 
death and pose a risk of TLS.  To mitigate the risk for TLS all subjects enrolled in to the 
study will need TLS prophylaxis and monitoring.  For subjects at higher risk for TLS, 
additional mitigation measures with more intensive laboratory monitoring and 
intervention should be implemented.  Lower starting dose of venetoclax/placebo may be 
considered.  Prophylactic reductions of potassium, inorganic phosphorus or uric acid 
above normal range are recommended prior to beginning study treatment and continue 
based on the ongoing risk of TLS.
Below are the minimum requirements for TLS prophylaxis and management for all 
subjects enrolled into the study.  All other prophylaxis and monitoring procedures for 
TLS will be implemented as per regional guidelines/institutional standards:
●
All subjects will be hospitalized on or before Day 1 of Cycle 1 prior to 
administration of the initial dose of study treatment and remain in the hospital 
for at least for 24 hours after reaching the final dose of venetoclax/placebo.
●
All subjects must receive uric acid reducing agent, adequate oral and 
intravenous hydration as tolerated while monitoring the fluid status of the 
subject prior to and during the ramp up of venetoclax/placebo.  The uric acid 
reducing agent, type of fluids and the rate of infusion will be determined by the 
investigator based on regional standards or institutional guidelines.
●
TLS chemistry tests to be drawn (calcium, inorganic phosphorus, potassium, 
uric acid, and creatinine) on the first day of venetoclax/placebo dosing and 
each day of a new dose at 0 (within 4 hours prior to dosing) and 6 – 8 hours 
post dose.
●
Additional laboratory assessments may be performed, per investigator 
discretion, post-dose during ramp up and up to 48 hours after reaching final 
dose if clinically indicated.
 

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●
Abnormal chemistry tests during ramp up should be corrected promptly.  If a 
subject meets criteria for clinically significant laboratory or clinical TLS 
please follow institutional guidelines or recommendations in Appendix G, no 
additional venetoclax/placebo dose should be administered until resolution.41  
For continued dosing of venetoclax/placebo, monitor for evidence of TLS 
during study treatment, and manage abnormalities of serum creatinine, and 
electrolytes promptly.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
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 (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  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 adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
 

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Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
Investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitor(s):
 

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used for safety analyses.  The full analysis set consists of all randomized subjects.  The 
full analysis set will be used for efficacy analyses.  
8.1.2
Baseline Characteristics
All baseline summary statistics and analyses will be based on characteristics prior to the 
initiation of any component of study drug (or randomization for non-treated subjects).  
Unless otherwise stated, baseline for a given variable will be defined as the last value for 
that variable obtained prior to the first dose of any component of study drug. 
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviation, minimum, maximum, and range.  Frequencies and percentages 
will be computed for categorical data (e.g., sex, race, number of prior therapies, 
geography, and baseline ECOG performance status).
8.1.3
Pharmacokinetics
Plasma concentrations of venetoclax and/or azacitidine will be listed for each subject by 
arm and scheduled visit.  Summary statistics will be computed for each arm and dose 
level by scheduled visit.  Samples with significant sampling time deviations will be 
excluded from summary statistics calculations.
8.1.4
Efficacy Endpoints
8.1.4.1
Primary Efficacy Endpoint
8.1.4.1.1
Primary Efficacy Endpoint in US and US Reference 
Countries
For US and US reference countries, this study has single primary efficacy endpoint of 
overall survival (OS), with significance level of 0.05 (two-sided).
Overall survival will be defined as the number of days from the date of randomization to 
the date of death.  Subjects that have not died will be censored at the last known date to be 
alive.  The distribution of overall survival will be estimated for each treatment arm using 
 

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Kaplan-Meier methodology and compared between treatment arms using the log-rank test 
stratified by age (18 – < 75, ≥ 75) and cytogenetics (intermediate risk, poor risk).
8.1.4.1.2
Primary Efficacy Endpoints in EU and EU Reference 
Countries 
For Japan, EU and EU reference countries, this study has dual primary endpoints of CR + 
CRi rate (as assessed by investigator) and overall survival (OS).  The significance level of 
0.05 (two sided) will be split between the dual primary endpoints to give a 0.01 
significance level to the CR + CRi rate analysis (based on the investigator assessment) 
and an overall 0.04 significance level to the OS analysis.  
The proportion of subjects with complete remission or complete remission with 
incomplete marrow recovery (CR + CRi) will be calculated based on the modified IWG 
criteria for AML.  Subjects who are randomized but have no IWG disease assessment will 
be considered as non-responders for CR + CRi rate.  CR + CRi rate will be compared 
between treatment arms using CMH test stratified by age (18 – < 75, ≥ 75) and 
cytogenetics (intermediate risk, poor risk).  In addition, 95% confidence interval will be 
constructed for CR + CRi rate.
8.1.4.2
Secondary Efficacy Endpoints
Fixed sequence testing procedure will be used for analyses of the primary and key 
secondary efficacy endpoints.  If statistical test is not significant for the primary efficacy 
endpoint(s), then statistical significance will not be declared for any of the secondary 
efficacy endpoints.  
For US and US reference countries, the key secondary efficacy endpoints are CR + CRi 
rate, CR + CRh rate, CR + CRi at initiation of Cycle 2, CR rate, post-baseline transfusion 
independence rates for RBC and/or platelets, the rates of conversion from baseline 
transfusion dependence to post-baseline transfusion independence post-baseline.  
For Japan, EU and EU reference countries, the key secondary efficacy endpoints are CR + 
CRh rate, CR + CRi at initiation of Cycle 2, CR rate, post-baseline transfusion 
 

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independence rates for RBC and/or platelets, the rates of conversion from baseline 
transfusion dependence to post-baseline transfusion independence post-baseline.   
Additional secondary efficacy endpoints are: MRD response rate among subjects with CR 
+ CRi and subjects with CR + CRh:  CR + CRi rate in biomarker subgroups (e.g., FLT3, 
IDH1, IDH2), CR + CRh rate in biomarker subgroup (e.g., FLT3, IDH1, IDH2), OS in 
biomarker subgroup (e.g., FLT3, IDH1, IDH2), change from baseline in PROMIS Cancer 
Fatigue SF 7a global fatigue score, change from baseline in GHS/QoL scale from the 
EORTC QLQ-C30, and event free survival (EFS).
To adjust for multiple testing of the key secondary efficacy endpoints, a fixed sequence 
testing procedure will be used.  The key secondary efficacy endpoints and corresponding 
ranking will be specified in the statistical analysis plan (SAP) prior to the primary analysis 
of CR + CRi.  Unless otherwise specified, all response/progression related endpoints 
(e,g., CR/CRi and EFS) will be based on the investigator assessment.
CRh (Complete remission with partial hematologic recovery) is a derived response based 
on bone marrow blast and hematology lab values.  A response of CRh is achieved when 
the following criteria are met:
●
Bone marrow with < 5% blasts 
●
peripheral blood neutrophil count of > 0.5 × 103/µL*
●
peripheral blood platelet count of > 0.5 × 105/µL*
*
For a bone marrow sample collected before the last cycle of study treatment, the hematology lab results collected 
from the date of the bone marrow sample collection up to the Day 1 of a subsequent cycle of study treatment will 
be used for CRh analysis.
*
For a bone marrow sample collected during or after the last cycle of study treatment, the hematology lab results 
collected within 14 days after bone marrow sample collection date will be used for CRh analysis.
*
platelet transfusion independence for ≥ 7 days prior to the hematology lab results
The same analysis planned for CR + CRi rate will be performed for CR + CRh rate.  
The proportion of subjects with complete remission or complete remission with 
incomplete marrow recovery (CR + CRi) by the initiation of Cycle 2 will be calculated 
 

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based on the modified IWG criteria for AML.  Subjects who are randomized but have no 
IWG disease assessment will be considered as non-responders for CR + CRi rate by the 
initiation of Cycle 2.  CR + CRi rate by the initiation of Cycle 2 will be compared 
between treatment arms using CMH test stratified by age (18 – < 75, ≥ 75) and 
cytogenetics (intermediate risk, poor risk).  In addition, 95% confidence interval will be 
constructed for CR + CRi rate by the initiation of Cycle 2.
Post baseline transfusion independence rate will be calculated as the portion of subjects 
who achieved transfusion independence post baseline.  Transfusion independence is 
defined as a period of at least 56 days with no transfusion between the first dose of study 
drug and the last dose of study drug + 30 days.  In addition, the rate of conversion will be 
calculated as proportion of subjects being post-baseline transfusion independent from 
baseline transfusion dependence.  The transfusion independence rate will be evaluated for 
1) RBC 2) platelet.  All randomized subjects will be included to estimate the post-baseline 
transfusion independence rate.  The post-baseline transfusion independence rates will be 
compared between two arms using CMH test stratified by age (18 – < 75, ≥ 75) and 
cytogenetics (intermediate risk, poor risk).  In addition, 95% confidence interval will be 
constructed for the post-baseline transfusion independence rates.  The rates of conversion 
from baseline transfusion dependence to post-baseline transfusion independence will be 
estimated.  The conversion rate will be evaluated for 1) RBC 2) platelet.
EFS will be defined as the number of days from randomization to the date of progressive 
disease, relapse from CR or CRi, treatment failure defined as failure to achieve CR, CRi 
or MLFS after at least 6 cycles of study treatment, or death from any cause.  If a specified 
event does not occur, subjects will be censored at the date of last disease assessment.  
Data for subjects without any disease assessments performed after randomization will be 
censored at the date of randomization.  The distribution of EFS will be estimated for each 
treatment arm using Kaplan-Meier methodology and compared between treatment arms 
using the log-rank test stratified by age (18 – < 75, ≥ 75) and cytogenetics (intermediate 
risk, poor risk).
 

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The proportion of subjects (CR + CRi, or CR + CRh) achieving an MRD response will be 
calculated and 95% confidence interval will be constructed.  MRD response will be 
defined using a threshold of less than 0.1% of residual blasts per leukocytes as measured 
in bone marrow.  Additional thresholds may also be explored and correlated with efficacy 
outcomes.  The response rates (CR + CRi, or CR + CRh, or CR) and overall survival in 
molecular subgroups may be evaluated.
Fatigue will be assessed using the PROMIS Cancer Fatigue SF 7a global fatigue score.  
Scores will be computed according to the procedures outlined in the PROMIS Fatigue 
scoring manual, available at https://www.assessmentcenter.net/Manuals.aspx.  A linear 
mixed effects regression model with a variable covariance structure will be fitted to the 
longitudinal data to test for differences between the two treatment arms.
Quality of life will be assessed using the GHS/QoL scale from the EORTC QLQ-C30.  
Scores will be computed according to procedures outlined in the EORTC QLQ-C30 
scoring manual, available at http://groups.eortc.be/qol/manuals.  A linear mixed effects 
regression model with a variable covariance structure will be fitted to the longitudinal data 
to test for differences between the two treatment arms.
8.1.4.3
Exploratory Efficacy Endpoint
Exploratory analyses comparing the effects of venetoclax + azacitidine versus placebo + 
azacitidine will be performed on the following PRO measures:  EQ-5D-5L, and the 
subscales/items from the EORTC QLQ-C30 and PROMIS Cancer Fatigue SF 7a.  
Descriptive statistics will be calculated as per the scoring manuals for all scales/items of 
the EORTC QLQ-C30, PROMIS Cancer Fatigue SF 7a, the EQ-5D-5L utility score, and 
the EQ-5D VAS score at each assessment.  Linear mixed effects regression models will be 
used to test for differences between treatment arms, and mean change in values at each 
assessment will be calculated to identify any statistically significant differences versus 
baseline.  Within-group changes from baseline at each assessment will also be assessed.  
Additional analyses will include an assessment of time to deterioration and time to 
improvement.
 

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8.1.5
Efficacy Endpoints per Independent Review Committee
An Independent Review Committee (IRC) will evaluate response and disease progression.  
The following efficacy endpoints, described in Section 8.1.4.2, will also be summarized 
based on this IRC review in addition to the investigators' assessments:  CR + CRi rate, 
event-free survival, and CR + CRi rate by the initiation of Cycle 2.
8.1.6
Timing of Efficacy Analyses
The primary analysis for CR + CRi will occur 6 months after the first 225 subjects are 
randomized.  A significance level of 0.01 will be allocated for this analysis.
There will be three planned analyses for the primary endpoint of overall survival. 
●
At the same time as the CR + CRi analysis.  An administrate spending of 
0.0001 significance level will be allocated to this analysis.
●
An interim analysis at the time of approximately 270 OS events (75% of the 
total 360 events). 
●
Final analysis at the time of approximately 360 OS events. 
A formal interim analysis for safety will be performed and reviewed by the Independent 
Data Monitoring Committee (IDMC) after approximately 20 subjects have been dosed 
and followed by 3 months.  In addition, IDMC will review safety data every 3 months 
after the formal interim analysis for safety.  
For Japan, EU and EU reference countries, two interim analyses for efficacy will be 
performed.  The first interim analysis will be performed when 225 subjects have been 
randomized and followed up for 6 months.  Only the CR + CRi endpoint will be analyzed 
and reviewed by IDMC.  This is the Final Analysis for CR + CRi and will be based on 
investigator's assessment.  The second interim analysis will be performed when 
approximately 270 death events (75% information time for OS) occur.
 

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For US and US reference countries, only one interim analysis for efficacy will be 
performed at the 75% information time for OS (same timing as the second interim 
analysis for Japan, EU and EU reference countries).
The details of primary endpoint efficacy boundaries will be described in SAP.
8.1.7
Safety
The safety of venetoclax in combination with azacitidine will be assessed by evaluation of 
study drug exposure, adverse events, serious adverse events, deaths, and changes in 
laboratory determinations and vital sign parameters.
8.1.7.1
Study Drug Exposure
The number of days and/or cycles that subjects were exposed to study drug will be 
summarized.
8.1.7.2
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug.  Analyses will not include 
those that have an onset greater than 30 days after the last dose of study drug.  Treatment-
emergent adverse events will be summarized by preferred terms within a System Organ 
Class according to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary.42  In addition, the percentage of subjects experiencing an adverse event at a 
given NCI CTCAE Version 4.0343 toxicity grade and relationship to study drug will be 
provided.
8.1.7.3
Serious Adverse Events
Serious adverse events will be summarized as described for Adverse Events above.
 

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8.1.7.4
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of randomization, (2) for deaths occurring within 60 days of randomization, (3) for deaths 
occurring within 30 days of the last dose of study drug, (4) for deaths occurring more than 
30 days of the last dose of study drug, and (5) for all deaths in this study regardless of the 
number of days after the last dose of study drug.
8.1.7.5
Laboratory Tests and Vital Signs
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as vital sign 
parameters.  If more than one measurement exists for a subject on a particular day, then an 
arithmetic average will be calculated.  This average will be considered to be that subject's 
measurement for that day.  Post-baseline measurements more than 30 days after the last 
dose of study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post-baseline measurements will not be included. 
Where applicable, blood chemistry and hematology laboratory determinations will be 
categorized according to NCI CTCAE (version 4.03) grades, and shifts from baseline NCI 
CTCAE grades to maximum and final post-baseline grades will be assessed.  The baseline 
and final grades will be defined respectively as the grade of the last measurement 
collected prior to the first dose of study drug, and as the last post-baseline measurement 
collected no more than 30 days after the last dose of study drug.  The percentage of 
subjects experiencing a shift from baseline grades of 0 to 2 to maximum post-baseline 
grades of 3 to 4, and from baseline grades of 0 to 2 to final post baseline grades of 3 to 4 
will be summarized.
8.1.7.6
Special Safety Evaluation of Venetoclax Among Chinese 
Subjects
When there are nine evaluable Chinese AML subjects enrolled to receive open-label 
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Chinese subjects will be temporarily suspended until the safety evaluation is performed on 
these nine Chinese subjects.  Assessment of Dose Limiting Toxicities in these subjects is 
described in Appendix K.  Once the safety is deemed acceptable, Chinese sites will be 
fully open to enrollment for the double blind, randomized portion of the study.  Open-
label Chinese subjects will also be included in the safety analyses only.
8.2
Determination of Sample Size
For US and countries using the US as the reference country, the study includes single 
primary endpoint of overall survival.  For Japan, EU and countries using EU as reference 
for obtaining approval, the study includes dual-primary endpoints of overall survival (OS) 
and CR + CRi rate.  
The sample size calculation is based on the following assumptions:
●
The significance level (two-sided 0.05) will be split to give a 0.01 significance 
level to the CR + CRi rate analysis and an overall 0.04 significance level to the 
OS analysis.
●
Median OS of 10.4 months for placebo plus azacitidine arm
●
Median OS of 14.9 months for venetoclax plus azacitidine arm (hazard ratio of 
0.7)
●
Interim analysis of OS at 75% of death events with O'Brien-Fleming boundary
●
2:1 randomization ratio to venetoclax plus azacitidine, and placebo plus 
azacitidine arm
With the above assumptions, a total of 360 death events will provide 86.7% power to 
detect statistically significant difference in OS between treatment arms at alpha level of 
0.04.  A total of approximately 400 subjects (267 in venetoclax in combination with 
azacitidine arm, and 133 in placebo with azacitidine arm) will be randomized into the 
study to obtain the 360 death events.  The subject randomization will be stratified by age 
(18 – < 75, ≥75), cytogenetics based on NCCN guidelines for AML Version 2.2016 
(intermediate risk, poor risk) and region (US, EU, China, Japan Rest of world).  With 
twelve subjects in the open label Chinese safety cohort required per the CFDA, the overall 
 

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sample size will be approximately 412, as described in Appendix K.  The subjects from 
China who participate in the open label safety cohort described in Appendix K will not be 
included in the efficacy analysis and will not count towards the 360 death events.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Serious adverse events that meet the reporting criteria, as dictated by local regulations, 
will be reported to both responsible Ethics Committees and Regulatory Agencies as 
required by local regulations.  During the conduct of the study, the investigator should 
promptly provide written reports (e.g., ICH Expedited Reports or any additional reports 
required by local regulations) to the IEC/IRB of any changes that affect the conduct of the 
study and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) GCP guidelines, applicable regulations and guidelines governing 
 

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clinical study conduct and ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., phone contacts or 
virtual site visits), alternative locations for data collection (e.g., use of a local lab instead 
of a central lab), and shipping investigational product and/or supplies direct to subjects to 
ensure continuity of treatment where allowed.  Refer to Section 5.3.1.1, Study Procedures 
and Appendix C, Study Activities, for additional details.  In all cases, these alternative 
measures must be allowed by local regulations and permitted by IRB/IEC.  Investigators 
should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
 

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In the event a subject withdraws consent to participate from the study, stored biomarker 
and exploratory research samples will continue to be used for research and analysis.  In 
the event that a subject would like to withdraw consent for research using these samples, 
the subject may request that their samples be withdrawn.  Once AbbVie receives the 
request, remaining biomarker and exploratory research samples will be destroyed.  If the 
subject changes his/her consent, and the samples have already been tested, those results 
will still remain as part of the overall research data.
A separate informed consent, approved by an IRB/IEC, must be voluntarily signed and 
dated before samples are collected for the optional exploratory research.  The nature of 
the testing should be explained and the subject given an opportunity to ask questions.  
This separate informed consent must be signed before the samples are collected and any 
testing is performed.  If the subject does not consent to provide samples for the optional 
exploratory research, it will not impact their participation in the study.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
 

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10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRFs) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an EDC system called Rave® provided by the technology vendor Medidata 
Solutions Incorporated, NY, USA.  The EDC system and the study-specific eCRFs will 
comply with Title 21 Code of Federal Regulations (CFR) Part 11.  The documentation 
related to the validation of the EDC system is available through the vendor, Medidata, 
while the validation of the study-specific eCRFs will be conducted by AbbVie and will be 
maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
 

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performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
Investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
Patient-reported data must be completed for each subject enrolled in this study.  These 
data are being collected with an Electronic Patient Reported Outcome (ePRO) system 
called Trialmax, provided by the technology vendor Signant Health of Blue Bell, PA, 
USA.  The ePRO system is in compliance with Title 21 CFR Part 11.  The documentation 
related to the system validation of the ePRO system is available through the vendor, CRF 
Health, while the user acceptance testing of the study specific PRO design will be 
conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device, except in cases where 
completion by interview is necessary due to COVID-19 restrictions; the data will be 
uploaded to a server.  The data on the server will be considered source, and maintained 
and managed by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
 

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on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media.
The ePRO data will be collected electronically via a tablet device into which the patient 
will directly enter the required pieces of information, except in cases where completion by 
interview is necessary due to COVID-19 restrictions.  The electronic device will be 
programmed to allow data entry for only the visits specified in the protocol and will not 
allow for patients to complete more than one of the same assessments at any one visit.  All 
data entered on the device will be immediately stored to the device itself and 
automatically uploaded to a central server administrated by CRF Health.  The Investigator 
and delegated staff will be able to access all uploaded patient entered data via a password 
protected website, up until the generation, receipt and confirmation of the study archive.  
If the PRO data is collected by phone interview, the delegated staff will enter the subject's 
responses into TrialMax.  Completion of PROs by phone interview should be approved by 
the site's IRB/EC.
11.0
Data Quality Assurance
Prior to enrolling any subject in the study, an initiation meeting will be held with AbbVie 
personnel, the Investigator(s), and the study coordinators/project manager(s).  This 
meeting will include a detailed discussion and review of the protocol and essential 
documents, performance of study procedures, case report form completion and specimen 
collection methods.
The AbbVie monitor will monitor the study site throughout the study.  Source document 
review will be made against entries on the case report forms and a quality assurance check 
will be performed to ensure that the Investigator is complying with the protocol and 
regulations.  In addition, after the case report forms are retrieved, a review of the data will 
be conducted by a physician or representative at AbbVie.
 

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All data hand-entered in the database will be verified at AbbVie.  Any discrepancies will 
be reviewed against the hard-copy case report form and corrected on-line.  After 
completion of the entry process, computer logic and manual checks will be created to 
identify such items as inconsistent study dates.  Any necessary corrections will be made to 
the database via the appropriate change form/electronic CRF.
Routine hematology, serum chemistry and serology, and urinalysis tests will be conducted 
using a certified clinical laboratory.  Laboratory reference ranges will be obtained prior to 
the initiation of the study and updated as necessary throughout the course of the study.  A 
review of all laboratory results will be conducted by the AbbVie monitor, the Investigator 
and other appropriate personnel from AbbVie.
12.0
Use of Information
All information concerning venetoclax processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
venetoclax.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical Investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the Investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
 

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The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any research that may be done using research samples from this study will be 
experimental in nature and the results will not be suitable for clinical decision making or 
subject management.  Hence, the subject will not be informed of individual results, should 
analyses be performed, nor will anyone not directly involved in this research.  
Correspondingly, researchers will have no access to subject identifiers.  Individual results 
will not be reported to anyone not directly involved in this research other than for 
regulatory purposes.  Data from research may be provided to investigators, used in 
scientific publications, or presented at medical conventions.  Research information will be 
published or presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the Investigator and AbbVie.  The Investigator 
(Director of the Site in Japan) will provide a final report to the IEC/IRB following 
conclusion of the study, and will forward a copy of this report to AbbVie or their 
representative.
The Investigator (Director of the Site in Japan) must retain any records related to the study 
according to local requirements.  If the Investigator (Director of the Site in Japan) is not 
able to retain the records, he/she must notify AbbVie to arrange alternative archiving 
options.
 

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AbbVie will select the signatory coordinating Investigator from the Investigators who 
participate in each multi-center study.  Selection criteria for this signatory Investigator 
will be based on level of participation, and significant knowledge of the clinical research, 
investigational drug, and study protocol.  The signatory Investigator for the study will 
review and sign the final study report in accordance with the European Agency for the 
Evaluation of Medicinal Products (EMEA) Guidance on Investigator's Signature for Study 
Reports.
The end of study is defined as the date of the last subject's last visit.
 

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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for venetoclax and the 
product labeling for azacitidine.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
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
Protocol Date:
01 July 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 

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15.0
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19.
Thein MS, Ershler WB, Jemal A, et al.  Outcome of older patients with acute 
myeloid leukemia:  an analysis of SEER data over 3 decades.  Cancer.  
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Konopleva M, Pollyea DA, Potluri J, et al.  A phase 2 study of ABT-199 
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DiNardo C, Pollyea DA, Pratz K, et al.  A phase 1b study of venetoclax 
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Dombret H, Seymour JF, Butrym A, et al.  International phase 3 study of 
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26.
Garcia SF, Cella D, Clauser SB, et al.  Standardizing patient-reported outcomes 
assessment in cancer clinical trials:  a patient-reported outcomes measurement 
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Cella D, Riley W, Stone A, et al.  The patient-reported outcomes measurement 
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estimated for six PROMIS Cancer scales in advanced-stage cancer patients.  J Clin 
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Research and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use 
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Herdman M, Gudex C, Lloyd A, et al.  Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L).  Qual Life Res.  
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31.
Oppe M, Devlin NJ, van Hout B, et al.  A program of methodological research to 
arrive at the new international EQ-5D-5L valuation protocol.  Value Health.  
2014;17(4):445-53.
32.
Cella D, Pickard AS, Duh MS, et al.  Health-related quality of life in patients with 
advanced renal cell carcinoma receiving pazopanib or placebo in a randomized 
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Pickard AS, Neary MP, Cella D.  Estimation of minimally important differences in 
EQ-5D utility and VAS scores in cancer.  Health Qual Life Outcomes.  
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Alibhai SMH, Leach M, Kermalli H, et al.  Fatigue in older adults with acute 
myeloid leukemia:  predictors and associations with quality of life and functional 
status.  Leukemia.  2007;21(4):845.
 

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35.
Sekeres MA, Stone RM, Zahrieh D, et al.  Decision-making and quality of life in 
older adults with acute myeloid leukemia or advanced myelodysplastic syndrome.  
Leukemia.  2004;18(4):809-16.
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Cornely OA, Maertens J, Winston DJ, et al.  Posaconazole vs. fluconazole or 
itraconazole prophylaxis in patients with neutropenia.  N Engl J Med.  
2007;356(4):348-59.
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Agarwal SK, Salem AH, Danilov AV, et al.  Effect of ketoconazole, a strong 
CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in 
patients with non-hodgkin lymphoma.  Br J Clin Pharmacol.  2016.  
doi:  10.1111/bcp.13175.  [Epub ahead of print].
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Agarwal SK, DiNardo C, Potluri J, R et al.  Management of venetoclax-
posaconazole interaction in acute myeloid leukemia patients:  evaluation of dose 
adjustments.  Clin Ther.  2017.  In press.
39.
Montesinos P, Lorenzo I, Martín G, et al.  Tumor lysis syndrome in patients with 
acute myeloid leukemia:  identification of risk factors.  Haematologica.  
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Mato AR, Riccio BE, Qin L, et al.  A predictive model for the detection of tumor 
lysis syndrome during AML induction therapy.  Leuk Lymphoma.  
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Coiffier B, Altman A, Pui CH, et al.  Guidelines for the management of pediatric 
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43.
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14_QuickReference_5x7.pdf.
 

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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
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., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
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 investigation and all amendments.
 

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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 

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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Director
Statistics
Director
Statistics
Head of Statistics, Late Oncology
Statistics
Study Project Manager II
Clinical
Executive Medical Director
Therapeutic Area
Principal Bioanalytical Investigator
Bioanalysis
Senior Medical Director
Therapeutic Area
Director
Clinical Pharmacology and 
Pharmacometrics
 

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Appendix C.
Study Activities
Procedures
Screeninga
Day 
–1
Cycle 1
Day 1 
of 
Each 
Cycle
Day 1 
of 
Every 
Other 
Cycle
End of 
Cycle 1 
and Every 
3 Cycles 
Thereafter
Final 
Visitb
30-Day 
Safety 
F/U
PT 
F/Uc
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Days 
8, 
15, 
22
Informed Consent
Xd
Medical/Oncology History 
Assessment
X
Xe
AE/Concomitant Medication 
Assessmentu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytogenetic Testingf
X
Tumor Lysis Syndrome 
Prophylaxisg
X
X
X
X
X
X
Physical Exam (including 
weight)h,u
Xi
X
Xj
X
X
X
Vital Signsh,u
X
X
X
X
X
Pregnancy Testu
X
Xs
X
ECOG Performance Statush,u
X
X
X
X
X
Hematology/Chemistryk,u
X
X
X
X
X
Xt
X
X
X
X
Coagulationh
X
X
X
Urinalysish
X
X
X
12-lead ECG
X
Xl
Pulmonary Function Testm
X
MUGA (preferred)/2D 
Echocardiogram w/Dopplerm
X
 

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Procedures
Screeninga
Day 
–1
Cycle 1
Day 1 
of 
Each 
Cycle
Day 1 
of 
Every 
Other 
Cycle
End of 
Cycle 1 
and Every 
3 Cycles 
Thereafter
Final 
Visitb
30-Day 
Safety 
F/U
PT 
F/Uc
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Days 
8, 
15, 
22
Disease Assessments
X
X
X
X
Bone Marrow Aspirate and 
Biopsy for Local Disease 
Assessment
Xn
Xn,o,p
X
PROMIS Cancer Fatigue SF 
7aq,v
X
X
X
EORTC QLQ-C30q,v
X
X
X
EQ-5D-5Lq,v
X
X
X
Dispense Venetoclax/Placebow
X
Dispense Subject 
Calendar/Diary
Xr
X
Collect venetoclax and Subject 
Calendar/Diary
X
X
Administer Azacitidineu,*
X
X
X
X
X
X
X
Survival Assessments
X
F/U = Follow-Up; PT = Post Treatment
a.
Screening procedures must be performed within 21 days prior to initial study drug administration.
b.
Final Visit procedures should be performed when a subject discontinues from the study.
c.
Post Treatment and survival visits will be performed every 2 months after the last study visit or as needed until end of study, defined as last subject last visit.
d.
Obtain informed consent prior to performing any screening or study-specific procedures.
e.
On Cycle 1 Day 1, additional medical history that is observed after signing of the informed consent but prior to initial venetoclax or azacitidine administration and not 
considered related to study-required procedures will be recorded in the subject's medical history.
 

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f.
Cytogenetic testing should be performed if not completed within 1 month prior to Screening.
g.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to refer to Section 6.1.7.1, 
Management of Tumor Lysis Syndrome and Appendix I – Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome 
(TLS) for further information.
h.
For all study visits after Cycle 3, physical examination, vital signs, ECOG performance status, coagulation and urinalysis may be performed within 3 days before the 
scheduled visit.  Under certain circumstances, these assessments may be performed within 3 days after the scheduled visit with discussion and approval by the AbbVie 
medical monitor TA MD.  PROs can be completed within 3 days prior to Cycle 1 Day 1 Visit.
i.
Height will be measured only at Screening.
j.
All subjects must have Physical exam prior to discharge from the hospital.  Subjects should remain hospitalized no less than 24 hours post dosing of their designated 
venetoclax dose.
k.
Only hematology required for disease assessment.  TLS chemistry tests to be drawn (calcium, inorganic phosphorus, potassium, uric acid, and creatinine) on the first day of 
venetoclax/placebo dosing and each day of a new dose at 0 (within 4 hours prior to dosing) and 6 – 8 hours post dose (see Section 6.1.7.1).
l.
Final visit ECG may be obtained within ± 2 days of visit.
m.
Only required if ECHO or MUGA, DLCO or FEV1 is being used to confirm eligibility for subjects ≥ 18 to 74 years of age.
n.
Historical bone marrow aspirates and biopsies assessed locally to confirm the diagnosis could be used as baseline assessment to satisfy eligibility criteria as long as the 
samples were taken within 30 days prior to randomization.  A bone marrow aspirate and biopsy must be performed for all subjects during screening to collect mandatory 
samples for biomarker assessments.  Bone marrow aspirate and biopsy samples must be collected for all subjects for each of the disease assessments.  Bone marrow core 
biopsy sample collection is considered an optional procedure only for subjects enrolled at sites in countries where an aspirate evaluation by morphologic assessment and flow 
cytometry is considered standard of care.  For these subjects if the aspirate sample is inadequate or unevaluable for disease assessment, repeat bone marrow aspirate and 
biopsy must be performed within 7 days.  The corresponding local laboratory pathology report should be sent to the central laboratory for IRC review for each local disease 
assessment.  Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will no longer be performed by the IRC.
o.
End of Cycle 1 bone marrow aspirate and biopsy must be performed within ± 3 days of Cycle 1 Day 28.  Assessments should be performed and resulted by Day 31 prior to the 
administration of study drugs for Cycle 2.  Cycle 1 venetoclax/placebo dosing should continue until bone marrow aspirate result is available.  For subjects who require a delay 
in study treatment for blood count recovery after a bone marrow evaluation, hematology values for up to 2 weeks can be used to determine the IWG response.  For all subjects 
a bone marrow aspirate and biopsy must be performed at end of Cycle 4 and every 3 cycles (± 1 week) and upon concern for relapse.  The corresponding local laboratory 
pathology/bone marrow report will be sent to the central laboratory for IRC review Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will 
no longer be performed by the IRC.
p.
For subjects with resistant disease at end of Cycle 1 a repeat bone marrow must be performed at the end of Cycle 2 or Cycle 3 based on the hematologic recovery to confirm 
response.
 

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q.
PRO assessments should be completed after a blood sample is taken to confirm the subject is able to receive study treatment at the study visit, but prior to any other 
procedures or clinical assessments and prior to dosing.  PROs can be completed within 3 days prior to Cycle 1 Day 1 dosing.
r.
Diaries will be dispensed upon discharge from the hospital.
s.
Urine pregnancy test must be obtained at Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy results at screening.  Pregnancy test should be repeated 
on Day 1 of each cycle and evaluated prior to dosing.
t.
Additional laboratory assessments may be performed, per investigator discretion, up to 48 hours after reaching final dose if clinically indicated.
u.
Procedure may be performed in the subject's home or local hospital/clinic by adequately trained personnel if required due to COVID-19 restrictions.
v.
ePROs may be performed virtually/phone interview by delegated personnel only if required due to COVID-19 restrictions.
w.
Venetoclax/placebo may be shipped directly to a subject's home only if required due to COVID-19 restrictions.
*
AZA is administered for 7 days for each cycle starting with Day 1.
 

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Appendix D.
Schedule of Biomarker/Pharmacodynamic/Pharmacogenetic 
Sample Collection (Not Applicable for China)
Sample Collections
Screening
Cycle 1
End of Cycle 1a
and Every 
3 Cycles 
Cycle 3
Final 
Visit/ 
Time of 
Relapsea
Comments
Day 1
Day 1
Plasma
X
X
X
4 mL blood at 
screening and 
20 mL at all 
other plasma 
collection time 
points
Disease 
Assessment/MRD by 
Flow
X
X
X
1 – 2 mL bone 
marrow 
aspirate
AML Mutational 
Profiling
X
X
1 mL bone 
marrow 
aspirate
Translational 
Research
X
X
X
4 mL bone 
marrow 
aspirate at 
Screening, and 
Final Visit.  
1 mL at all 
other collection 
assessments.
Bone Marrow Biopsy 
Core for BCL 2 
Family Protein 
Analysis
X
X
FFPE Block or 
6 – 10 FFPE 
slides
Pharmacogenetics 
(DNA and RNA)b
X
X
X
6.5 mL Blood
a.
Sample should be split from the bone marrow aspirate for disease assessment.  In subjects, that have two successive 
samples which indicate CR or CRi, bone marrow aspirates are no longer required for response assessments, 
therefore, the bone marrow aspirate biomarker samples will also not be collected for those subjects.  Plasma will 
still be collected at those visits.
b.
Sample is optional and collected only if patient has signed the optional informed consent.
 

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Appendix E.
Schedule of Blood Collection for Venetoclax and Azacitidine Assay 
(Pharmacokinetic Sampling) 
Procedures
Cycle 1 
Days 1 – 5
Cycle 2, 4, 6, and 8 
Day 5
Venetoclax
8 hours post-dosea
0 hour (pre-dose)
Azacitidine
End of Infusionb,c
End of Infusionc
a.
The 8-hour post-dose PK sample on Days 1 – 5 of Cycle 1 will be collected if venetoclax is initiated or escalated to 
a new dose level.  If there is a delay in the escalation step, the 8-hour post-dose PK sample will be delayed 
accordingly.  The PK collection performed 8 hours post-dose after each dose escalation may be taken up to 1 hour 
prior or up to 20 minutes after the scheduled time to allow for processing, if necessary.
b.
Cycle 1 Day 5 only.
c.
For azacitidine given subcutaneously, PK samples should be drawn 30 minutes post end of injection.

All "pre-dose" samples in venetoclax PK sampling are relative to venetoclax/placebo administration.

The date and time (start and end times to the nearest minute) of each azacitidine infusion/injection taken, will 
be recorded on the eCRF.

The date and time (to the nearest minute) of each venetoclax/placebo dose taken will be recorded on the eCRF 
for every scheduled venetoclax PK day and for the 2 doses prior to every scheduled venetoclax PK day.
 

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Appendix F.
NCCN Risk Categorization:  Guidelines for AML Version 2.2016
Risk Category
Cytogenetics
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)
 

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Appendix G.
Tumor Lysis Syndrome Classification
Metabolic 
Abnormality
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome*
Criteria for Classification of 
Clinical Tumor Lysis Syndrome**
Hyperuricemia
Uric acid > 8 mg/dL (475.8 μmol/liter)
N/A
Hyperphosphatemia
Phosphorus > 4.5 mg/dL 
(1.5 mmol/liter)
N/A
Hyperkalemia
Potassium > 6 mmol/liter
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL
(1.75 mmol/liter) or ionized calcium 
< 1.12 mg/dL (0.3 mmol/liter)#
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau's sign, Chvostek's sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure 
probably or definitely caused by 
hypocalcemia
Acute Kidney 
Injury!
N/A
Increase in the serum creatinine level 
of 0.3 mg/dL (26.5 μmol/liter) or the 
presence of oliguria (average urine 
output of < 0.5 mL/kg/hr over a
6-hour period)
*
Laboratory TLS requires two or more metabolic abnormalities must be present during the same 24-hour period 
within 3 days before the start of therapy or up to 7 days afterward.
**
Clinical TLS requires the presence of Laboratory TLS plus one or more findings from the Clinical TLS column.
#
Corrected calcium = measured calcium level in mg/dL + 0.8 × (4 – albumin in gm/dL).
!
Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory TLS 
are not satisfied.
*
Not directly or probably attributable to therapeutic agent.
†
If no institutional ULN is specified, age/sex ULN creatinine may be defined as follows:  > 1 to < 12 years of age, 
both male and female, 61.6 μmol/L; ≥ 12 to < 16 years, both male and female, 88 μmol/L; ≥ 16 years, female 
105.6 μmol/L, male 114.4 μmol/L.
Note:
Laboratory tumor lysis syndrome and at least one clinical complication.
Cross reference:  Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  2011;364(19):1844-54.
 

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Note:  This is not an exhaustive list.  For an updated list, see the following link:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm
In addition to the medications listed in this table, subjects receiving venetoclax should not 
consume grapefruit, grapefruit products, Seville oranges (including marmalade containing 
Seville oranges) or starfruits.
 

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Appendix I.
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (TLS)
Abnormality
Management Recommendations
Hyperkalemia (including rapidly rising potassium)
Potassium ≥ 0.5 mmol/L 
increase from prior value 
(even if potassium within 
normal limits [WNL])

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.  If further ≥ 0.2 mmol/L increase in potassium, but still 
< upper limit of normal (ULN), manage as per potassium ≥ ULN.  
Otherwise recheck in 1 hour.

Resume per protocol testing if change in potassium is < 0.2 mmol/L, 
and potassium < ULN, and no other evidence of tumor lysis.

At discretion of investigator, may recheck prior to hospitalization.  If 
stable or decreased, and still WNL, hospitalization is at the discretion 
of the investigator.  Potassium, phosphorus, uric acid, calcium and 
creatinine must be rechecked within 24 hours.
Potassium > upper limit 
of normal

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) notification with 
consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer calcium gluconate 100 – 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias.

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.

If potassium < ULN 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium and creatinine 1, 2 and 4 hours, if no other evidence of 
tumor lysis.
Potassium ≥ 6.0 mmol/L 
(6.0 mEq/L) and/or 
symptomatic 
(e.g., muscle cramps, 
weakness, paresthesias, 
nausea, vomiting, 
diarrhea)

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) assessment with 
consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.

Administer sodium bicarbonate 1 – 2 mEq/kg IV push.

If sodium bicarbonate is used, rasburicase should not be used as this 
may exacerbate calcium phosphate precipitation.

Administer calcium gluconate 100 – 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias.  Do not 
administer in same IV line as sodium bicarbonate.

Recheck potassium, phosphorus, uric acid, calcium and creatinine 
every hour STAT.
 

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Abnormality
Management Recommendations
Hyperuricemia
Uric acid ≥ 8.0 mg/dL 
(476 µmol/L)

Consider rasburicase (prior to rasburicase administration please refer 
to local label for tests to be performed, contraindications and 
precautions.  Dosing is per institutional guidelines).

If rasburicase is used, sodium bicarbonate should not be used as this 
may exacerbate calcium phosphate precipitation.

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.
Uric acid ≥ 10 mg/dL 
(595 µmol/L) 
OR 
Uric acid ≥ 8.0 mg/dL 
(476 µmol/L) with 25% 
increase and creatinine 
increase ≥ 0.3 mg/dL 
(≥0.027 mmol/L) from 
pre-dose level

Administer rasburicase (prior to rasburicase administration please 
refer to local label for tests to be performed, contraindications and 
precautions.  Dosing is per institutional guidelines).

If rasburicase is used, sodium bicarbonate should not be used as this 
may exacerbate calcium phosphate precipitation.

Notify nephrology (or other acute dialysis service).

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.

If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium and creatinine 2 and 4 hours later, if no other 
evidence of tumor lysis.
Hypocalcemia
Calcium ≤ 7.0 mg/dL 
(1.75 mmol/L) 
AND 
Patient symptomatic 
e.g., muscle cramps, 
hypotension, tetany, 
cardiac arrhythmias)

Administer calcium gluconate 50 – 100 mg/kg IV slowly with ECG 
monitoring.

Telemetry.

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.

If calcium normalized 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium and creatinine 2 and 4 hours later, if no other evidence 
of tumor lysis.

Calculate corrected calcium and check ionized calcium if albumin 
low.
Hyperphosphatemia
Phosphorus ≥ 5.0 mg/dL 
(1.615 mmol/L) with 
≥0.5 mg/dL 
(0.16 mmol/L) increase

Administer a phosphate binder (e.g., aluminum hydroxide, calcium 
carbonate, sevelamer hydroxide, or lanthanum carbonate).

Nephrology (or other acute dialysis service) notification (dialysis 
required for phosphorus ≥ 10 mg/dL).

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 
1 hour STAT.

If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium and creatinine 2 and 4 hours later, if no other 
evidence of tumor lysis.
 

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Abnormality
Management Recommendations
Creatinine
Increase ≥ 25% from 
baseline
Start or increase rate of IV fluids.
Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 –
2 hours STAT.
 

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Appendix J.
Japan Specific Information
1.0
Clinical Expense and Compensation
1.1
Expenditure of the Clinical Expense
The sponsor will pay the expenses related to this study to the investigative site in 
accordance with "Special Healthcare Expenditure."  The expenses of screening test, etc. 
will be paid based on the contract concluded with each investigative site.  To lighten the 
burden imposed on the subject with participation to the study, transportation expenses, 
etc. will be paid to the subjects via participating investigative site in accordance with the 
rules of the investigative site.
1.2
Compensation for Health Impairment and Insurance
1.
If a subject suffers some sort of health impairment due to this study, the 
investigative site will provide treatment and take other necessary measures.  
Among the expenses required for the treatment, the amount not covered by health 
insurance that the patient must pay directly will be borne by the sponsor only 
when the event is associated with the use of the study drug.
2.
When a subject suffers health impairment during this study and a dispute occurs or 
might occur between the investigative site and the subject, the investigative site 
will report it to the sponsor immediately, and resolve it.  The sponsor will 
cooperate with the investigative site in resolving the problem.
3.
When the investigative site must compensate to the subject's health impairment 
caused by this study, the compensation paid by the investigative site and the 
expenses related to any dispute will be borne in full by the sponsor, except in cases 
where the responsibility for the problem is attributed to the investigative site.  This 
shall not apply to cases where the health impairment occurred because the 
investigative site performed the study with marked deviation from the GCP or the 
protocol or because of a deliberate action or a major error by investigative site.
 

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4.
When a subject suffers health impairment during this study and liability for 
compensation arises, the sponsor will compensate in accordance with the SOP 
regarding the compensation prepared in advance.
5.
The sponsor will obtain clinical study insurance and will take other necessary 
measures to cover the claims and compensation required in such cases.
1.3
Pharmacogenetic Testing
Pharmacogenetic testing on samples collected in Japan will be restricted to the subject's 
response to study treatment in terms of pharmacokinetics, efficacy, tolerability, and 
safety.
 

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Appendix K.
Safety Cohort for Evaluation of Venetoclax in AML Chinese 
Subjects
1.0
Objectives
The objective of the Chinese (enrolled at sites in mainland China) AML safety cohort is to 
evaluate the safety and PK profile of venetoclax at 400 mg daily dose in combination with 
azacitidine in a subset of up to 12 Chinese AML prior to allowing China to be fully open 
to enrollment into the double blind, randomized portion of the study.
2.0
Safety Cohort Procedures
Chinese subjects with AML will be enrolled to receive venetoclax plus azacitidine 
combination treatment at mainland China sites according to the eligibility criteria and 
procedures described in Section 5.2.  Per Exclusion Criteria Section 5.2.2 strong and 
moderate CYP3A inhibitors/inducers will be excluded from 7 days prior to the initiation 
of study treatment through the entire dose limiting toxicity (DLT)/safety evaluation 
period.  The first 9 evaluable Chinese AML subjects for DLT will be treated in an 
open-label manner.  When the first 9 evaluable subjects are enrolled, consenting and 
enrollment of Chinese AML subjects will be temporarily suspended until the safety and 
PK evaluation is performed on these subjects.
●
A subject who has interrupted venetoclax dosing during the DLT evaluation 
period due to an adverse event that is believed to be possibly or probably 
related to venetoclax will be included in the safety evaluation.
●
If a subject discontinues the study for any reason other than an adverse event 
possibly or probably related to venetoclax before the DLT evaluation period of 
28 days is complete, the subject will be replaced within the Chinese AML 
safety cohort.
●
The discontinued subject(s) will not be replaced in the main study and will 
follow procedures in the main protocol as outlined in Appendix C for the Final 
Visit and Post-Treatment Follow-Up assessments.
 

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Chinese AML safety cohort will receive the same venetoclax plus azacitidine treatment as 
the subjects in Arm A of the Phase 3 study as described in Section 5.1.  The blood 
samples for venetoclax PK evaluation in the safety cohort will be collected according to 
the below schedule.  All other study procedures should be conducted as outlined in 
Appendix C.
●
Cycle 2 Day 4:  PK samples will be collected at 0 (pre-dose), 2, 4, 6, 8 hours 
after venetoclax dosing.
The date and time of the venetoclax doses on Cycle 2 Day 4 will be captured on the 
eCRF.
PK samples should be collected and processed according to the instructions provided in 
the current Study M15-656 laboratory manual.
3.0
Safety Cohort DLT Evaluation
The Chinese AML safety cohort will be monitored for a DLT evaluation period, defined 
as 4 weeks (during Cycle 1, for 28 days) beginning the first day of venetoclax dosing, to 
assess the safety of the 400 mg QD dose in combination with azacitidine.
Safety data collected during the DLT evaluation period will be reviewed and the incidence 
of DLTs will be assessed based on the following definitions:
Definition of DLT:
●
Subjects who entered the study with Grade 3 or 4 anemia, neutropenia, or 
thrombocytopenia will be un-evaluable for hematology related DLT. 
●
Any of the following events, which are considered possibly or probably related 
to the administration of venetoclax, will be considered a dose limiting toxicity 
(DLT):
○
Grade 3, 4, or 5 anemia, neutropenia or thrombocytopenia with a 
hypocellular bone marrow and no greater than or equal to 5% marrow 
blasts lasting for 42 days or more.
 

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●
NCI CTCAE Grade ≥ 3 non-hematological toxicity with the exception of 
nausea, vomiting, anorexia, diarrhea, constipation and electrolyte abnormality 
which are controlled with an intervention and which the investigator judges 
not to be a DLT.
Any DLT will require an interruption and possible discontinuation of venetoclax or 
azacitidine.  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 
seventh day of the dose interruption, the event should not be designated as a DLT.
If DLTs occur in < 50% of the Chinese AML safety cohort subjects (e.g., DLT incidence 
≤ 4 out of 9 subjects), venetoclax dosing can be considered to be tolerable in Chinese 
AML subjects and the enrollment of Chinese AML subjects will resume into the study.  If 
the same DLTs occur in ≥ 50% of the Chinese AML safety cohort subjects (e.g., DLT 
incidence ≥ 5 out of 9 subjects), enrollment of Chinese AML subjects will NOT resume 
and the study will not continue with enrollment in mainland China.  If different DLTs 
occur in ≥ 50% of the Chinese AML safety cohort subjects (e.g., DLT incidence ≥ 5 out 
of 9 subjects), the data will be reviewed by AbbVie and the investigator(s) to determine if 
additional subjects should be enrolled into the Chinese AML safety cohort or if the study 
should not continue with enrollment in mainland China.
●
If the same DLT occurs in 4 subjects before 9 Chinese AML subjects have 
been enrolled, additional Chinese AML subjects will NOT be enrolled and the 
study will not continue with enrollment in mainland China.
●
If 2 or 3 different DLTs occur in 4 subjects before 9 Chinese AML subjects 
have been enrolled, or in the opinion of AbbVie and/or the investigator(s) the 
event is considered clinically significant, the following actions may be taken 
by AbbVie (in consultation with the investigator[s]):
○
Enrollment of Chinese AML subjects will be suspended and the data will 
be reviewed by AbbVie and the investigator(s) to determine if additional 
subjects should be enrolled into the AML safety cohort or if the study 
should not continue with enrollment in mainland China.
 

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○
If the DLT is considered an unmanageable and lethal event, enrollment of 
Chinese AML subjects will not be continued in mainland China.  If the 
DLT is not considered an unmanageable and lethal event, enrollment of 
Chinese AML subjects should be continued until 9 subjects are enrolled in 
the cohort.
For subjects who experience a DLT, the toxicity should be managed according to 
Section 6.1.7 and the subjects should continue on study until discontinuation criteria, as 
outlined in Section 5.4.1, are met.  Post-treatment assessments will be collected via eCRF 
at monthly intervals (or as requested by sponsor to support data analysis) for all Chinese 
AML safety cohort subjects after the last study visit until the endpoint of death or until the 
subject has become lost-to follow-up or until study termination by AbbVie.
4.0
Planned PK Analysis
Values for the pharmacokinetic parameters of venetoclax including maximum observed 
plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the area under the plasma 
concentration-time curve (AUC) will be determined using noncompartmental methods if 
the data warrants.  Additional parameters may be calculated if useful in the interpretation 
of the data.  Additional analyses may be performed if useful in the interpretation of the 
data.
 

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Appendix L.
Venetoclax and Azacitidine Dose Modifications
Treatment Cycle
Efficacy Assessments
Hematology Results
Action
Modifications
After Cycle 1a
CRi
MLFS
Incomplete count recovery
Delay 
upcoming 
cycle
Venetoclax/placebo should be interrupted to allow for ANC recovery 
from Day 29 until ANC ≥ 500/μL OR up to 14 days (until Day 42), 
whichever is earlier.  If there is no recovery by Day 42, discussion 
between the PI and the TA MD is required
Cycle 2 administration of azacitidine will also be delayed until ANC 
≥ 500/μL OR up to 14 days (venetoclax/placebo and azacitidine will 
resume on the same day after the interruption)
After Cycle 2
CR, CRi
MLFS
at end of Cycle 1 or 
subsequent cycles
New Grade 4 Neutropenia after 
recovery lasting for more than 1 week 
(unless due to the underlying disease 
e.g., relapse)
Delay 
upcoming 
cycle
Venetoclax/placebo dosing should be interrupted once cycle is
completed until ANC is ≥ 500/μL OR up to 14 days (unless 
medically necessary to study drug interrupt within cycle)
After Cycle 3
CR
CRi
MLFS
at end of Cycle 1 or 
subsequent cycles
Subjects requiring interruption or delay 
of study drug administration for 
cytopenias 
(neutropenia/thrombocytopenia)
Reduce 
venetoclax/ 
placebo 
duration
Venetoclax/placebo should be administered for 21 days out of 
28 days during each of the subsequent cycles and the treatment cycle 
should also be delayed to allow for count recovery until ANC 
≥500/μL and/or platelet count ≥ 50 × 103/μL or for up to 14 days.
 

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Treatment Cycle
Efficacy Assessments
Hematology Results
Action
Modifications
After Cycle 4
(azacitidine dose 
reduction)
Applicable after 
reduced 
venetoclax/placebo 
duration
CR
CRi
MLFS
at end of Cycle 1 or 
subsequent cycles
Hematologic recovery (ANC 
≥1,000/µL OR PLT ≥ 100,000/µL) is 
achieved within 14 days after 
completion of the cycle
No 
azacitidine 
reduction
The duration of venetoclax/placebo is reduced to 21 days of the 
cycle.
Hematologic recovery (ANC OR PLT) 
with more than 25% increase above the 
nadir (mid-cycle) is not seen by Day 28.
Monitor 
counts and 
reassess
Reassess counts every 7 days or as often as needed.  Refer to the line 
below.
If a 25% increase in nadir (mid-cycle) 
has not been achieved within 14 days 
after the completion of a cycle
Reduce 
azacitidine 
dose
If recovery is not achieved within 21 Days, azacitidine dose 
adjustment on next cycle can be made as follows:

Bone Marrow Cellularity* (15 – 50%):  50%

Bone Marrow Cellularity* (< 15%):  33%
*
For Bone Marrow Cellularity, use the most recent value.
a.
RD or PR:  there is no delay of next cycle.  Once these subjects achieve CRi/MLFS, follow steps above in the sequence listed.  CRi (ANC < 1,000/µL or PLT < 100,000/µL); 
MLFS (ANC < 1,000/µL & PLT < 100,000/µL).
 

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Appendix M.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.2  Synopsis
Subsection Number of Subjects to be Enrolled:
Previously read:
Approximately 400 to 412 subjects
Has been changed to read:
Approximately 400 to 412 subjects (Enrollment completed with 443 subjects)
Section 1.2  Synopsis
Subsection Methodology:
Heading "Cycle Length – 28 Days"
Add:  new second sentence
Subjects will continue to receive the assigned study treatment without cross over until 
treatment discontinuation.
Section 1.2  Synopsis
Subsection Methodology:
Heading "Cycle Length – 28 Days"
Add:  new last sentence
Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will 
no longer be performed by the IRC.
Section 3.2  Benefits and Risks
Add:  new fourth paragraph
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  No additional risk to study subjects is 
 

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anticipated with the use of venetoclax/placebo in this population with limited treatment 
options for their underlying AML.
Section 5.1  Overall Study Design and Plan:  Description
Second paragraph previously read:
Approximately 400 subjects will be randomized to meet scientific and regulatory 
objectives without enrolling an undue number of subjects in alignment with ethical 
considerations.  Therefore, if the target number of subjects has been enrolled, there is a 
possibility that additional subjects in screening will not be enrolled.
Has been changed to read:
443 subjects were randomized to meet scientific and regulatory objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.
Section 5.1.3  Treatment Period
Subsection Cycle Length – 28 Days
First paragraph
Add:  new second sentence
Subjects will continue to receive the assigned study treatment without cross over until 
treatment discontinuation.
Section 5.1.3  Treatment Period
Subsection Cycle Length – 28 Days
Last paragraph
Add:  new fourth sentence
Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will 
no longer be performed by the IRC.
Section 5.1.4  Post Treatment Follow-Up
First and second paragraph previously read:
Survival information and post treatment follow up (i.e., the date and cause of death, all 
post treatment cancer therapies including stem cell transplantation, regimens, dates of 
 

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initiation and completion, etc.) will be collected (e.g., via telephone calls and/or clinical 
visits) every 2 months after the last study visit for a period of 2 years after the last subject 
has been enrolled into the study.
Post treatment follow up for subjects who discontinue study drugs for reasons other than 
disease progression, hematology and disease assessments data will be collected every 
2 months for 1 year after the last subject has been enrolled into the study.
Has been changed to read:
Survival information and post treatment follow up (i.e., the date and cause of death, all 
post treatment cancer therapies including stem cell transplantation, regimens, dates of 
initiation and completion, etc.) will be collected (e.g., via telephone calls and/or clinical 
visits) every 2 months after the last study visit or as needed to allow for more frequent 
survival analyses until end of study, defined as last subject last visit.
Post treatment follow up for subjects who discontinue study drugs for reasons other than 
disease progression, hematology and disease assessments data will be collected every 
2 months or as needed to allow for more frequent survival analyses until end of study, 
defined as last subject last visit.
Section 5.3.1.1  Study Procedures
Add:  new second paragraph
Study visits may be impacted by changes in local regulations due to the COVID-19 
pandemic.  Every effort should be made to ensure the safety of subjects, while 
maintaining the integrity of the study.  If visits cannot be conducted onsite due to travel 
restrictions or other pandemic-related reasons, follow the details in this section and 
Appendix C on how to proceed.
 

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Section 5.3.1.1  Study Procedures
Subsection Informed Consent
Due to the COVID-19 pandemic, modifications to the protocol procedures may be 
necessary.  Subjects should be informed of the changes to the conduct of the study 
relevant to their participation (e.g., cancellation of visits, change in laboratory testing site, 
drug delivery method, etc.).  Documentation of this notification and verbal consent should 
be maintained at the site.  A signed and dated informed consent form should be obtained 
from the subject afterwards as soon as possible.
Section 5.3.1.1  Study Procedures
Subsection Patient-Reported Outcome (PRO) Variables
Add:  new last paragraph
Due to the COVID-19 pandemic and any local restrictions, sites may administer PRO 
instruments over the phone as needed.  Delegated site staff may read the PRO questions 
and response options to the subject and record the subject's responses.  Sites may send the 
questionnaires (email or hard copy) to the subjects to allow them to read/understand the 
questions and responses when the subject is providing responses over the phone.  The date 
and time of PRO data collection should be recorded along with who collected the 
information.  Subject responses will be entered into Trialmax, the Electronic Patient 
Reported Outcome (ePRO) system, instead of the electronic tablet, by the site staff.  
IRB/EC approval should be obtained prior to completing PROs by phone interview.
Section 5.3.1.1  Study Procedures
Subsection Bone Marrow Aspirate and Biopsy For Disease Assessment
Last paragraph, fourth sentence previously read:
The corresponding local laboratory pathology/bone marrow report should be sent to the 
central laboratory for each local disease assessment which is conducted.
Has been changed to read:
The corresponding local laboratory pathology/bone marrow report should be sent to the 
central laboratory for each local disease assessment.
 

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Section 5.3.1.1  Study Procedures
Subsection Bone Marrow Aspirate and Biopsy For Disease Assessment
Last paragraph
Add:  new last sentence
Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will 
no longer be performed by the IRC.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Add:  new second and third paragraph
Due to travel restrictions and other changes in local regulations in light of the COVID-19 
pandemic, if possible, arrange for subjects to have laboratory work done at a local lab, 
hospital, or other facility.  Local lab results should be obtained along with reference 
ranges and kept within the subjects' source documentation.  Local lab results should be 
reviewed by the investigator as soon as possible for subject safety and to determine the 
next cycle of study treatment.
If laboratory samples cannot be obtained, study drug administration cannot be continued 
unless the investigator has reviewed all prior laboratory results as close to the planned 
new cycle of study treatment, confirms and discusses with the subject that there is no 
safety concern for the subject to continue use of the study drug in the absence of current 
labs.  The subject should be scheduled for laboratory draws as soon as feasible within 
approximately 3 days from the scheduled visit.
Section 5.4.1  Discontinuation of Individual Subjects from Treatment
First paragraph, last sentence previously read:
In addition, the investigator will discontinue a subject from the study at any time if the 
investigator considers it necessary for any reason including:
Has been changed to read:
In addition, the investigator will discontinue a subject from the study treatment at any 
time if the investigator considers it necessary for any reason including:
 

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Section 5.4.1  Discontinuation of Individual Subjects from Treatment
Add:  new fifth paragraph
Due to the COVID-19 pandemic, temporary study drug interruption may occur.  Refer to 
the Section 5.3.1.1, Study Procedures and Appendix C for details on how to handle study 
activities/procedures accordingly.  Study drug interruptions due to COVID-19 restrictions 
should be captured in EDC.
Section 5.5.5.1  Blinding of Investigational Product
First paragraph previously read:
All AbbVie personnel with direct oversight conduct and management of the trial (with the 
exception of AbbVie Clinical Drug Supply Management and AbbVie Pharmacovigilance 
Team), the Investigator, the study site personnel, and the subject will remain blinded to 
each subject's treatment with venetoclax/placebo throughout the course of the study.
Has been changed to read:
The Investigator, the study site personnel, AbbVie site monitoring team and the subject 
will remain blinded to each subject's treatment with venetoclax/placebo throughout the 
course of the study.  Limited AbbVie personnel have been unblinded following the 
planned second interim analysis, including AbbVie Clinical Drug Supply Management 
and AbbVie Pharmacovigilance Team.
Section 5.5.5.1  Blinding of Investigational Product
Add:  new last paragraph
If the blind is broken for a subject currently on study treatment by the investigator, that 
subject would need to be discontinued from study treatment and post treatment or survival 
follow-up would commence.
Section 5.5.6  Treatment Compliance
Add:  new third and fourth paragraph
Depending on local regulations due to the COVID-19 pandemic, provision of study drug 
for direct-to-patient (DTP) and direct-frompatient (DFP) transfer will be available upon 
 

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request.  AbbVie has contracted with a third party vendor, Marken, for sites to ship study 
drug DTP and DFP.  Sites will be able to use Marken and/or another local courier for drug 
shipment, as needed.  If necessary, notify AbbVie if DTP and/or DFP shipping will be 
used.
Sites will be responsible to:
●
Meet IRB/IEC reporting requirements and submit the booking form (which 
will be provided) to the local IRB/IEC, as applicable.
●
Submit the booking form at least 72 business hours before the drug needs to be 
picked up.
●
Discuss the DTP and DFP process with the subject including:
○
Obtain consent to provide delivery information to Marken and/or local 
courier and document this in the source.
○
Obtain results of required safety procedures (e.g., urine pregnancy testing) 
before registering subject dispensation of study drug in IRT.
○
Confirm the subject will be available to accept delivery.
○
Confirm the subject will maintain the drug containers, as well as any 
unused drug for return to site.
●
Follow up with the subject after shipment is received.
●
Retain documentation of the shipment for IP accountability and monitoring.
Section 6.1  Medical Complaints
First paragraph, third sentence previously read:
For serious adverse events considered as having "no reasonable possibility" of being 
associated with study drug, the investigator will provide an Other cause of the event.
Has been changed to read:
For serious adverse events considered as having "no reasonable possibility" of being 
associated with study drug, the investigator will provide an "Other cause of the event."
 

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Section 6.1.1.1  Adverse Events
Add:  new last paragraph
COVID-19 infections should be captured as adverse events.  If the event meets the criteria
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol.
Section 6.1.5  Adverse Event Reporting
Add:  new last paragraph
Due to the COVID-19 pandemic and evolving local regulations, urgent safety measures 
may need to be employed in order to protect participating subjects from any immediate 
hazard.  Such events and measures should be reported to the sponsor emergency medical 
contact listed above immediately.
Section 6.1.7  Toxicity Management
Subsection Management of Cytopenias and Infections
Third paragraph, last sentence previously read:
Treatment cycle should also be delayed to allow for count recovery until ANC ≥ 500/μL 
or platelet count ≥ 50 × 103/μL or for up to 14 days whichever occurs earlier.
Has been changed to read:
Treatment cycle should also be delayed to allow for count recovery until ANC ≥ 500/μL 
and/or platelet count ≥ 50 × 103/μL or for up to 14 days whichever occurs earlier.
 

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should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard.
Section 10.2  Case Report Forms
Fifth paragraph, second sentence previously read:
These data are being collected with an Electronic Patient Reported Outcome (ePRO) 
system called Trialmax, provided by the technology vendor CRF Health of Plymouth 
Meeting, PA, USA.
Has been changed to read:
These data are being collected with an Electronic Patient Reported Outcome (ePRO) 
system called Trialmax, provided by the technology vendor Signant Health of Blue Bell, 
PA, USA.
Section 10.2  Case Report Forms
Sixth paragraph, first sentence previously read:
The subject will be entering the data on an electronic device; the data will be uploaded to 
a server.
Has been changed to read:
The subject will be entering the data on an electronic device, except in cases where 
completion by interview is necessary due to COVID-19 restrictions; the data will be 
uploaded to a server.
Section 10.2  Case Report Forms
Last paragraph, first sentence previously read:
The ePRO data will be collected electronically via a tablet device into which the patient 
will directly enter the required pieces of information.
 

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Has been changed to read:
The ePRO data will be collected electronically via a tablet device into which the patient 
will directly enter the required pieces of information, except in cases where completion by 
interview is necessary due to COVID-19 restrictions.
Section 10.2  Case Report Forms
Last paragraph
Add:  new fifth and sixth sentence
If the PRO data is collected by phone interview, the delegated staff will enter the subject's 
responses into TrialMax.  Completion of PROs by phone interview should be approved by 
the site's IRB/EC.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Director
Statistics
Study Project Manager II
Clinical
Group Medical Director
Therapeutic Area
Principal Bioanalytical Investigator
Bioanalysis
Senior Medical Director
Therapeutic Area
Director
Clinical Pharmacology and 
Pharmacometrics
 

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Has been changed to read:
Name
Title
Functional Area
Director
Statistics
Director
Statistics
Head of Statistics, Late Oncology
Statistics
Study Project Manager II
Clinical
Executive Medical Director
Therapeutic Area
Principal Bioanalytical Investigator
Bioanalysis
Senior Medical Director
Therapeutic Area
Director
Clinical Pharmacology and 
Pharmacometrics
 

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Appendix C.  Study Activities
Previously read:
Procedures
Screeninga
Day 
–1
Cycle 1
Day 1 
of 
Each 
Cycle
Day 1 
of 
Every 
Other 
Cycle
End of 
Cycle 1 
and Every 
3 Cycles 
Thereafter
Final 
Visitb
30-Day 
Safety 
F/U
PT 
F/Uc
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Days 
8, 
15, 
22
Informed Consent
Xd
Medical/Oncology History 
Assessment
X
Xe
AE/Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytogenetic Testingf
X
Tumor Lysis Syndrome 
Prophylaxisg
X
X
X
X
X
X
Physical Exam (including 
weight)h
Xi
X
Xj
X
X
X
Vital Signsh
X
X
X
X
X
Pregnancy Test
X
Xs
X
ECOG Performance Statush
X
X
X
X
X
Hematology/Chemistryk
X
X
X
X
X
Xt
X
X
X
X
Coagulationh
X
X
X
Urinalysish
X
X
X
12-lead ECG
X
Xl
Pulmonary Function Testm
X
 

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Procedures
Screeninga
Day 
–1
Cycle 1
Day 1 
of 
Each 
Cycle
Day 1 
of 
Every 
Other 
Cycle
End of 
Cycle 1 
and Every 
3 Cycles 
Thereafter
Final 
Visitb
30-Day 
Safety 
F/U
PT 
F/Uc
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Days 
8, 
15, 
22
MUGA (preferred)/2D 
Echocardiogram w/Dopplerm
X
Disease Assessments
X
X
X
X
Bone Marrow Aspirate and 
Biopsy for Local Disease 
Assessment
Xn
Xn,o,p
X
PROMIS Cancer Fatigue SF 7aq
X
X
X
EORTC QLQ-C30q
X
X
X
EQ-5D-5Lq
X
X
X
Dispense Venetoclax/Placebo
X
Dispense Subject 
Calendar/Diary
Xr
X
Collect venetoclax and Subject 
Calendar/Diary
X
X
Administer Azacitidine*
X
X
X
X
X
X
X
Survival Assessments
X
F/U = Follow-Up; PT = Post Treatment
a.
Screening procedures must be performed within 21 days prior to initial study drug administration.
b.
Final Visit procedures should be performed when a subject discontinues from the study.
c.
Post Treatment and survival visits will be performed every 2 months after the last study visit for a period of 2 years after the last subject has been enrolled into the study.
d.
Obtain informed consent prior to performing any screening or study-specific procedures.
 

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e.
On Cycle 1 Day 1, additional medical history that is observed after signing of the informed consent but prior to initial venetoclax or azacitidine administration and not 
considered related to study-required procedures will be recorded in the subject's medical history.
f.
Cytogenetic testing should be performed if not completed within 1 month prior to Screening.
g.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to refer to Section 6.1.7.1, 
Management of Tumor Lysis Syndrome and Appendix I – Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome 
(TLS) for further information.
h.
For all study visits after Cycle 3, physical examination, vital signs, ECOG performance status, coagulation and urinalysis may be performed within 3 days before the 
scheduled visit.  Under certain circumstances, these assessments may be performed within 3 days after the scheduled visit with discussion and approval by the AbbVie 
medical monitor TA MD.  PROs can be completed within 3 days prior to Cycle 1 Day 1 Visit.
i.
Height will be measured only at Screening.
j.
All subjects must have Physical exam prior to discharge from the hospital.  Subjects should remain hospitalized no less than 24 hours post dosing of their designated 
venetoclax dose.
k.
Only hematology required for disease assessment.  TLS chemistry tests to be drawn (calcium, inorganic phosphorus, potassium, uric acid, and creatinine) on the first day of 
venetoclax/placebo dosing and each day of a new dose at 0 (within 4 hours prior to dosing) and 6 – 8 hours post dose (see Section 6.1.7.1).
l.
Final visit ECG may be obtained within ± 2 days of visit.
m.
Only required if ECHO or MUGA, DLCO or FEV1 is being used to confirm eligibility for subjects ≥ 18 to 74 years of age.
n.
Historical bone marrow aspirates and biopsies assessed locally to confirm the diagnosis could be used as baseline assessment to satisfy eligibility criteria as long as the 
samples were taken within 30 days of first dose.  A bone marrow aspirate and biopsy must be performed for all subjects during screening to collect mandatory samples for 
biomarker assessments.  Bone marrow aspirate and biopsy samples must be collected for all subjects for each of the disease assessments.  Bone marrow core biopsy sample 
collection is considered an optional procedure only for subjects enrolled at sites in countries where an aspirate evaluation by morphologic assessment and flow cytometry is 
considered standard of care.  For these subjects if the aspirate sample is inadequate or unevaluable for disease assessment, repeat bone marrow aspirate and biopsy must be 
performed within 7 days.  The corresponding local laboratory pathology report should be sent to the central laboratory for IRC review for each local disease assessment which 
is conducted.
o.
End of Cycle 1 bone marrow aspirate and biopsy must be performed within ± 3 days of Cycle 1 Day 28.  Assessments should be performed and resulted by Day 31 prior to the 
administration of study drugs for Cycle 2.  Cycle 1 venetoclax/placebo dosing should continue until bone marrow aspirate result is available.  For subjects who require a delay 
in study treatment for blood count recovery after a bone marrow evaluation, hematology values for up to 2 weeks can be used to determine the IWG response.  For all subjects 
a bone marrow aspirate and biopsy must be performed at end of Cycle 4 and every 3 cycles (± 1 week) and upon concern for relapse.  The corresponding local laboratory 
pathology/bone marrow report will be sent to the central laboratory for IRC review.
 

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p.
For subjects with resistant disease at end of Cycle 1 a repeat bone marrow must be performed at the end of Cycle 2 or Cycle 3 based on the hematologic recovery to confirm 
response.
q.
PRO assessments should be completed after a blood sample is taken to confirm the subject is able to receive study treatment at the study visit, but prior to any other 
procedures or clinical assessments and prior to dosing.  PROs can be completed within 3 days prior to Cycle 1 Day 1 dosing.
r.
Diaries will be dispensed upon discharge from the hospital.
s.
Urine pregnancy test must be obtained at Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy results at screening.  Pregnancy test should be repeated 
on Day 1 of each cycle and evaluated prior to dosing.
t.
Additional laboratory assessments may be performed, per investigator discretion, up to 48 hours after reaching final dose if clinically indicated.
*
AZA is administered for 7 days for each cycle starting with Day 1.
Has been changed to read:
Procedures
Screeninga
Day 
–1
Cycle 1
Day 1 
of 
Each 
Cycle
Day 1 
of 
Every 
Other 
Cycle
End of 
Cycle 1 
and Every 
3 Cycles 
Thereafter
Final 
Visitb
30-Day 
Safety 
F/U
PT 
F/Uc
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Days 
8, 
15, 
22
Informed Consent
Xd
Medical/Oncology History 
Assessment
X
Xe
AE/Concomitant Medication 
Assessmentu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytogenetic Testingf
X
Tumor Lysis Syndrome 
Prophylaxisg
X
X
X
X
X
X
Physical Exam (including 
weight)h,u
Xi
X
Xj
X
X
X
Vital Signsh,u
X
X
X
X
X
 

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Procedures
Screeninga
Day 
–1
Cycle 1
Day 1 
of 
Each 
Cycle
Day 1 
of 
Every 
Other 
Cycle
End of 
Cycle 1 
and Every 
3 Cycles 
Thereafter
Final 
Visitb
30-Day 
Safety 
F/U
PT 
F/Uc
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Days 
8, 
15, 
22
Pregnancy Testu
X
Xs
X
ECOG Performance Statush,u
X
X
X
X
X
Hematology/Chemistryk,u
X
X
X
X
X
Xt
X
X
X
X
Coagulationh
X
X
X
Urinalysish
X
X
X
12-lead ECG
X
Xl
Pulmonary Function Testm
X
MUGA (preferred)/2D 
Echocardiogram w/Dopplerm
X
Disease Assessments
X
X
X
X
Bone Marrow Aspirate and 
Biopsy for Local Disease 
Assessment
Xn
Xn,o,p
X
PROMIS Cancer Fatigue SF 
7aq,v
X
X
X
EORTC QLQ-C30q,v
X
X
X
EQ-5D-5Lq,v
X
X
X
Dispense Venetoclax/Placebow
X
Dispense Subject 
Calendar/Diary
Xr
X
Collect venetoclax and Subject 
Calendar/Diary
X
X
 

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Procedures
Screeninga
Day 
–1
Cycle 1
Day 1 
of 
Each 
Cycle
Day 1 
of 
Every 
Other 
Cycle
End of 
Cycle 1 
and Every 
3 Cycles 
Thereafter
Final 
Visitb
30-Day 
Safety 
F/U
PT 
F/Uc
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Days 
8, 
15, 
22
Administer Azacitidineu,*
X
X
X
X
X
X
X
Survival Assessments
X
F/U = Follow-Up; PT = Post Treatment
a.
Screening procedures must be performed within 21 days prior to initial study drug administration.
b.
Final Visit procedures should be performed when a subject discontinues from the study.
c.
Post Treatment and survival visits will be performed every 2 months after the last study visit or as needed until end of study, defined as last subject last visit.
d.
Obtain informed consent prior to performing any screening or study-specific procedures.
e.
On Cycle 1 Day 1, additional medical history that is observed after signing of the informed consent but prior to initial venetoclax or azacitidine administration and not 
considered related to study-required procedures will be recorded in the subject's medical history.
f.
Cytogenetic testing should be performed if not completed within 1 month prior to Screening.
g.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to refer to Section 6.1.7.1, 
Management of Tumor Lysis Syndrome and Appendix I – Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome 
(TLS) for further information.
h.
For all study visits after Cycle 3, physical examination, vital signs, ECOG performance status, coagulation and urinalysis may be performed within 3 days before the 
scheduled visit.  Under certain circumstances, these assessments may be performed within 3 days after the scheduled visit with discussion and approval by the AbbVie 
medical monitor TA MD.  PROs can be completed within 3 days prior to Cycle 1 Day 1 Visit.
i.
Height will be measured only at Screening.
j.
All subjects must have Physical exam prior to discharge from the hospital.  Subjects should remain hospitalized no less than 24 hours post dosing of their designated 
venetoclax dose.
k.
Only hematology required for disease assessment.  TLS chemistry tests to be drawn (calcium, inorganic phosphorus, potassium, uric acid, and creatinine) on the first day of
venetoclax/placebo dosing and each day of a new dose at 0 (within 4 hours prior to dosing) and 6 – 8 hours post dose (see Section 6.1.7.1).
l.
Final visit ECG may be obtained within ± 2 days of visit.
m.
Only required if ECHO or MUGA, DLCO or FEV1 is being used to confirm eligibility for subjects ≥ 18 to 74 years of age.
 

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n.
Historical bone marrow aspirates and biopsies assessed locally to confirm the diagnosis could be used as baseline assessment to satisfy eligibility criteria as long as the 
samples were taken within 30 days prior to randomization.  A bone marrow aspirate and biopsy must be performed for all subjects during screening to collect mandatory 
samples for biomarker assessments.  Bone marrow aspirate and biopsy samples must be collected for all subjects for each of the disease assessments.  Bone marrow core 
biopsy sample collection is considered an optional procedure only for subjects enrolled at sites in countries where an aspirate evaluation by morphologic assessment and flow 
cytometry is considered standard of care.  For these subjects if the aspirate sample is inadequate or unevaluable for disease assessment, repeat bone marrow aspirate and 
biopsy must be performed within 7 days.  The corresponding local laboratory pathology report should be sent to the central laboratory for IRC review for each local disease 
assessment.  Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will no longer be performed by the IRC.
o.
End of Cycle 1 bone marrow aspirate and biopsy must be performed within ± 3 days of Cycle 1 Day 28.  Assessments should be performed and resulted by Day 31 prior to the 
administration of study drugs for Cycle 2.  Cycle 1 venetoclax/placebo dosing should continue until bone marrow aspirate result is available.  For subjects who require a delay 
in study treatment for blood count recovery after a bone marrow evaluation, hematology values for up to 2 weeks can be used to determine the IWG response.  For all subjects 
a bone marrow aspirate and biopsy must be performed at end of Cycle 4 and every 3 cycles (± 1 week) and upon concern for relapse.  The corresponding local laboratory 
pathology/bone marrow report will be sent to the central laboratory for IRC review Upon unblinding at the 75% Overall Survival Interim Analysis, disease assessments will 
no longer be performed by the IRC.
p.
For subjects with resistant disease at end of Cycle 1 a repeat bone marrow must be performed at the end of Cycle 2 or Cycle 3 based on the hematologic recovery to confirm 
response.
q.
PRO assessments should be completed after a blood sample is taken to confirm the subject is able to receive study treatment at the study visit, but prior to any other 
procedures or clinical assessments and prior to dosing.  PROs can be completed within 3 days prior to Cycle 1 Day 1 dosing.
r.
Diaries will be dispensed upon discharge from the hospital.
s.
Urine pregnancy test must be obtained at Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy results at screening.  Pregnancy test should be repeated
on Day 1 of each cycle and evaluated prior to dosing.
t.
Additional laboratory assessments may be performed, per investigator discretion, up to 48 hours after reaching final dose if clinically indicated.
u.
Procedure may be performed in the subject's home or local hospital/clinic by adequately trained personnel if required due to COVID-19 restrictions.
v.
ePROs may be performed virtually/phone interview by delegated personnel only if required due to COVID-19 restrictions.
w.
Venetoclax/placebo may be shipped directly to a subject's home only if required due to COVID-19 restrictions.
*
AZA is administered for 7 days for each cycle starting with Day 1.
 

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Appendix L.  Venetoclax and Azacitidine Dose Modifications
Treatment Cycle "After Cycle 3," column "Modifications" previously read:
Venetoclax/placebo should be administered for 21 days out of 28 days during each of the 
subsequent cycles and the treatment cycle should also be delayed to allow for count 
recovery until ANC ≥ 500/μL or platelet count ≥ 50 × 103/μL or for up to 14 days.
Has been changed to read:
Venetoclax/placebo should be administered for 21 days out of 28 days during each of the 
subsequent cycles and the treatment cycle should also be delayed to allow for count 
recovery until ANC ≥ 500/μL and/or platelet count ≥ 50 × 103/μL or for up to 14 days.