Clinical trial NCT03069352
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Acute Myeloid Leukemia Leukemia Treatment naïve Venetoclax Cytarabine
Sponsor: AbbVie
Start date: 2017-05-23; Completion date: 2025-07-23
Enrollment: 211 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate if venetoclax when co administered with low-dose cytarabine (LDAC) improves overall survival (OS) versus LDAC and placebo, in treatment-naïve patients with acute myeloid leukemia (AML).

Detailed description:
Acute myeloid leukemia (AML) is an aggressive and rare cancer of myeloid cells (a white blood cell responsible for fighting infections). Successful treatment of AML is dependent on what subtype of AML the patient has, and the age of the patient when diagnosed.

Venetoclax is an experimental drug that kills cancer cells by blocking a protein (part of a cell) that allows cancer cells to stay alive. This study is designed to see if adding venetoclax to cytarabine works better than cytarabine on its own.

This is a Phase 3, randomized, double-blind (treatment unknown to patients and doctors), placebo-controlled, multicenter study in patients with AML who are 18 or more years old and have not been treated before. Patients who take part in this study should not be suitable for intensive induction chemotherapy (usual starting treatment). Abbvie is funding this study which will take place at approximately 125 hospitals globally. In this study, 2/3 of patients will receive venetoclax every day with cytarabine and the remaining 1/3 will receive placebo (dummy) tablets with cytarabine.

Participants will continue to have study visits and receive treatment for as long as they are having a clinical benefit. The effect of the treatment on AML will be checked by taking blood, bone marrow, scans, measuring side effects and by completing health questionnaires. Blood and bone marrow tests will be completed to see why some people respond better than others.

Arms: arm 1: Venetoclax 600 mg orally every day (QD) plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle. arm 2: Matching placebo to venetoclax orally QD plus LDAC 20 mg/m² subcutaneously on Days 1 to 10 of each 28-day cycle.
Interventions: intervention 1: Placebo intervention 2: Venetoclax intervention 3: Cytarabine
Intervention descriptions: intervention 1: tablet intervention 2: tablet intervention 3: Subcutaneous injection

Protocol documents:
Prot_001.pdf: 
Venetoclax (ABT-199)
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1.0
Title Page
Clinical Study Protocol M16-043
A Randomized, Double-Blind, Placebo Controlled 
Phase 3 Study of Venetoclax Co-Administered with 
Low Dose Cytarabine Versus Low Dose Cytarabine 
in Treatment Naïve Patients with Acute Myeloid 
Leukemia Who Are Ineligible for Intensive 
Chemotherapy
Incorporating Administrative Change 1, 2, and 3 and 
Amendments 1, 1.01 (China Only), 1.02 (UK Only), 2, 
3, 4, and 5
AbbVie Investigational
  Product:
Venetoclax (ABT-199/GDC-0199)
Date:
29 May 2019
Development Phase:
3
Study Design:
This is a randomized, double-blind, placebo controlled, multicenter 
trial evaluating efficacy and safety of venetoclax co-administered with 
low dose cytarabine versus low dose cytarabine co-administered with 
placebo in treatment naïve patients with Acute Myeloid Leukemia who 
are ineligible for intensive chemotherapy.  
EudraCT Number:
2016-003900-30
Investigator:
Investigator information on file at AbbVie
Sponsor:
AbbVie Inc.
Sponsor/Emergency
  Contact:
* 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.
NCT03069352


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1.1
Protocol Amendment: Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
10 November 2016
Amendment 1
17 February 2017
Amendment 1.01 (China Only)
29 March 2017
Amendment 1.02 (UK Only)
02 August 2017
Amendment 2
06 October 2017
Administrative Change 1
09 October 2017
Administrative Change 2
10 November 2017
Amendment 3
22 June 2018
Administrative Change 3
11 September 2018
Amendment 4
29 November 2018
The purpose of this amendment is to:
●
Update Section 5.4.1, Discontinuation of Individual Subjects from Treatment 
and Section 5.5.5.1, Blinding of Investigational Product to allow the sponsor to 
unblind subjects' treatment assignments and provide to the investigators 
following the final analysis results.
Rationale:  Final analysis results has been completed and to allow 
investigators to make decisions for their subjects' treatment.
●
Update Synopsis, Section 5.1.3, Treatment Period, Section 5.3.1.1, Study 
Procedures, Section 5.3.1.2, Collection and Handling of Biomarker and 
Exploratory Research Samples (Not Applicable for China), Section 5.3.3, 
Efficacy Variables, Appendix C, Study Activities, and Appendix D, Schedule 
of Biomarker/Pharmacodynamic/Pharmacogenetic Sample collection (Not 
Applicable for China) to remove the requirement of bone marrow collection 
and disease assessments for subjects who are unblinded following the final 
analysis results at the timepoints of every 3 cycles starting at the end of 
Cycle 4 and collection after CRi to confirm CR.  The requirement to obtain 
2 consecutive CR or CRi results is also removed.  Bone marrows should be 


Venetoclax (ABT-199)
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collected upon suspicion of relapse or progressive disease, at Final Visit, and 
per institutional standard of care.  For inadequate or un-evaluable samples, a 
repeat sample can be performed per institutional standard of care instead of 
within 7 days. 
Rationale:  Final efficacy analysis has been performed and no further formal 
efficacy analyses are planned, however sites can still follow subjects per 
institutional standard of care regarding safety and efficacy.
●
Update Section 5.3.1.1, Study Procedures and Appendix C, Study Activities to 
state that redacted local laboratory pathology reports should be sent to the 
central lab until otherwise instructed by the Sponsor.
Rationale:  Final efficacy analysis has been performed and no further formal 
efficacy analyses are planned.
●
Update Section 5.3.1.2, Collection and Handling of Biomarker and 
Exploratory Research Samples (Not Applicable for China) and Appendix D, 
Schedule of Biomarker/Pharmacodynamic/Pharmacogenetic Sample collection 
(Not Applicable for China) to remove the collection requirements of plasma 
and bone marrow aspirate biomarkers for subjects who are unblinded 
following the final analysis results at the timepoints of every 3 cycles starting 
at the end of Cycle 4.  Bone marrow aspirates completed as per institutional 
standard of care should continue to be split for these assessments.
Rationale:  Final efficacy analysis has been performed and no further formal 
efficacy analyses are planned, but exploratory analyses may be continued.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix L.


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-043
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:  29 May 2019
Protocol Title:  A Randomized, Double-Blind, Placebo Controlled Phase 3 Study of Venetoclax Co-
Administered with Low Dose Cytarabine Versus Low Dose Cytarabine in Treatment Naïve Patients with 
Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy
Objectives:  
Primary Objective:
•
To evaluate if venetoclax when co-administered with low dose cytarabine (LDAC) improves 
overall survival (OS) versus LDAC and placebo, in treatment naïve subjects with acute myeloid 
leukemia (AML).
Secondary Objectives:
•
To evaluate if venetoclax when co-administered with LDAC improves composite complete 
remission rate (complete remission + complete remission with incomplete blood count 
recovery, CR + CRi).
•
To evaluate if venetoclax when co-administered with LDAC improves complete remission and 
complete remission with partial hematologic recovery rate (CR + CRh).
•
To evaluate if venetoclax when co-administered with LDAC improves the proportion of 
subjects achieving a composite CR (CR + CRi) by the initiation of Cycle 2.
•
To evaluate if venetoclax when co-administered with LDAC improves complete remission rate 
(CR).
•
To evaluate if venetoclax when co-administered with LDAC reduces fatigue based on patient 
reported outcome (PRO) assessment of the Patient Reported Outcomes Measurement 
Information System (PROMIS), and Fatigue Short Form (SF) 7a. 
•
To evaluate if venetoclax when co-administered with LDAC improves subjects Global Health 
Status/Quality of Life (GHS/QoL) based on the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30).
•
To evaluate if venetoclax when co-administered with LDAC improves event-free survival 
(EFS).
•
To evaluate if venetoclax when co-administered with LDAC improves the transfusion 
independence rates.
•
To evaluate if venetoclax when co-administered with LDAC improves the proportion of 
subjects achieving complete remission and complete remission with partial hematologic 
recovery (CR + CRh) by the initiation of Cycle 2.
•
To evaluate if venetoclax when co-administered with LDAC improves the minimal residual 
disease (MRD) response rate.


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Objectives (Continued):  
•
To evaluate if venetoclax when co-administered with LDAC improves the response rates and 
overall survival in molecular subgroups (e.g., IDH1/2, FLT3).
Exploratory Objectives:
•
Exploration of biomarkers predictive of venetoclax activity and duration of response may be 
performed.  These analyses may be part of a multi-study assessment to compare responses to 
the therapies and/or disease state.  Potential analysis may include, but will not be limited to:
o
To evaluate BCL-2 expression and outcome measures of overall survival and complete 
remission rate
•
To evaluate the impact of venetoclax based on remaining subscales/items from the EORTC 
QLQ-C30 and EQ-5D-5L.
Investigators:  Investigator information on file at AbbVie.
Study Sites:  Approximately 125 sites
Study Population:  Patients with treatment-naïve AML who are ineligible for intensive induction 
chemotherapy due to comorbidities.
Number of Subjects to be Enrolled:  Approximately 210 subjects
Methodology:  
This is a randomized, double-blind, placebo controlled, multicenter trial.
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 LDAC
•
Arm B:  Placebo plus LDAC 
Study Treatment
All subjects in Arm A will receive venetoclax orally once daily (QD) plus LDAC (QD) beginning on 
Cycle 1 Day 1.  Venetoclax should be taken within 30 minutes of food intake, preferably breakfast.  
Subjects will receive LDAC on Days 1 – 10 of each cycle.
All subjects in Arm B will receive placebo orally (QD) plus LDAC (QD) beginning on Cycle 1 Day 1.  
Placebo should be taken within 30 minutes of food intake.  Subjects will receive LDAC on Days 1 – 10 
of each cycle.
Cycle Length – 28 Days
•
Venetoclax 600 milligram (mg) or Placebo Daily on Days 1 – 28
•
LDAC 20 mg/m2 Subcutaneous (SC) Daily on Days 1 – 10


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Methodology (Continued):  
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).  Accordingly, subjects may, in rare occasions, continue 
treatment after documented disease progression if the investigator believes it is in the best interest of the 
patient.  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.  PRO measures should generally be completed prior 
to other procedures, clinical assessments, and the administration of study treatment; however, they may 
be administered following confirmation that the subject is able to receive study treatment at the visit.  
Disease assessments by IWG criteria will be performed at end of Cycle 1 (± 3 days).  Subjects with 
resistant disease at the end of Cycle 1 will repeat assessment at the end of Cycle 2 or Cycle 3 based on 
the hematologic recovery to confirm a suspected response, and every 3 cycles thereafter starting at the 
end of Cycle 4 and continuing until disease progression per the modified IWG criteria until 2 successive 
disease assessments result in CR or CRi, or the subject withdraws consent.  For subjects achieving 2 
successive disease assessments that result in CR or CRi, disease assessments consist of laboratory and 
physical examination, bone marrow evaluation required upon concern for relapse.  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.  Disease assessments should also occur at the Final Visit and any other 
time the patient features suggest relapse or progressive disease.  For subjects who are unblinded 
following the final analysis results, bone marrow collection every 3 cycles starting at the end of Cycle 4 
and bone marrow collection after CRi to confirm CR are not required.  Bone marrow collection until 
2 successive disease assessments resulting in CR or CRi is not required.  Bone marrow collection can be 
completed as per institutional standard of care.  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.
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 (bone marrow samples and peripheral blasts used for AML diagnosis can be 
collected within 30 days prior to randomization).
1.
Subject must have histological confirmation of AML by WHO criteria, be ineligible for intensive 
induction chemotherapy and either be:
•
≥ 75 years of age 
OR


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
•
≥ 18 to 74 years of age and fulfill at least one criteria associated with lack of fitness for 
intensive induction chemotherapy:
o
Eastern Cooperative Oncology Group (ECOG) Performance status of 2 – 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
o
Other comorbidity that the physician judges to be incompatible with conventional 
intensive chemotherapy which must be reviewed and approved by the study medical 
monitor before study enrollment
2.
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 between 18 to 74 years of age
3.
Subject must have a projected life expectancy of at least 12 weeks.
4.
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.
5.
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*
o
Subjects who are < 75 years of age may have bilirubin of ≤ 3.0 × ULN
*
Unless considered to be due to leukemic organ involvement.
6.
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
•
A Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified 
method of birth control starting at Study Day 1 through at least 180 days after the last dose of 
study drug.
7.
Male subjects who are sexually active, must agree, from Study Day 1 through at least 180 days after 
the last dose of study drug, to practice protocol-specified methods of contraception (Section 5.2.4).  
Male subjects must agree to refrain from sperm donation from initial study drug administration 
through at least 180 days after the last dose of study drug.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
8.
Females 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.
•
Subjects with borderline pregnancy tests at Screening must have a serum pregnancy test 
≥3 days later to document continued lack of a positive result. 
9
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.
Main Exclusion:  
1.
Subject has received any prior treatment for AML with the exception of hydroxyurea, allowed 
through the first cycle of study treatment.  Note:  Prior treatment for Myelodysplastic Syndrome is 
allowed except for use of cytarabine.
2.
Subject had an antecedent myeloproliferative neoplasm (MPN) including myelofibrosis, essential 
thrombocytosis, polycythemia vera, or chronic myelogenous leukemia (CML) with or without 
BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
3.
Subjects that have acute promyelocytic leukemia (APL).
4.
Subject has known CNS involvement with AML.
5.
Subject has known HIV infection (due to potential drug-drug interactions between antiretroviral 
medications and venetoclax).  HIV testing will be performed at Screening, if required per local 
guidelines or institutional standards.
6.
Subject is known to be positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.  
Inactive hepatitis carrier status or low viral hepatitis titer on antivirals (non-exclusionary 
medications) are not excluded.
7.
Subject has received strong or moderate CYP3A inducers 7 days prior to the initiation of study 
treatment.
•
Chinese subjects are excluded from receiving strong and/or moderate CYP3A inhibitors 7 days 
prior to the initiation of study treatment through the end of intensive PK collection (24 hours 
post dose on Cycle 1 Day 10).
8.
Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment
9.
Subject has cardiovascular disability status of New York Heart Association Class > 2.  Class 2 is 
defined as cardiac disease which subjects are comfortable at rest but ordinary physical activity 
results in fatigue, palpitations, dyspnea, or angina pain.
10. 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 LDAC that in the opinion of the investigator would adversely affect his/her 
participating in this study.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
11. Subject has a malabsorption syndrome or other condition that precludes enteral route of 
administration.
12. Subject exhibits evidence of other clinically significant uncontrolled systemic infection requiring 
therapy (viral, bacterial or fungal).
13. Subject has a history of other malignancies 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.
14. Subject has a white blood cell count > 25 × 109/L.  (Note:  Hydroxyurea administration or 
leukapheresis is permitted to meet this criterion).
15. Previous treatment with venetoclax and/or current participation in any other research study with 
investigational products.
Investigational Product:
Venetoclax, 100 mg/50 mg/10 mg tablet
Dose:
600 mg QD
Mode of Administration:
Oral
Reference Therapy:
Placebo (to match venetoclax 100 mg/50 mg/10 mg tablet)
Dose:
Not Applicable
Mode of Administration:
Oral
Reference Therapy:
LDAC
Dose:
20 mg/m2; Days 1 – 10 of all cycles,
Cycle = 28 days QD
Mode of Administration:
Subcutaneous (SC)
Duration of Treatment:  
Subjects will receive venetoclax/placebo/LDAC until documented disease progression per Investigator 
assessment, unacceptable toxicity or intolerance, withdrawal of consent, or the subject meets other 
criteria for discontinuation per study protocol (whichever occurs first).


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Criteria for Evaluation:
Efficacy:
Bone marrow biopsies and aspirates must be performed at screening for all subjects.  Cytogenetic 
assessment will be done at a local lab during screening.  Samples for molecular markers and baseline 
disease assessment for potential MRD evaluation must be collected at screening.  Bone marrow aspirate 
and biopsy must be performed at the end of Cycle 1.  For all subjects a bone marrow aspirate and biopsy 
must be performed at end of Cycle 4 and every 3 cycles (± 1 week) thereafter, however, these collections 
are not required for subjects who are unblinded following the final analysis results.  Bone marrow 
collection can be completed as per institutional standard of care.  Bone marrow aspirate and biopsy 
should also be performed upon concern for relapse or progressive disease and at the Final Visit (if no 
bone marrow was collected within the last 6 – 8 weeks, or if relapse or progression of disease has 
already been confirmed).  Bone marrow will be obtained until two successive samples indicate CR or 
CRi, however, these collections are not required for subjects who are unblinded following the final 
analysis results.  For subjects achieving 2 successive disease assessments that result in CR or CRi, 
disease assessments consist of laboratory and physical examination, bone marrow evaluation required 
upon concern for relapse.  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, however, these collections are not required for subjects who are 
unblinded following the final analysis results.  Subjects will be assessed for response rate according to 
modified IWG criteria for AML (Cheson et al J Clin Oncol 2003).  Progressive disease is defined per 
European LeukemiaNet (ELN) 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 the next cycle of study treatment for blood count 
recovery after a bone marrow evaluation, hematology values up to pre-dose labs from Day 1 of the next 
cycle or 2 weeks from the bone marrow if there is no additional dosing can be used to determine the 
IWG response.
All subjects who complete 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 discontinue study treatment 
prior to completion of Cycle 1 will be deemed non-evaluable for response assessment.


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Criteria for Evaluation (Continued):
Efficacy (Continued):
CR:
No morphologic evidence of AML and 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 (1,000/μL) or 
thrombocytopenia < 105/μL (100,000/μL).  If all criteria for CR are met except for RBC 
transfusion independence, this also fulfills CRi criteria.
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 leukemia cells, absence of 
extramedullary disease, and absolute neutrophils < 103/μL (1,000/μL) and 
thrombocytopenia < 105/μL (100,000/μL).
RD:
Failure to achieve CR, CRi, PR; 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 [50000/μL] non-transfused); or
•
50% increase in peripheral blasts (WBC × % blasts) to > 25 × 109/L (> 25000/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 investigator's assessment using the modified IWG response criteria, complete remission 
with partial hematologic recovery (CRh) will be derived by the sponsor for each subject's assessments.
Pharmacokinetic:
Sparse pharmacokinetic (PK) samples will be collected and analyzed for venetoclax and cytarabine.  
Venetoclax results may be incorporated into a population PK analysis to estimate parameters such as 
clearance.


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Criteria for Evaluation (Continued):
Safety:
Adverse event (AE) monitoring, vital signs, physical examination, and laboratory values will be 
assessed.  Any additional clinically significant cardiac, pulmonary, or radiographic testing will be 
assessed and recorded.  Note:  All subjects will be hospitalized during the venetoclax ramp-up period 
during Cycle 1 (i.e., Day 1 through Day 5).  Subjects will remain in the hospital for at least for 24 hours 
after reaching the final dose of venetoclax or longer as needed for bone marrow recovery and 
management of disease complications during the escalation of venetoclax dose from 100 to 600 mg.
Patient-Reported Outcomes:
PROs will be evaluated using the following measures at specific time points throughout the study:  
PROMIS Fatigue SF 7a, EORTC QLQ-C30, EQ-5D-5L, and the GHS/QoL.
Statistical Methods:
Efficacy:
Primary 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.
Secondary Efficacy Endpoints:
Composite Complete Remission Rate:
The proportion of subjects with complete remission or complete remission with incomplete blood count 
recovery (CR + CRi) will be calculated based on the modified IWG criteria for AML.
Complete Remission and Complete Remission With Partial Hematologic Recovery:
The proportion of subjects with complete remission or complete remission with partial hematologic 
recovery (CR + CRh) will be calculated.
Composite Complete Remission Rate by Initiation of Cycle 2:
The proportion of subjects with complete remission or complete remission with incomplete blood count 
recovery (CR + CRi) by the initiation of Cycle 2 will be calculated based on the modified IWG criteria 
for AML.
Complete Remission Rate:
The proportion of subjects with complete remission (CR) will be calculated based on the modified IWG 
criteria for AML.
Patient-Reported Outcomes:
Fatigue as assessed by the PROMIS 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.


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Statistical Methods (Continued):
Event-Free Survival (EFS):
EFS will be defined as the number of days from randomization to the date of progressive disease, relapse 
of 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.
Post Baseline RBC Transfusion Independence:
Post baseline red blood cell (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 plus 30 days.  All randomized subjects will be included to 
estimate the post-baseline transfusion independence rates.
Post Baseline Platelets Transfusion Independence:
Post baseline Platelets transfusion independence rate will be calculated as the portion of subjects who 
achieved Platelets transfusion independence post baseline.  The Platelets Transfusion independence is 
defined as a period of at least 56 days with no Platelets transfusion between the first dose of study drug 
and the last dose of study drug plus 30 days.  All randomized subjects will be included to estimate the 
post-baseline transfusion independence rates.
The Rate of Conversion (RBC):
The rate of conversion will be calculated as proportion of subjects being post-baseline RBC 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.
Complete Remission and Complete Remission With Partial Hematologic Recovery by Initiation of 
Cycle 2:
The proportion of subjects with complete remission or complete remission with partial hematologic 
recovery (CR + CRh) by the initiation of Cycle 2 will be calculated.
Minimal Residual Disease (MRD) Response Rate:
The proportion of subjects achieving CR + CRi and MRD or CR + CRh and MRD response status may 
be calculated.  
CR + CRi Rate, CR + CRh rate, and OS in molecular subgroups:
CR + CRi rate, CR + CRh rate, and OS will be evaluated for molecular subgroups (e.g., FLT3, IDH1/2 
etc.).
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., characterization of Bcl-2 family members and MRD status) may be assessed to compare patient 
responses in the two arms in order to identify markers that may be predictive of venetoclax activity.


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Statistical Methods (Continued):
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.
Exploratory Endpoints:
Patient-Reported Outcomes:
Additional subscales and items from 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 Fatigue SF 7a, EORTC QLQ-C30, and 
EQ-5D-5L.
Sample Size:
The primary endpoint of the study is overall survival.  The sample size calculation is based on the 
following assumptions:
•
Median OS of 6 months for placebo plus LDAC arm
•
Median OS of 11 months for venetoclax plus LDAC arm (hazard ratio of 0.545)
•
Interim analysis of OS at 75% of death events with O'Brien-Fleming boundary
•
2:1 randomization ratio to venetoclax plus LDAC, and placebo plus LDAC
With the above assumptions, a total of 133 death events will provide 90% power to detect a statistically 
significant difference between treatment arms at an alpha level of 0.05.  A total of approximately 
210 subjects (140 in the venetoclax plus LDAC arm and 70 in the placebo plus LDAC arm) will be 
randomized into the study to obtain the 133 death events.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AE
Adverse Event
ALL
Acute Lymphocytic Leukemia
ALT
Alanine Aminotransferase (also called SGPT)
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
APL
Acute Promyelocytic Leukemia
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
ASD
Amorphous solid dispersion
AST
Aspartate aminotransferase (also called SGOT)
BCL-2 
B-Cell Lymphoma 2 
BUN
Blood Urea Nitrogen
CHF
Congestive Heart Failure
CLL
Chronic Lymphocytic Leukemia
CMH
Cochran Mantel Haenszel
CML
Chronic Myelogenous Leukemia
Cm
Centimeter
CNS
Central Nervous System
CR
Complete Remission
CRh
Complete Remission with Partial Hematologic Recovery
CRi
Complete Remission with Incomplete Blood Count Recovery
CS
Clinically Significant
CT
Computed Tomography
CTC
Common Toxicity Criteria
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
CYP2D6
Cytochrome P450 2D6


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CYP3A4
Cytochrome P450 3A4
DDI
Drug-Drug Interaction
DLBCL
Diffuse Large B-cell Lymphoma
DLCO
Diffusing Capacity of the Lung for Carbon Monoxide
DLT
Dose-Limiting Toxicity
DOR
Duration of Response
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EFS
Event Free Survival
ELN
European LeukemiaNet
EMA
European Medicines Agency
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Core
EQ-5D-5L
EuroQol EQ-5D-5L
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 Second
FFPE
Formalin Fixed Paraffin Embedded
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GHS/QoL
Global Health Status/Quality of Life
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
HMA
Hypomethylating Agent
HNSTD
Highest Non-severely Toxic Dose
HR
Hematologic Response
Hr
Hour
HRQoL
Health-related quality of life
HSCT
Hematopoietic Stem Cell Transplantation
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee


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IHC
Immunohistochemistry
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IV
Intravenous
IDMC
Independent Data Monitoring Committee
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
IWG
International Working Group
Kg
Kilogram
LDAC
Low Dose Cytarabine
LDH
Lactate Dehydrogenase
MCHC
Mean Corpuscular Hemoglobin Concentration
MCL
Mantle Cell Lymphoma
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
μg
Microgram
Mg
Milligram
mL
Milliliter
μM
Micromolar
MLFS
Morphologic Leukemia Free State
MM
Multiple Myeloma
MPN
Myeloproliferative Neoplasm
MPV
Mean Platelet Volume
MR
Morphologic Relapse
MRD
Minimal Residual Disease
mRNA
Messenger Ribonucleic Acid
MTD
Maximum Tolerated Dose
NCCN
National Cooperative Cancer Network
NCI
National Cancer Institute
NHL
Non-Hodgkin's Lymphoma
nM
Nanomolar
ORR
Overall Response Rate
OS
Overall Survival


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PD
Progressive Disease
PFS
Progression Free Survival
PHI
Protected Health Information
PK
Pharmacokinetic
PO
Per Os Orally
PR
Partial Remission
PRO
Patient Reported Outcome
PROMIS
Patient Reported Outcomes Measurement Information System
PT
Prothrombin Time
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
RS
Richter's Syndrome
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SGOT
Serum Glutamic-oxaloacetic Transaminase (also called AST)
SGPT
Serum Glutamic-pyruvic Transaminase (also called ALT)
SLE
Systemic Lupus Erythematosus
SLL
Small Lymphocytic Lymphoma
SmPC
Summary of Product Characteristics
STD
Severely Toxic Dose
TEAE
Treatment Emergent Adverse Event
TLS
Tumor Lysis Syndrome
TTP
Time to Progression
ULN
Upper Limit of Normal
USPI
United States Prescribing Information
VAS
Visual Analog Scale
WBC
White Blood Cell
WHO
World Health Organization


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WOCBP
Women of Child Bearing Potential
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..............................................................................32
3.2
Benefits and Risks....................................................................................32
4.0
Study Objectives....................................................................33
4.1
Primary Objective ....................................................................................33
4.2
Secondary Objectives...............................................................................33
4.3
Exploratory Objectives ............................................................................34
5.0
Investigational Plan...............................................................34
5.1
Overall Study Design and Plan:  Description ..........................................34
5.1.1
Screening..................................................................................................35
5.1.2
Rescreening..............................................................................................35
5.1.3
Treatment Period......................................................................................36
5.1.4
Post Treatment Follow-Up.......................................................................38
5.2
Selection of Study Population..................................................................39
5.2.1
Inclusion Criteria .....................................................................................40
5.2.2
Exclusion Criteria ....................................................................................42
5.2.3
Prior and Concomitant Therapy...............................................................45
5.2.4
Contraception Recommendations ............................................................47
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Biomarkers, 
Pharmacogenetic and Safety Assessments/Variables ..............................49
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................49
5.3.1.1
Study Procedures .....................................................................................49
5.3.1.2
Collection and Handling of Biomarker and Exploratory Research 
Samples (Not Applicable for China)........................................................64
5.3.1.3
Samples for Optional Pharmacogenetic Exploratory Research 
(Not Applicable for China) ......................................................................67


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5.3.1.4
Meals and Dietary Requirements.............................................................67
5.3.2
Drug Concentration Measurements .........................................................68
5.3.2.1
Collection of Samples for Analysis .........................................................68
5.3.2.2
Handling/Processing of Samples .............................................................68
5.3.2.3
Disposition of Samples ............................................................................68
5.3.2.4
Measurement Methods.............................................................................69
5.3.3
Efficacy Variables....................................................................................69
5.3.4
Safety Variables.......................................................................................71
5.3.5
Pharmacokinetic Variables ......................................................................71
5.3.6
Biomarker and Optional Exploratory Research Variables (Not 
Applicable for China) ..............................................................................72
5.4
Removal of Subjects from Therapy or Assessment.................................73
5.4.1
Discontinuation of Individual Subjects from Treatment..........................73
5.4.2
Discontinuation of Entire Study...............................................................75
5.5
Treatments................................................................................................76
5.5.1
Treatments Administered.........................................................................76
5.5.2
Identity of Investigational Products.........................................................76
5.5.2.1
Packaging and Labeling...........................................................................77
5.5.2.2
Storage and Disposition of Study Drug(s) ...............................................77
5.5.3
Method of Assigning Subjects to Treatment Groups...............................78
5.5.4
Selection and Timing of Dose for Each Subject......................................78
5.5.5
Blinding....................................................................................................78
5.5.5.1
Blinding of Investigational Product.........................................................78
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ....................................................................................................79
5.5.6
Treatment Compliance.............................................................................79
5.5.7
Drug Accountability.................................................................................80
5.6
Discussion and Justification of Study Design..........................................80
5.6.1
Discussion of Study Design and Choice of Control Groups....................80
5.6.2
Appropriateness of Measurements...........................................................81
5.6.3
Suitability of Subject Population .............................................................81
5.6.4
Selection of Doses in the Study ...............................................................82


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5.6.4.1
Dose Adjustments for Venetoclax Upon Co-Administration with 
Anti-Fungal Agents..................................................................................83
6.0
Complaints .............................................................................84
6.1
Medical Complaints.................................................................................84
6.1.1
Definitions................................................................................................85
6.1.1.1
Adverse Events ........................................................................................85
6.1.1.2
Serious Adverse Events ...........................................................................86
6.1.1.3
Adverse Events Expected due to Study Related Endpoints.....................87
6.1.1.3.1
Deaths ......................................................................................................87
6.1.2
Adverse Event Severity............................................................................88
6.1.3
Relationship to Study Drug......................................................................89
6.1.4
Adverse Event Collection Period.............................................................90
6.1.5
Adverse Event Reporting.........................................................................91
6.1.6
Pregnancy.................................................................................................93
6.1.7
Toxicity Management ..............................................................................93
6.1.7.1
Management of Tumor Lysis Syndrome (TLS).......................................96
6.2
Product Complaint ...................................................................................97
6.2.1
Definition .................................................................................................97
6.2.2
Reporting..................................................................................................98
7.0
Protocol Deviations................................................................98
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................100
8.1
Statistical and Analytical Plans..............................................................100
8.1.1
Definition for Analysis Populations.......................................................100
8.1.2
Baseline Characteristics.........................................................................100
8.1.3
Pharmacokinetics ...................................................................................100
8.1.4
Efficacy Endpoints.................................................................................100
8.1.4.1
Primary Efficacy Endpoint ....................................................................100
8.1.4.2
Secondary Efficacy Endpoints...............................................................101
8.1.4.3
Exploratory Efficacy Endpoint ..............................................................104
8.1.5
Efficacy Endpoints per Independent Review Committee......................105
8.1.6
Timing of Efficacy Analyses .................................................................105
8.1.7
Safety .....................................................................................................105


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8.1.7.1
Study Drug Exposure.............................................................................105
8.1.7.2
Adverse Events ......................................................................................105
8.1.7.3
Serious Adverse Events .........................................................................106
8.1.7.4
Deaths ....................................................................................................106
8.1.7.5
Laboratory Tests and Vital Signs...........................................................106
8.2
Determination of Sample Size ...............................................................107
9.0
Ethics.....................................................................................107
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................107
9.2
Ethical Conduct of the Study .................................................................108
9.3
Subject Information and Consent...........................................................108
9.3.1
Informed Consent Form and Explanatory Material ...............................109
9.3.2
Revision of the Consent Form and Explanatory Material .....................109
10.0
Source Documents and Case Report Form 
Completion ...........................................................................110
10.1
Source Documents .................................................................................110
10.2
Case Report Forms.................................................................................110
11.0
Data Quality Assurance ......................................................112
12.0
Use of Information...............................................................113
13.0
Completion of the Study .....................................................114
14.0
Investigator's Agreement....................................................116
15.0
Reference List ......................................................................117
List of Tables
Table 1.
Excluded Food/Medications ....................................................................46
Table 2.
Dose Modifications for Venetoclax:  Moderate and Strong 
CYP3A Inhibitor Use...............................................................................47
Table 3.
Patient-Reported Outcome Assessments .................................................53
Table 4.
Clinical Laboratory Tests.........................................................................60
Table 5.
Identity of Investigational Product...........................................................76
Table 6.
Predicted Geometric Mean (and 90% CI) AUC24 Exposures of 
Venetoclax When Administered Alone and in Presence of Strong 
CYP3A Inhibitor......................................................................................84


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Table 7.
Dose Reduction Guidelines for Management of Persistent 
Neutropenia or Thrombocytopenia ..........................................................94
List of Figures
Figure 1.
Dosing Schematic ....................................................................................37
Figure 2.
Adverse Event Collection ........................................................................90
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................121
Appendix B.
List of Protocol Signatories....................................................................123
Appendix C.
Study Activities......................................................................................124
Appendix D.
Schedule of Biomarker/Pharmacodynamic/Pharmacogenetic 
Sample Collection (Not Applicable for China) .....................................128
Appendix E.
Schedule of Blood Collection for Venetoclax and LDAC Assay 
(Pharmacokinetic Sampling)..................................................................129
Appendix F.
NCCN Risk Categorization:  Guidelines for AML Version 2.2016......130
Appendix G.
Tumor Lysis Syndrome Classification...................................................131
Appendix H.
Cell Lines Table.....................................................................................132
Appendix I.
Sample List of Excluded and Cautionary Medication ...........................134
Appendix J.
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (TLS) ..............136
Appendix K.
Japan Specific Information ....................................................................139
Appendix L.
Protocol Amendment:  List of Changes.................................................141


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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 myelogenous leukemia 
(AML).1
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 (Appendix H).  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 (Appendix H) 
  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 
has been studied in 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 


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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 
(Appendix H).  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.  
 
 
 
 
 
.  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.  
 


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Venetoclax Preclinical Toxicology
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the current Investigator's Brochure.9
Acute Myeloid Leukemia
Acute myeloid leukemia is characterized by the clonal expansion of myeloid blasts in the 
bone marrow, peripheral blood and extramedullary tissues which disrupts normal 
haematopoiesis.  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 the World Health Organization (WHO) as a myeloid 
neoplasm with 20% or more blasts in the peripheral blood or bone marrow.10  It is the 
most common form of acute leukemia in adults with an estimated 19,950 new cases and 
10,430 deaths in 2016 in the United States.11  The incidence is approximately 36,000 in 
the US alone.  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.
For many patients with AML, initial treatment recommendations are a function of the 
patient's ability to receive and benefit from anthracycline-containing induction 
chemotherapy.  Most younger adults diagnosed with AML are considered fit enough to 
receive an anthracycline-containing induction chemotherapy regimen.  For fit patents, 
standard treatment for newly diagnosed AML consists of remission induction therapy 
with cytarabine and an anthracycline, usually daunorubicin or idarubicin (7 + 3), followed 
by consolidation therapy.  
Though some older patients receive anthracycline-containing induction chemotherapy, 
most older patients do not receive intensive induction chemotherapy but rather receive 
less-intensive therapy such as LDAC or a hypomethylating therapy.  Indeed, AML in 
older patients is often a biologically and clinically distinct disease with a diminished 
response to chemotherapy, low remission rates, and short disease-free/overall survival.  In 
older patients higher proportions of unfavorable cytogenetics, higher frequency of 


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antecedent hematologic disorders or prior therapy for previous malignancies, and more 
frequent expression of the multidrug resistance phenotype contribute to 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 often associated with AML therapy.  Though less 
common than for older patients, some younger patients may also be unfit to receive 
anthracycline-containing chemotherapy for reasons such as severe cardiac, pulmonary, 
renal, or other comorbidities.  Several studies have also demonstrated the benefits of 
active therapy over supportive care only, with respect to survival and quality of life, 
suggesting that treatment should be offered to nearly all patients diagnosed with AML. 
Venetoclax Clinical Data
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.


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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 (LDAC) (Study M14-387).  
To 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.12  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., one 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 blood count recovery (CRi) in 4 (13%) subjects.  


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Anti-leukemic activity was observed in and additional 7 (22%) subjects, with ≥ 50% bone 
marrow reduction with hematologic recovery in 4 of these subjects. 
Overview of Ongoing Phase 1b Study (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 
three 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.
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 one 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 three dose levels, was 62.2% (28 of 45), with CR in 12 (26.7%), CRi in 
15 (33.3%), and PR in one (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 


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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.
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 without a prior MPN treated with 
a 600 mg venentoclax target dose and LDAC as of 31 March 2016 (ASH abstract 2016).  
The CR + CRi rate was 78%.
Of the 25 subjects enrolled across all doses at the 28 November 2015 data cut, 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%); 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 one 
subject each.  Fatal adverse events occurred in 5 (20.0%) subjects:  2 events of malignant 
neoplasm progression and one 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.9


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3.1
Differences Statement
This is the first randomized study comparing venetoclax in combination with LDAC 
versus placebo in combination with LDAC in subjects with AML who are treatment naïve 
and are considered ineligible for treatment with an anthracycline-containing induction 
regimen due to age, co-morbidity or other risk factors.
3.2
Benefits and Risks
Initial studies from the Acute Leukemia Group B, over 40 years ago, reported that 15% –
20% of patients with AML receiving LDAC at dose of 10 – 30 mg/m2 achieved a CR.13  
Subsequently, a meta-analysis including 293 previously untreated patients with newly 
diagnosed acute non-lymphocytic leukemia reported a CR rate of 32% with LDAC.14  
More recently, a large, international trial for newly diagnosed patients using modern and 
more sensitive methods to determine the depth of clinical response reported a CR + CRi 
rate of approximately 11% for the patients randomized to LDAC.15
There are currently no therapies approved by the US FDA specifically for elderly patients 
with AML who are ineligible to receive intensive chemotherapy, though low-intensity 
therapies including LDAC, azacitdine, or decitabine are relatively common treatment 
approaches worldwide.
As detailed in Section 3.0, preliminary efficacy and safety results of venetoclax in 
combination with LDAC are favorable and support further evaluation in treatment naive 
AML patients who are not eligible to receive intensive induction chemotherapy. 
Rapid AML cell death in patients can result in risk of tumor lysis syndrome (TLS) during 
initial dosing.  Because of the known background risk of TLS in AML patients, 
venetoclax dose will be gradually increased to the final dose during initiation of study 
treatment in Cycle 1 combined with of LDAC to optimize disease control and enable 
close subject monitoring. 
For additional safety and efficacy data please refer to the current Investigator Brochure.


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4.0
Study Objectives
4.1
Primary Objective
The primary objective is: 
●
To evaluate if venetoclax when co-administered with LDAC improves overall 
survival (OS) versus LDAC and placebo, in treatment naïve subjects with 
acute myeloid leukemia (AML).
4.2
Secondary Objectives
The secondary objectives are:
●
To evaluate if venetoclax when co-administered with LDAC improves 
composite complete remission rate (complete remission + complete remission 
with incomplete blood count recovery, CR + CRi).
●
To evaluate if venetoclax when co-administered with LDAC improves 
complete remission and complete remission with partial hematologic recovery 
rate (CR + CRh).
●
To evaluate if venetoclax when co-administered with LDAC improves the 
proportion of subjects achieving composite CR (CR + CRi) by the initiation of 
Cycle 2.
●
To evaluate if venetoclax when co-administered with LDAC improves 
complete remission rate (CR).
●
To evaluate if venetoclax when co-administered with LDAC reduces fatigue 
based on patient reported outcome (PRO) assessments (Patient Reported 
Outcomes Measurement Information System (PROMIS), and Fatigue Short 
Form (SF) 7a).
●
To evaluate if venetoclax when co-administered with LDAC improves subjects 
Global Health Status/Quality of Life (GHS/QoL) based on the European 
Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core (EORTC QLQ-C30).


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●
To evaluate if venetoclax when co-administered with LDAC improves event-
free survival (EFS).
●
To evaluate if venetoclax when co-administered with LDAC improves the 
transfusion independence rates.
●
To evaluate if venetoclax when co-administered with LDAC improves the 
proportion of subjects achieving complete remission and complete remission 
with partial hematologic recovery (CR + CRh) by the initiation of Cycle 2.
●
To evaluate if venetoclax when co-administered with LDAC improves the 
MRD response rate.
●
To evaluate if venetoclax when co-administered with LDAC improves the 
response rates and overall survival in molecular subgroups (e.g., IDH1/2, 
FLT3).
4.3
Exploratory Objectives
The exploratory objectives are: 
●
Exploration of biomarkers predictive of venetoclax activity and duration of 
response may be performed.  These analyses may be 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:
○
To evaluate BCL-2 expression and outcome measures of overall survival 
and complete remission rate.
●
To evaluate the impact of venetoclax based 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 study of 
venetoclax co-administered with LDAC versus LDAC in treatment naïve patients with 
acute myeloid leukemia who are ineligible for intensive induction chemotherapy 


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sponsored by AbbVie.  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 600 mg orally QD on Days 1 – 28 plus LDAC 20 mg/m2
SC QD on Days 1 – 10
●
Arm B:  Placebo 600 mg orally QD on Days 1 – 28 plus LDAC 20 mg/m2 SC 
QD on Days 1 – 10 
Approximately 210 subjects will be randomized to meet scientific and regulatory 
objectives without enrolling an undue number of subjects in alignment with ethical 
considerations.
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 and Section 5.2.2
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, with the exception 
of bone marrow samples and peripheral blasts used for AML diagnosis which can be 
collected within 30 days prior to randomization.  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
Rescreening may be performed upon investigator discussion with the AbbVie Medical 
Monitor and subsequent agreement.


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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 (venetoclax/placebo and LDAC) on Cycle 1 
Day 1.  Subjects in Arm A will receive venetoclax orally QD plus LDAC SC 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 LDAC SC QD beginning on Cycle 1 Day 1.  Placebo should be taken 
within 30 minutes after completion of a meal (preferably breakfast).  Subjects will receive 
LDAC on Days 1 – 10 of each cycle beginning on Cycle 1.
Dosing Schedule Overview – for Venetoclax/Placebo and LDAC
Venetoclax or placebo for venetoclax will be administered with a 4-day ramp up 
beginning with 100 mg dose on Day 1, 200 mg dose on Day 2, 400 mg dose on Day 3 and 
600 mg dose on Day 4 of Cycle 1.  Subjects will be hospitalized during the venetoclax 
ramp-up period during Cycle 1 (i.e., Day 1 through Day 5).  Subjects will remain in the 
hospital for at least 24 hours after reaching the final dose of venetoclax on Day 4.  
Venetoclax or placebo for venetoclax will be continued at 600 mg daily thereafter.  LDAC 
will be administered SC daily per protocol at 20 mg/m2 daily on Days 1 – 10 of each 
cycle.


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Figure 1.
Dosing Schematic
Cycle Length – 28 Days
●
Venetoclax 600 mg or Placebo 600 mg QD on Days 1 – 28
●
LDAC 20 mg/m2 SC Daily on Days 1 – 10
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).  Study 
treatments may be administered in the hospital, clinic or in a non-hospital/clinic 
environment (home), as allowed per local regulations.
On cycles where LDAC is administered in a non-hospital/clinic environment (home), 
subjects will still visit the site within 3 days prior of Day 1 to have procedures completed 
so that subjects can be medically monitored for safety.  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.  PRO measures scheduled for administration 
should generally be completed prior to other procedures, clinical assessments, and the 


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administration of study treatment; however, they may be administered following 
confirmation that the subject is able to receive study treatment at the visit.  
Disease assessments by the modified IWG criteria will be performed at end of Cycle 1 
(± 3 days), subjects with resistant disease at end of Cycle 1 will repeat assessment at the 
end of Cycle 2 or Cycle 3 based on the hematologic recovery to confirm a suspected 
response, and every 3 cycles starting at the end of Cycle 4 and continuing until disease 
progression as defined per ELN16 criteria thereafter until 2 successive disease assessments 
result in CR or CRi, or the subject withdraws consent.  For subjects achieving 2 
successive disease assessments that result in CR or CRi, disease assessments consist of 
laboratory and physical examination, bone marrow evaluation required upon concern for 
relapse. For subjects who are unblinded following the final analysis results, bone marrow 
collections every 3 cycles starting at the end of Cycle 4 and bone marrow collection after 
CRi to confirm CR are not required. Bone marrow collection until 2 successive disease 
assessments resulting in CR or CRi is not required for these unblinded subjects. Bone 
marrow collection can be completed as per institutional standard of care.  In addition to 
being reviewed by investigators, in conjunction with their hematopathologists, all 
pertinent information for disease assessment will be reviewed by an Independent Review 
Committee (IRC) to provide response assessment.  Interpretations of the central 
hematopathologist from the IRC will not be shared with sites.  A charter will outline the 
review process for the IRC's determination of response.  An Independent Data Monitoring 
Committee (IDMC) 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
After study treatment has ended and subjects have completed their Final Visit, subjects 
will be followed for overall survival, progressive disease and post-therapy disease status 
(if applicable).  Survival information and post treatment follow up (i.e., the date and cause 
of death, all post treatment cancer therapies including transplantation, regimens, dates of 
initiation and completion, etc.) will be collected (e.g., via telephone calls and/or clinical 
visits) every 2 months until the end of the study.  All subjects will be followed for 


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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 
publically available records such as death certificates or funeral notices.
For subjects who had CR, CRi, MLFS, or PR at time of study drug discontinuation, 
hematology and disease assessments data will also be collected every 2 months 
(± 14 days) for 2 years after the last subject has been enrolled into the study.
For subjects who had RD, MR or PD at time of study drug discontinuation, survival 
phone calls will be conducted every 2 months (± 14 days) for 2 years after the last subject 
has been enrolled into the study.
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 
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 anthracycline-containing intensive induction chemotherapy.  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.


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5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria 
within 21 days prior to randomization (bone marrow samples and peripheral blasts used 
for AML diagnosis can be collected within 30 days prior to randomization):
1.
Subject must have histological confirmation of AML by WHO criteria, is ineligible 
for intensive induction chemotherapy and either is:
●
≥ 75 years of age
OR
●
≥ 18 to 74 years of age and fulfill at least one criteria associated with lack of 
fitness for intensive induction chemotherapy:
○
Eastern Cooperative Oncology Group (ECOG) Performance status of 2 – 3
○
Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or 
chronic stable angina
○
DLCO ≤ 65% or FEV1 ≤ 65%
○
Creatinine clearance ≥ 30 mL/min to < 45 ml/min
○
Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN
○
Other comorbidity that the physician judges to be incompatible with 
conventional intensive chemotherapy which must be reviewed and 
approved by the study medical monitor before study enrollment
2.
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 between 18 to 74 years of age
3.
Subject must have a projected life expectancy of at least 12 weeks. 
4.
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


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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)
5.
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*
○
Subjects who are < 75 years of age may have bilirubin of ≤ 3.0 × ULN
*
Unless considered to be due to leukemic organ involvement.
6.
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
●
A Woman of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control starting at Study Day 1 through at least 
180 days after the last dose of study drug.
7.
Male subjects who are sexually active must agree, from Study Day 1 through at 
least 180 days after the last dose of study drug, to practice protocol-specified 


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methods of contraception (Section 5.2.4).  Male subjects must agree to refrain from 
sperm donation from initial study drug administration through at least 180 days 
after the last dose of study drug.
8.
Females 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.
●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result. 
9.
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.
Rationale for Inclusion Criteria
1 – 5
In order to select the appropriate subject population with 
appropriate disease characteristics for evaluation
6 – 8
The impact of venetoclax on pregnancy is unknown
9
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject has received any prior treatment for AML with the exception of 
hydroxyurea, allowed through the first cycle of study treatment.  Note:  Prior 
treatment for Myelodysplastic Syndrome is allowed except for use of cytarabine.


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2.
Subject had an antecedent myeloproliferative neoplasm (MPN) including 
myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic 
myelogenous leukemia (CML) with or without BCR-ABL1 translocation and AML 
with BCR-ABL1 translocation.
3.
Subjects that have acute promyelocytic leukemia (APL).
4.
Subject has known CNS involvement with AML.
5.
Subject has known HIV infection (due to potential drug-drug interactions between 
antiretroviral medications and venetoclax).  HIV testing will be performed at 
Screening, if required per local guidelines or institutional standards.
6.
Subject is known to be positive for hepatitis B virus (HBV), or hepatitis C virus 
(HCV) infection.  Inactive hepatitis carrier status or low viral hepatitis titer on 
antivirals (non-exclusionary medications) are not excluded. 
7.
Subject has received strong or moderate CYP3A inducers 7 days prior to the 
initiation of study treatment.
●
Chinese subjects are excluded from receiving strong and/or moderate CYP3A 
inhibitors 7 days prior to the initiation of study treatment through the end of 
intensive PK collection (24 hours post dose on Cycle 1 Day 10).
8.
Subject has consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Star fruit within 3 days prior to the 
initiation of study treatment. 
9.
Subject has cardiovascular disability status of New York Heart Association 
Class > 2.  Class 2 is defined as cardiac disease which subjects are comfortable at 
rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or 
angina pain.  Class 3 is defined as cardiac disease which subjects are comfortable at 
rest but less than ordinary activity causes fatigue, palpitation, or dyspnea.  Class 4 
is defined as cardiac disease which subjects have an inability to carry on any 
physical activity without discomfort, symptoms of heart failure at rest, and if any 
physical activity is undertaken then discomfort increases.


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10.
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 
LDAC that in the opinion of the investigator would adversely affect his/her 
participating in this study.
11.
Subject has a malabsorption syndrome or other condition that precludes enteral 
route of administration.
12.
Subject exhibits evidence of other clinically significant uncontrolled systemic 
infection requiring therapy (viral, bacterial or fungal).
13.
Subject has a history of other malignancies 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.
14.
Subject has a white blood cell count > 25 × 109/L.  (Note:  Hydroxyurea 
administration or leukapheresis is permitted to meet this criterion).
15.
Previous treatment with venetoclax and/or current participation in any other 
research study with investigational products.
Rationale for Exclusion Criteria
1 – 7 
In order to ensure safety of the subjects throughout the study
8 – 15
In order to avoid bias for the evaluation of efficacy and safety, including 
concomitant use of other medications


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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 Medical Monitor or designee (refer to Section 6.1.5) should be contacted if 
there are any questions regarding prior and concomitant therapies.
Vaccination with a live vaccine should be avoided.  Killed or inactivated vaccines may be 
administered; however the response to such vaccines may be diminished.  General 
guidelines regarding excluded, cautionary and allowed medications are summarized in 
Table 1 and Appendix I.


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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 Drugs
•
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 as described in Table 2.
•
Moderate CYP3A Inducers^
Exclude during ramp-up phase and consider alternative medications.  If subject requires use of 
these medications, use with caution and contact AbbVie Medical Monitor or designee (refer to 
Section 6.1.7) 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 and coumarin derivatives* 
•
P-gp substrates**
•
BCRP substrates
•
OATP1B1/1B3 substrates
•
BCRP inhibitors
^
Chinese subjects are prohibited to take strong CYP3A inhibitors, moderate CYP3A inhibitors and inducers 7 days 
prior to the initiation of study treatment through the end of intensive PK collection (24 hours post dose on Cycle 1 
Day 10).
*
Closely monitor International Normalization 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
Assigned Venetoclax Dose
Modified Dose if 
Co-Administered with a Moderate 
CYP3A or P-gp Inhibitor
Modified Dose if 
Co-Administered with a 
Strong CYP3A Inhibitor
100 mg
50 mg 
10 mg 
200 mg
100 mg 
20 mg 
400 mg
200 mg 
50 mg 
600 mg
300 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 this section of the protocol can be found in Appendix I.  It is not 
possible to produce a comprehensive 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 and notify the AbbVie Medical Monitor and discuss 
the investigator's intended use of these medications with the subject in question and the 
investigator's plans to medically monitor the potential study subject. 
Commonly used anti-infective agents for prophylaxis (including ciprofloxacin and azole 
anti-fungal medications) and calcium channel blockers (diltiazem and verapamil) have 
CYP3A inhibitory properties and dose reductions of venetoclax/placebo are required. 
Steroid therapy during study participation should be limited to lower dose and short 
duration if medically indicated.  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.  


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If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) or a Woman of Childbearing Potential, 
practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 180 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 
180 days after the last dose of study 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 180 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 
(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).


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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 
180 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 
180 days after the last dose of study drug.  Prior to starting treatment, counselling on 
sperm storage will be provided to all eligible male subjects.
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Biomarkers, 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
This study is designed to assess Pharmacokinetic, Biomarker, Exploratory Research, and 
Safety data.  Exploratory efficacy analyses may be performed on all subjects enrolled 
unless otherwise specified and may not be included in the clinical study report.  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.
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.  The highest grade of cytopenias will be recorded in the subject's medical 
history, including any transfusion support and prophylaxis received, regardless if 
screening value indicates a lesser grade.


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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.  
Rescreening may be performed upon investigator discussion with the AbbVie Medical 
Monitor and subsequent agreement.
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.
Medical and Oncologic History
The following will be collected during the Screening Visit:
●
Complete medical history, including documentation of any clinically 
significant medical conditions
●
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.


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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 only be recorded as a serious or non-serious adverse 
event if considered by the Investigator to be causally related to the study-required 
procedures.  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.
Cytogenetic Assessment
Cytogenetic analysis must be performed locally from diagnostic bone marrow (preferred) 
or from peripheral blood if an adequate number of circulating blasts (> 109/L) are present.  
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 
screening bone marrow sample at a laboratory designated by AbbVie.  
Patient-Reported Outcome (PRO) Variables
PRO assessments include PROMIS 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, on Day 1 
of every other cycle throughout the trial, and at the Final Visit per Appendix C.  PRO 
assessments will be self-administered by subjects using the electronic tablets supplied by 


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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 or 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.  
PROMIS Fatigue SF 7a
PROMIS® is a system of highly reliable, precise measures of patient-reported health 
status for physical, mental, and social well-being.17  PROMIS instruments measure 
concepts such as pain, fatigue, physical function, depression, anxiety and social function.  
Fatigue will be assessed using the PROMIS Fatigue SF that has been developed for use in 
oncology populations.18,19  PROMIS 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.20  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 3.21  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) will be 
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.22,23  The EQ-5D-5L has five dimensions:  mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression.  These dimensions are measured on a five-point 
scale:  no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  The scores for the five 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 7.24,25
Table 3.
Patient-Reported Outcome Assessments
Administration Order
Test
Administration Time
1
PROMIS 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
●
Prior to discharge from the hospital after reaching designated cohort dose in 
Cycle 1
●
Day 1 of every cycle
●
Final Visit
●
30-Day Safety Follow-up


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The targeted physical exam includes an assessment of heart, lung, and abdomen, as well 
as any body system, guided by the examiner's observations or subject complaints on new 
or 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 seven 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 Cycle 3 may be performed within 3 days before or after 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 LDAC per Appendix C.  These will be measured at:
●
Screening
●
Cycle 1 Day 1 
●
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.  Vital Signs after Cycle 3 may be performed within 3 days 
before or after the scheduled visit.


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ECOG Performance Status
The ECOG performance status per Appendix C will be assessed at:
●
Screening
●
Cycle 1 Day 1
●
Day 1 of every cycle. 
●
Final Visit
●
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.
ECOG Performance Status after Cycle 3 may be performed within 3 days before or after 
the scheduled visit.
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


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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 (no talking, 
laughing, deep breathing, sleeping or swallowing) 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.
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.


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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 if needed to confirm 
eligibility for subjects ≥ 18 to 74 years of age.  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.
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 Assessments
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 (bone 
marrow collection until two successive samples indicate CR or CRi is not required for 
subjects who are unblinded following the final analysis results):
●
Screening (for baseline Disease Assessment)
●
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.


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●
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.  This is not required for 
subjects who are unblinded following the final analysis results.
●
For all subjects a bone marrow aspirate and biopsy must be performed at end 
of Cycle 4 and every 3 cycles (± 1 week) thereafter.  This is not required for 
subjects who are unblinded following the final analysis results. Bone marrow 
aspirate and/or biopsy can be completed as per institutional standard of care.
●
Upon concern for relapse or progressive disease. 
●
Final Visit (if no BM collected within the last 6 – 8 weeks.  Disease 
assessment is not required if relapse of disease has already been confirmed.)
A bone marrow aspirate and biopsy must be performed for all subjects during screening to 
confirm diagnosis and to collect mandatory samples for mandatory biomarker 
assessments.  Historical bone marrow aspirates and biopsies assessed locally to confirm 
the diagnosis may be used as baseline assessment to satisfy eligibility criteria if they were 
collected as standard of care within 30 days prior to randomization.  During screening, 
after informed consent is signed, bone marrow aspirates and biopsies may be collected to 
confirm the diagnosis to satisfy eligibility criteria.
During screening, after informed consent is signed, a bone marrow aspirate must be 
performed for all subjects to collect samples for mandatory biomarker assessments 
(biomarker collections are not applicable to subjects enrolled in China).  
Bone marrow aspirate and biopsy samples must be collected for all subjects at each of the 
disease assessments.  Bone marrow core biopsy sample collection will be considered an 
optional procedure 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 a bone marrow aspirate sample is inadequate or un-evaluable, a repeat aspirate 
sample and/or biopsy can be performed as per institutional standard of care.  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.  The 


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corresponding protected health information (PHI) redacted local laboratory pathology 
report/bone marrow report should be sent to the central laboratory for each local disease 
assessment which is conducted, until otherwise instructed by the Sponsor.  The local 
laboratory's pathology 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 in the current Study M16-043 
laboratory manual.
Flow cytometry may be used to detect the presence of abnormal cell phenotypes (based on 
the inappropriate expression of myeloid lineage markers).  Minimal residual disease 
(MRD) status may be determined either using the phenotypic markers detected or specific 
mutations identified in the screening sample.  
Note:  For all study visits after Cycle 2 Day 1, bone marrow aspirates and/or biopsies may 
be performed within ± 14 days of the scheduled subsequent cycle and delays, counting 
from the start of the previous cycle.  This may be appropriate for subjects whose platelets 
and neutrophils are continuing to recover from nadir.  
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 a 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 
test results (performed by either urine or serum pregnancy testing),


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●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result.
Day 1 of each additional cycle until all study drug are permanently withdrawn 
(performed by either urine or serum pregnancy testing)
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 hematology, chemistry coagulation, labs and urinalysis listed in Table 4.  These 
data will be used for all data analysis.  The appropriate certifications will be collected 
from the local laboratories.  
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)
Blast count (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not 
acceptable)
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)
Chloride
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)


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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.
●
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 a minimum, at:
●
Screening
●
Cycle 1 Days 1, 2, 3, 4, 5, 6,* 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 before or after 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.
Further, additional hematology and chemistry laboratory assessments will be performed 
based on the clinical indications per institutional guidelines and regional standards 


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between Cycle 1 the beginning of Cycle 2 Day 1 and throughout the study for subjects 
who have not achieved and maintained a CR.
For chemistry labs performed for TLS prophylaxis and monitoring during the dose ramp 
up period in Cycle 1, refer to Section 6.1.7.1, Management of Tumor Lysis Syndrome, 
and Appendix J Recommendations for Initial Management of Electrolyte Abnormalities 
and Prevention of Tumor Lysis Syndrome (TLS) for specific requirements.
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
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 (preferably breakfast).


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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 
once the subject has signed the informed consent and a study-specific procedure has been 
performed (e.g., labs are drawn).  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 5.5.4 and will receive a separate unique 
randomization 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.  Once the screening number is assigned, if the 
subject is not randomized into the study, the reason for screen failure will be documented 
in the source document and will be captured in the IRT and eCRF.  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 kits of venetoclax/placebo to 
be dispensed to a subject.  Prior to each drug dispensation, site personnel must contact the 
IRT for kit number assignment.  Venetoclax/placebo cannot be dispensed without 


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contacting the IRT.  AbbVie or designee (refer to Section 7.0) will provide specific 
instructions on the use of the 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 5.5.2.2.  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 LDAC
The IRT will assign every vial of LDAC which was supplied by AbbVie to be dispensed 
for use by the site.  Prior to each drug dispensation, site personnel must contact the IRT 
for vial number assignment.  AbbVie supplied LDAC cannot be dispensed without 
contacting the IRT.  AbbVie or designee (refer to Section 7.0) will provide specific 
instructions on the use of the IRT.LDAC which is to be supplied locally will be dispensed 
and tracked per the normal practices of those sites.
5.3.1.2
Collection and Handling of Biomarker and Exploratory 
Research Samples (Not Applicable for China)
Mandatory biospecimens (e.g., blood, plasma, bone marrow aspirate, and bone marrow 
core biopsy tissue) will be collected per Appendix D.  Subjects will also have the option 
to provide samples for additional exploratory research.  Subjects may still participate in 
the main study even if they decide not to participate in the optional exploratory research.  
Samples 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).


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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 M16-043 Laboratory Manual.
Blood Collection for Plasma:
Approximately 4 mL or 20 mL of blood will be collected prior to dose at:
●
Screening visit (4 mL)
●
End of Cycle 1 (20 mL)
●
Response assessments:  every 3 cycles after end of Cycle 1 assessment 
(20 mL). For subjects who are unblinded following the final analysis results, 
sample collection every 3 cycles after end of Cycle 1 visit is not required.
●
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 8 mL of the bone marrow aspirate should be collected for biomarker 
assessments to be shipped to the central laboratory.  For subjects, where bone marrow 
aspirates are no longer required for response assessments, the bone marrow biomarker 
samples will also not be collected at those timepoints, but the peripheral blood biomarker 


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samples will be collected.  For subjects who are unblinded following the final analysis 
results, peripheral blood biomarker sample collection every 3 cycles after end of Cycle 1 
visit is not required.  Detailed processing will be outlined in the most current version of 
the Study M16-043 Laboratory Manual for the following:
Bone Marrow Collection for Disease Assessment by Flow Cytometry
NOTE:  This specimen will be used for detection of residual blasts (i.e., MRD) at the 
response assessments and should be the first tube drawn from the bone marrow aspirate 
collection.
Approximately 1 to 2 mL of bone marrow aspirate at:
●
Screening visit
●
Response Assessments: End of Cycle 1 and every 3 Cycles after end of 
Cycle 1 visit. For subjects who are unblinded following the final analysis 
results, sample collection every 3 cycles after end of Cycle 1 visit is not 
required. Bone marrow aspirate completed as per institutional standard of care 
should continue to split for this 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:
Bone marrow aspirate will be collected at:
●
Screening visit (4 mL)
●
Response assessments:  end of Cycle 1, and every 3 Cycles after end of 
Cycle 1 visit (1 mL). For subjects who are unblinded following the final 


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analysis results, sample collection every 3 cycles after end of Cycle 1 visit is 
not required. Bone marrow aspirate completed as per institutional standard of 
care should continue to split for this assessment.
●
Final Visit/Time of Relapse (4 mL)
Bone Marrow Biopsy for BCL-2 Family Analysis  
Either an FFPE block or approximately 6 to 10 slides from the diagnostic/response 
assessment biopsy should be collected for immunohistochemistry analysis 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, Cycle 3 Day 1 and Final Visit/Time of Relapse 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 M16-043 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 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 
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.


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5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples for pharmacokinetic assay of venetoclax, cytarabine, 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 3 blood samples (4 ml) for cytarbine will be 
collected from approximately 75 subjects.  The total number of venetoclax 
pharmacokinetic samples planned is 1225 and at minimum 225 cytarabine 
pharmacokinetic samples for analysis.
Additionally, for the Chinese subjects from China mainland sites, intensive 
pharmacokinetic samples will be obtained on Cycle 1 Day 10 as indicated in Appendix E.
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 M16-043 laboratory manual.
Blood Samples for Cytarabine PK Assay (Only Australia, Canada, France, 
Germany, Japan and the US)
Detailed sample collection and processing instructions for the cytarabine PK will be 
provided in the current Study M16-043 laboratory manual.
5.3.2.3
Disposition of Samples
The frozen plasma pharmacokinetic samples for venetoclax 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 the 
package.  Please refer to current Study M16-043 laboratory manual for complete shipping 
instructions.


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5.3.2.4
Measurement Methods
Plasma concentrations of venetoclax will be determined by the Drug Analysis Department 
at AbbVie using a validated method.  Plasma concentration of possible venetoclax 
metabolite(s) may be determined with validated or non-validated methods.  Plasma 
concentrations of cytarabine will be determined under the supervision of the Drug 
Analysis Department at AbbVie using validated or non-validated methods.
5.3.3
Efficacy Variables
Efficacy Assessments
Responses will be evaluated based on the revised guidelines by the modified International 
Working Group (IWG) for AML.  Progressive disease is defined per European 
LeukemiaNet (ELN) 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 the next cycle of study treatment for blood count recovery after a 
bone marrow evaluation, hematology values up to pre-dose labs from Day 1 of the next 
cycle or 2 weeks from the bone marrow if there is no additional dosing can be used to 
determine the modified 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:  No morphologic evidence of AML and 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 (1,000/μL) or 
thrombocytopenia < 105/μL (100,000/μL).  If all criteria for CR are met except 
for RBC transfusion independence, this also fulfills CRi criteria.
●
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 leukemia 
cells, absence of extramedullary disease, and absolute neutrophils < 103/μL 
(1,000/μL) and thrombocytopenia < 105/μL (100,000/μL).
●
RD:  Failure to achieve CR, CRi, PR; 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:  reappearance* of ≥ 5% blasts post 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 one 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 [50000/μL] non-transfused); or
○
50% increase in peripheral blasts (WBC × % blasts) to > 25 × 109/L 
(> 25000/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.  For subjects who are unblinded following the final 
analysis results, assessments every 3 cycles thereafter are not required. Bone marrow 
collection can be completed as per institutional standard of care.  Subject will be assigned 
to one or more of the following categories by investigators:
1.
complete remission;


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2.
complete remission with incomplete blood count recovery;
3.
partial remission;
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 sites 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 LDAC 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.


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5.3.6
Biomarker and Optional Exploratory Research Variables 
(Not Applicable for China)
Mandatory Biomarker Research Variables
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 assessment of 
minimal residual disease levels present after therapy, analyses of biomarkers related to the 
pathway(s) targeted by the study drug (i.e., BCL-2 family protein expression levels) or 
biomarkers believed to be related to the disease or to drug response.  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.  
Given the exploratory in nature of these assessments, the biomarker analyzes may or may 
not be conducted in accordance with GLP/GCP guidelines and may not be included in the 
clinical study report.  
Minimal or measurable residual disease (MRD), defined as persistence of leukemic cells 
after therapy, represents a potential biomarker for the depth of response to the therapy and 
a possible predictor for the response duration.  Given the fact that AML is a phenotypic 
and molecularly heterogenetic disease, a single definition for meaningful measurable 
disease in this patient population has yet to be identified.  Therefore, MRD may be 
explored in this study using two different technology platforms; multicolor flow 
cytometry (MFC) for a phenotypic assessment of residual disease and next generation 
sequencing (NGS) for a genetic assessment of leukemic-specific molecular abnormalities 
that would indicate residual disease.  Another consequence of the disease heterogeneity in 
AML is the fact that the sensitivities of these MRD assays may vary for each subject 
depending upon the specific phenotypic or genetic aberrancy.  Published literature 
suggests that most subjects are capable of achieving an MRD sensitivity of 10–3
(Araki 2016),26 therefore, this cut-off as well as others may be explored as definitions of 


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MRD negativity and correlated with outcome measures of efficacy and/or overall
survival.
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).
Optional Exploratory Research Variables
Pharmacogenetic DNA and RNA samples may be sequenced and data analyzed for 
genetic factors contributing to the disease or the subject's response to venetoclax or other 
study treatment in terms of pharmacokinetics, efficacy, tolerability, and safety.  Such 
genetic factors may include genes for drug metabolizing enzymes, drug transport proteins, 
genes within the target pathway, other genes believed to be related to drug response, or 
genes related to the disease state.  Some genes currently insufficiently characterized or 
unknown may be understood to be important at the time of analysis.  The samples may be 
analyzed as part of a multi-study assessment of genetic factors involved in the response to 
venetoclax, drugs of this class, or the disease state.  The samples may also be used for the 
development of diagnostic tests related to venetoclax, drugs of this class, or the disease 
state.  The results of PG analyses may not be reported with the study summary.
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 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;
●
The subject's response to therapy is unsatisfactory, as evidenced by 
progression of disease while on study drug;


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●
The subject experiences toxicities related to study drug that require more than 
a 4-week (one cycle) dose interruption of venetoclax or LDAC, in the absence 
of clinical benefit;
●
The subject requires any radiotherapy or alternate chemotherapy during the 
study period (with the exception of hydroxyurea [allowed in first month 
only]);
●
The occurrence of an adverse event that precludes further LDAC 
administration;
●
Noncompliance with the protocol.
●
Treatment failure, defined as failure to achieve CR, CRi, PR, or MLFS.
●
The subject becomes pregnant while on study drug.
Treatment will be continued as long as the patient continues to derive clinical benefit or 
until documented disease progression or develops unacceptable toxicity.
Accordingly, subjects may, in rare occasions, continue treatment after documented disease 
progression if the investigator believes it is in the best interest of the patient.
Following the final analysis results, the subjects will be unblinded by the Sponsor to the 
treatment assignment and subjects will be allowed to continue the assigned treatment arm 
as long as they derive clinical benefit from the treatment in the opinion of the investigator, 
or until transition to commercial supply is available, or until protocol criteria for 
discontinuation is met.
The investigator or study site personnel will inform AbbVie prior to discontinuing a 
subject from the study by contacting the Medical Monitor 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 
Treatment 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 


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Post Treatment Follow Up as outlined in Section 5.1.4 and follow all necessary 
procedures per Appendix C.
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 or placebo orally in the form of tablets.  Venetoclax or 
placebo should be dosed before LDAC on days of LDAC administration.  Subjects will 
self-administer venetoclax or placebo by mouth QD.  Tablets must be swallowed whole 
and must not be broken, chewed, or crushed.
LDAC must be prepared as per the applicable Summary of Product Characteristics 
(SmPC), package insert or prescribing information and administered subcutaneously by a 
trained provider meeting local qualifications for administration of subcutaneous 
cytarabine.
5.5.2
Identity of Investigational Products
Table 5.
Identity of Investigational Product
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Venetoclax
N/A
100 mg Tablet
Oral
AbbVie
Venetoclax
N/A
50 mg Tablet
Oral
AbbVie
Venetoclax
N/A
10 mg Tablet
Oral
AbbVie
Matching Placebo for 
Venetoclax (100 mg Tablet) 
N/A
0 mg Tablet
Oral
AbbVie
Matching Placebo for 
Venetoclax (50 mg Tablet) 
N/A
0 mg Tablet
Oral
AbbVie
Matching Placebo for 
Venetoclax (10 mg Tablet) 
N/A
0 mg Tablet
Oral
AbbVie
Cytarabine
N/A
100 mg/5 ml vial
SC
Brand/Generic
AbbVie will provide venetoclax, and placebo for venetoclax, and may also provide 
cytarabine for the study.  Sites located in countries where cytarabine is approved for AML 
may obtain cytarabine commercially via the site's pharmacy.  AbbVie will provide 
cytarabine as a labeled investigational product to sites who do not supply their own 
commercially available cytarabine.  


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Identity of Non-Investigational Product(s)
Sites may be responsible for obtaining cytarabine.  For operational or regulatory purposes, 
Abbvie may provide non-investigational products depending on local requirements.  
Cytarabine 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 non-investigational products 
dispensed by the site.
5.5.2.1
Packaging and Labeling
Venetoclax tablets or placebo for venetoclax tablets will be packaged in high density 
polyethylene (HDPE) plastic bottles.  Each bottle of the venetoclax 50 mg tablets or 
placebo for venetoclax 50 mg tablets will contain 28 tablets.  Each bottle of the 
venetoclax 10 mg tablets or placebo for venetoclax will contain 5 tablets.  Each bottle of 
the venetoclax 100 mg tablets or placebo for venetoclax 100 mg tablets will contain 
186 tablets.  All bottles will be labeled per local regulatory requirements.
LDAC will be provided as 20 mg/ml per single use vial.  Each vial and carton will be 
labeled per local regulatory requirements.  Each vial must be administered per the 
applicable US prescribing information (USPI), Summary of Product Characteristics 
(SmPC) or local label.
5.5.2.2
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).  LDAC 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 + 
LDAC or placebo + LDAC).  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 AML status (secondary, de novo), age (18 –
< 75, ≥75) 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 600 mg daily after ramp up in Cycle 1.  During 
Cycle 1 Days 1 – 4, the dose will ramp up from 100 mg on Day 1, 200 mg on Day 2, 
400 mg on Day 3 and 600 mg on Day 4. 
Each dose of venetoclax/placebo should be taken with approximately 240 mL of water 
within 30 minutes after the completion of a meal, preferably breakfast.  LDAC 
(20 mg/m2) should be given QD following administration of venetoclax or placebo on 
Days 1 – 10 of every cycle.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
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.
All subjects will be treated with open-label LDAC.


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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.  
Following the final analysis results, the Investigator, the study site personnel, the subjects, 
and AbbVie personnel will be unblinded by the Sponsor to subjects' treatment assignment.
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.  
Aggregate clinical safety data will be reviewed on a real-time basis 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 LDAC 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.
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, such as 
study treatment diaries, as necessary to the study coordinator at scheduled study visits.  
Compliance will be monitored and documented by the designated study site personnel on 


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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.
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 LDAC compared to an active control of placebo plus LDAC.  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 LDAC.


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LDAC is a standard treatment option in many countries worldwide and is often referred to 
as low intensity therapy for AML.  Low intensity therapy, such as LDAC, azacitidine, or 
decitabine are considered appropriate treatment approaches by the National Cooperative 
Cancer Network (NCCN)26 and European LeukemiaNet (ELN)28 for patients who are not 
candidates for intensive chemotherapy induction or HSCT.  Two Phase 3 trials have 
compared azacitidine29 and decitabine30 to physician's choice therapy for older patients 
with newly diagnosed AML to evaluate if either provided a statistically significantly 
longer survival when given as the initial treatment for AML.  To date, neither agent has 
been found to provide a significantly longer survival for patients with newly diagnosed 
AML than for those randomized to physician choice.  The most common treatment, in 
both studies, amongst the patients randomized to physician choice was LDAC.  The 
response rates to LDAC when administered as monotherapy are substantially lower than 
what is seen in Study M14-387 in combination with venetoclax and preliminary 
projections for median survival times also appear better than for the aforementioned 
historical experiences with LDAC monotherapy.31
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 and 
include a generic HRQoL measure (EQ-5D-5L), a cancer-specific HRQoL measure that 
includes functional and symptom scales as well as a global health status scale (EORTC 
QLQ-C30), and a symptom-based measure to assess fatigue (PROMIS Fatigue SF 7a).  
The specific symptoms and functional aspects assessed by these measures are considered 
to be among the most impactful to AML patients.32,33
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 LDAC 


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control arm may be enrolled.  Study M14-387, 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 M14-387, an 
ongoing Phase 1b/2 study of escalating doses of venetoclax in combination with LDAC 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.  In the dose 
escalation phase, LDAC was administered subcutaneously at 20 mg/m2 QD on 
Days 1 – 10 of each 28-day cycle of therapy.  Venetoclax began on Day 2, to allow PK 
assessments of monotherapy LDAC of Cycle 1 followed by a ramp up to continuous daily 
dosing at the designated doses of 600 mg for Cohort 1 and 800 mg for Cohort 2.  
Eighteen subjects were enrolled in the Phase 1 dose escalation portion (10 subjects at the 
800 mg dose and 8 subjects at 600 mg dose) and an additional 53 subjects were enrolled 
in the Phase 2 portion of the study at the 600 mg dose.  Two of the 10 subjects enrolled to 
the 800 mg venetoclax cohort with LDAC experienced a dose-limiting toxicity identifying 
600 mg venetoclax as the maximum tolerated dose (MTD) in co-administration with 
LDAC.  
An exposure-response analysis was conducted across the 71 enrolled subjects to establish 
the relationship between venetoclax exposure and response rates to support venetoclax 
dose selection in Study M16-043.  
 


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In summary, based on the preliminary results of exposure-response analysis and the 
observed tolerability data, the 600 mg dose of venetoclax in combination with LDAC was 
selected to maximize the response rates while avoiding dose-limiting toxicities.  
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. Azole agents, all of which are CYP3A inhibitors, are widely used in these 
patients for prophylaxis and treatment of invasive fungal infections.  As venetoclax is 
predominantly metabolized by CYP3A, co-administration with antifungal agents which 
are strong or moderate CYP3A inhibitors will 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 single dose of venetoclax in 12 subjects with NHL34 and a cohort of 
12 untreated elderly AML subjects in Study M14-358 was enrolled to assess the effect of 
posaconazole given twice daily on exposures of venetoclax given once daily.35  
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, 400 mg on Day 3 and 600 mg QD from Day 4 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 


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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.  
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.  The investigational product in this study is defined as venetoclax, LDAC or 
placebo.  
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For AEs, please refer to Sections 6.1 through 
6.1.7.1.  For product complaints, please refer to Section 6.2.
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 


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considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an alternative 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 
medical intervention, meet protocol specific criteria (see Section 6.1.7) regarding toxicity 
management and/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.


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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 
LDAC is administered until 30 days have elapsed following discontinuation of 
venetoclax/placebo and LDAC administration.
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:
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 or hospitalization for respite care.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.


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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.
6.1.1.3
Adverse Events Expected due to Study Related Endpoints
Disease progression is an endpoint of this study.  Disease progression should not be 
reported as an adverse event.
6.1.1.3.1
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 deaths during the protocol specified 


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adverse event collection period, regardless of relationship to study drug, must be recorded 
on the Adverse Event eCRF and Death eCRF and immediately reported to the Sponsor 
(Section 6.1.5).  All deaths occurring after adverse event collection period should be 
collected in Death eCRF.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be reported.  
The term "sudden death" should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without pre-existing 
heart disease, within one hour of the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.
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 values 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.  
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.


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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).
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 judgement, 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 judgement, 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 LDAC.  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.


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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
All protocol-related serious adverse events and nonserious adverse events must be 
collected from the signing of the study specific informed consent until study drug 
administration.
Serious and nonserious adverse events occurring after the study-specific informed consent 
is signed but prior to the initial dose of venetoclax/placebo, or LDAC will be collected 
only if they are considered by the Investigator to be causally related to the study-required 
procedures.
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.


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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: 
FAX to
For safety concerns, contact the Oncology Safety Management Team at:
Oncology Safety Management
AbbVie
1 North Waukegan Road
North Chicago, IL  60064


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For any subject safety concerns, please contact the physician listed below:
AbbVie TA Medical Monitor:
In emergency situations involving study subjects when the AbbVie Medical Monitor is 
not available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline 
where your call will be re-directed to a designated backup AbbVie SDP:
Phone: 
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  
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.


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In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
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.  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 180 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.
6.1.7
Toxicity Management
Management of Cytopenias, Infections, and Other Adverse Events
Myelosuppression and the related adverse events (thrombocytopenia, anemia, 
neutropenia, and febrile neutropenia) are common in both treated and untreated subjects 
with AML.  Subjects with baseline neutropenia or have significant bone marrow 
involvement may be particularly at high risk.  If a participant achieves a CRi or a 
morphologic leukemia free bone marrow, and has Grade 4 neutropenia or 
thrombocytopenia persisting beyond Day 28, venetoclax should be interrupted from 
Day 28 until ANC ≥ 500 – 1000/μL and platelet count ≥ 25 – 100 × 103/μL.  Typically, if 
persistent AML remains in the bone marrow, concurrent cytopenias are thought to be 
attributable to the disease process of AML and continued treatment with venetoclax and 


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LDAC may continue on schedule.  In subsequent cycles, if a subject with previous CR 
presents with new onset Grade 4 neutropenia or thrombocytopenia lasting more than one 
week, unless it is due to the underlying disease, venetoclax dosing may be interrupted 
until ANC recovery to ≥ 500 – 1000/μL and platelet count ≥ 25 – 100 × 103/μL per 
investigator discretion in consultation with the AbbVie medical monitor.  Venetoclax may 
be re-initiated at a lower dose, or discontinued if a minimal dose is not tolerable, per 
discussion with the AbbVie medical monitor.
Administration of venetoclax in subjects with lymphoproliferative disorders has been 
associated with clinically significant lymphopenia (B and T lymphocyte subtypes).  Anti-
infective prophylaxis for viral, fungal, bacterial or Pneumocystis 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 I for a 
description of excluded and cautionary medications and implement dose reductions for 
venetoclax/placebo as necessary.
If a subject is continuing to respond based on the bone marrow assessment after Cycle 2 
of treatment, but has persistent cytopenias (cytopenias that occur after Day 28 of a Cycle 
during Cycle 2 and beyond), venetoclax dose may be reduced as follows:
Table 7.
Dose Reduction Guidelines for Management of Persistent 
Neutropenia or Thrombocytopenia
Venetoclax Dose/Duration
New Venetoclax Dose/Duration
600 mg daily × 28 day cycles
600 mg daily × 21 days with 7 day interruption
600 mg daily × 21/28 day cycles
600 mg daily × 14 days with 14 day interruption
600 mg daily × 14/28 day cycles
400 mg daily × 14 days with 14 day interruption
Cytopenias during Cycle 1 or 2 may be due to bone marrow involvement by AML and 
therefore dose reductions during Cycle 1 or 2 are not typically recommended.  If an 


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investigator believes a particular patient would benefit from a dose reduction during 
Cycle 1 or 2, the investigator should discuss with the medical monitor.
If dose reductions or interruptions for events other than cytopenias or infections are 
thought to be necessary by the investigator, a discussion with the AbbVie medical monitor 
is required and may be approved upon consultation.  Delays greater than 21 days must be 
discussed with the AbbVie medical monitor or a designee.
Standard Therapy:  Low – Dose Cytarabine
In a recent international clinical trial, subjects receiving LDAC experienced the following 
treatment emergent CTCAE grade 3 or 4 adverse events at a rate of at least 10%:  
thrombocytopenia 35%, anemia 27%, febrile neutropenia 25%, disease progression 22%, 
neutropenia 20%, pneumonia 19%, general physical health deterioration 16%, and 
leukopenia 10%.36  It is unknown whether the aforementioned adverse events are 
attributable to receiving treatment with LDAC or were attributable to the underlying 
health condition of AML.  Complications of myelosuppression, including infections and 
bleeding, may be exacerbated by treatment with LDAC.  During Cycle 2 and subsequent 
cycles, study treatments may be delayed at the discretion of the investigator, if the subject 
experiences myelosuppression associated complications, such as those described below:
●
Febrile neutropenia (temperature ≥ 38.5°C and ANC < 1,000/μL)
●
Active viral, bacterial or fungal infection (i.e., requiring IV anti-infectives or 
extensive supportive care)
●
Hemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets 
< 25,000/μL or any central nervous system hemorrhage)
Treatment with LDAC may be resumed once the above conditions have improved or have 
been stabilized with adequate treatment (anti-infective therapy, transfusions, or growth 
factors).
Myelosuppression caused by LDAC is reversible. Complete blood and platelet counts 
should be performed regularly, as clinically indicated and prior to each treatment cycle.  


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In the presence of myelosuppression or its complications, treatment with LDAC may be 
interrupted or supportive measures instituted.
LDAC dose reductions are not typically recommended.  If a dose reduction is believed to 
be necessary a discussion with the AbbVie medical monitor is required.
6.1.7.1
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.  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 the study will 
need TLS prophylaxis and monitoring.  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.  For subjects at higher risk for 
TLS (i.e., circulating blasts, high burden of leukemia involvement in bone marrow, 
elevated pretreatment LDH levels, or renal dysfunction), additional mitigation measures 
including more intensive laboratory monitoring and interventions should be implemented.  
Lower starting dose of venetoclax/placebo may be considered (i.e., 50 mg).
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.
●
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.


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●
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.
●
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.  
For continued dosing of venetoclax/placebo, monitor for evidence of TLS 
during study treatment, and manage abnormalities of serum creatinine and 
electrolytes promptly.
For continued dosing of venetoclax/placebo, monitor for evidence of TLS during 
treatment, and manage abnormalities of serum creatinine, uric acid and electrolytes 
promptly.  For subjects at higher risk (i.e., circulating blasts), more intensive measures 
should considered.
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.


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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.
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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Primary Contact:
AbbVie Medical Monitor:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.  
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.


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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
8.1.1
Definition for Analysis Populations
The safety analysis set consists of all subjects who take at least one dose of study drug 
(either venetoclax/placebo or LDAC).  The safety analysis set will be 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 cytarabine will be listed for each subject by 
arm and scheduled visit.  Summary statistics will be computed for each arm and dose 
level (as applicable) 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
The primary efficacy endpoint is overall survival (OS).  


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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 
Kaplan-Meier methodology and compared between treatment arms using the log-rank test 
stratified by AML status (secondary, de novo) and age (18 – < 75, ≥ 75).
8.1.4.2
Secondary Efficacy Endpoints
Fixed sequence testing procedure will be used for analyses of the secondary efficacy 
endpoints.  If statistical test is not significant for the primary efficacy endpoint of OS, then 
statistical significance will not be declared for any of the secondary efficacy endpoints.  
Secondary efficacy endpoints are CR + CRi rate, CR + CRh rate, CR + CRi rate by the 
initiation of Cycle 2, CR + CRh rate by the initiation of Cycle 2, CR rate, fatigue based on 
the PROMIS Fatigue SF 7a, a global health status/quality of life scale (GHS/QoL) scale 
from the EORTC QLQ-C30, event free survival (EFS), transfusion independence rates for 
RBC or platelets, CR + CRi and MRD response rate, CR + CRh and MRD response rate, 
CR + CRi rate in biomarker subgroups (e.g., FLT3, IDH1/2), CR + CRh rate in biomarker 
subgroups (e.g., FLT3, IDH1/2), and OS in biomarker subgroups (e.g., FLT3, IDH1/2).  
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).
The proportion of subjects with complete remission or complete remission with 
incomplete blood count recovery (CR + CRi) will be calculated based on the modified 
IWG criteria for AML.  CR + CRi rate will be compared between treatment arms using 
CMH test stratified by AML status (secondary, de novo) and age (18 – < 75, ≥ 75).  In 
addition, 95% confidence interval will be constructed for CR + CRi.
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 


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●
Peripheral blood neutrophil count of > 0.5 × 103/μL*
●
Peripheral blood platelet count of > 0.5 × 105/μL*
●
A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology 
lab collection
*
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.
The proportion of subjects with complete remission or complete remission with partial 
hematological recovery (CR + CRh) will be calculated based on the modified IWG 
criteria for AML.  CR + CRh rate will be compared between treatment arms using CMH 
test stratified by AML status (secondary, de novo) and age (18 - < 75, ≥ 75).  In addition, 
95% confidence interval will be constructed for CR + CRh.
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.  CR + CRi rate by the initiation of Cycle 2 
will be compared between treatment arms using CMH test stratified by AML status 
(secondary, de novo) and age (18 – < 75, ≥ 75).  In addition, 95% confidence interval will 
be constructed for CR + CRi rate by the initiation of Cycle 2.
The proportion of subjects with complete remission will be calculated based on the 
modified IWG criteria for AML.  CR rate will be compared between treatment arms using 
CMH test stratified by AML status (secondary, de novo) and age (18 – < 75, ≥ 75).  In 
addition, 95% confidence interval will be constructed for CR.
Fatigue will be assessed using the PROMIS 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 treatment arms.


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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 treatment arms.
EFS will be defined as the number of days from randomization to the date of progressive 
disease, relapse from CR to CRi, treatment failure defined as failure to achieve CR, CRi, 
PR, or MFLS, 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 
AML status (secondary, de novo) and age (18 – < 75, ≥ 75).
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 plus 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 and 2) platelets.  All randomized subjects will be included to estimate the post-
baseline transfusion independence rate.  
Post baseline transfusion independence rate will be estimated as the proportion of subjects 
known to achieve transfusion independence during the evaluation period.  Transfusion 
independence rate will be compared between treatment arms using CMH test stratified by 
AML status (secondary, de novo) and age (18 – < 75, ≥ 75).  In addition, 95% confidence 
interval will be constructed for transfusion independence rate.


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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 and 
2) platelets.
The proportion of subjects with complete remission or complete remission with partial 
hematologic recovery (CR + CRh) by the initiation of Cycle 2 will be calculated.  CR + 
CRh rate by the initiation of Cycle 2 will be compared between treatment arms using 
CMH test stratified by AML status (secondary, de novo) and age (18 – < 75, ≥ 75).  In 
addition, 95% confidence interval will be constructed for CR + CRh rate by the initiation 
of Cycle 2.
The proportion of subjects achieving CR + CRi and MRD or CR + CRh and MRD 
response status may be calculated.  All randomized subjects will be included in the 
analyses.  Subjects who are randomized but have no MRD assessment will be considered 
as non-negative for the calculation of MRD response status.  MRD response will be 
defined using a threshold of less than 10–3 of residual blasts per leukocytes as measured in 
bone marrow.  The MRD response rates may be compared between treatment arms using 
CMH test stratified by AML status (secondary, de novo) and age (18 – < 75, ≥ 75).  In 
addition, 95% confidence interval will be constructed. 
The response rates (e.g., CR + CRi, CR + CRh, or CR) and overall survival in molecular 
subgroups (e.g., IDH1/2, FLT3) may be evaluated. 
8.1.4.3
Exploratory Efficacy Endpoint
Exploratory analyses comparing the effects of venetoclax + LDAC versus placebo + 
LDAC will be performed on the following PRO measures:  EQ-5D-5L, EORTC QLQ-
C30, and PROMIS Fatigue SF 7a.  Descriptive statistics will be calculated as per the 
scoring manuals for all scales/items of the EORTC QLQ-C30, PROMIS 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 


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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.
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 be summarized based 
on this IRC review:  CR rate, CR + CRi rate, event-free survival and CR + CRi rate by the 
initiation of Cycle 2.
8.1.6
Timing of Efficacy Analyses
An interim analysis will be performed at the time of the 100th death event. Final analysis
will be performed at the time of the 133rd death event.
8.1.7
Safety
The safety of venetoclax in combination with LDAC 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 venetoclax or LDAC, whichever 
comes first.  Analyses will not include those that have an onset greater than 30 days after 
the last dose of venetoclax or LDAC, whichever comes later.  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.  In 


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addition, the percentage of subjects experiencing an adverse event at a given NCI CTCAE 
Version 4.03 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.
8.1.7.4
Deaths
The number of subject deaths will be summarized (1) for all deaths in this study 
regardless of the number of days after the last dose of venetoclax.  (2) for deaths occurring 
within 30 days of randomization, (3) for deaths occurring within 60 days of 
randomization, (4) for deaths occurring within 30 days of the last dose of venetoclax, and 
(5) for deaths occurring more than 30 days of the last dose of venetoclax.
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 


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will be summarized.  In addition, the shift that is worsening from baseline value of at least 
one grade post baseline will be provided.
8.2
Determination of Sample Size
The primary endpoint of the study is overall survival and sample size calculation is based 
on the following assumptions:
●
Median OS of 6 months for placebo plus LDAC arm
●
Median OS of 11 months for venetoclax plus LDAC arm (hazard ratio of 
0.545)
●
Interim analysis of OS at 75% of death events with O'Brien-Fleming boundary
●
2:1 randomization ratio to venetoclax plus LDAC, and placebo plus LDAC 
arm
With the above assumptions, a total of 133 death events will provide 90% power to detect 
statistically significant different between treatment arms at alpha level of 0.05.  A total of 
approximately 210 subjects (140 in venetoclax plus LDAC arm and 70 in placebo plus 
LDAC arm) will be randomized into the study to obtain the 133 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.


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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 and all other 
applicable regulatory requirements.
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 
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.
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.


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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.
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 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 


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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.
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 Awareness Date (SAE CRF) may serve 
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
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.


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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 
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 CRF Health of Plymouth Meeting, 
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.


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The subject will be entering the data on an electronic device; 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 
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.  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.
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 


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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.
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.


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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.
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 (mandatory biomarkers 
and/optional research) 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 (Director of the Site in Japan) 
and AbbVie.  The Investigator 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 (In Japan, the Investigator will provide a final report to the Director of the 
Site following conclusion of the study.  Upon receiving the report, the Director of the Site 
will notify AbbVie or their representative and IEC/IRB of the conclusion of the study).


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The Investigator (Director of the Site in Japan) must submit, maintain, and archive any 
records related to the study according to ICH GCP and all other applicable regulatory 
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.
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 LDAC.
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 Co-Administered with Low Dose Cytarabine Versus 
Low Dose Cytarabine in Treatment Naïve Patients with Acute 
Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy
Protocol Date:
29 May 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Souers AJ, Leverson JD, Boghaert ER, et al.  ABT-199, a potent and selective 
BCL-2 inhibitor, achieves antitumor activity while sparing platelets.  Nat Med.  
2013;19(2):202-8.
2.
Konopleva M, Contractor R, Tsao T, et al.  Mechanisms of apoptosis sensitivity 
and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.  Cancer 
Cell.  2006;10(5):375-88.
3.
Tsao T, Shi Y, Kornblau S, et al.  Concomitant inhibition of DNA 
methyltransferase and BCL-2 protein function synergistically induce mitochondrial 
apoptosis in acute myelogenous leukemia cells.  Ann Hematol.  
2012;91(12):1861-70.
4.
Pan R, Hogdal LJ, Benito JM, et al.  Selective BCL-2 inhibition by ABT-199 
causes on-target cell death in acute myeloid leukemia.  Cancer Discov.  
2014;4(3):362-75.
5.
van Delft MF, Wei AH, Mason KD, et al.  The BH3 mimetic ABT-737 targets 
selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is 
neutralized.  Cancer Cell.  2006;10(5):389-99.
6.
Tahir SK, Yang X, Anderson MG, et al.  Influence of Bcl-2 family members on the 
cellular response of small-cell lung cancer cell lines to ABT-737.  Cancer Res.  
2007;67(3):1176-83.
7.
Touzeau C, Dousset C, Bodet L, et al.  ABT-737 induces apoptosis in mantle cell 
lymphoma cells with a Bcl-2high/Mcl-1 low profile and synergizes with other 
antineoplastic agents.  Clin Cancer Res.  2011;17(18):5973-81.
8.
Wei G, Margolin AA, Haery L, et al.  Chemical genomics identifies small-
molecule MCL1 repressors and BCL-xL as a predictor of MCL1 sensitivity.  
Cancer Cell.  2012;21(4):547-62.
9.
AbbVie.  Venetoclax (ABT-199) Investigator's Brochure Edition 9.  
08 March 2018.


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10.
Arber DA, Orazi A, Hasserjian R, et al.  The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia.  Blood.  
2016;127(20):2391-405.
11.
SEER Stat Fact Sheets:  Acute Myeloid Leukemia (AML).  Available from:  
http://seer.cancer.gov/statfacts/html/amyl.html.  Accessed on:  30 April 2016.
12.
Konopleva M, Pollyea DA, Potluri J, et al.  A phase 2 study of ABT-199 (GDC 
0199) in patients with acute myelogenous leukemia (AML).  Presented at:  
56th Annual Meeting of the American Society of Hematology; December 6-9, 
2014; San Francisco, CA.  Abstract 118.
13.
Ellison RR, Holland JF, Weil M, et al.  Arabinosyl cytosine:  a useful agent in the
treatment of acute leukemia in adults.  Blood.  1968;32(4):507-23.
14.
Cheson BD and Simon R.  Low-dose ara-C in acute nonlymphocytic leukemia and 
myelodysplastic syndromes:  A review of 20 years' experience.  Semin Oncol.  
1987; 14 (2 Suppl 1):126-33.
15.
Kantarjian HM, Thomas XG, Dmoszynska A, et al.  Multicenter, randomized, open 
label, phase III trial of decitabine versus patient choice, with physician advice, of 
either supportive care or low-dose cytarabine for the treatment of older patients 
with newly diagnosed acute myeloid leukaemia.  J Clin Oncol.  
2012;30(21):2670-7.
16.
Döhner H, Estey E, Grimwade D, et al.  Diagnosis and management of AML in 
adults:  2017 ELN recommendations from an international expert panel.  Blood.  
2017;129(4):424-47.
17.
Cella D, Yount S, Rothrock N, et al.  The patient-reported outcomes measurement 
information system (PROMIS):  progress of an NIH roadmap cooperative group 
during its first 2 years.  Med Care.  2007;45 (5 Suppl 1):S3-11.
18.
Garcia SF, Cella D, Clauser SB, et al.  Standardizing patient-reported outcomes 
assessment in cancer clinical trials:  a patient-reported outcomes measurement 
information system initiative.  J Clin Oncol.  2007;25(32):5106-12.


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19.
Cella D, Riley W, Stone A, et al.  The patient-reported outcomes measurement 
information system (PROMIS) developed and tested its first wave of adult self 
reported health outcome item banks:  2005-2008.  J Clin Epidemiol.  
2010;63(11):1179-94.
20.
Yost KJ, Eton DT, Garcia SF, et al.  Minimally important differences were 
estimated for six PROMIS Cancer scales in advanced-stage cancer patients.  J Clin 
Epidemiol.  2011;64(4):507-16.
21.
Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use 
in international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.
22.
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.  
2011;20(10):1727-36.
23.
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.
24.
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 
phase III trial.  Eur J Cancer.  2012;48(3):311-23.
25.
Pickard AS, Neary MP, Cella D.  Estimation of minimally important differences in 
EQ-5D utility and VAS scores in cancer.  Health Qual Life Outcomes.  
2007;5:70-8.  
26.
Araki D, Wood BL, Othus M, et al.  Allogeneic hematopoietic cell transplantation 
for acute myeloid leukemia:  time to move toward a minimal residual disease-based 
definition of complete remission?  J Clin Oncol.  2016;34(4):329-36.
27.
https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf accessed 8/17/2016;  
version 2.2016.
28.
Blood 2010 115:453-474; doi:10.1182.


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29.
Dombret H, Seymour JF, Butrym A, et al.  International phase 3 study of 
azacitidine vs conventional care regimens in older patients with newly diagnosed 
AML with > 30% blasts.  Blood.  2015;126(3):291-9.
30.
Kantarjian HM, Thomas XG, Dmoszynska A, et al.  Multicenter, randomized, 
open-label, phase III trial of decitabine versus patient choice, with physician 
advice, of either supportive care or low-dose cytarabine for the treatment of older 
patients with newly diagnosed acute myeloid leukaemia.  J Clin Oncol.  
2012;30(21):2670-7.
31.
Lin, Tara.  Phase 1B/2 study of venetoclax with low-dose cytarabine in treatment-
naive patients aged 65 years with acute myelogenous leukemia.  ASCO 2016.  
Presentation.
32.
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):845-8.
33.
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.
34.
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.  [Epub ahead of 
print].
35.
Agarwal SK, DiNardo C, Potluri J, et al.  Management of venetoclax-posaconazole 
interaction in acute myeloid leukemia patients:  evaluation of dose adjustments.  
Clin Ther.  2017.  In press.
36.
Ellison RR, Holland JF, Weil M, et al.  Arabinosyl cytosine:  a useful agent in the 
treatment of acute leukemia in adults.  Blood.  1968;32(4):507-23.


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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
Statistics
Clinical
Biomarkers
Bioanalysis
Therapeutic Area
Therapeutic Area
Clinical Pharmacology and 
Pharmacometrics


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Appendix C.
Study Activities
Procedures
Screeninga
D –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
D 
1
D 
2
D 
3
D 
4
D 
5
D 
6
D 
7
D 
8
D 
9
D 
10
D 
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
X
X
X
Cytogenetic Testingf
X
Tumor Lysis Syndrome 
Prophylaxisg
X
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,h
X
X
X
X
X
X
Xt
X
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
D –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
D 
1
D 
2
D 
3
D 
4
D 
5
D 
6
D 
7
D 
8
D 
9
D 
10
D 
15, 
22
MUGA or 2D 
Echocardiogram 
w/Dopplerm
X
Disease Assessment
Xu
Xo
X
X
Bone Marrow Aspirate 
and Biopsy for Local 
Disease Assessment
Xn
Xn,o,p
X
PROMIS 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 LDAC*
X
X
X
X
X
X
X
X
X
X
Survival Assessments
X
F/U = Follow-Up; PT = Post Treatment
*
LDAC will be administered for 10 days for each cycle starting with Day 1.
a.
Screening procedures must be performed within 21 days prior to randomization.  Bone marrow samples and peripheral blasts used for AML diagnosis can be collected within 
30 days prior to randomization. 
b.
Final Visit procedures should be performed when a subject discontinues from the study.


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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.
e.
On Cycle 1 Day 1, additional medical history that is observed after signing of the informed consent but prior to initial venetoclax or LDAC 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 J – 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, hematology and chemistry, coagulation and urinalysis may be performed within 
3 days before or after the scheduled visit.  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.
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.
A bone marrow aspirate and biopsy must be performed for all subjects during screening to confirm diagnosis and to collect mandatory samples for mandatory biomarker 
assessments.  Historical bone marrow aspirates and biopsies assessed locally to confirm the diagnosis may be used as baseline assessment to satisfy eligibility criteria if they 
were collected as standard of care within 30 days prior to randomization.  During screening, after the informed consent is signed, bone marrow aspirates and biopsies may be 
collected to confirm the diagnosis to satisfy eligibility criteria.  During screening, after informed consent is signed, a bone marrow aspirate must be performed for all subjects 
to collect samples for mandatory biomarker assessments (biomarker collections are not applicable to subjects enrolled in China).  Bone marrow aspirate and biopsy samples 
must be collected for all subjects at each of the disease assessments.  Bone marrow core biopsy sample collection will be considered an optional procedure 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 a bone marrow 
aspirate sample is inadequate or un-evaluable, a repeat aspirate sample and/or biopsy can be performed per institutional standard of care.  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.  The corresponding PHI redacted 
local laboratory pathology report/bone marrow report should be sent to the central laboratory for each local disease assessment which is conducted, until otherwise instructed 
by the Sponsor.  


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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 prior to the 
administration of study drugs for Cycle 2.  For subjects who require a delay in study treatment for blood count recovery after a bone marrow evaluation, hematology values up 
to pre-dose labs from Day 1 of the next cycle or 2 weeks from the bone marrow if there is no additional dosing 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 or progressive disease unless otherwise 
indicated in Section 5.3.1.1.  For subjects who are unblinded following the final analysis results, bone marrow collection every 3 cycles starting at the end of Cycle 4 are not 
required. Bone marrow collection can be completed as per institutional standard of care.  The corresponding PHI redacted local laboratory pathology report will be sent to the 
central laboratory for IRC review, until otherwise instructed by the Sponsor.
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 generally be completed prior to any other procedures or 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.  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.
Serum or Urine pregnancy test must be obtained at Cycle 1 Day 1, if it has been > 7 days since obtaining the pregnancy results at screening.  Subjects with borderline serum 
pregnancy tests at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of a positive result.
t.
Additional laboratory assessments may be performed, per investigator discretion, up to 48 hours after reaching final dose if clinically indicated.
u.
Disease Assessment at screening is to document baseline disease status; Disease Assessment at all other time points is to document disease response.


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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 1, 
End of Cycle 4 and 
Every 3 Cycles 
Thereaftera,c
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 
by Flow (MRD)
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 Screen and 
Final Visit.  
1 mL at End of 
Cycle 1 and all 
other response 
assessments.
Bone Marrow Biopsy 
for BCL 2 Family 
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 assessment for disease assessment.  
b.
Sample is optional and collected only if patient has signed the optional informed consent.
c.
For subjects, where bone marrow aspirates are no longer required for response assessments, the bone marrow 
biomarker samples will also not be collected at those time points, the plasma samples should still be collected. For 
subjects who are unblinded following the final analysis results, bone marrow and plasma sample collection at end 
of cycle 4 and every 3 cycles thereafter is not required. Bone marrow aspirates completed as per institutional 
standard of care should continue to split for these assessments.
Notes:
•
No result will be sent from the Central Laboratory, as all of them are "exploratory."
•
The remainders of the biopsy sample will be returned to the site upon request


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Appendix E.
Schedule of Blood Collection for Venetoclax and LDAC Assay 
(Pharmacokinetic Sampling)
For Subjects Enrolled Outside China
Procedures
Cycle 1
Days 1 – 4
Cycle 2, 4 and 8
Day 5
Venetoclax
6 hours post-dosea
0 hour (pre-dose)
Cytarabine
15 minutes post injection
For Subjects Enrolled in China
Procedures 
Cycle 1 
Days 1 – 4
Cycle 1 Day 10 
(Intensive PK Schedule)
Cycle 2, 4 and 8 
Day 5
Venetoclax
6 hours post-dosea
0 hour (pre-dose), 2, 4, 6, 
8 and 24 hours post-dose
0 hour (pre-dose)
a.
The 6-hour post-dose PK sample on Days 1 – 4 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 6-hour post-dose PK sample will be delayed 
accordingly.  
•
All "pre-dose" samples in venetoclax PK sampling are relative to venetoclax/placebo administration and will 
be collected within 1 hour prior to dosing.  Postdose samples for both venetoclax and cytarabine will be 
collected at the time points indicated with a window of ± 10%.
•
The date and time (start and end times to the nearest minute) of each LDAC 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
Cytogenetic
Favorable Risk
Core binding factor:  inv(16) or t(16;16)
or t(8;21)
t(15;17)
Intermediate Risk
Normal cytogenetics
+8 alone
t(9;11)
Other non-defined
Poor Risk
Complex (≥ 3 clonal chromosomal abnormalities)
Monosomal karyotype
-5,5q-,-7,7q-
11q23-non t(9;11)
inv(3),t(3;3)
t(6;9)
t(9;22)


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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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Appendix H.
Cell Lines Table
Venetoclax is potent against AML cell lines treated in vitro.  AML cell lines were treated 
with increasing concentrations of venetoclax for 48 hours before assessing cell viability.  
Venetoclax cell killing IC50 values are shown for each cell line.
Cell Line
Venetoclax IC50 (μM)
Genetic Lesions
MOLM-13
MLL- and FLT3-mutant
GDM-1
nd
EOL-1
MLL-mutant
HL-60
MV4-11
MLL- and FLT3-mutant
ML-2
MLL-mutant
SIG-M5
nd
OCI-AML2
nd
MOLM-16
nd
OCI-AML5
nd
THP-1
Kasumi-1
t(8;21) translocation
KG-1
nd
HNT-34
nd
PL-21
FLT3-mutant
SKM-1
nd
UKE-1
JAK2-mutant
SET-2
JAK2-mutant
HEL
JAK2-mutant
OCI-M2
nd
OCI-AML3
OCI-M1
nd
NOMO-1
MLL-mutant
ME-1
and inv16
nd = not determined


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Cell Line
Venetoclax Combination with 5-Aza
MOLM-13
0
RI-1
0
EOL-1
0
SUP-B15
0
MV4-11
0
ML-2
0
OCI-AML2
0
MOLM-16
0
OCI-AML5
0
KG-1
0
HNT-34
1.0
SKM-1
0
UKE-1
0
SET-2
0
HEL
0
OCI-M2
0
OCI-AML3
0.5
NOMO-1
1.0
KU812
0
PL-21
0.5
0 = additive; 0.5 = weak synergy; 1.0 = strong synergy; –1.0 = antagonism




Venetoclax (ABT-199)
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Note that 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.


Venetoclax (ABT-199)
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Appendix J.
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 (dose per institutional guidelines).
o
If rasburicase is used, consider screening for G6PD deficiency 
prior to administration in patients at higher risk for G6PD 
deficiency (e.g., patients of African or Mediterranean ancestry) 
prior to starting rasburicase.  Please refer to local label for tests to 
be performed, contraindications and precautions.
•
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 (dose per institutional guidelines).
•
If rasburicase is used, consider screening for G6PD deficiency prior to 
administration in patients at higher risk for G6PD deficiency 
(e.g., patients of African or Mediterranean ancestry) prior to starting 
rasburicase.  Please refer to local label for tests to be performed, 
contraindications and precautions.
•
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.


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Abnormality
Management Recommendations
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.
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.


Venetoclax (ABT-199)
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Appendix K.
Japan Specific Information
1.0
Clinical Expense and Compensation




Venetoclax (ABT-199)
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Appendix L.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.2  Synopsis
Subsection Methodology:  
Heading "Study Treatment"
Last paragraph, tenth sentence previously read:
Disease assessments should also occur at the Final Visit and any other time the patient 
features suggest relapse.
Has been changed to read:
Disease assessments should also occur at the Final Visit and any other time the patient 
features suggest relapse or progressive disease. For subjects who are unblinded following 
the final analysis results, bone marrow collection every 3 cycles starting at the end of 
Cycle 4 and bone marrow collection after CRi to confirm CR are not required. Bone 
marrow collection until 2 successive disease assessments resulting in CR or CRi is not 
required. Bone marrow collection can be completed as per institutional standard of care.  
Section 1.2  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
First paragraph, sixth, seventh, and eighth sentence previously read:
For all subjects a bone marrow aspirate and biopsy must be performed at end of Cycle 4 
and every 3 cycles (± 1 week) thereafter.  Bone marrow aspirate and biopsy should also be 
performed upon concern for relapse and at the Final Visit (if no bone marrow was 
collected within the last 6 – 8 weeks, or if relapse of disease has already been confirmed).  
Bone marrow will be obtained until two successive samples indicate CR or CRi.  


Venetoclax (ABT-199)
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Has been changed to read:
For all subjects a bone marrow aspirate and biopsy must be performed at end of Cycle 4 
and every 3 cycles (± 1 week) thereafter, however, these collections are not required for 
subjects who are unblinded following the final analysis results. Bone marrow collection 
can be completed as per institutional standard of care.  Bone marrow aspirate and biopsy 
should also be performed upon concern for relapse or progressive disease and at the Final 
Visit (if no bone marrow was collected within the last 6 – 8 weeks, or if relapse or 
progression of disease has already been confirmed).  Bone marrow will be obtained until 
two successive samples indicate CR or CRi, however, these collections are not required 
for subjects who are unblinded following the final analysis results.  
Section 1.2  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
First paragraph, tenth sentence previously read:
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.
Has been changed to read:
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, however, these collections are not required for subjects 
who are unblinded following the final analysis results.  
Section 5.1.3  Treatment Period
Subsection Cycle Length – 28 Days
Last paragraph
Add:  new third, fourth and fifth sentence 
For subjects who are unblinded following the final analysis results, bone marrow 
collections every 3 cycles starting at the end of Cycle 4 and bone marrow collection after 


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CRi to confirm CR are not required. Bone marrow collection until 2 successive disease 
assessments resulting in CR or CRi is not required for these unblinded subjects. Bone 
marrow collection can be completed as per institutional standard of care.  
Section 5.3.1.1  Study Procedures
Subsection Bone Marrow Aspirate and Biopsy for Disease Assessments
First paragraph previously read:
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:
Has been changed to read:
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 (bone 
marrow collection until two successive samples indicate CR or CRi is not required for 
subjects who are unblinded following the final analysis results):
Section 5.3.1.1  Study Procedures
Subsection Bone Marrow Aspirate and Biopsy for Disease Assessments
Fourth, fifth, and sixth bullet previously read:
●
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) thereafter.
●
Upon concern for relapse. 
Has been changed to read:
●
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.  This is not required for 
subjects who are unblinded following the final analysis results.


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●
For all subjects a bone marrow aspirate and biopsy must be performed at end 
of Cycle 4 and every 3 cycles (± 1 week) thereafter.  This is not required for 
subjects who are unblinded following the final analysis results. Bone marrow 
aspirate and/or biopsy can be completed as per institutional standard of care.
●
Upon concern for relapse or progressive disease. 
Section 5.3.1.1  Study Procedures
Subsection Bone Marrow Aspirate and Biopsy for Disease Assessments
Fourth paragraph, third sentence previously read:
For these subjects, if a bone marrow aspirate sample is inadequate or un-evaluable, a 
repeat aspirate sample and biopsy must be performed within 7 days.
Has been changed to read:
For these subjects, if a bone marrow aspirate sample is inadequate or un-evaluable, a 
repeat aspirate sample and/or biopsy can be performed as per institutional standard of 
care.
Section 5.3.1.1  Study Procedures
Subsection Bone Marrow Aspirate and Biopsy for Disease Assessments
Fourth paragraph, fifth sentence previously read:
The corresponding protected health information (PHI) redacted local laboratory pathology 
report/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 protected health information (PHI) redacted local laboratory pathology 
report/bone marrow report should be sent to the central laboratory for each local disease 
assessment which is conducted, until otherwise instructed by the Sponsor.


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Section 5.3.1.2  Collection and Handling of Biomarker and Exploratory Research 
Samples (Not Applicable for China)
Subsection Blood Collection for Plasma:
Third bullet
Add:  new last sentence 
For subjects who are unblinded following the final analysis results, sample collection 
every 3 cycles after end of Cycle 1 visit is not required.
Section 5.3.1.2  Collection and Handling of Biomarker and Exploratory Research 
Samples (Not Applicable for China)
Subsection Bone Marrow Collection for Disease Assessment by Flow Cytometry
Second bullet
Add:  new second and third sentence 
For subjects who are unblinded following the final analysis results, sample collection 
every 3 cycles after end of Cycle 1 visit is not required. Bone marrow aspirate completed 
as per institutional standard of care should continue to split for this assessment.
Section 5.3.1.2  Collection and Handling of Biomarker and Exploratory Research 
Samples (Not Applicable for China)
Subsection Bone Marrow Collection for Translational Research:
Add:  new second and third sentence 
For subjects who are unblinded following the final analysis results, sample collection 
every 3 cycles after end of Cycle 1 visit is not required. Bone marrow aspirate completed 
as per institutional standard of care should continue to split for this assessment.
Section 5.3.1.2  Collection and Handling of Biomarker and Exploratory Research 
Samples (Not Applicable for China)
Subsection Bone Marrow Aspirate and Biopsy Collections
Second bullet
Add:  new fourth sentence 
For subjects who are unblinded following the final analysis results, peripheral blood 
biomarker sample collection every 3 cycles after end of Cycle 1 visit is not required.  


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Section 5.3.3  Efficacy Variables
Subsection Reporting of Results
First paragraph
Add:  new third and fourth sentence
For subjects who are unblinded following the final analysis results, assessments every 
3 cycles thereafter are not required. Bone marrow collection can be completed as per 
institutional standard of care.
Section 5.4.1  Discontinuation of Individual Subjects from Treatment
Add:  new fourth paragraph
Following the final analysis results, the subjects will be unblinded by the Sponsor to the 
treatment assignment and subjects will be allowed to continue the assigned treatment arm 
as long as they derive clinical benefit from the treatment in the opinion of the investigator, 
or until transition to commercial supply is available, or until protocol criteria for 
discontinuation is met.
Section 5.5.5.1  Blinding of Investigational Product
Add:  new last paragraph
Following the final analysis results, the Investigator, the study site personnel, the subjects, 
and AbbVie personnel will be unblinded by the Sponsor to subjects' treatment assignment.


Venetoclax (ABT-199)
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Appendix C.  Study Activities
Procedures "Disease Assessment" previously read:
Procedures
Screeninga
D –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
D 
1
D 
2
D 
3
D 
4
D 
5
D 
6
D 
7
D 
8
D 
9
D 
10
D 
15, 
22
Disease Assessment
Xu
X
X
X
Has been changed to read:
Procedures
Screeninga
D –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
D 
1
D 
2
D 
3
D 
4
D 
5
D 
6
D 
7
D 
8
D 
9
D 
10
D 
15, 
22
Disease Assessment
Xu
Xo
X
X


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Appendix C.  Study Activities
Table note "n." and "o." previously read:
n.
A bone marrow aspirate and biopsy must be performed for all subjects during screening to confirm diagnosis and to 
collect mandatory samples for mandatory biomarker assessments.  Historical bone marrow aspirates and biopsies 
assessed locally to confirm the diagnosis may be used as baseline assessment to satisfy eligibility criteria if they 
were collected as standard of care within 30 days prior to randomization.  During screening, after the informed 
consent is signed, bone marrow aspirates and biopsies may be collected to confirm the diagnosis to satisfy 
eligibility criteria.  During screening, after informed consent is signed, a bone marrow aspirate must be performed 
for all subjects to collect samples for mandatory biomarker assessments (biomarker collections are not applicable 
to subjects enrolled in China).  Bone marrow aspirate and biopsy samples must be collected for all subjects at each 
of the disease assessments.  Bone marrow core biopsy sample collection will be considered an optional procedure 
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 a bone marrow aspirate sample is inadequate or un-
evaluable, a repeat aspirate sample and biopsy must be performed within 7 days.  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.  The corresponding PHI redacted local laboratory pathology report/bone marrow report 
should be sent to the central laboratory 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 prior to the administration of study drugs for Cycle 2.  For subjects 
who require a delay in study treatment for blood count recovery after a bone marrow evaluation, hematology values 
up to pre-dose labs from Day 1 of the next cycle or 2 weeks from the bone marrow if there is no additional dosing 
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 unless otherwise indicated in 
Section 5.3.1.1.  The corresponding PHI redacted local laboratory pathology report will be sent to the central 
laboratory for IRC review.
Has been changed to read:
n.
A bone marrow aspirate and biopsy must be performed for all subjects during screening to confirm diagnosis and to 
collect mandatory samples for mandatory biomarker assessments.  Historical bone marrow aspirates and biopsies 
assessed locally to confirm the diagnosis may be used as baseline assessment to satisfy eligibility criteria if they 
were collected as standard of care within 30 days prior to randomization.  During screening, after the informed 
consent is signed, bone marrow aspirates and biopsies may be collected to confirm the diagnosis to satisfy 
eligibility criteria.  During screening, after informed consent is signed, a bone marrow aspirate must be performed 
for all subjects to collect samples for mandatory biomarker assessments (biomarker collections are not applicable 
to subjects enrolled in China).  Bone marrow aspirate and biopsy samples must be collected for all subjects at each 
of the disease assessments.  Bone marrow core biopsy sample collection will be considered an optional procedure 
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 a bone marrow aspirate sample is inadequate or un-
evaluable, a repeat aspirate sample and/or biopsy can be performed per institutional standard of care.  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.  The corresponding PHI redacted local laboratory pathology report/bone 
marrow report should be sent to the central laboratory for each local disease assessment which is conducted, until 
otherwise instructed by the Sponsor.  


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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 prior to the administration of study drugs for Cycle 2.  For subjects 
who require a delay in study treatment for blood count recovery after a bone marrow evaluation, hematology values 
up to pre-dose labs from Day 1 of the next cycle or 2 weeks from the bone marrow if there is no additional dosing 
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 or progressive disease unless 
otherwise indicated in Section 5.3.1.1.  For subjects who are unblinded following the final analysis results, bone
marrow collection every 3 cycles starting at the end of Cycle 4 are not required. Bone marrow collection can be 
completed as per institutional standard of care.  The corresponding PHI redacted local laboratory pathology report 
will be sent to the central laboratory for IRC review, until otherwise instructed by the Sponsor.
Appendix D.  Schedule of Biomarker/Pharmacodynamic/Pharmacogenetic Sample 
Collection (Not Applicable for China)
Table note "c." 
Add:  new second and third sentence 
For subjects who are unblinded following the final analysis results, bone marrow and 
plasma sample collection at end of cycle 4 and every 3 cycles thereafter is not required.  
Bone marrow aspirates completed as per institutional standard of care should continue to 
split for these assessments.



SAP_000.pdf: 
Venetoclax (ABT-199)
M16-043 – Statistical Analysis Plan
Version 3.0 – 30 Nov 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M16-043
A Randomized, Double-Blind, Placebo Controlled 
Study of Venetoclax Co-Administered with Low Dose 
Cytarabine Versus Low Dose Cytarabine in 
Treatment Naïve Patients with Acute Myeloid 
Leukemia Who Are Ineligible for Intensive 
Chemotherapy
Date:  30 Nov 2018
Version 3.0
NCT03069352


Venetoclax (ABT-199)
M16-043 – Statistical Analysis Plan
Version 3.0 – 30 Nov 2018
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Study Design and Plan............................................................................ 7
4.3
Sample Size............................................................................................ 7
4.4
Interim Analysis..................................................................................... 8
5.0
Analysis Sets ..........................................................................9
5.1
Definition for Analysis Sets.................................................................... 9
5.2
Variables Used for Stratification of Randomization ................................ 9
6.0
Analysis Conventions ..........................................................10
7.0
Subject Disposition..............................................................13
8.0
Demographics, Baseline Characteristics, Medical 
History, Prior Medications, Concomitant 
Medications, and Post-treatment Therapies......................14
8.1
General Consideration.......................................................................... 14
8.2
Demographic and Baseline Characteristics ........................................... 14
8.3
Medical History.................................................................................... 16
8.4
Prior Medications, Concomitant Medications, and Post-treatment 
Therapies.............................................................................................. 16
9.0
Study Treatment Exposure and Compliance.....................17
10.0
Efficacy Analysis .................................................................18
10.1
General Considerations......................................................................... 18
10.2
Primary Efficacy Analysis.................................................................... 19
10.2.1
Overall Survival ................................................................................... 19
10.3
Secondary Efficacy Analyses ............................................................... 19
10.3.1
CR + CRi Rate ..................................................................................... 19
10.3.2
CR + CRh Rate .................................................................................... 20
10.3.3
CR + CRh and CR + CRi rate by the Initiation of Cycle 2 .................... 21
10.3.4
Complete Remission (CR) Rate............................................................ 21


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10.3.5
Transfusion Independence Rates........................................................... 22
10.3.6
Minimal Residual Disease (MRD) Response Rates............................... 23
10.3.7
Quality of Life (QoL) ........................................................................... 23
10.3.8
Event-free Survival............................................................................... 25
10.4
Exploratory Efficacy Endpoint ............................................................. 26
10.4.1
Additional Quality of Life Analyses ..................................................... 26
10.4.2
Duration of CR + CRi........................................................................... 27
10.5
Efficacy Analysis per Independent Review Committee......................... 29
10.6
Additional Efficacy Analysis................................................................ 29
10.7
Handling of Multiplicity....................................................................... 30
10.8
Efficacy Subgroup Analyses................................................................. 33
11.0
Safety Analysis.....................................................................33
11.1
Analysis of Treatment-Emergent Adverse Events................................. 33
11.2
Deaths.................................................................................................. 35
11.3
Analysis of Laboratory and Vital Signs Data ........................................ 36
11.3.1
Analysis of Mean Changes from Baseline in Clinical Laboratory 
and Vital Signs Data............................................................................. 36
11.3.2
Analyses of Shift from Baseline in Clinical Laboratory Data ................ 37
11.4
Safety Subgroup Analysis..................................................................... 39
12.0
Pharmacokinetic (PK) Analyses.........................................39
13.0
References............................................................................39
14.0
Appendix..............................................................................41
List of Tables
Table 1.
Planned Stopping Boundaries at the IA and FA of OS Endpoint ............. 9
Table 2.
Time Windows for Analysis of Hematology, Chemistry, and Vital 
Signs Parameters .................................................................................. 12
Table 3.
Time Windows for Analysis of PROMIS Cancer Fatigue SF 7a, 
EORTC QLQ-C30, and EQ-5D-5L....................................................... 13
Table 4.
Event/Censor and Corresponding Event/Censor Time for EFS ............. 26
Table 5.
Event/Censor and Corresponding Event/Censor Time for Duration 
of CR + CRi ......................................................................................... 28


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Version 3.0 – 30 Nov 2018
4
Table 6.
Calculation of Information Fraction (IF)............................................... 30
Table 7.
Alpha-spending Boundary (One-sided p-value) for Each Ranked 
Endpoint for EU and EU Reference Countries...................................... 31
Table 8.
Alpha-spending Boundary (One-sided p-value) for Each Ranked 
Endpoint for US and US Reference Countries ...................................... 32
Table 9.
Selected Adverse Events....................................................................... 35
Table 10.
Clinical Laboratory Tests ..................................................................... 37


Venetoclax (ABT-199)
M16-043 – Statistical Analysis Plan
Version 3.0 – 30 Nov 2018
5
3.0
Introduction
This statistical analysis plan (SAP) describes the full efficacy and safety statistical 
analyses for venetoclax Study M16-043 (Viale-c) Protocol Amendment 4 dated
29 November 2018.  It will provide details of statistical methods and describe analysis 
conventions to guide the statistical programming work.
Unless noted otherwise, all analyses will be performed using SAS® version 9.3 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of this study is to evaluate if venetoclax when co-administered with 
low dose cytarabine (LDAC) improves overall survival (OS) versus LDAC and placebo, 
in treatment naïve subjects with acute myeloid leukemia (AML).
The secondary objectives of the study are 
●
To evaluate if venetoclax when co-administered with LDAC improves 
composite complete remission rate (complete remission + complete remission 
with incomplete blood count recovery, CR + CRi).
●
To evaluate if venetoclax when co-administered with LDAC improves 
complete remission and complete remission with partial hematologic recovery 
rate (CR + CRh).
●
To evaluate if venetoclax when co-administered with LDAC improves the 
proportion of subjects achieving a composite CR (CR + CRi) by the initiation 
of Cycle 2.
●
To evaluate if venetoclax when co-administered with LDAC improves 
complete remission rate (CR).
●
To evaluate if venetoclax when co-administered with LDAC reduces fatigue 
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Outcomes Measurement Information System (PROMIS), and Fatigue Short 
Form (SF) 7a.
●
To evaluate if venetoclax when co-administered with LDAC improves subjects 
Global Health Status/Quality of Life (GHS/QoL) based on the European 
Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core (EORTC QLQ-C30).
●
To evaluate if venetoclax when co-administered with LDAC improves event-
free survival (EFS).
●
To evaluate if venetoclax when co-administered with LDAC improves the 
transfusion independence rates.
●
To evaluate if venetoclax when co-administered with LDAC improves the 
proportion of subjects achieving complete remission and complete remission 
with partial hematologic recovery (CR + CRh) by the initiation of Cycle 2.
●
To evaluate if venetoclax when co-administered with LDAC improves the 
MRD response rate.
●
To evaluate if venetoclax when co-administered with LDAC improves the 
response rates and overall survival in molecular subgroups (e.g., IDH1/2, 
FLT3).
The exploratory objectives of this study are
●
Exploration of biomarkers predictive of venetoclax activity and duration of 
response may be performed.  These analyses may be 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:
○
To evaluate BCL-2 expression and outcome measures of overall survival 
and complete remission rate.
●
To evaluate the impact of venetoclax based on the remaining subscales/items 
from the EORTC QLQ-C30 and EQ-5D-5L.


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4.2
Study Design and Plan
This is a Phase 3, randomized, double-blind, placebo controlled, multicenter study of 
venetoclax co-administered with LDAC versus LDAC in treatment naïve patients with 
acute myeloid leukemia who are ineligible for intensive induction chemotherapy 
sponsored by AbbVie.  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 600 mg orally QD on Days 1 – 28 plus LDAC 20 mg/m2
SC QD on Days 1 – 10
●
Arm B:  Placebo for venetoclax 600 mg orally QD on Days 1 – 28 plus LDAC 
20 mg/m2 SC QD on Days 1 – 10 
Approximately 210 subjects will be randomized to meet scientific and regulatory 
objectives without enrolling an undue number of subjects in alignment with ethical 
considerations.  
4.3
Sample Size
The primary endpoint of the study is overall survival and sample size calculation is based 
on the following assumptions:
●
Median OS of 6 months for placebo plus LDAC arm
●
Median OS of 11 months for venetoclax plus LDAC arm (hazard ratio of 
0.545)
●
Interim analysis of OS at 75% of death events with O'Brien-Fleming boundary
●
2:1 randomization ratio to venetoclax plus LDAC, and placebo plus LDAC 
arm
With the above assumptions, a total of 133 death events will provide 90% power to detect 
statistically significant difference between treatment arms at two-sided alpha level of 0.05.  
A total of approximately 210 subjects (140 in venetoclax plus LDAC arm and 70 in 


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placebo plus LDAC arm) will be randomized into the study to obtain the 133 death 
events.
4.4
Interim Analysis
To ensure subject safety, an Independent Data Monitoring Committee (IDMC) will 
review unblinded safety data at the following proposed time points:
●
The first meeting to review the unblinded safety data will occur approximately 
3 months after the 20th patients has been randomized and dosed
●
The subsequent reviews of unblinded safety data will occur approximately 
every 3 months after the first review of unblinded safety data. 
Additional ad hoc meetings may occur as needed for the IDMC to fulfill its 
responsibilities.
Further, one interim analysis (IA) of OS will be performed once 100 death events (75% of 
the total 133 events) are observed.  The Lan-DeMets alpha spending function with 
O'Brien-Fleming boundary will be used to ensure that the one-sided false positive rate 
will be 0.025 or less for overall survival.  The IDMC will make a recommendation based 
on overall survival to either to stop for success at IA or proceed to the final analysis using 
pre-specified stopping rule.  The planned stopping boundaries are further described in 
Table 1 below for IA and final analyses (FA) of OS endpoints.  The actual stopping 
boundaries at IA and FA of OS endpoint will be derived using Lan-DeMets alpha 
spending function, based on the observed number of death events in the extracted 
database.  The actual stopping boundaries will be presented in the IDMC charter 
addendum.  Details of the IDMC review will be presented in the IDMC charter.
For the IA, if the IDMC inform the sponsor that OS data is statistically significant in favor 
of Arm A, upon notification from the Sponsor Steering Committee after consultation with 
regulatory authorities as required, the sponsor will then unblind the study to prepare 
regulatory submissions globally.  Otherwise, study will remain blinded and continue to 
follow protocol specified procedures until the FA.


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Table 1.
Planned Stopping Boundaries at the IA and FA of OS Endpoint
Look
# of Events
Efficacy Stopping Boundaries (One-Sided p-Value)
IA
100
0.010
FA
133
0.022
Interim statistical analyses and summaries for presentation to IDMC will be prepared by 
Axios.  AbbVie personnel will not have access to the interim analyses prepared for the 
IDMC.
5.0
Analysis Sets
5.1
Definition for Analysis Sets
Two study populations will be analyzed, defined as follows:
●
The full analysis set consists of all subjects randomized by IVRS/IWRS.  The 
full analysis set will be used for efficacy analyses.  The data from full analysis 
set will be analyzed by the treatment arm assignment given at the time of 
randomization, even if the subject takes the incorrect drugs that do not match 
the assigned treatment, or does not receive any treatment, or does not follow 
the protocol until completion.
●
The safety analysis set consists of all subjects who take at least one dose of 
venetoclax/placebo or LDAC.  The safety analysis set will be used for safety 
analyses.  The data from safety analysis set will be analyzed by the actual 
treatment that subject received.  
5.2
Variables Used for Stratification of Randomization
The subject randomization will be stratified by AML status (de novo, secondary), age 
(18 – < 75, ≥ 75), and region (US, EU, China, Japan (JP), Rest of World (ROW)).


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6.0
Analysis Conventions
General Considerations
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤ 0.05.  The date of randomization is defined as the 
date that the IVRS/IWRS issues a randomization number.
Definition of Study Drug
Unless otherwise specified, the study drug in this document refers to venetoclax/placebo 
and LDAC.  The first dose date of study drug is defined as the date the 1st dose of 
venetoclax/placebo or LDAC, whichever occurs first, is administrated.  The last dose date 
of study drug is defined as the date the last dose of venetoclax/placebo or LDAC, 
whichever occurs later, is administrated.
Definition of Baseline
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 or 
randomization for non-treated subjects. 
Definition of Final Observation
The final observation in Table 2 and Table 3 is defined as the last non-missing 
observation collected after the first dose of study drug to the last dose of study 
drug + 30 days.
Definition of Data Cutoff Date
The data cutoff date for interim analysis (IA) will be the projected date of the 100th death 
occurred in the full analysis set.  The data cutoff date for final analysis (FA) will be the 
projected date of the 133th death occurred in the full analysis set.


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The same data cutoff date will be implemented for both efficacy and safety analyses.
Stratification Factor for Efficacy Analyses
AML status (secondary, de novo) and age (18 – < 75, ≥ 75) will be used in all stratified 
analyses of the efficacy endpoints.  The stratification factor value under which the subject 
is randomized by the IVRS/IWRS will be used in the efficacy analyses.
Definition of Cycle Rx Days in Each Cycle
Cycle Rx Days for each cycle are calculated for each time point relative to first dose of 
study drug in each cycle.  The day of the first dose of study drug in each cycle is defined 
as Cycle Rx Day 1, while the day prior to the first dose of study drug is defined as Cycle 
Rx Day –1 (there is no Cycle Rx Day 0).
Definition of Analysis Windows
All time points and corresponding time windows are defined for each cycle are based on 
Cycle Rx Day 1 of each cycle.
For visit-wise clinical laboratory analyses, vital signs analyses, and quality of life 
analyses, the time windows specified in Table 2 and Table 3 describe how efficacy and 
safety data are assigned to protocol specified visits respectively.  Analysis time windows 
are constructed using the following algorithm:
●
Determine the nominal Cycle Rx day for each scheduled visit.
●
Determine the window around a specific nominal Cycle Rx day as in Table 2
and Table 3.
●
If more than one assessment are included in a time window of the assessment, 
the one closest to the nominal day should be used.  If there are 
two observations with equal distance to the nominal day, the later one will be 
used in analyses.  If multiple values are collected on the same day, the 
arithmetic average will be calculated and used as the value of that day for the 
mean change analyses.  


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●
For analysis of tumor lysis syndrome (TLS) laboratory variables meeting the 
Howard criteria where multiple values were collected over the course of a day 
(within 4 hours prior to dosing and 6 – 8 hours post dose), all values will be 
used and no averages will be taken.
●
For analysis of liver enzyme laboratory variables meeting criteria for potential 
drug-induced liver injury, all values will be used and no averages will be 
taken.
●
For laboratory shift tables, the Common Terminology Criteria (CTC) grade 
will be assigned based on all observed laboratory values and no averages will 
be taken. If multiple grades are collected on the same day, the worst grade will 
be used as the value of that day for the shift table analyses.
Table 2.
Time Windows for Analysis of Hematology, Chemistry, and Vital 
Signs Parameters
Scheduled Visit
Nominal Cycle Rx Day
Time Window (Cycle Rx Day Range)
Baseline
≤ 1
See the baseline definition (Section 6.0)
Cycle 1 Day 2
2
[2]
Cycle 1 Day 3
3
[3]
Cycle 1 Day 4
4
[4]
Cycle 1 Day 5
5
[5]
Cycle 1 Day 8
8
[6, 11]
Cycle 1 Day 15
15
[12, 18]
Cycle 1 Day 21
21
[19, 25]
Cycle 2 Day 1
1
[–3, 10]
Every Cycle from Cycle 3 
Day 1
1
[–10, 10]
Final Observation
NA
The last non-missing observation collected 
after the first dose of study drug to the last 
dose of study drug + 30 days 
Note:
Hematology and chemistry samples will be collected at visits specified in the protocol.  Vital signs will be 
measured at visits specified in the protocol.  


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Table 3.
Time Windows for Analysis of PROMIS Cancer Fatigue SF 7a, 
EORTC QLQ-C30, and EQ-5D-5L
Scheduled Visit
Nominal Cycle Rx Day
Time Window (Cycle Rx Day Range)
Baseline
≤ 1
See the baseline definition (Section 6.0)
Every Other Cycle from 
Cycle 3 Day 1
1
[–10, 10]
Note:
PROMIS Cancer Fatigue SF 7a, EORTC QLQ-C30, and EQ-5D-5L will be assessed at visits specified in the 
protocol.
7.0
Subject Disposition
The screen failure reasons will be summarized for the screen failure subjects.  Analyses 
for the subject disposition will be performed on the full analysis set.
The number and percentage of subjects will be summarized overall, by treatment arm, by 
country, and by site, for each of the following categories:
●
Subjects randomized into the study
●
Subjects who received at least one dose of study drug 
●
Subjects who randomized but not treated with any component of study drug
Additionally, the number and percentage of subjects will be summarized overall, and by 
treatment arm for each of the following categories:
●
Subjects who discontinued venetoclax/placebo due to all reasons and primary 
reason
●
Subjects who discontinued LDAC due to all reasons and primary reason
●
Subjects who discontinued study due to all reasons and primary reason
●
Subjects enrolled under each Protocol Amendment
There will be no statistical comparison for the subject disposition between the two 
treatment arms.


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8.0
Demographics, Baseline Characteristics, Medical 
History, Prior Medications, Concomitant 
Medications, and Post-treatment Therapies
8.1
General Consideration
All demographic, baseline characteristics, medical history, prior and concomitant 
medication summaries will be performed by treatment arm, on full analysis set as 
described in Section 5.1.  
8.2
Demographic and Baseline Characteristics
All baseline characteristic summary statistics and analyses are based on characteristics 
prior to the first dose of study drug or date of randomization for non-treated subjects.  
Distributions of the continuous demographic and baseline characteristic variables will be 
summarized by treatment arm with the number of non-missing observations, mean, 
standard deviation, and median, as well as the minimum and maximum values.
For the categorical demographic and baseline characteristic variables, the frequency and
percentages of subjects within each category will be summarized by treatment arm.  The 
number of subjects with missing information will also be summarized.
There will be no statistical comparison for the demographic and baseline characteristics 
between the two treatment arms. 
The following demographic and baseline characteristics will be summarized:
Demographics:
●
age (years) and age categories (18 – < 75 years, ≥ 75 years)
●
gender (male/female)
●
race (white, black or African American, Asian, and other)
●
region (US, EU, China, JP, and ROW)
●
height (cm)


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●
weight (kg)
Baseline and Disease-Related Characteristics: 
●
ECOG performance status (0, 1, 2, 3)
●
AML Status (de novo, secondary)
●
Type of secondary AML (therapy related, post MDS/CMML)
●
AML with myelodysplasia related changes (AML-MRC) (Yes, No)
●
Cytogenetics risk (favorable, intermediate, poor)
●
Bone marrow blast count (< 30%, ≥ 30% – < 50%, ≥ 50%)
●
Bone marrow blast count (%)
●
CTC grade of neutropenia 
●
Neutrophils value (× 109/L)
●
CTC grade of anemia 
●
Hemoglobin value (G/L)
●
CTC grade of thrombocytopenia 
●
Platelet count (× 109/L)
●
Reasons for being not eligible for standard induction therapy
●
Prior HMA used (Yes, No)
●
Antecedent hematologic history of MDS (Yes, No)
●
Baseline RBC transfusion dependence (Yes, No)
●
Baseline platelet transfusion dependence (Yes, No)
●
Molecular marker via central lab (FLT3, IDH1/2, TP53, NPM1)
●
Hepatic impairment (Yes, No)
●
Renal impairment (Yes, No)
The cross tabulation of the following demographic and baseline characteristics captured in 
IVRS/IWRS and CRF will be generated:
●
Age categories (18 – < 75, ≥ 75 years)
●
AML status (de novo, secondary)


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●
Cytogenetics risk (favorable, intermediate, poor)
●
Region (US, EU, China, JP, and ROW)
8.3
Medical History
Medical history data will be coded for conditions/diagnoses by system organ class and 
preferred term.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized by system organ class and preferred term.  
Subjects reporting more than one condition/diagnosis within a system organ class will be 
counted only once for that system organ class.  There will be no statistical comparison for 
the medical history between the two treatment arms.
8.4
Prior Medications, Concomitant Medications, and Post-
treatment Therapies
A prior medication is defined as any medication taken on or prior to the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the 
first dose of study drug, and continued to be taken after the first dose of study drug, or any 
medication that started after the first dose of study drug, but not after the last dose of 
study drug.  All medications are considered prior medications for subjects who were 
randomized but did not receive any study drug.  A post-treatment therapy for the 
treatment of AML is defined as any medications taken after the discontinuation of study 
drug and entered via Post Treatment eCRFs.  
The number and percentage of subjects who have taken medications will be summarized 
by generic drug name coded by WHO Drug dictionary 2017Q1 or a more recent version 
for prior medications, prior oncology therapies, concomitant medication, and post-
treatment therapies.  The number and percentage of subjects who have taken TLS 
prophylaxis agents including intravenous hydration on or prior to the first dose of study 
drug and concomitant to the study treatment will be summarized separately.  The number 
and percentage of subjects who have taken transfusions on or prior to first dose of study 


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drug will be summarized by transfusion type.  There will be no statistical comparison 
between the two treatment arms for the aforementioned summaries.
For summaries of concomitant medications, if an incomplete or missing start date was 
collected for a medication, the medication will be assumed to be a concomitant 
medication, or prior medication for subjects who did not receive any study drug, unless 
there is evidence that confirms that the medication was not a concomitant medication 
(e.g., the medication end date was prior to the first dose of study drug).
A subject who reports the use of two or more medications will be counted only once in the 
summary of "Any Concomitant Medication."  A subject who reports two or more uses of 
the same medication will be counted only once in the total for the associated generic drug 
name.  Similar rules apply to prior medications and post-treatment therapy as well.
9.0
Study Treatment Exposure and Compliance
The duration of exposure to venetoclax/placebo will be summarized by treatment arm, for 
safety analysis set as described in Section 5.1.  Duration of exposure is defined for each 
subject as (last dose date – first dose date) + 1.  Duration of exposure will be summarized 
using the following statistics (months):  sample size (N), mean, standard deviation, 
median, and range.  In addition, the number and percentage of subjects exposed to 
venetoclax/placebo will be summarized for the following categories of exposure duration:  
●
0 to 4 weeks (0 to 28 days), 
●
> 4 weeks to 8 weeks (28 to 56 days), 
●
> 8 weeks to 12 weeks (57 to 84 days), 
●
> 12 weeks to 16 weeks (85 to 112 days), 
●
> 16 weeks to 20 weeks (113 to 140 days), 
●
> 20 weeks to 24 weeks (141 to 168 days), 
●
> 24 weeks to 28 weeks (169 to 196 days), 
●
> 28 weeks to 32 weeks (197 to 224 days), 
●
> 32 weeks to 36 weeks (225 to 252 days), 


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●
> 36 weeks to 52 weeks (253 to 364 days), 
●
> 52 weeks (> 364 days).
The number of cycles that subjects are exposed to study drug will be summarized by 
treatment arm.  There will be no statistical comparison for the study treatment exposure 
between the two treatment arms.
10.0
Efficacy Analysis
10.1
General Considerations
Unless otherwise noted, for all statistical analysis, statistical significance will be 
determined by a two-sided P value ≤ 0.05 (when rounded to three decimal places).  
When the 133st death in the full analysis set occurs, there will be a final review of the 
eCRF data.  After the data collection is completed and reviewed for completeness and all 
data management quality assurance (QA) and quality control (QC) procedures are 
performed, the study blind will be broken and clinical database data will be extracted for 
documentation and statistical analyses of the efficacy and safety data.  Efficacy analyses 
will be performed on the full analysis set.
Unless otherwise specified, the primary analysis of all response/progression related 
endpoints (e.g., CR/CRi) will be based on the investigator assessment.  Sensitivity 
analyses will be performed based on Independent Review Committee's assessment. 
For the analysis of all response/progression related endpoints, MRD response rate, and 
transfusion independence rate, the data collected after the data cutoff date or initiation of 
post treatment therapy, whichever comes earlier, will be excluded.
Censoring Dates for Prematurely Blind Broken Subjects
For all efficacy endpoints except OS, if the subject's blind has prematurely broken by sites 
before "Cutoff" date, the date of premature blind break will be set as "Cutoff" date for the 
subject.


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10.2
Primary Efficacy Analysis
10.2.1
Overall Survival 
Overall survival will be defined as the number of days from the date of randomization to 
the date of death.  All events of death will be included, regardless of whether the event 
occurred while the subject was still taking study drug, or after the subject discontinued 
study drug.  If a subject has not died, then the data will be censored at the date the subject 
was last known to be alive on or before the cutoff date.  The date of the last known alive 
will be determined by selecting the last available date of the following study procedures 
for a subject:  start date of adverse event, bone marrow collection, disease assessment, 
vital signs assessment, clinical laboratory collection, study drug administration, start date 
of concomitant medicine, transfusion procedure, survival follow-up, biospecimen sample 
collection, quality of life assessments, and performance status.  All subjects in the full 
analysis set will be included in the analysis.
The distribution of overall survival will be estimated for each treatment arm using 
Kaplan-Meier methodology and compared between treatment arms using the log-rank test, 
stratified by AML status (de novo, secondary) and age (18 – < 75, ≥ 75).  The hazard ratio 
between treatment arms will be estimated using the Cox proportional hazards model, 
stratified by AML status (de novo, secondary) and age (18 – < 75, ≥ 75).
10.3
Secondary Efficacy Analyses
10.3.1
CR + CRi Rate
CR + CRi rate will be defined as the proportion of subjects who achieve a complete 
remission or complete remission with incomplete blood count recovery (CR + CRi) at any 
time point during the study per the modified IWG criteria for AML.  Subjects who are 
randomized but have no IWG disease assessment will be considered to be non-responders 
in the calculation of CR + CRi rate.  All subjects in the full analysis set will be included in 
the analysis.


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CR + CRi rate will be compared between treatment arms using Cochran-Mantel-Haenszel 
(CMH) test, stratified by AML status (de novo, secondary) and age (18 – < 75, ≥ 75).  In 
addition, the 95% confidence interval for CR + CRi rate based on the binomial 
distribution (Clopper-Pearson exact method) by treatment arms will be provided.  The risk 
difference and 95% confidence interval for the risk difference (exact unconditional 
confidence limits) will also be provided.
10.3.2
CR + CRh Rate
CRh (Complete remission with partial hematologic recovery) is a derived response based 
on bone marrow blast and hematology lab values.  A subject achieves a CRh when 
meeting the following criteria:
●
Bone marrow with < 5% blasts and
●
Peripheral blood neutrophil count of > 0.5 × 103/μL and
●
Peripheral blood platelet count of > 0.5 × 105/μL and
●
A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology 
lab collection.
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.
CR + CRh rate will be defined as the proportion of subjects who achieve a complete 
remission (CR) or complete remission with partial hematologic recovery (CRh) at any 
time point during the study.  Subjects who are randomized but have no disease assessment 
will be considered as non-responders in the calculation of CR + CRh rate.  All subjects in 
the full analysis set will be included in the analysis.


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CR + CRh rate will be compared between treatment arms using Cochran-Mantel-Haenszel 
(CMH) test stratified by AML status (de novo, secondary) and age (18 – < 75, ≥ 75).  In 
addition, the 95% confidence interval for CR + CRh rate based on the binomial 
distribution (Clopper-Pearson exact method) by treatment arms will be provided.  The risk 
difference and the 95% confidence interval for the risk difference (exact unconditional 
confidence limits) will also be provided.
10.3.3
CR + CRh and CR + CRi rate by the Initiation of Cycle 2
CR + CRh rate by the initiation of Cycle 2 will be defined as the proportion of subjects 
who achieved a complete remission (CR) or complete remission with partial hematologic 
recovery (CRh) by the initiation of Cycle 2.  Subjects who are randomized but have no 
disease assessments by the initiation of Cycle 2 will be considered to be non-responders in 
the calculation of CR + CRh rate by the initiation of Cycle 2.  For subjects who 
discontinue the treatment before initiation of Cycle 2, all disease assessments evaluated 
before the cutoff date and the initiation of post treatment therapy, whichever occurs 
earlier, will be included.  All subjects in the full analysis set will be included in the 
analysis. 
CR + CRh rate by the initiation of Cycle 2 will be compared between treatment arms 
using Cochran-Mantel-Haenszel (CMH) test stratified by AML status (de novo, 
secondary) and age (18 – < 75, ≥ 75).  In addition, the 95% confidence interval for CR + 
CRh rate by the initiation of Cycle 2 based on the binomial distribution (Clopper-Pearson 
exact method) by treatment arms will be provided.  The risk difference and the 95% 
confidence interval for the risk difference (exact unconditional confidence limits) will also 
be provided.
Similar analyses will be performed for CR + CRi rate by the initiation of Cycle 2.
10.3.4
Complete Remission (CR) Rate
CR rate will be defined as the proportion of subjects who achieved a complete remission 
(CR) at any time point during the study per the modified IWG criteria for AML.  Subjects 


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who are randomized but have no IWG disease assessment will be considered to be non-
responders in the calculation of CR rate.  All subjects in the full analysis set will be 
included in the analysis.
CR rate will be compared between treatment arms using Cochran-Mantel-Haenszel 
(CMH) test, stratified by AML status (de novo, secondary) and age (18 – < 75, ≥ 75).  In 
addition, the 95% confidence interval for CR rate based on the binomial distribution 
(Clopper-Pearson exact method) by treatment arms will be provided.  The risk difference 
and 95% confidence interval for the risk difference (exact unconditional confidence 
limits) will also be provided.
10.3.5
Transfusion Independence Rates
Post baseline transfusion independence rate will be calculated as the proportion of 
subjects who achieved transfusion independence post baseline.  Transfusion independence 
is defined as a period of at least 56 days (≥ 56 days) with no transfusion after the first dose 
of study drug and on or before the last dose of study drug + 30 days or before death or 
before the initiation of post-treatment therapy, whichever is earlier.  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 and 2) platelets.  All subjects in the full analysis set will be 
included in the analysis.  Subjects who did not receive any study drug are considered as 
transfusion dependent.  
The post-baseline transfusion independence rates will be compared between two arms 
using CMH test stratified by AML status (de novo, secondary) and age (18 – < 75, ≥ 75).  
In addition, 95% confidence interval based on the binomial distribution (Clopper-Pearson 
exact method) by treatment arms will be provided for the post-baseline transfusion 
independence rate.  The risk difference and 95% confidence interval for the risk 
difference (exact unconditional confidence limits) will also be provided.


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The rates of conversion from baseline transfusion dependence to post-baseline transfusion 
independence for 1) RBC and 2) platelets will be estimated and the 95% confidence 
interval based on the binomial distribution (Clopper-Pearson exact method) by treatment 
arms will be provided.  The risk difference and 95% confidence interval for the risk 
difference (exact unconditional confidence limits) will also be provided.
10.3.6
Minimal Residual Disease (MRD) Response Rates
The proportion of subjects achieved 1) CR + CRi and MRD response 2) CR + CRh and 
MRD response will be calculated among all subjects in the full analysis.  The MRD 
response will be defined using a threshold of less than 10–3 of residual blasts per 
leukocytes as measured in bone marrow.  Subjects who are randomized but have no MRD 
assessment will be considered as non-responders for the calculation of MRD response 
rate.  All subjects in the full analysis set will be included in the analysis.
The proportion of subjects who achieved CR + CRi and MRD response or CR + CRh and 
MRD response will be compared between two arms using CMH test stratified by age 
(18 – < 75, ≥ 75) and AML status (de novo, secondary).  In addition, 95% confidence 
interval based on the binomial distribution (Clopper-Pearson exact method) by treatment 
arms will be provided.  The risk difference and 95% confidence interval for the risk 
difference (exact unconditional confidence limits) will also be provided.
10.3.7
Quality of Life (QoL)
Any subject who does not have baseline measurement or any post-baseline measurements 
in the full analysis set will not be included in QoL analyses.  Post-baseline measurements 
will be obtained according to the visit window as in Table 3.
PROMIS Cancer Fatigue SF 7a
PROMIS instruments measure concepts such as pain, fatigue, physical function, 
depression, anxiety and social function.  
(https://www.assessmentcenter.net/documents/PROMIS%20Fatigue%20Scoring%20Man
ual.pdf).  Fatigue will be assessed using the PROMIS Cancer Fatigue SF that has been 


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developed for use in oncology populations.  PROMIS Cancer Fatigue SF 7a is a 
seven item questionnaire that assesses the impact and experience of fatigue over the past 
7 days.  All questions employ the following five response options:  1 = Never, 2 = Rarely, 
3 = Sometimes, 4 = Often, and 5 = Always. 
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 an appropriate covariance structure will be fitted to 
the longitudinal data to test for differences between the two treatment arms.  For the linear 
mixed effects regression model, stratification factors (age (18 – < 75, ≥ 75) and AML 
status (de novo, secondary)) and treatment arm will be included as fixed factors.  
Furthermore, time and treatment by time interaction will be included in the model.  The 
repeated correlation structure in the timepoints will be assessed by using the Bayesian 
Information Criterion (BIC).  The following covariance structures will be explored:  
Unstructured (TYPE = UN), compound symmetry (TYPE = CS) and first-order 
autoregressive (TYPE = AR(1)).  The type resulting in model convergence and the lowest 
BIC will be used for analysis.  Change in the PROMIS Fatigue score from baseline will 
be compared between the two treatment arms for each post baseline visit except the final 
observation.  
EORTC QLQ-C30
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."
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 an appropriate covariance structure will be fitted to the longitudinal 


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data to test for differences between the two treatment arms.  For the linear mixed effects 
regression model, stratification factors (age (18 – < 75, ≥ 75) and AML status (de novo, 
secondary)) and treatment group will be included as fixed factors.  Furthermore, time and 
treatment by time interaction will be included in the model.  The repeated correlation 
structure in the timepoints will be assessed by using the Bayesian Information Criterion 
(BIC).  The following covariance structures will be explored:  Unstructured (TYPE = 
UN), compound symmetry (TYPE = CS) and first-order autoregressive (TYPE = AR(1)).  
The type resulting in model convergence and the lowest BIC will be used for analysis.  
Change in the PROMIS Fatigue score from baseline will be compared between the 
two treatment arms for each post baseline visit except the final observation.
10.3.8
Event-free Survival
Event-free Survival (EFS) will be defined as the number of days from randomization to 
the date of progressive disease, confirmed morphologic relapse from CR or CRi, 
treatment failure defined as failure to achieve CR, CRi or MLFS after at least 6 cycles of 
study treatment collected on study drug completion eCRF or death from any cause.  The 
confirmation is required for morphologic relapse (MR).  Based on the IWG criteria 
implemented in the protocol, if the bone marrow blasts are between 5 - 10%, a repeated 
bone marrow assessment should be conducted to distinguish between bone marrow 
regeneration and relapse.  For MR with bone marrow blast ≤ 10% and followed by a non-
PD/non-MR response prior to start of post-treatment therapy, this MR is considered an 
unconfirmed MR and therefore, the subject is still considered to be a responder.   
If the specified event does not occur, subjects will be censored.  The detailed censoring 
rule is described in Table 4.  Data for subjects without any disease assessments performed 
after randomization will be censored at the time of randomization.  


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Table 4.
Event/Censor and Corresponding Event/Censor Time for EFS
Situation
Event/Censor
Event Time/Censor Time
PD, confirmed morphologic relapse (MR),* and 
treatment failure events on or prior to any post-
treatment therapy and data cutoff date, whichever 
is earliest
Event
Earliest PD, MR or treatment 
failure event date
Death event on or prior to data cutoff date 
regardless whether it occurred after any post-
treatment therapy initiated
Event
Death date
No PD, confirmed MR,* treatment failure, or 
death events, and without post-treatment therapy 
initiated on or prior to the data cutoff date
Censor
Last disease assessment date 
(bone marrow or hematology lab 
collection date) on or prior to the 
data cutoff date
No confirmed MR,* PD, or treatment failure on or 
prior to post-treatment therapy initiated on or prior 
to the data cutoff date, and no death on or prior to 
data cutoff
Censor
Start date of post-treatment 
therapy
*
An un-confirmed MR is defined as a MR with bone marrow blast ≤ 10% and followed by non-PD/Non-MR prior to 
the post-treatment therapy.  Otherwise, MR is considered to be a confirmed MR.
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 
AML status (de novo, secondary) and age (18 – < 75, ≥ 75).  Median EFS will be 
calculated and 95% confidence interval for median EFS will be presented by treatment 
arm.  The hazard ratio between treatment arms will be estimated using the Cox 
proportional hazards model stratified by age (18 – < 75, ≥ 75) and AML status (de novo, 
secondary).
10.4
Exploratory Efficacy Endpoint 
10.4.1
Additional Quality of Life Analyses 
EQ-5D-5L
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.  


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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.  
Additional exploratory analyses comparing the effects of venetoclax + cytarabine versus 
placebo + LDAC 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.  Scores 
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 similar to that 
described in Section 10.3.7 will be used to test for differences between treatment arms.  
Within-group changes from baseline and between-group comparisons at each assessment 
will also be assessed.  Additional analyses may include an assessment of time to 
deterioration and time to improvement.
10.4.2
Duration of CR + CRi
Duration of CR + CRi will be defined as the number of days from the date of 
first response (CR or CRi) per the modified IWG criteria for AML to the earliest evidence 
of confirmed morphologic relapse, progressive disease or death due to disease 
progression.  If a subject is still responding at the data cutoff date, then the subject will be 
censored.  The disease assessment data after the onset of any post-treatment therapy will 
not be included in the duration of CR + CRi analysis.  The detailed censoring rule is 
described in Table 5.  Duration of CR + CRi will be analyzed for all randomized subjects 
who achieve the best response of CR or CRi.


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Table 5.
Event/Censor and Corresponding Event/Censor Time for Duration 
of CR + CRi
Situation
Event/Censor
Event Time/Censor Time
Confirmed morphologic relapse (MR)* or 
progressive disease (PD) on or prior to any post-
treatment therapy and data cutoff date, whichever is 
earliest
Event
Earliest MR or PD event date
Death due to disease progression on or prior to data 
cutoff date regardless whether it occurred after any 
post-treatment therapy initiated
Event
Death date
No confirmed MR,* PD, or death due to disease 
progression events and without post-treatment 
therapy initiated on or prior to the data cutoff date
Censor
Last disease assessment date 
(bone marrow or hematology 
lab collection date) on or prior 
to the data cutoff date
No confirmed MR,* or PD on or prior to post-
treatment therapy initiated on or prior to the data 
cutoff date, no death due to disease progression on 
or prior to data cutoff date
Censor
Start date of post-treatment 
therapy
*
An un-confirmed MR is defined as a MR with bone marrow blast ≤ 10% and followed by non-PD/Non-MRprior to 
the post-treatment therapy.  Otherwise, MR is considered to be a confirmed MR.
The distribution of duration of CR + CRi will be estimated for each treatment arm using 
Kaplan-Meier methodology.  Median duration of CR + CRi will be calculated and 95% 
confidence interval for median duration of CR + CRi will be presented by treatment arm.
Analysis of modified duration of CR + CRi that includes death from all causes by the 
cutoff date will be performed as a sensitivity analysis.
10.4.3
Duration of CR
Duration of CR will be defined as the number of days from the date of first CR per the 
modified IWG criteria for AML to the earliest evidence of morphologic relapse, 
progressive disease, or death due to disease progression.  The censoring rule described in
Table 5 will be applied to the analysis of duration of CR.
Analysis of modified duration of CR that includes death from all causes by the cutoff date
will be performed as a sensitivity analysis.


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10.4.4
Duration of CR + CRh
Duration of CR + CRh will be defined as the number of days from the date of first 
response (CR or CRh) to the earliest evidence of morphologic relapse, progressive disease 
or death due to disease progression.  The censoring rule described in Table 5 will be 
applied to the analysis of duration of CR + CRh.
Analysis of modified duration of CR + CRh that includes death from all causes by the 
cutoff date will be performed as a sensitivity analysis.
10.5
Efficacy Analysis per Independent Review Committee
An Independent Review Committee (IRC) will evaluate disease assessment data on all 
randomized subjects.  The analysis for the following efficacy endpoints, described in 
Section 10.3 and Section 10.3.8, will be conducted based on this IRC review: 
●
CR rate
●
CR + CRi rate 
●
CR + CRi rate by the initiation of Cycle 2 
●
EFS
10.6
Additional Efficacy Analysis
In addition to the stratified log-rank test for the primary and secondary efficacy endpoints, 
the following analyses may be performed for the comparison of OS, CR rate, CR + CRi 
rate, CR + CRh rate, CR + CRi rate by the initiation of Cycle 2, and CR + CRh rate by the 
initiation of Cycle 2 between the two treatment groups.
●
Un-stratified log-rank test and the Cox proportional hazards model for OS 
●
CMH test for CR rate and CR + CRi rate using IRC data
●
Fisher's exact test for CR rate and CR + CRi rate using investigator assessment 
data and IRC data


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●
Modified analyses for OS, CR rate, CR + CRi rate, CR + CRi rate by the 
initiation of Cycle 2, CR + CRh rate, and CR + CRh rate by the initiation of 
Cycle 2 to use all data available in the extracted database (no "Cutoff" date).
10.7
Handling of Multiplicity
The fixed sequence testing procedure will be performed with a significance level of 0.05 
for the primary endpoint OS and key secondary efficacy endpoints sequentially.  If 
statistical test is not significant for the primary efficacy endpoint of OS, then statistical 
significance will not be declared for any of the secondary efficacy endpoints.  The Lan-
DeMets alpha spending function with O'Brien-Fleming boundary will be used at the 
interim and final analysis to ensure that the false positive rate for each primary or key 
secondary efficacy endpoint is 0.05 or less.
For CR + CRi rate, CR + CRi rate by the initiation of Cycle 2, CR + CRh rate, CR + CRh 
rate by the initiation of Cycle 2, CR rate, transfusion independence rates, and MRD 
response rate, the information fraction to be used at IA (100 death events) is calculated as 
detailed in Table 6.
Table 6.
Calculation of Information Fraction (IF)
Endpoint
Information Fraction
CR + CRi rate
Portion of subjects with at least 6 months follow up since randomization
CR + CRh rate
Portion of subjects with at least 6 months follow up since randomization
MRD response rate
Portion of subjects with at least 6 months follow up since randomization
CR + CRi rate by the 
initiation of Cycle 2
Portion of subjects who started Cycle 2 Day 1 dosing or discontinued 
treatment by the end of Cycle 1
CR + CRh rate by the 
initiation of Cycle 2
Portion of subjects who started Cycle 2 Day 1 dosing or discontinued 
treatment by the end of Cycle 1
CR rate
Portion of subjects with at least 9 months follow up since randomization
Transfusion independence 
rates (RBC/Platelet) 
Portion of subjects with at least 9 months follow up since randomization


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Table 7 (for EU and EU reference countries) and Table 8 (for US and US reference 
countries) present the hierarchical ranking and alpha spending for each ranked primary 
and secondary endpoints at IA and FA.
Table 7.
Alpha-spending Boundary (One-sided p-value) for Each Ranked 
Endpoint for EU and EU Reference Countries
Endpoint
Timing of Analysis
IA
FA
1
OS
As specified in Table 2
As specified in Table 2
2
CR + CRi ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
3
Post-baseline platelet transfusion 
independencea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
4
CR + CRi rate in IDH1/2 subgroupa,b
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
5
CR ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
6
CR + CRi by the initiation of Cycle 2a
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
7
Post-baseline RBC transfusion 
independencea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
8
MRD and CR + CRi response ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
9
EORTC QLQ-C30
0.0001
0.025
10
PROMIS Cancer Fatigue SF 7a
0.0001
0.025
11
OS in IDH1/2 subgroupb
0.0001
0.025
12
OS in FLT3 subgroupb
0.0001
0.025
13
CR + CRi rate in FLT3 subgroupb
0.0001
0.025
14
EFS
0.0001
0.025
a.
The Lan DeMets with O'Brien-Fleming approach will be applied to determine the efficacy boundaries of the 
following ranked secondary endpoints with the information fraction define in Table 6.
b.
If the size of identified subgroup population is less than 30 or randomization ratio between Venetoclax + LDAC 
arm and placebo + LDAC arm is higher than 3:1 at the time of IA and FA, the endpoint will be ranked below EFS 
in the fixed sequence testing procedure.


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Table 8.
Alpha-spending Boundary (One-sided p-value) for Each Ranked 
Endpoint for US and US Reference Countries
Endpoint
Timing of Analysis
IA
FA
1
OS
As specified in Table 2
As specified in Table 2
2
CR + CRh ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
3.
CR + CRi ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
4
Post-baseline platelet transfusion 
independencea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
5
CR + CRh rate in IDH1/2 subgroupa,b
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
6
CR ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
7
CR + CRh by the initiation of Cycle 2a
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
8
Post-baseline RBC transfusion 
independencea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
9
MRD and CR + CRh response ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
10
MRD and CR + CRi response ratea
To be calculated with IF 
as specified in Table 6
To be calculated with IF 
as specified in Table 6
11
PROMIS Cancer Fatigue SF 7a
0.0001
0.025
12
EORTC QLQ-C30
0.0001
0.025
13
OS in IDH1/2 subgroupb
0.0001
0.025
14
OS in FLT3 subgroupb
0.0001
0.025
15
CR + CRh rate in FLT3 subgroupb
0.0001
0.025
16
EFS
0.0001
0.025
a.
The Lan DeMets with O'Brien-Fleming approach will be applied to determine the efficacy boundaries of the 
following ranked secondary endpoints with the information fraction define in Table 6.
b.
If the size of identified subgroup population is less than 30 or randomization ratio between Ven + LDAC arm and 
placebo + LDAC arm is higher than 3:1 at the time of IA and FA, the endpoint will be ranked below EFS in the 
fixed sequence testing procedure.


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10.8
Efficacy Subgroup Analyses
To evaluate the impact of demographic and baseline characteristics on efficacy, subgroup 
analyses will be performed, but not limited to, for CR rate, CR + CRi rate, CR + CRh rate, 
CR + CRi rate by the initiation of Cycle 2, CR + CRh rate by the initiation of Cycle 2, and 
overall survival.  The subgroups in the full analysis set including, but not limited to, those 
defined below will be used for these analyses: 
1.
Gender (Male, Female)
2.
Age (18 – < 65 years, 65 – < 75 years, ≥ 75 years)
3.
AML status (de novo, secondary)
4.
Type of secondary AML (therapy related, post MDS/CMML)
5.
Region (US, EU, China, JP, ROW)
6.
Baseline ECOG (< 2, ≥ 2)
7.
Subjects who received prior HMA for MDS (Yes, No)
8.
Cytogenetic risk categorization (Favorable, Intermediate, Poor)
9.
Molecular marker(FLT3, IDH1/2, TP53, NPM1)
10.
AML with Myelodysplasia related changes (AML-MRC)
11.0
Safety Analysis
Safety assessments will only include subjects in the safety analysis set as described in 
Section 5.1.  Safety will be assessed by treatment received for the safety analysis set.  
11.1
Analysis of Treatment-Emergent Adverse Events
All summaries/analyses involving AEs will include treatment-emergent adverse events 
(TEAE) only, unless otherwise specified.  TEAEs are defined as any adverse event with 
onset after the first dose of study drug and no more than 30 days after the last dose of 


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study drug.  Events where the onset date is the same as the study drug start date are 
assumed to be treatment-emergent.  If an incomplete or missing onset date was collected 
for an AE, the AE will be assumed to be treatment-emergent unless there is evidence that 
confirms that the AE was not treatment-emergent (e.g., the AE end date was prior to the 
date of the first dose of study drug).
For summaries of AEs related (reasonable possibility) to study drug, at each level of 
summation (overall, SOC, and PT) each subject is counted only once.  If a subject has an 
AE with unknown relationship, then the subject will be counted in the relationship 
category of "unknown," even if the subject has another occurrence of the same event with 
a relationship of "no reasonable possibility" present.  The only exception is if the subject 
has another occurrence of the same AE with the relationship of "reasonable possibility."  
In this case, the subject will be counted under the reasonable possibility category.
Adverse event data will be summarized and presented using primary MedDRA system 
organ classes (SOCs) and preferred terms (PTs) according to the MedDRA coding 
dictionary version 21.0 or higher.
The number and percentage of subjects experiencing treatment-emergent adverse events 
will be summarized for the following adverse event summaries:
●
Any treatment-emergent adverse event.
●
Any treatment-emergent adverse event with NCI toxicity (CTCAE V4.03) 
grade 3, 4, or 5 adverse events.
●
Any treatment-emergent serious adverse event.
●
Any treatment-emergent adverse event with reasonable possibility related to 
venetoclax/placebo by the investigator.
●
Any treatment-emergent adverse event leading to discontinuation of 
venetoclax/placebo.
●
Any treatment-emergent adverse event leading to venetoclax/placebo 
interruption.


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●
Any treatment-emergent adverse event leading to venetoclax/placebo 
reduction.
●
Any treatment-emergent adverse event with reasonable possibility related to 
LDAC by the investigator.
●
Any treatment-emergent adverse event leading to discontinuation of LDAC.
●
Any treatment-emergent adverse event leading to LDAC interruption.
●
Any treatment-emergent adverse event leading to LDAC reduction.
●
Any treatment-emergent adverse event leading to death.
In addition, the treatment emergent AEs and serious AEs for selected grouped preferred 
terms (PTs) including, but not limited to, those listed in Table 9, will be summarized.
Table 9.
Selected Adverse Events
Selected Adverse Events
Search Criteria
Tumor Lysis Syndrome (AE)
SMQ – "Tumor Lysis Syndrome" (narrow)
Grade ≥ 3 neutropenia
PT terms – "neutropenia," "neutrophil count decreased," "febrile 
neutropenia," "agranulocytosis," "neutropenic infection," and 
"neutropenic sepsis"
Grade ≥ 3 infection, including 
opportunistic infections
SOC of "infections and infestations"
Haemorrhages
SMQ – "Haemorrhages" (narrow)
Anemia
PT terms – "Anaemia" and "Haemoglobin decreased"
Thrombocytopenia
PT terms – "Thrombocytopenia" and "Platelet count decreased"
There will be no statistical comparison for TEAEs between two treatment arms.
11.2
Deaths
The number of subject deaths will be summarized (1) for all deaths in this study 
regardless of the number of days after the last dose of study drug, (2) for deaths occurring 
within 30 days of the first dose of study drug, (3) for deaths occurring within 60 days of 
the first dose of study drug, (4) for deaths occurring within 30 days of the last dose of 


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study drug, and (5) for deaths occurring more than 30 days of the last dose of study drug.  
There will be no statistical comparison for above analyses.
11.3
Analysis of Laboratory and Vital Signs Data
The value for baseline used in laboratory is defined in Section 6.0.  Post baseline visits 
windows are specified in Table 2.  There will be no statistical comparison for laboratory 
data between two treatment arms.
11.3.1
Analysis of Mean Changes from Baseline in Clinical 
Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each chemistry, hematology, and vital sign 
parameters at scheduled post-baseline visits and the final observation (Table 2).  
Descriptive statistics including mean, standard deviation and median for baseline, and 
mean, standard deviation, median, minimum and maximum for change from baseline will 
be presented for baseline, each scheduled post-baseline visit, and final observation by 
each treatment arm.  Laboratory tests to be summarized are included in Table 10 (if data is 
available).


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Table 10.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Blast count
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not acceptable)
Blood urea nitrogen (BUN)
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
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH)
Chloride
Bicarbonate
Coagulation
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
11.3.2
Analyses of Shift from Baseline in Clinical Laboratory Data
For shifts relative to National Cancer Institute Common Toxicity Criteria for Adverse 
Events (NCI CTCAE version 4.03), baseline and post-baseline laboratory observations 
will be categorized as grade 0, grade 1, grade 2, grade 3, or grade 4 according to 
NCI CTCAE grade version 4.03.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected on or prior to the first dose of study drug (or randomization for 
non-treated subjects), and as the last post-baseline measurement collected no more than 
30 days after the last dose of study drug.  
The maximum NCI toxicity grade value is the value with highest NCI toxicity grade 
collected after the first dose of study drug and within 30 days following the last dose of 


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study drug.  In cases where multiple values are collected on the same day, the maximum 
grade value will be selected as the value for that day.
For each variable, shift tables will be generated that cross tabulate the number of subjects 
with baseline values of grade 0, grade 1, grade 2, grade 3, or grade 4 versus maximum 
post-baseline/final observations of grade 0, grade 1, grade 2, grade 3, or grade 4.  All 
treated subjects will be included in the cross tabulation regardless whether baseline or 
post-baseline measurements are collected.
The separate laboratory shifts tables, based on the two criteria below will be generated for 
each laboratory tests related to CTCAE:
1.
Shifts from Grade 0 (Normal) at baseline to grade 1 - 4 Post-baseline (maximum) 
and worsening from an abnormal baseline value of at least one grade up post-
baseline (maximum)
2.
Shits from Grade 0 - 2 at baseline to grade 3 or 4 Post-baseline (maximum) and 
from grade 3 at baseline value to Grade 4 post-baseline (maximum).
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug will be included in these 
listings.
Number and percentage of subjects with liver Enzyme value meeting the criteria for 
potential drug-induced liver injury (ALT > 3 × ULN or AST > 3 × ULN and TBILI > 2 × 
ULN within 72 hours of each other) will be presented.  
Number and percentage of subjects meeting the Howard criteria for Laboratory TLS will 
be presented.  Laboratory TLS requires two or more metabolic abnormalities must be 
present during the same 24-hour period.  The evaluation period for TLS is after the first 
dose of study drug during Cycle 1 until 7 days from the first dose of study drug.  


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●
uric acid > 476 mcmol/l, 
●
potassium > 6 mmol/l, 
●
inorganic phosphorus > 1.5 mmol/l 
●
calcium < 1.75 mmol/l.
11.4
Safety Subgroup Analysis
Safety analysis as described in Section 11.1, Section 11.2, and Section 11.3, may also be 
summarized for the subgroups in the safety analysis set including, but not limited to, those 
defined below: 
●
Region (US, EU, China, JP, ROW)
●
Gender (Male, Female)
●
Age (18 – < 65 years, 65 – < 75 years, ≥ 75 years)
●
Hepatic impairment at baseline (Yes, No)
●
Renal impairment at baseline (Yes, No)
12.0
Pharmacokinetic (PK) Analyses
Plasma concentrations of study drug 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.  For Chinese subjects enrolled in China, pharmacokinetic parameter values will be 
tabulated for each subject, and summary statistics will be computed for each 
pharmacokinetic parameter.  Samples with significant sampling time deviations will be 
excluded from summary statistics calculations.
13.0
References
1.
Cheson BD, Bennett JM, Kopecky KJ, et al.  International working group for 
diagnosis, standardization of response criteria, treatment outcomes, and reporting 
standards for therapeutic trials in acute myeloid leukemia.  Revised 
recommendations of the international working group for diagnosis, standardization 


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of response criteria, treatment outcomes, and reporting standards for therapeutic 
trials in acute myeloid leukemia.  J Clin Oncol.  2003;21(24):4642-9.
2.
Döhner H, Estey E, Grimwade D, et al.  Diagnosis and management of AML in 
adults:  2017 ELN recommendations from an international expert panel.  Blood.  
2017;129(4):424-47.
3.
Lan KKG, DeMets DL.  Discrete sequential boundaries for clinical trials.  
Biometrika.  1983;70(3):659-63.
4.
Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  
2011;364(19):1844-54.
5.
Xu T, Qin Q, Wang X.  Defining information fraction in group sequential clinical 
trials with multiple endpoints.  Contemp Clin Trials Commun.  2018;10:77-9.


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14.0
Appendix
List of Abbreviations
AML
acute myeloid leukemia
BCL
B cell lymphocyte
BTD
Breakthrough Therapy Designation
CI
confidence interval
CR
complete remission
CRi
complete remission with incomplete blood count recovery
CRh
complete remission with partial hematologic recovery
CTC
Common Terminology Criteria
ECOG
Eastern Cooperative Oncology Group
EFS
event-free survival
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core
FEV1
forced expiratory volume in 1 second
FLT3
FMS-like tyrosine kinase 3
GFR
glomerular filtration rate
HCT
hematopoietic stem cell transplantation
HCT-CI
Hematopoietic Stem Cell Transplant Co-Morbidity Index
HMA
hypomethylating agent
DMC
data monitoring committee
IRC
independent review committee
ITD
internal tandem duplication FLT3
IWG
International Working Group
LDAC
low-dose cytarabine
MDS
myelodysplastic syndrome
MLFS
morphologic leukemia-free state
MR
morphologic relapse
MRD
minimal residual disease
OS
overall survival
PD
progressive disease
PR
partial remission
PROMIS
Patient Reported Outcomes Measurement Information System


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QD
once daily
TLS
tumor lysis syndrome
US
United States