Clinical trial NCT02287233
Conditions: Acute Myelogenous Leukemia AML
Keywords: Myelogenous Leukemia Treatment Naive AML Untreated AML
Sponsor: AbbVie
Start date: 2014-12-31; Completion date: 2021-08-10
Enrollment: 94 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study consists of two parts: A Phase 1 dose-escalation part that will evaluate the safety and pharmacokinetic profile of venetoclax in combination with low-dose cytarabine (LDAC), define the maximum tolerated dose (MTD), and generate data to support a recommended Phase 2 dose (RPTD) in treatment-naïve participants with acute myelogenous leukemia (AML); and a Phase 2 part that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy.

Detailed description:

Arms: arm 1: Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.

Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. arm 2: Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.

Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. arm 3: Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.

Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
Interventions: intervention 1: Venetoclax intervention 2: Cytarabine
Intervention descriptions: intervention 1: Venetoclax will be taken orally once daily. intervention 2: Low-dose cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.

Protocol documents:
Prot_000.pdf: 
Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
1
1.0
Title Page
Clinical Study Protocol M14-387
A Phase 1/2 Study of Venetoclax in Combination 
with Low-Dose Cytarabine in Treatment-Naïve 
Subjects with Acute Myelogenous Leukemia Who 
Are ≥60 Years of Age and Who Are Not Eligible for 
Standard Anthracycline-Based Induction Therapy
Incorporating Administrative Change 1 and 
Amendments 1, 2, 3, 4, 5, 6 and 7
AbbVie Investigational
  Product:
Venetoclax (ABT-199/GDC-0199)
Date:
22 October 2020
Development Phase:
1/2
EudraCT
2014-002610-23
Study Design:
This is a Phase 1/2 open-label, non-randomized, multicenter 
study consisting of two phases.  A Phase 1, or 
dose-escalation portion, which will evaluate the safety and 
pharmacokinetic profile of venetoclax 
(ABT-199/GDC-0199) administered orally in combination 
with low-dose cytarabine (LDC) with the objective of 
defining the maximum tolerated dose (MTD) and generating 
data to support the recommended Phase 2 dose (RPTD) in 
treatment-naïve subjects with Acute Myelogenous 
Leukemia (AML) who are ≥60 years of age and who are 
not eligible for standard induction therapy due to 
co-morbidity or other factors.  A subsequent initial Phase 2 
portion will evaluate if the RPTD has sufficient efficacy and 
acceptable toxicity to warrant further development of the 
combination therapy.  Subsequently, within Phase 2, 
Cohort C will evaluate the overall response rate (ORR) for 
subjects allowed additional supportive medications (strong 
CYP3A inhibitors) if medically indicated.
Investigator:
Investigator information on file at AbbVie
Sponsor:
AbbVie*
NCT02287233


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
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Sponsor/Emergency 
  Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Fax:
*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.


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
05 August 2014
Amendment 1
11 November 2015
Administrative Change 1
25 November 2015
Amendment 2
28 November 2016
Amendment 3
31 May 2017
Amendment 4
24 January 2018
Amendment 5
22 March 2019
Amendment 6
27 February 2020
The purpose of this amendment is to:
●
Section 3.3 - included information on the re-evaluation of the benefit and risk 
with consideration of Coronavirus Disease 2019 present in subject's region.
●
Section 5.3.1 - added instructions for necessary changes to activities or 
procedures in the event of temporary study [drug] interruption/halt.
●
Section 5.5.1 - included instructions that in the event the subject cannot pick 
up venetoclax onsite, DTP shipment can be done as needed and permitted by 
local regulations.
●
Section 7.0 - clarified that protocol deviations may include modifications due 
to COVID-19.
●
Section 9.2 - noted that AbbVie will modify the study protocol as necessary 
due to the pandemic. Investigators must also notify AbbVie if any urgent 
safety measures are taken.
●
Section 10.1 - noted that remote monitoring may be employed as needed.
●
Modified the language for survival and post treatment follow up time frames to 
permit a shorter duration of follow up if all patients have discontinued and 
most patients have expired.
●
Editorial changes throughout the protocol.


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
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An itemized list of all changes made to this protocol amendment can be found in 
Appendix I.


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-387
Name of Study Drug:  venetoclax 
(ABT-199/GDC-0199) 
Phase of Development:  1/2
Name of Active Ingredient:  ABT-199
Date of Protocol Synopsis:  22 October 2020
Protocol Title:  A Phase 1/2 Study of Venetoclax in Combination with Low-Dose Cytarabine in 
Treatment Naïve Subjects with Acute Myelogenous Leukemia Who Are ≥ 60 Years of Age and Who 
Are Not Eligible for Standard Anthracycline-Based Induction Therapy
Objectives:  
Primary Objectives:

The primary objectives of the Phase 1 portion are to assess the safety profile, characterize 
pharmacokinetics (PK), determine the dose schedule, the maximum tolerated dose (MTD), and the 
recommended Phase 2 dose (RPTD) of venetoclax (ABT-199/GDC-0199) in combination with 
LDC in treatment-naïve subjects with AML who are ≥65 years of age and who are not eligible for 
standard induction therapy due to co-morbidity or other factors.

The primary objectives of the initial Phase 2 portion of the study are to evaluate the preliminary 
estimates of efficacy including the overall response rate (ORR) and to characterize the toxicities of 
the combination at the RPTD.

The primary objective of Phase 2 Cohort C is to evaluate the ORR for subjects allowed additional 
supportive medications (strong CYP3A inhibitors) if medically indicated.
Secondary Objective:

The secondary objectives of the initial Phase 2 portion and Phase 2 Cohort C are to evaluate 
leukemia response (rates of CR, CRi, PR, and MLFS), duration of response (DOR) and overall 
survival (OS).
Exploratory Objective:

Additional exploratory objectives of both phases of the study may be evaluated to find biomarkers 
that may serve as surrogates or predictors for clinical outcomes in future studies of venetoclax in 
AML.
Investigators:  Investigator information on file at AbbVie
Study Sites:  Approximately 10 sites globally
Study Population:  Adult subjects ≥ 65 years of age with untreated AML for whom standard induction 
therapy is not appropriate due to age, co-morbidity, or other factors.  Additionally, in Phase 2 Cohort C 
only, subjects aged 60 – 64 may be enrolled if they have specified co-morbidities that preclude treatment 
with anthracycline-containing induction chemotherapy.
Number of Subjects to be Enrolled:  Up to 42 subjects will be enrolled in the Phase 1 portion.  
Approximately 50 subjects will be enrolled in the initial Phase 2 portion.  In addition, approximately 
20 subjects will be enrolled in Phase 2 Cohort C.


Venetoclax (ABT-199/GDC-0199)
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Methodology:
This is a Phase 1/2, open-label, multicenter study that will evaluate the PK, safety and preliminary 
efficacy of venetoclax combined with LDC in treatment-naïve subjects with AML ≥65 years old and 
who are not eligible for standard induction therapy due to age, co-morbidity or other factors.  This study 
will consist of two distinct portions or phases.  The first portion of the study is a Phase 1, or 
dose-escalation portion, that will evaluate the safety and PK profile of venetoclax administered with 
LDC with the objectives of defining the MTD and generating data to support a RPTD.  A subsequent 
initial Phase 2 portion will evaluate whether the RPTD has sufficient efficacy and acceptable toxicity to 
warrant further development of the combination therapy.  Subsequently, a cohort of subjects, Phase 2 
Cohort C, will be enrolled permitting a broader range of supportive medication (strong CYP3A 
inhibitors) co-administration.  Age entry criteria for these subjects will be ≥ 60 years.
For the Phase 1 portion, a classical 3 + 3 design is utilized to define the MTD of venetoclax in 
combination with a standard LDC regimen.  Subjects are enrolled in cohorts of three.  The first subject 
from the subsequent cohort should not begin their intended dosing regimen until it is declared by the 
sponsor that no dose limiting toxicities (DLTs) have occurred during Cycle 1 of the previous dose level.  
For this trial, a DLT is defined as experiencing a Common Terminology Criteria for Adverse Events 
(CTCAE) grade 4 or 5 toxicity, unless such events are in the common list of health events due to AML, 
or not recovering platelets to at least 25,000/μL and absolute neutrophil count (ANC) to 500/μL within 
14 days of the last dose of venetoclax unless such cytopenias are due to residual leukemia effect.  Should 
1 subject experience a DLT, an additional 3 subjects will be enrolled at the same dose level (a total of 
6 subjects at this dose level).  Should 2 subjects at a dose level experience a DLT, that dose level is 
considered too toxic.  The dose level below the too toxic dose level may be considered the MTD.  
Additional subjects are then enrolled at the putative MTD to bring the total number enrolled at the MTD 
to 6.  If, during this cohort expansion, a total of 2 subjects at this dose level also experience a DLT, this 
level would also be considered too toxic and the method continues thusly until the maximal dose level is 
achieved where 6 subjects can be treated through Cycle 1 and no more than one subject experiences a 
DLT to define the MTD.
Biomarkers (such as cytogenetics, molecular markers, characterization of Bcl-2 and associated proteins 
or ex vivo testing of AML subject samples) that may be predictive of venetoclax will be assessed 
throughout the trial and may be used to enrich for subjects likely to respond to venetoclax.


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
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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 the first day of therapy:
1.
Subject must be ≥ 65 years of age in Phase 1 and initial Phase 2.  Subjects enrolled in Phase 2 
Cohort C must be either:

≥ 75 years of age;
OR

≥ 60 to 74 years will be eligible if the subject has at least one of the following co-morbidities, 
which make the subject unfit for intensive chemotherapy:
o
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 (calculated by Cockcroft-Gault formula)
o
Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 ×ULN
o
Any other comorbidity that the physician judges to be incompatible with intensive 
chemotherapy must be reviewed and approved by the study medical monitor before study 
enrollment
2.
Subject must have a projected life expectancy of at least 12 weeks.
3.
Subject must have histological confirmation of AML and be ineligible for treatment with a standard 
cytarabine and anthracycline induction regimen due to co-morbidity or other factors.
4.
Subject must have received no prior treatment for AML with the exception of hydroxyurea, allowed 
through the first cycle of study treatment.  Note:  Subject may have been treated for prior 
Myelodysplastic Syndrome.
5.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status;

of 0 to 2 for subjects ≥ 75 years of age

of 0 to 3 for subjects ≥ 60 to 74 years of age, if 0 – 1 another co-morbidity is required to make 
subject eligible.
6.
Subject must have adequate renal function as demonstrated by a creatinine clearance ≥30 mL/min; 
determined via urine collection for 24-hour creatinine clearance or by the Cockcroft-Gault formula.
Note:
Investigators should consider measuring a 24-hour creatinine clearance for subjects who are 
morbidly obese, have fluctuating renal function, or who in the investigator's clinical 
judgment may yield a more accurate clearance when measured than when calculated.
7.
Subject must have adequate liver function as demonstrated by:

aspartate aminotransferase (AST) ≤ 2.5 × ULN*

alanine aminotransferase (ALT) ≤ 2.5 × ULN*

bilirubin ≤ 1.5 × ULN for all subjects age 75 and older*
o
Subjects who are < 75 years of age must have a bilirubin of  < 3.0 × ULN
*
Unless considered due to leukemic organ involvement.


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
Note:
Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN per discussion between 
the investigator and AbbVie medical monitor.
8.
Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug 
administration until 180 days after the last dose of study drug.
9.
Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or 
study-specific procedures.
10. If female, subject must be either:

Postmenopausal defined as no menses for 12 or more months without an alternative medical 
cause,
OR

Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
Main Exclusion:  
A subject will be eligible for study participation if he/she does not meet the following criteria within 
21 days prior to the first day of therapy:
1.
Subject has received treatment with cytarabine for a pre-existing myeloid disorder.
2.
Subject has acute promyelocytic leukemia (French-American-British Class M3 AML).
3.
Subject has known active CNS involvement with AML.
4.
Subject has tested positive for HIV (due to potential drug-drug interactions between antiretroviral 
medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that 
may potentially increase the risk of opportunistic infections).  Note:  HIV testing is not required.
5.
Subject has received the following within 7 days prior to the initiation of study treatment:

Strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and 
St. John's wort.
6.
This criterion has been removed.
7.
Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
8.
Subject has a cardiovascular disability status of New York Heart Association Class > 2.  Class 2 is 
defined as cardiac disease in which subjects are comfortable at rest but ordinary physical activity 
results in fatigue, palpitations, dyspnea, or anginal pain.
9.
Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, 
immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of 
the investigator would adversely affect his/her participating in this study.
10. Subject has chronic respiratory disease that requires continuous oxygen use.
11. Subject has a malabsorption syndrome or other condition that precludes enteral route of 
administration.
12. Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not 
limited to:

Uncontrolled systemic infection requiring IV therapy (viral, bacterial or fungal).
13. Subject has a history of other malignancies prior to study entry, with the exception of:


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):  

Adequately treated in situ carcinoma of the breast or cervix uteri;

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 is permitted to meet this 
criterion.
15. Subject is a candidate for a bone marrow or stem cell transplant within 12 weeks after study 
enrollment.
16. Subject has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, 
myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.
Investigational Product:
Venetoclax
Dose:
20 mg QD to 2000 mg QD of venetoclax
Dose Level –2*
Cycle 1:  Day 2:  20 mg, Day 3:  50 mg, Day 4:  100 mg, Day 5:  200 mg, 
Day 6 – Day 28:  200 mg
Cycle 2 through Treatment Discontinuation:  200 mg QD, of a 28-Day 
Cycle
Dose Level –1*
Cycle 1:  Day 2:  20 mg, Day 3: 50 mg, Day 4:  100 mg, Day 5:  200 mg, 
Day 6 – Day 28:  400 mg
Cycle 2 through Treatment Discontinuation:  400 mg QD, of a 28-Day 
Cycle
*
These dose levels will only be implemented if Dose Level 1 (the initial 
dose level) is found to be above the MTD.
Dose Level 1 (STARTING DOSE LEVEL)
Cycle 1:  Day 2:  50 mg, Day 3:  100 mg, Day 4:  200 mg, Day 5:  400 mg, 
Day 6 – Day 28:  600 mg
Cycle 2 through Treatment Discontinuation:  600 mg QD of a 28-Day 
Cycle
Dose Level 2
Cycle 1:  Day 2:  100 mg, Day 3:  200 mg, Day 4:  400 mg, Day 5:  
600 mg, Day 6 – Day 28:  800 mg
Cycle 2 through Treatment Discontinuation:  800 mg QD of a 28-Day 
Cycle
Dose Level 3
Cycle 1:  Day 2:  100 mg, Day 3:  200 mg, Day 4:  400 mg, Day 5:  
800 mg, Day 6 – Day 28:  1200 mg
Cycle 2 through Treatment Discontinuation:  1200 mg QD, of a 28-Day 
Cycle


Venetoclax (ABT-199/GDC-0199)
M14-387 Protocol Amendment 7
EudraCT 2014-002610-23
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Dose (Continued):
Dose Level 4
Cycle 1:  Day 2:  100 mg, Day 3:  200 mg, Day 4:  400 mg; Day 5:  
800 mg; Day 6:  1200 mg, Day 7 – Day 28:  1600 mg
Cycle 2 through Treatment Discontinuation:  1600 QD of a 28-Day Cycle
Dose Level 5
Cycle 1:  Day 2:  100 mg, Day 3:  300 mg, Day 4:  600 mg; Day 5:  
1000 mg; Day 6:  1500 mg, Day 7 – Day 28:  2000 mg
Cycle 2 through Treatment Discontinuation:  2000 QD of a 28-Day Cycle
Note:  Subjects will be hospitalized during the ramp-up period of study 
treatment devoted to venetoclax dose escalation (e.g., Day –1 to Day 7 for 
Dose Level –2 through Dose Level 3 and Day –1 to Day 8 for Dose 
Level 4 and Dose Level 5).
Phase 2 Cohort C** 
Cycle 1:  Day 1:  100 mg, Day 2: 200 mg, Day 3:  400 mg, Day 4 –
Day 28:  600 mg
Cycle 2 through Treatment Discontinuation:  600 mg QD of a 28-Day 
Cycle
**
Applies to subjects enrolled in Amendment 2.
Mode of Administration:
Venetoclax will be self-administered orally QD within 30 minutes after the 
completion of a meal, preferably breakfast.
Days 1 – 28 of all cycles, Cycle = 28 days
Reference Therapy:
Low-Dose Cytarabine
Dose:
20 mg/m2/QD
Days 1 – 10 of all cycles, Cycle = 28 days
Mode of Administration:
Subcutaneous (SC)
Duration of Treatment:
Subjects with controlled disease who have tolerable side effects should continue to receive treatment 
with venetoclax and cytarabine up to 4 years after the last subject is enrolled or until subject 
discontinuation criteria are met.
Criteria for Evaluation:
Efficacy:
Bone marrow biopsies and aspirates must be performed at screening for all subjects.  Cytogenetic and 
molecular profiling must be performed at screening.  In addition, it is recommended that screening bone 
marrow aspiration samples be analyzed by flow cytometry.  Bone marrow aspirate and biopsy must be 
performed prior to Cycle 2 Day 1, Cycle 4 Day 1, and then every 3 cycles thereafter until 
two consecutive samples confirm Complete Remission (CR), again if clinical suspicion of recurrence, 
and at the end-of-study visit for all subjects.
Based on these results, all dosed subjects will be assessed based on the International Working Group 
(IWG) criteria for AML (Cheson et al.  J Clin Oncol.  2003) at each post-baseline visit by the 
investigators.


Venetoclax (ABT-199/GDC-0199)
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EudraCT 2014-002610-23
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Criteria for Evaluation (Continued):
Efficacy (Continued):
CR:
absolute neutrophil count ≥ 103/µL, platelets ≥ 105/µL, red cell transfusion independence, 
and bone marrow with < 5% blasts.
CRi:
bone marrow with < 5% blasts, and peripheral neutrophils of < 103/µL or platelets 
< 105/µL.
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 and/or bone marrow core sample.  There should be no 
blasts with Auer rods or persistence of extramedullary disease.  The presence of a unique 
phenotype (by flow cytometry) identical to what was found in the pretreatment specimen 
(e.g., CD34, CD7 coexpression) should be viewed as persistence of leukemia.
RD:
failure to achieve CR, CRi, PR; only including subjects surviving at least 7 days following 
completion of initial treatment cycle, with evidence of persistent leukemia by blood and/or 
bone marrow examination.
PD:
one or more of the following:  ≥ 50% decrement from maximum response levels in 
neutrophils or platelets, a reduction in hemoglobin by at least 2 g/dL, or transfusion 
dependence not due to other toxicities and bone marrow blast ≥ 5%.
In addition to the response determination using the above IWG AML response criteria, each subject will 
also be evaluated for Hematologic Response (HR) and complete remission with partial hematologic 
recovery (CRh).
CR = complete remission; CRi = CR with incomplete blood count recovery; PR = partial remission; 
MLFS = morphologically leukemia free status; RD = resistant disease; PD = progressive disease
Pharmacokinetic:
Venetoclax PK samples will be collected at 8 hours post-dose on the day of the first venetoclax dose 
administration and for each new escalated dose in all subjects enrolled in the study.  Intensive PK 
samples will be collected for venetoclax in Phase 1.  Sparse PK samples will be collected for venetoclax 
in both the Phase 1 and Phase 2 portions of the study.  For the intensive PK days of venetoclax, values 
for the PK parameters including the maximum observed plasma concentration (Cmax), the time to Cmax
(peak time, Tmax), the area under the plasma concentration-time curve (AUC) from 0 to the time of the 
last measurable concentration (AUCt) and AUC over a 24-hour dose interval (AUC0-24) will be 
determined using noncompartmental methods.  Intensive PK samples will be collected for cytarabine in 
the dose escalation phase.  For the intensive PK days of cytarabine, values for the PK parameters 
including Cmax, Tmax, half-life (t1/2), AUCt, AUC from 0 to infinity (AUC∞) and clearance (CL/F) will be 
determined using noncompartmental methods.  Additional analyses may be performed if useful in the 
interpretation of the data.


Venetoclax (ABT-199/GDC-0199)
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EudraCT 2014-002610-23
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Criteria for Evaluation (Continued):
Pharmacodynamic and Predictive Biomarker Analysis:
A reduction in leukocytosis or blast counts may be evaluated as a measure of venetoclax-induced 
pharmacodynamic activity.  Exploratory research may also be conducted to find biomarkers that may 
serve as surrogates for clinical endpoints in future venetoclax studies or that may be predictive of 
venetoclax activity.  Peripheral blood and bone marrow aspirate samples will be obtained at study 
specified time points.  Biomarker assays may include, but are not limited to, BH3 profiling and ex vivo 
sensitivity testing.  Subject sub-populations (e.g., based on parameters such as cytogenetics, mutation 
profiles or ex vivo venetoclax sensitivities) may be enriched in Phase 2 of the study to increase the 
potential for response to venetoclax.  If necessary, aliquots from PK samples will be utilized for 
biomarker analyses.  Exploratory research analyses may not be included in the clinical study report.
Pharmacogenetics:
DNA samples may be analyzed for genetic factors contributing to the disease or the subject's response to 
venetoclax in terms of pharmacokinetics, tolerability and safety.
Safety:
Adverse event (AE) monitoring, vital signs, physical examination, electrocardiogram (ECG) and 
laboratory values will be assessed.  Guidelines for Tumor Lysis Syndrome (TLS) management are 
provided.  Note:  All subjects will be hospitalized during dose ramp-up and longer as needed, per 
investigator judgment, for bone marrow recovery or for management of disease complications during the 
escalation from each subjects starting dose through at least 24 hours beyond each subject receiving their 
maximal venetoclax dose level.  Chemistry labs pertinent to TLS (including potassium, calcium, uric 
acid, phosphorus, and creatinine) will be performed at pre-dose, 6, and 12 hours post-dose for the 
first dose and each escalated dose, and also as deemed necessary to monitor for TLS.  Chemistries will 
also be performed at 24 hours after administration of the highest venetoclax dose level.
Statistical Methods:
Efficacy:
Analyses of ORR as defined by CR + CRi + PR, CR rate, CRi rate, CRh rate, CR + CRi rate, CR + CRh 
rate, duration of response (DOR), event free survival (EFS), overall survival (OS), the exploratory 
analysis of the proportion of all subjects who achieve minimal residual disease (MRD) negativity, the 
proportion of subjects who are transfusion independent post baseline, and the proportion of subjects who 
undergo subsequent stem cell transplant will be performed for subjects who received study drugs.
Pharmacokinetic:
Plasma concentrations and PK parameter values of venetoclax and cytarabine will be tabulated for each 
subject, visit, and dose regimen, and summary statistics will be computed for each sampling time and 
each parameter.
The dose proportionality of venetoclax and the potential interaction between venetoclax and cytarabine 
will be assessed using linear mixed effect model.
Safety:
A safety analysis will be performed for all dosed subjects unless otherwise indicated.  For the study as a 
whole, adverse events will be evaluated and summarized.  Laboratory test results and vital signs will be 
explored for trends and summarized as appropriate.


Venetoclax (ABT-199/GDC-0199)
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EudraCT 2014-002610-23
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ABT-199
Study Drug Compound, "venetoclax"
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALL
Acute Promyelocytic Leukemia
ALT
Alanine Aminotransferase (also called SGPT)
AML
Acute Myelogenous Leukemia
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASD
Amorphous solid dispersion
AST
Aspartate aminotransferase (also called SGOT)
Bcl
B-Cell Lymphoma
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CHF
Congestive Heart Failure
CLL
Chronic lymphocytic leukemia 
CML
Chronic Myelogenous Leukemia
CNS
Central Nervous System
COVID-19
Coronavirus Disease-2019
CR
Complete Remission
CRi
Complete Remission with Incomplete Blood Count Recovery
CRh
Complete Remission with Partial Blood Hematologic Recovery
CS
Clinically significant 
CTCAE
Common Terminology Criteria for Adverse Events
CYP1A2
Cytochrome P450 1A2
CYP2B6
Cytochrome P450 2B6
CYP2C8
Cytochrome P450 2C8
CYP2C9
Cytochrome P450 2C9
CYP2C19
Cytochrome P450 2C19
CYP2D6
Cytochrome P450 2D6
CYP3A4
Cytochrome P450 3A4
DLCO
Diffusion Capacity of Carbon Monoxide


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DLT
Dose-Limiting Toxicity
DOR
Duration of Response
DTP
Direct-to-patient
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EFS
Event Free Survival
EMA
European Medicines Agency
EMEA
European Agency for the Evaluation of Medicinal Products
FEV1
Forced Expiratory Volume in One Second
GCP
Good Clinical Practice
HDPE
High Density Polyethylene
HR
Hematologic Response
hr
Hour
ICH
International Conference on Harmonization
ICSR
Individual Case Safety Report
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
Kg
Kilogram
L
Liter
LDC
Low-dose cytarabine
LDH
Lactate Dehydrogenase
m
meter
MAD
Multiple Ascending Dose
MCHC
Mean Corpuscular Hemoglobin Concentration
MCL
Mantle Cell Lymphoma
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities


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MLFS
Morphologically Leukemia Free Status
MM
Multiple Myeloma
µg
Microgram
mg
Milligram
µL
Microliter
mL
Milliliter
µM
Micromolar
MPN
Myeloproliferative Neoplasm
MPV
Mean Platelet Volume
MRD
Minimal Residual Disease
MTD
Maximum tolerated dose
MUGA
Multiple Gated Acquisition Scan
NCI
National Cancer Institute
NCS
Not clinically significant
NHL
Non-Hodgkin's Lymphoma
nM
Nanomolar
NOAEL
No-observed-adverse-effect-level
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PFS
Progression Free Survival
PK
Pharmacokinetic
PO
Per Os Orally
PR
Partial Remission
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
SAD
Single Ascending Dose 


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SAE
Serious Adverse Event
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
SUSAR
Suspected Unexpected Serious Adverse Reactions
TLS
Tumor Lysis Syndrome
ULN
Upper Limit of Normal
WBC
White Blood Cell
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
AUCt
Area under the plasma concentration-time curve from time zero to the last 
measureable concentration
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


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................5
1.3
List of Abbreviations and Definition of Terms........................................13
2.0
Table of Contents...................................................................17
3.0
Introduction ...........................................................................23
3.1
Study Rationale........................................................................................31
3.2
Differences Statement..............................................................................33
3.3
Benefits and Risks....................................................................................33
4.0
Study Objective......................................................................34
5.0
Investigational Plan...............................................................35
5.1
Overall Study Design and Plan:  Description ..........................................35
5.2
Selection of Study Population..................................................................47
5.2.1
Inclusion Criteria .....................................................................................47
5.2.2
Exclusion Criteria ....................................................................................50
5.2.3
Prior and Concomitant Therapy...............................................................52
5.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenetic, Safety 
and Efficacy, Assessments/Variables ......................................................54
5.3.1
Safety and Efficacy Measurements Assessed and Flow Chart ................54
5.3.1.1
Study Procedures .....................................................................................64
5.3.1.2
Confinement.............................................................................................75
5.3.1.3
Meals and Dietary Requirements.............................................................75
5.3.1.4
Blood Samples for Pharmacogenetic Analysis ........................................76
5.3.1.5
Pharmacodynamic and Predictive Biomarker Testing.............................76
5.3.2
Drug Concentration Measurements .........................................................79
5.3.2.1
Collection of Samples for Analysis .........................................................79
5.3.2.2
Handling/Processing of Samples .............................................................82
5.3.2.3
Disposition of Samples ............................................................................82
5.3.2.4
Measurement Methods.............................................................................82
5.3.3
Efficacy Variables....................................................................................82
5.3.4
Safety Variables.......................................................................................84


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5.3.5
Pharmacokinetic Variables ......................................................................85
5.3.6
Pharmacogenetic Variables......................................................................85
5.3.7
Pharmacodynamic Variables....................................................................85
5.4
Removal of Subjects from Therapy or Assessment.................................87
5.4.1
Discontinuation of Individual Subjects....................................................87
5.4.2
Discontinuation of Entire Study...............................................................89
5.5
Treatments................................................................................................90
5.5.1
Treatments Administered.........................................................................90
5.5.2
Identity of Investigational Products.........................................................92
5.5.2.1
Packaging and Labeling...........................................................................92
5.5.2.2
Storage and Disposition of Study Drug ...................................................92
5.5.3
Method of Assigning Subjects to Treatment Groups...............................93
5.5.4
Selection and Timing of Dose for Each Subject......................................93
5.5.5
Blinding....................................................................................................93
5.5.6
Treatment Compliance.............................................................................93
5.5.7
Drug Accountability.................................................................................94
5.6
Discussion and Justification of Study Design..........................................94
5.6.1
Discussion of Study Design and Choice of Control Groups....................94
5.6.2
Appropriateness of Measurements...........................................................95
5.6.3
Suitability of Subject Population .............................................................95
5.6.4
Selection of Doses in the Study ...............................................................95
6.0
Complaints .............................................................................97
6.1
Medical Complaints.................................................................................97
6.1.1
Definitions................................................................................................98
6.1.1.1
Adverse Event..........................................................................................98
6.1.1.2
Serious Adverse Events ...........................................................................99
6.1.1.3
Adverse Events Commonly Associated with Acute Myelogenous 
Leukemia Study Population and/or Progression of Acute 
Myelogenous Leukemia.........................................................................100
6.1.2
Adverse Event Severity..........................................................................101
6.1.3
Adverse Events Expected Due to Study Related Endpoints..................102
6.1.3.1
Deaths ....................................................................................................102
6.1.3.2
Lack of Efficacy or Worsening of Disease ............................................102


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6.1.4
Relationship to Study Drug....................................................................102
6.1.5
Adverse Event Collection Period...........................................................103
6.1.6
Adverse Event Reporting.......................................................................104
6.1.7
Pregnancy...............................................................................................106
6.1.8
Toxicity Management ............................................................................107
6.1.8.1
Definition – Dose Limiting Toxicity .....................................................107
6.1.8.2
Prophylaxis and Management of Tumor Lysis Syndrome (TLS)..........108
6.1.8.3
Management of Myelosuppresion (Cytopenias)....................................111
6.1.8.4
Management of Decreased Spermatogenesis.........................................113
6.1.8.5
Management of Other Toxicities ...........................................................113
6.1.8.6
Determination of the MTD ....................................................................114
6.1.8.7
Determination of the RPTD...................................................................114
7.0
Protocol Deviations..............................................................114
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................115
8.1
Statistical and Analysis Plans ................................................................115
8.1.1
Baseline Characteristics.........................................................................116
8.1.1.1
Demographics ........................................................................................116
8.1.1.2
Medical History .....................................................................................116
8.1.2
Pharmacokinetics ...................................................................................116
8.1.2.1
Tabulations and Summary Statistics......................................................116
8.1.2.2
Model and Tests.....................................................................................116
8.1.2.3
Missing Values and Model Violations...................................................118
8.1.3
Efficacy Summaries...............................................................................118
8.1.3.1.1
Overall Response Rates .........................................................................119
8.1.3.1.2
Duration of Response.............................................................................120
8.1.3.1.3
Event-Free Survival ...............................................................................120
8.1.3.1.4
Overall Survival.....................................................................................120
8.1.3.1.5
MRD Negativity Rate ............................................................................121
8.1.3.1.6
Proportion of Subjects Who Undergo Transplant..................................121
8.1.3.1.7
Post Baseline Transfusion Independence (RBC/Platelet)......................121
8.1.4
Safety .....................................................................................................121
8.1.4.1
Adverse Events ......................................................................................121


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8.1.4.2
Serious Adverse Events .........................................................................122
8.1.4.3
Deaths ....................................................................................................122
8.1.4.4
Longitudinal Analyses of Laboratory and Vital Signs Data..................122
8.1.4.5
Analyses of Laboratory Data Using NCI CTCAE.................................122
8.2
Determination of Sample Size ...............................................................123
9.0
Ethics.....................................................................................124
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................124
9.2
Ethical Conduct of the Study.................................................................125
9.3
Subject Information and Consent...........................................................126
10.0
Source Documents and Case Report Form 
Completion ...........................................................................127
10.1
Source Documents .................................................................................127
10.2
Case Report Forms.................................................................................127
11.0
Data Quality Assurance ......................................................128
12.0
Use of Information...............................................................129
13.0
Completion of the Study .....................................................130
14.0
Investigator's Agreement....................................................132
15.0
Reference List ......................................................................133
List of Tables
Table 1.
Excluded and Cautionary Medications and Dietary Restrictions 
(See Appendix C for Examples of the Medications) ...............................53
Table 2.
Dose Modifications for Venetoclax:  Moderate and Strong 
CYP3A Inhibitor Use...............................................................................54
Table 3.
Study Activities (Phases 1 and 2 {Including Cohort C}) ........................55
Table 4.
Treatment Schedule (Phase 1 and Initial Phase 2)...................................58
Table 5.
Treatment Schedule (Phase 2 Cohort C)..................................................59
Table 6.
Schedule of Biomarker/Pharmacogenetic/Pharmacodynamic 
Sample Collection (Phase 1 and 2 {Including Cohort C}) ......................60
Table 7.
Schedule of Blood Collection for Venetoclax and Cytarabine 
Assay (Pharmacokinetic Sampling) – Phase 1 Only................................62


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Table 8.
Schedule of Blood Collection for Venetoclax Assay 
(Pharmacokinetic Sampling) – Initial Phase 2 Only................................62
Table 9.
Schedule of Blood Collection for Venetoclax Assay 
(Pharmacokinetic Sampling) – Phase 2 Cohort C....................................63
Table 10.
Clinical Laboratory Tests.........................................................................71
Table 11.
Identity of Investigational Products.........................................................92
Table 12.
Dose Reduction Guidelines for Management of Persistent 
Neutropenia or Thrombocytopenia ........................................................112
Table 13.
95% Confidence Intervals for Assumed Observed Rates Based on 
Sample Size of 50 Subjects....................................................................124
Table 14.
95% Confidence Intervals for Assumed Observed Rates Based on 
Sample Size of 20 Subjects....................................................................124
List of Figures
Figure 1.
Overall Study Design...............................................................................36
Figure 2.
Dose Level –2 Cycle 1.............................................................................38
Figure 3.
Dose Level –1 Cycle 1.............................................................................38
Figure 4.
Dose Level 1 Cycle 1 (Starting Dose Level) ...........................................39
Figure 5.
Dose Level 2 Cycle 1...............................................................................39
Figure 6.
Dose Level 3 Cycle 1...............................................................................40
Figure 7.
Dose Level 4 Cycle 1...............................................................................40
Figure 8.
Dose Level 5 Cycle 1...............................................................................41
Figure 9.
Dose Level 1 Cycle 1 (Starting Dose Level) ...........................................44
Figure 10.
Phase 2 Cohort C** .................................................................................45
Figure 11.
Adverse Event Collection ......................................................................104
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................138
Appendix B.
List of Protocol Signatories....................................................................140
Appendix C.
Sample List of Excluded and Cautionary Medications..........................141
Appendix D.
NCCN Risk Categorization:  Guidelines for AML Version 2.2014......142


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Appendix E.
Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (TLS) ..............143
Appendix F.
Adverse Events Commonly Associated with Acute Myelogenous 
Leukemia Study Population and/or Progression of Acute 
Myelogenous leukemia ..........................................................................145
Appendix G.
Cell Lines Table.....................................................................................148
Appendix H.
Tumor Lysis Syndrome Classification...................................................149
Appendix I.
Protocol Amendment:  List of Changes.................................................150


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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 (ABT-199/GDC-0199) 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).3  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 leukemias (AML).3  Venetoclax was especially potent against Non-Hodgkin 
lymphoma (NHL) cell lines expressing high levels of Bcl-2 protein due to the t(14;18) 
chromosome translocation, amplification of the Bcl-2 gene locus, or aberrantly activated 
signaling mechanisms.  Venetoclax also demonstrated potent killing of multiple myeloma 
(MM) cell lines and primary tumor samples bearing the t(11;14) translocation, which tend 
to express high levels of Bcl-2 relative to Mcl-1.
Bcl-2 over-expression has 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.4,5  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 cytarabine4 or 
azacitidine.5 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 G).  The sensitivity of primary AML patient samples was 
comparable to that observed for primary CLL samples, with a median IC50 = 0.010 µM 
(n = 57) for AML6 (Appendix G) versus a median IC50 = 0.003 µM (n = 35) for CLL 
(AbbVie R&D/10/1025, AbbVie R&D/12/538).  Venetoclax has also demonstrated killing 
of AML leukemic stem/progenitor cells ex vivo and antitumor efficacy in vivo, inhibiting 


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the growth of AML cell lines or AML patient-derived primary cells systemically 
engrafted into immunocompromised mice.6
However, not all AML cell lines, primary patient samples, or patients treated with single 
agent venetoclax were found to be sensitive, and there is biologic rationale for combining 
venetoclax with certain chemotherapeutic agents in the treatment of AML.  The Mcl-1 
protein can act as a resistance factor for Bcl-2 family inhibitors7,8 including in AML.4  
Therapeutic agents such as the DNA methyltransferase inhibitor azacitidine,6 the DNA 
synthesis inhibitor cytarabine9 and the anthracycline doxorubicin10 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.4  Combinations of venetoclax and 
chemotherapeutic agents commonly used in the treatment of AML were 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 G).  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 patients with AML.  In mouse, rat, monkey, and dog, the venetoclax PK 
profile was characterized by low plasma clearance (CLp = 0.02 to 0.27 L/hr•kg) and low 
volumes of distribution (Vss = 0.3 to 1.1 L/kg).  Half-lives ranged from 2.2 hours in 
monkey to 12.0 hours in dog.  Formulation-dependent oral bioavailability was noted in all 
species.  Studies in both rat and dog have defined the behavior of the amorphous solid 
dispersion (ASD) for both toxicology and first-in-human evaluation.  Plasma 
concentrations obtained from fed dogs were 30% to 50% higher than those obtained from 
fasted animals.
Venetoclax is not a potent inhibitor of CYP3A4, CYP1A2, CYP2C19, CYP2B6, or 
CYP2D6 (IC50 > 30 μM).  At concentrations of 1, 3, and 10 μM, venetoclax did not 
induce CYP3A4 or CYP1A2 expression in vitro.  Venetoclax was metabolized by 
CYP3A4; thus its exposure could be affected when potent inhibitors or inducers of 


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CYP3A4 are co-administered.  Venetoclax is a substrate for P-gp and BCRP.  Active 
uptake of venetoclax or M27 was not observed in cells overexpressing OATP1B1, 
OATP1B3 or OCT1.  Venetoclax is a P-gp, BCRP and OATP1B1 inhibitor in vitro.
Venetoclax Preclinical Toxicology
The primary toxicities associated with repeat-dose oral administration of venetoclax were 
effects on the hematologic system (decreased lymphocytes and red blood cell mass) in 
mice, rats, and dogs, the male reproductive system (testicular germ cell depletion) in dogs, 
and embryo-fetal toxicity in mice.  Other noteworthy findings in dogs were epithelial 
single cell necrosis in multiple tissues and hair coat color change towards white.  In 
general, the primary toxicities and other noteworthy findings were consistent with the 
expected pharmacologic effects of venetoclax, a selective Bcl-2 inhibitor.
In mice, rats, and dogs, venetoclax produced decreases in lymphocytes in the peripheral 
blood (up to –75% in mice, –64% in rats, and –81% in dogs) and in lymphoid tissues, 
generally following 2 to 4 weeks or more of daily dosing (but after a single dose in dogs).  
Lymphocyte decreases were expected on the basis of venetoclax pharmacology and, when 
sustained over periods of 6 to 9 months in chronic venetoclax toxicity studies, were not 
associated with opportunistic infections.16
In mice, total lymphocyte counts at the high dose of 600 mg/kg/day after 4 weeks of 
dosing were minimally decreased –21% to –26% relative to concurrent controls at the end 
of the 4-week recovery period, indicating partial recovery.  In dogs, the recovery of 
peripheral blood decreases in total lymphocytes and lymphocyte subsets (CD4+ T-cells, 
CD8+ T-cells, and CD21+ B-cells) was prolonged, requiring up to 18 weeks after a single 
dose or 2 weeks of daily dosing.  B-cells were the most sensitive lymphocyte subtype 
based on the magnitude of decrease (> –90%) and/or the length of time required for 
recovery.  Lymphocyte decreases in lymphoid tissues were reversible in mice and dogs; 
but, as with peripheral blood lymphocytes, required up to 18 weeks in dogs.


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Venetoclax produced dose-related decreases in red blood cell (RBC) mass due to altered 
hemoglobinization and decreased RBC production in mice, rats, and dogs.  Based on a 
criterion of hemoglobin decreases of ≥ –20% as compared to control and/or baseline, 
these effects were considered adverse at the highest dosages in the 4-week mouse and dog 
studies (observed decreases of –21 to –23%) but were reversible following a 4-week 
recovery period.  In studies designed to select dose levels for possible carcinogenicity 
assessment, RBC mass decreases were also observed in rats and were generally more 
severe (hemoglobin decreases to –49%) than in mice or dogs.
Venetoclax produced adverse, non dose-related microscopic findings of testicular germ 
cell depletion (spermatogonial loss with maturation depletion) in dogs at all doses tested.  
Reversibility was assessed after 4 weeks of dosing and a 4-week recovery period; there 
was no evidence of reversibility.  Testicular germ cell loss may be related to venetoclax 
pharmacology, as Bcl-2 plays a role in spermatogonial maintenance.17,18  There were no 
testicular effects in mice or rats at venetoclax exposures overlapping those in dogs.
Venetoclax resulted in increased post-implantation loss and decreased fetal body weights 
in the mouse embryo-fetal development study at the highest dosage administered 
(150 mg/kg/day); the no-observed-adverse-effect-level was defined at the mid-dose of 
50 mg/kg/day.  In mice and rabbits, venetoclax was not teratogenic, and there were no 
other effects on development or fertility.
Additional noteworthy effects of venetoclax included minimal to mild single cell necrosis 
in multiple epithelial tissues (gallbladder, exocrine pancreas, epididymides, prostate, and 
stomach) in dogs and a change in the hair coat towards white in dogs (occurring after 
approximately 3 months of dosing in the 9-month study).  None of these effects was 
considered to be adverse.  Hair follicle melanocytes are critically dependent on Bcl-2 for 
survival during the normal hair replenishment cycle in mice, suggesting that the decrease 
in hair pigmentation in dogs was a likely effect of Bcl-2 inhibition.19  In regards to single-
cell necrosis, Bcl-2 is expressed in epithelial tissues and may regulate survival in rapidly 
dividing cell populations.20-22  Venetoclax appears to increase the rate of normally 


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occurring apoptosis without adversely affecting the normal tissue architecture or functions 
of these tissues.
There was no evidence of in vitro or in vivo genetic toxicity of venetoclax, nor was there 
evidence of phototoxicity (tested in vivo in hairless mice).  In a juvenile toxicity study, 
mice were administered venetoclax at 10, 30 or 100 mg/kg/day by oral gavage from 7 to 
60 days of age.  Clinical signs of toxicity included decreased activity, dehydration, skin 
pallor and hunched posture at ≥ 30 mg/kg/day.  Mortality and body weight decreases 
occurred at 100 mg/kg/day.  Other venetoclax-related effects were reversible decreases in 
lymphocytes at ≥ 10 mg/kg/day; these findings were consistent with those in adult mice 
and considered non adverse.
The major human metabolite of venetoclax, M27, was characterized at steady-state in R/R 
CLL patient plasma with an average metabolite to parent AUC ratio of 0.48 at the 400 mg 
venetoclax clinical dose.  In contrast, ss plasma levels of M27 in mice and dogs were 
≤5.1% of human exposure, making M27 a disproportionate human metabolite.  The 
safety of M27 was evaluated by in vitro and in vivo studies.  M27 was negative in Ames 
and chromosome aberration in vitro assays, has at least 58-fold less in vitro potency than 
venetoclax, and demonstrates low off-target toxicity potential based on in vitro secondary 
pharmacology assays.  Additionally, no adverse effects were observed in a 4-week mouse 
toxicity study in which M27 was orally administered at dosages up to 300 mg/kg/day, 
achieving M27 AUC plasma exposures at or above those observed clinically.
Dogs at the high dosage of 150 mg/kg/day (AUC 572 µg•h/mL) in the 4-week toxicity 
study had clinical signs of swelling of the skin on the ears, head (cranial area), and 
forepaws and/or hind paws.  Most but not all animals (8 of 10 dogs) were affected, and in 
3 dogs the swelling reaction was observed after the first dose.  The clinical signs were 
limited to the 150 mg/kg/day dosage, were mild to moderate in severity and transient and 
sporadic in occurrence, and were absent during the 4-week recovery period.  A 
mechanistic basis for the swelling reactions was not established, but a histamine-like 
reaction to copovidone, a primary excipient in the formulation, is possible.23  There were 
no signs of anaphylaxis.


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Venetoclax was tested in a battery of safety pharmacology assays, and produced no 
effects in the CNS/neurobehavioral or respiratory studies in mice at oral doses up to and 
including the highest dose of 600 mg/kg.  To assess cardiovascular safety, venetoclax was 
tested in an in vitro human ether-a-go-go related gene (hERG) assay and in both 
conscious and anesthetized dogs.  In hERG, a 50% inhibition constant (IC50) could not be 
calculated due to limited solubility (1.5 µg/mL).  Only minimal effects on QT interval 
corrected for heart rate (QTc) were observed up to a maximum plasma concentration of 
46 µg/mL in dogs.  In conscious dogs, venetoclax did not produce any cardiovascular 
effects up to and including the highest oral dose of 150 mg/kg (Cmax = 16 µg/mL).  In the 
anesthetized dog at higher plasma concentrations, venetoclax produced mild reductions in 
myocardial contractility (–6% to –13%) and cardiac output (–11% to –19%) at plasma 
concentrations of ≥ 16 µg/mL and ≥ 32 µg/mL, respectively.  These concentrations are 
greater than the plasma concentration of venetoclax in humans (geometric mean 
Cmax = 3.46 µg/mL at the 1200 mg dose).
On the basis of nonclinical safety pharmacology and toxicology evaluations of 
venetoclax, and on the basis of nonclinical and human studies of related anti-apoptotic 
Bcl-2 family protein inhibitors, key potential mechanism-based toxicities may include 
lymphopenia and neutropenia,16 signs of tumor lysis, reduction in RBC mass, decreased 
spermatogenesis, skin swelling, and hair hypopigmentation.  The potential for 
development of hair color change in humans is unknown.  No adverse events of changes 
in hair color, skin pigmentation, or eye color have been reported in the venetoclax clinical 
studies to date.  Although no effects of venetoclax on female reproductive tissues have 
been observed in repeat-dose general toxicology studies, embryo-fetal toxicity studies in 
animals have identified a fetal toxicity risk.  Thrombocytopenia has not been observed in 
toxicology studies in mice and dogs.  These findings are consistent with venetoclax as a 
Bcl-2 specific (Bcl-XL sparing) inhibitor.  Consequently, thrombocytopenia is not 
expected to be a DLT clinically.  Overall, the toxicities observed in animals administered 
venetoclax are consistent with the expected pharmacologic effects of Bcl-2 inhibition.


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A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the Investigator's Brochure.25
Venetoclax Clinical Data
As of 28 November 2019, on the basis of data available in the clinical databases for 
company-sponsored studies with unblinded data, a total of 3974 subjects have been 
exposed to at least 1 dose of venetoclax across company-sponsored studies, as described 
in Section 8.0.  Of these subjects, 3962 are included in the overall pooled analyses for 
reporting Reference Safety Information (RSI) (Appendix A):  3610 oncology subjects, 
255 healthy volunteers, 12 from a study conducted outside the venetoclax development 
program, 24 subjects with hepatic impairment, and 73 SLE subjects.  Of the 
2590 oncology subjects, 3481 were adults in the venetoclax oncology program (1183 in 
monotherapy studies and 2298 in combination therapy studies):  1639 with CLL/SLL, 
597 with AML, 483 with MM, 572 with NHL, 144 with myelodysplastic syndrome 
(MDS), and 44 with ALL, 1 with rhabdomyocarcoma, and 1 with Evans tumor.  The 
remaining oncology subjects included 65 pediatric subjects in the venetoclax program 
(26 ALL/LL, 29 AML, 1 NHL, 6 neuroblastoma, 3 other solid tumors):  5 received 
monotherapy and 60 received combination therapy.  64 subjects from studies conducted 
under another investigational new drug (IND) compounds outside the venetoclax program 
(52 AML, 11 NHL, 1 unknown).  An additional 1125 subjects with blinded data have 
been treated with either venetoclax combination therapy or a comparator treatment in 
company-sponsored venetoclax oncology studies.  Based on nonclinical and clinical data 
available with venetoclax administration, important identified risks are tumor lysis 
syndrome (TLS), neutropenia, and serious infection.  Tumor lysis syndrome is a risk 
associated with venetoclax treatment and it is highest in CLL and MCL.  Other adverse 
events commonly observed with venetoclax include nausea, diarrhea, and other 
hematological effects (including, anemia, thrombocytopenia, and lymphopenia).  Events 
of anemia, neutropenia, and thrombocytopenia are also commonly observed with the 
underlying hematologic malignancies.  Infections, including serious infections, although 
also common with the underlying malignancies, have been reported with venetoclax 


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treatment and their incidence is higher with combination treatments.  Co-administration 
with CYP3A inducers and inhibitors can cause changes in venetoclax exposure.  
Decreased spermatogenesis has been observed in nonclinical studies with dogs.  
Embryofetal toxicity was observed in nonclinical studies; thus, venetoclax should not be 
used during pregnancy.  In addition, as venetoclax is being evaluated in subjects with R/R 
disease who had previously been treated with various cytotoxic agents, second primary 
malignancies are closely monitored.  Following multiple-dose administration, the 
maximum plasma concentration of venetoclax was attained 5 to 8 hours after dosing.  The
harmonic mean terminal phase elimination half-life (t1/2) ranged from 17 to 41 hours 
following a single oral dose of venetoclax.  In subjects with CLL, venetoclax showed 
minimal accumulation, and steady-state AUC increased proportionally over the dose 
range of 150 to 800 mg.  Venetoclax has been administered with food in all clinical 
studies, as food increased the bioavailability of venetoclax by approximately 3- to 5-fold.  
Venetoclax is highly bound to plasma proteins with unbound fraction (fu) < 0.01, and it is 
primarily eliminated as metabolites in feces with negligible renal elimination (< 0.1%).  
Drug-drug interaction (DDI) studies of venetoclax with ketoconazole, rifampin, warfarin, 
ritonavir, azithromycin, and digoxin were conducted to provide dosing recommendations 
for patients concomitantly taking CYP3A and/or P-gp inhibitors, inducers, and/or 
warfarin.  Pharmacokinetic studies were conducted in healthy Chinese subjects and in 
Japanese subjects to provide dosing recommendations for those specific populations.  
Additionally, a dedicated study to evaluate the pharmacokinetics of venetoclax in subjects 
with hepatic impairment was conducted.  Based on the population pharmacokinetic 
analysis, age, sex, race, weight, and mild and moderate renal or hepatic impairment do not 
have an effect on venetoclax clearance.
Updated data are described in detail in the Investigator's Brochure.25
Acute Myelogenous Leukemia
Acute myelogenous leukemia is characterized by the clonal expansion of myeloid blasts 
in the bone marrow, peripheral blood and extramedullary tissues.  It is the most common 
form of acute leukemia in adults.  An estimated 18,500 adults will be diagnosed with 


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AML in 2014 and 10,000 deaths will be attributed to the disease.26  The median age of 
diagnosis is 72 years, with individuals 80 – 85 years of age having the highest incidence 
rates.27  Elderly AML is a biologically and clinically distinct disease with a diminished 
response to chemotherapy with low remission rates and short disease-free and overall 
survival compared to AML that occurs in younger patients.  Higher proportion of 
unfavorable cytogenetics, higher frequency of antecedent hematologic disorders or prior 
therapy for previous malignancies, and more frequent expression of the multidrug 
resistance phenotype accounts for the poor outcomes associated with current therapy.  
Additionally, the presence and severity of comorbid conditions, compromised end organ 
function that enhance the toxicity of induction chemotherapy, and functional incapacity 
all decrease the ability for the elderly patient to tolerate induction chemotherapy and 
survive life-threatening infections often associated with AML therapy.28 Several studies 
have 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 all patients 
diagnosed with AML.29,30
3.1
Study Rationale
Currently, there is no consensus as to a single optimal therapy for older patients with 
AML who are not candidates for conventional induction treatment though subcutaneous 
low-dose cytarabine (LDC) is a common therapeutic approach.  A common approach that 
hemato-oncologists utilize to determine fitness for intensive induction therapy is to 
conduct a thorough clinical evaluation including history taking, physical examination, and 
review of pertinent laboratory and clinical tests.  This "clinical judgment" approach was 
supported by findings from a prospective study of 157 subjects with hematological 
malignancies that found "clinical judgment" to be the strongest prospective predictor of 
survival and was superior to formalized geriatric assessment without clinical judgment.31  
Another approach, suggested by Ferrara and colleagues,32,33 incorporates specified co-
morbidity criteria in addition to clinical judgment.  Conceptual criteria proposed to define 
subjects unfit for conventional intensive chemotherapy32 are:
1.
Advanced age (over 75 years)


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2.
Severe cardiac comorbidity
3.
Severe pulmonary comorbidity
4.
Severe renal comorbidity
5.
Severe hepatic comorbidity
6.
Active infection resistant to anti-infective therapy
7.
Cognitive impairment
8.
Low performance status (ECOG functional scale)
9.
Any other comorbidity that the physician judges to be incompatible with 
chemotherapy
Low-dose cytarabine is a standard treatment option for patients with AML who are 
ineligible for intensive induction therapy due to comorbidities.  Initial studies from the 
Acute Leukemia Group B, over 40 years ago, reported that 15% – 20% of patients with 
AML receiving LDC at dose of 10 – 30 mg/m2 achieved a CR.31  Subsequently, a meta-
analysis including 293 previously untreated patients with newly diagnosed acute non-
lymphocytic leukemia reported a CR rate of 32% with LDC.35 More recently, a large, 
international trial for newly diagnosed patients ages 65 years and older with AML and 
poor prognostic features reported a combined CR rate (CR + CR with incomplete blood 
count recovery) of 11% for those patients receiving LDC using modern and more 
sensitive methods to determine the depth of clinical response.30
Though LDC has been available for decades, the low response rate and associated short 
expected survival leaves a significant unmet medical need for patients with treatment-
naïve AML who are ≥60 with comorbidities making them poor candidates for standard, 
high dose, anthracycline-based induction chemotherapy.  Single-agent clinical activity 
observed in other advanced hematologic malignancies (Study M12-175) and AML 
(Study M14-212), along with activity demonstrated using venetoclax alone and in 
combination with cytarabine in AML cell lines and primary patient samples, suggest the 


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possibility of significant clinical activity in AML for the combination of venetoclax with 
LDC.  The clinical trial described in this protocol is designed to evaluate if venetoclax 
may be combined safely with LDC and whether potentially meaningful clinical activity 
can be observed.
3.2
Differences Statement
This is the first study of venetoclax in combination with LDC for subjects with AML.  
Venetoclax was tested in Phase 2 trial (Study M14-212) in subjects with relapsed, 
refractory AML or in a frontline setting in subjects who are unfit for intensive therapy to 
examine preliminary activity and safety as monotherapy.  A Phase 1b/2 trial 
(Study M14-358) was also initiated testing the combinations of venetoclax with either 
azacitidine or decitabine in subjects with naïve AML who are aged 65 and older and not 
eligible for intensive induction chemotherapy.  Clinical trials in other indications which 
employ venetoclax monotherapy include a Phase 1 clinical trial to ascertain the safety, 
PK, maximum tolerated dose, RPTD of venetoclax in subjects with relapsed or refractory 
CLL and NHL (Study M12-175) and a Phase 2 trial of venetoclax in subjects with 
relapsed/refractory CLL harboring 17 p deletion (Study M13-982).
3.3
Benefits and Risks
Based on the venetoclax studies, the regimen is designed to escalate the dose of 
venetoclax rapidly and safely with a standard dose and schedule of LDC to optimize the 
opportunity for achieving a response and enable close subject monitoring.  The dosing 
regimen will also enable interruptions and slower intra-subject dose escalation to target
assigned dose if rapid tumor lysis is observed.  Based on the ex vivo testing of primary 
subject AML samples that has shown significant variability among subjects, initial signs 
of leukemia response may occur at different doses of venetoclax when combined with 
LDC for different subjects.
Venetoclax was administered to 32 subjects with AML as monotherapy in Study M14-212.  
Safety data from 28 (87.5%) subjects who experienced adverse events of grade 3 and 
above, showed the most common events being febrile neutropenia (31.3%), malignant 


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neoplasm progression, (25.0%), hypokalemia, and pneumonia (21.9% each).  Serious 
adverse events were reported for 27 (84.4%) subjects, including febrile neutropenia (9 
subjects), malignant neoplasm progression (8 subjects), pneumonia (5 subjects), 
abdominal pain, sepsis, urinary tract infection, failure to thrive, renal failure acute, and 
hypotension (2 subjects each).  All other events occurred in 1 subject each.
Study M14-212 has completed with efficacy data available for 32 subjects, the majority of 
them (30, 94%) with R/R AML.  The ORR was 19% (6 of 32 subjects), with CR in 2 (6%) 
and CRi in 4 (13%) subjects.  Anti-leukemic activity was observed in an additional 
6 (19%) subjects.
For additional safety and efficacy data please refer to the current Investigator Brochure.25
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated. Subjects receiving venetoclax may be at 
an increased risk for COVID-19 infection or experience serious illness if infected. 
Management of these adverse events will be made on a case-by-case basis with 
consideration of benefit/risk. However, based on the population and disease being studied 
and the anticipation that COVID-19 related risks are not expected to differ substantially 
between study subjects and the broader population of subjects receiving treatment for 
AML, no change to the benefit/risk balance for subjects in this study is expected.
4.0
Study Objective
The primary objectives of the Phase 1 portion are to assess the safety profile, characterize 
PK, determine the dose schedule, the maximum tolerated dose (MTD), and the 
recommended Phase 2 dose (RPTD) of venetoclax (ABT-199/GDC-0199) in combination 
with LDC in treatment-naïve subjects with AML who are ≥65 years of age and who are 
not eligible for standard induction therapy due to co-morbidity or other factors.
The primary objectives of the initial Phase 2 portion of the study are to evaluate the 
preliminary estimates of efficacy including the overall response rate (ORR), and to 
characterize the toxicities of the combination at the RPTD.


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The primary objective of Phase 2 Cohort C is to evaluate the ORR for subjects allowed 
additional supportive medications (strong CYP3A inhibitors) if medically indicated.
The secondary objectives of the initial Phase 2 portion and Phase 2 Cohort C are to 
evaluate leukemia response (rates of CR, CRi, PR, and MLFS), duration of response 
(DOR) and overall survival (OS).
Additional exploratory objectives of both phases of the study may be evaluated to find 
biomarkers that may serve as surrogates or predictors for clinical outcomes in future 
studies of venetoclax in AML.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 1/2, open-label, non-randomized, multicenter study that will evaluate the 
PK, safety and efficacy of orally administered venetoclax combined with LDC in 
treatment-naïve subjects with AML ≥ 60 years old and who are not eligible for standard 
induction therapy due to co-morbidity or other factors.  This study is sponsored by 
AbbVie in collaboration with Genentech/Roche.
This study will consist of three distinct portions.  The first portion of the study is a 
Phase 1, or dose-escalation portion, that will evaluate the safety and PK profile of 
venetoclax administered with LDC with the objective of defining the MTD and generating 
data to support a RPTD.  A subsequent initial Phase 2 portion will evaluate if the RPTD 
has sufficient efficacy and acceptable toxicity to warrant further development of the 
combination therapy.  Subsequently, Phase 2 Cohort C, will evaluate the ORR for subjects 
allowed additional supportive medications (strong CYP3A inhibitors) if medically 
indicated.
The study is designed to enroll up to approximately 42 subjects in Phase 1.  For the initial 
Phase 2 portion, up to approximately 50 subjects will be treated at the RPTD and schedule 


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defined in the Phase 1 portion of the study.  Phase 2 Cohort C will enroll approximately 
20 subjects.
All efforts will be made to adhere to these specified enrollment numbers; however, 
recognizing the acute nature of the disease, it might not be possible to deny treatment to 
subjects in screening for ethical reasons or maintain individual subjects on therapy 
sufficiently long to evaluate safety or efficacy.
Figure 1.
Overall Study Design
Biomarkers (such as cytogenetics, molecular markers, characterization of Bcl-2 and 
associated proteins or ex vivo testing of AML subject samples) that may be predictive of 
venetoclax activity will be assessed throughout the trial and may be used to enrich for 
subjects likely to respond to venetoclax.
Dosing Schedule Overview – Venetoclax – Phase 1 Portion
Venetoclax will be administered orally once daily (QD) on Days 2 through 28 of Cycle 1 
of the 28-day cycle.  Beginning with Cycle 2, venetoclax will be administered Days 1 
through 28 of each 28-day cycle.  Each dose of venetoclax should be taken with 
approximately 240 mL of water within 30 minutes after the completion of a meal, 
preferably breakfast.  The dose should be administered at the same time each day.  On 
days the subject is given LDC, venetoclax should be given prior to LDC.  The regimen is 
designed to escalate the dose of venetoclax in combination with LDC rapidly toward the 
target dose to optimize the opportunity for achieving a response and enable close subject 
monitoring.  The dosing regimen will also enable interruptions, reductions (if necessary) 
and a slower intra-subject dose escalation if rapid tumor lysis or other toxicities are 
observed.


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The initial period, approximately one week, of therapy until the target dose of venetoclax 
is achieved is considered the venetoclax ramp-up period (Day 1 through Day 4, 6 or 7 of 
Cycle 1, based on the escalation steps in the cohort).
Dose modifications of venetoclax in the ramp-up period may be implemented for 
individual subject(s) at risk for TLS or any new adverse events > Grade 2.  Dose 
reductions must follow original dosing schema.  If the subject requires dose reductions or 
dose holds during the venetoclax ramp-up period, a discussion with the AbbVie medical 
monitor is required.
To mitigate the potential risk of TLS,36 subjects will receive TLS prophylaxis prior to any 
venetoclax dose escalation in combination with LDC (See Appendix E for specific 
allopurinol and IV fluid dosing guidance).  Subjects will be hospitalized during the ramp 
up period, with confinement recommended to begin by Study Day –1, and must occur by 
at least Day 1, through at least 24 hours after completion of the ramp-up period 
(e.g., Day –1 through Day 5 of Cycle 1 based on the escalation steps in Cohort C).  Tumor 
lysis syndrome prophylaxis will be initiated in all subjects starting at least the day before 
the first dose of venetoclax.  Refer to Section 6.1.8.2, Management of Tumor Lysis 
Syndrome, for the details on TLS prophylaxis, Appendix E – Recommendations for Initial 
Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome for 
procedures to follow, and Appendix H for information regarding how to recognize 
laboratory and clinical TLS.
If a subject develops any laboratory changes suggestive of TLS within the first 24 hours 
after either the first dose or during dose escalation, venetoclax dose escalation should be 
withheld or the dose should be reduced.  Dose reductions and dose holds during the 
ramp-up period require notification of the AbbVie medical monitor as do any occurrence 
of clinical TLS.


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Dosing Schemas for Phase 1 
Figure 2.
Dose Level –2 Cycle 1
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 200 mg.
Figure 3.
Dose Level –1 Cycle 1
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 400 mg.


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Figure 4.
Dose Level 1 Cycle 1 (Starting Dose Level)
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 600 mg.
Figure 5.
Dose Level 2 Cycle 1
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 800 mg.


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Figure 6.
Dose Level 3 Cycle 1
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 1200 mg.
Figure 7.
Dose Level 4 Cycle 1
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 1600 mg.


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Figure 8.
Dose Level 5 Cycle 1
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 2000 mg.
Low-Dose Cytarabine Dosing (Phase 1 and 2)
LDC (20 mg/m2) will be administered subcutaneously for 10 consecutive days at the start 
of each cycle during both Phase 1 and Phase 2.
Dose Escalation and Modification Guidelines for Venetoclax – Phase 1
During Phase 1, modifications in the ramp-up period may occur based on tolerability of 
the first week dose escalation in earlier dose levels.  Increases in starting dose and/or 
changes in the dosing increments may be implemented.  The initial dose in subsequent 
cohorts may be lowered based on the tolerability, including the presence of signs of 
clinically significant laboratory or clinical tumor lysis.  Dose escalation to the target dose 
may then occur in smaller increments.  Decisions to modify the ramp-up period will be 
made by AbbVie following discussion between the investigators and AbbVie medical 
monitor.  Historically, subjects receiving treatment for AML are at risk for developing 
TLS and accordingly TLS is an AESI in this protocol.  If a subject experiences clinical 
TLS while receiving protocol therapy, AbbVie's medical monitor and safety team will 
review safety data (both pertaining to the individual subject and in aggregate) to
determine if modifications to the first week dose escalation schedule or TLS prophylaxis 
are warranted.


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Once 3 subjects are enrolled to a dose level, dose escalation or de-escalation decisions to 
the next designated dose level will be made after subjects have been evaluated to 
determine if each experienced a DLT during the first cycle of therapy or not.  This will 
typically occur 28 ± 14 days from the last subject within a cohort starting therapy.
Subjects are enrolled in cohorts of three, and the first subject from the subsequent cohort 
should not begin their intended dosing regimen until it is declared by the sponsor that no 
DLTs have occurred during Cycle 1 of the previous cohort.  All efforts will be made to 
adhere to these specified enrollment numbers (e.g., cohorts of three); however, 
recognizing the acute nature of AML, it might not be possible to deny treatment to 
subjects in screening for ethical reasons or maintain individual subjects on therapy 
sufficiently long to evaluate safety or efficacy.  In the event that more than 3 subjects 
enroll into a cohort, only the first 3 subjects dosed and will be informative for defining the 
MTD.  Should more than 3 subjects initially enroll into a dose level, subsequent subject 
data may be used to replace initial subjects if any of those subjects become non-evaluable 
due to non-adherence or other reasons.
For this trial, DLTs are defined as experiencing a CTCAE grade 4 toxicity, unless such 
events are in the common list of health events due to AML (Appendix F), or not 
recovering platelets to at least 25,000/µL and ANC to 500/µL within 14 days of the last 
dose of venetoclax unless such cytopenias are due to residual leukemia effect.  Should 
1 subject experience a DLT, an additional 3 subjects will be enrolled at the same dose 
level (a total of 6 subjects at this dose level).  Should 2 subjects at a dose level experience 
a DLT, that dose level is considered too toxic.  The dose level below the too toxic dose 
level is considered the MTD.  Additional subjects are then enrolled at the MTD to bring 
the total number enrolled at the MTD to 6.  If during this cohort expansion, a total of 
2 subjects at this dose level also experience a DLT, this level would also be considered 
too toxic and the method continues thusly until the maximal dose level is achieved where 
6 subjects can be treated through Cycle 1 and no more than one subject experiences a 
DLT.  Additional subjects may be enrolled at the current dose level at the discretion of the 
AbbVie medical monitor, if enrolled subjects are not evaluable.  In addition, significant 


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adverse events occurring after Cycle 1 in previous dose levels and ongoing PK 
assessments may inform dose escalation decisions and should such unanticipated 
occurrences necessitate a modification to the planned cohort dose assignments, decisions 
will be communicated in writing to all investigators.
Dose Escalation Guidelines
Number of Subjects with DLT
Dose Escalation
0 of 3
Begin enrollment in the next dose level 
1 of 3
Enroll 6 subjects in current dose level
1 of 6 or < 33% DLTs
Begin enrollment in the next dose level
≥ 2 of 6 or ≥ 33% DLTs
Previous dose determined as the MTD or dose de-escalation
If a dose de-escalation occurs and < 33% of subjects enrolled experience a DLT at the 
reduced designated cohort dose, this dosing regimen will be declared the MTD.  If ≥ 33% 
of the subjects enrolled at the reduced designated cohort dose still experience a DLT, dose 
de-escalation of the designated cohort dose regimen will continue to be explored.
The MTD will be defined as the highest designated cohort dose level (and corresponding 
ramp-up period regimen, if applicable) at which < 33% of the subjects enrolled experience 
a DLT.
Subjects should experience a DLT and/or complete at least 80% of indicated venetoclax 
and cytarabine dosing in the first cycle to be considered evaluable regarding dose 
modification decisions.
Transition from Phase 1 to Phase 2
Once the MTD is determined, enrollment into the dose escalation portion of the study will 
end.  The dose level for the Phase 2 cohort will be communicated to all participating 
investigators prior to the start of Phase 2 enrollment.  Subjects from the dose escalation 
portion of the study are not eligible for enrollment in the Phase 2 portion of the study.


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Dosing Schema for Initial Phase 2
Figure 9.
Dose Level 1 Cycle 1 (Starting Dose Level)
*
Cycle = 28 days.  Venetoclax dose will be administered on Day 1 – Day 28 starting with Cycle 2, at the designated 
cohort dose of 600 mg.


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Dosing Schema for Phase 2 Cohort C
Figure 10.
Phase 2 Cohort C**
*
Cycle = 28 days.  Venetoclax dose will be administered at the designated cohort dose of 600 mg on Day 4 –
Day 28 of Cycle 1 and on Day 1 – Day 28 for all cycles starting Cycle 2.
**
Applies to subjects enrolled in Amendment 2.
Dosing Schedule Overview – Venetoclax – Initial Phase 2 Portion and Phase 2 
Cohort C
Once the MTD is declared, and the RPTD determined, a cohort of up to approximately 
50 – 100 additional eligible subjects will be enrolled at the RPTD in order to further 
define the toxicity profile and to estimate the efficacy of the combination.
Subjects enrolled in the initial Phase 2 portion will receive the RPTD of venetoclax that 
will be administered orally once daily (QD) on Days 2 through 28 of Cycle 1 of the 
28-day cycle.  Beginning with Cycle 2, venetoclax will be administered Days 1 through 
28 of each 28-day cycle.  Cytarabine 20 mg/m2/QD will be administered on Days 1 – 10 
of each cycle.


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Subjects enrolled in Phase 2 Cohort C will receive venetoclax on Days 1 through 28 
of each 28-day cycle, including Cycle 1.  Cytarabine 20 mg/m2/QD will be 
administered on Days 1 – 10 of each cycle.
Each dose of venetoclax should be taken with approximately 240 mL of water within 
30 minutes after the completion of a meal, preferably breakfast.  The dose should be 
administered at approximately the same time each day.  On days the subject is given LDC, 
venetoclax should be given prior to LDC.  The regimen is designed to escalate the dose of 
venetoclax in combination with LDC rapidly toward the target dose to optimize the 
opportunity for achieving a response and enable close subject monitoring.  The dosing 
regimen will also enable interruptions, reductions (if necessary) and a slower intra-subject 
dose escalation if rapid tumor lysis or other toxicities are observed.
The initial period, approximately one week, of therapy until the target dose of venetoclax 
is achieved is considered the venetoclax ramp-up period (e.g., Day 1 through Day 4 of 
Cycle 1 in Phase 2 Cohort C).
Dose modifications of venetoclax in the ramp-up period may be implemented for 
individual subject(s) at risk for TLS or any new adverse events > Grade 2.  Dose 
reductions must follow original dosing schema.  If the subject requires dose reductions or 
dose holds during the venetoclax ramp-up period, a discussion with the AbbVie medical 
monitor is required.
To mitigate the potential risk of TLS,36 subjects will receive TLS prophylaxis prior to any 
venetoclax dose escalation in combination with LDC.  Subjects will be hospitalized 
during the ramp-up period, Day –1 through 24 hours post highest cohort dose 
(e.g., Day –1 through Day 5 of Cycle 1 in Cohort C).  Tumor lysis syndrome prophylaxis 
will be initiated in all subjects starting at least the day prior to the first dose of venetoclax.  
Refer to Section 6.1.8.2, Management of Tumor Lysis Syndrome, for the details on TLS 
prophylaxis, Appendix E – Recommendations for Initial Management of Electrolyte 
Imbalances and Prevention of Tumor Lysis Syndrome (TLS) for procedures to follow, and 
Appendix H for information regarding how to recognize laboratory and clinical TLS.


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If a subject develops any laboratory changes suggestive of TLS within the first 24 hours 
after either the first dose or during dose escalation, venetoclax dose escalation should be 
withheld or the dose should be reduced.  Dose reductions and dose holds during the 
ramp-up period require notification of the AbbVie medical monitor as do any occurrence 
of clinical TLS.
Option to Continue Venetoclax Treatment 
Subjects enrolled in either Phase 1 or Phase 2 portion may discontinue LDC but may 
continue receiving venetoclax once daily as monotherapy for up to 4 years following the 
first dose of the last subject enrolled on study provided they complete LDC dosing, 
continue to tolerate venetoclax, have no evidence of disease progression, and do not meet 
any criteria for subject discontinuation (Section 5.4.1).  Additionally, should a subject 
discontinue venetoclax or LDC due to reasons other than progression or unacceptable 
toxicity, subjects may be allowed to subsequently resume treatment with venetoclax 
and/or LDC upon discussion between the AbbVie medical monitor and the investigator.
For subjects that continue to derive benefit after this 4 year period, AbbVie will work with 
the investigator to evaluate options for continuation of venetoclax.  Approval of a subject 
to transition to monotherapy and dose/schedule determination will also be based on 
review of other laboratory parameters and discussion between the AbbVie medical 
monitor and the investigator.
5.2
Selection of Study Population
Subjects will undergo screening procedures within 21 days prior to initial study drug 
administration.  Adult male and female subjects who meet the inclusion criteria and who 
do not meet any of the exclusion criteria will be eligible for enrollment into the study.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria 
within 21 days prior to the first day of therapy:


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1.
Subject must be ≥ 65 years of age in Phase 1 and initial Phase 2.  Subjects enrolled 
in Phase 2 Cohort C must be either:
●
≥ 75 years of age;
OR
●
≥ 60 to 74 years will be eligible if the subject has at least one of the following 
co-morbidities, which make the subject unfit for intensive chemotherapy:
○
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 (calculated by 
Cockcroft-Gault formula)
○
Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN
○
Any other comorbidity that the physician judges to be incompatible with 
intensive chemotherapy must be reviewed and approved by the study 
medical monitor before study enrollment
2.
Subject must have a projected life expectancy of at least 12 weeks.
3.
Subject must have histological confirmation of AML and be ineligible for 
treatment with a standard cytarabine and anthracycline induction regimen due to 
co-morbidity or other factors.
4.
Subject must have received no prior treatment for AML with the exception of 
hydroxyurea, allowed through the first cycle of study treatment.  Note:  Subject 
may have been treated for prior Myelodysplastic Syndrome.
5.
Subject must have an Eastern Cooperative Oncology Group (ECOG) performance 
status:
●
of 0 to 2 for subjects ≥ 75 years of age
●
of 0 to 3 for subjects ≥ 60 to 74 years of age, if 0 – 1 another co-morbidity is 
required to make subject eligible.


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6.
Subject must have adequate renal function as demonstrated by a creatinine 
clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine 
clearance or by the Cockcroft-Gault formula:
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)
Note:
Investigators should consider measuring a 24-hour creatinine clearance for subjects who are morbidly obese, 
have fluctuating renal function, or who in the investigator's clinical judgment may yield a more accurate 
clearance when measured than when calculated.
7.
Subject must have adequate liver function as demonstrated by:
●
aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN)*
●
alanine aminotransferase (ALT) ≤ 2.5 × ULN*
●
bilirubin ≤ 1.5 × ULN for all subjects age 75 and older*
○
Subjects who are < 75 years of age must have a bilirubin of  < 3.0 × ULN
*
Unless considered due to leukemic organ involvement.
Note:
Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN per discussion between the investigator 
and AbbVie medical monitor.
8.
Male subjects must agree to refrain from unprotected sex and sperm donation from 
initial study drug administration until 180 days after the last dose of study drug.
9.
Subject must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures.
10.
If female, subject must be either:
●
Postmenopausal defined as no menses for 12 or more months without an 
alternative medical cause,


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OR
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
Rationale for Inclusion Criteria
(1 – 7) 
To select the appropriate subject population for the evaluation
(8, 10) 
The impact of venetoclax on pregnancy is unknown
(9) 
In accordance with Harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will be eligible for study participation if he/she does not meet the following 
criteria within 21 days prior to the first day of therapy:
1.
Subject has received treatment with cytarabine for a pre-existing myeloid disorder.
2.
Subject has acute promyelocytic leukemia (French-American-British Class M3 
AML).
3.
Subject has known active CNS involvement with AML.
4.
Subject has tested positive for HIV (due to potential drug-drug interactions 
between antiretroviral medications and venetoclax, as well as anticipated 
venetoclax mechanism-based lymphopenia that may potentially increase the risk of 
opportunistic infections).  Note:  HIV testing is not required.
5.
Subject has received the following within 7 days prior to the initiation of study 
treatment:
●
Strong and moderate CYP3A inducers such as rifampin, carbamazepine, 
phenytoin, and St. John's wort (see Appendix C for examples).
6.
This criterion has been removed.


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7.
Subject has consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Starfruit within 3 days prior to the 
initiation of study treatment.
8.
Subject has a cardiovascular disability status of New York Heart Association 
Class > 2.  Class 2 is defined as cardiac disease in which subjects are comfortable 
at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or 
angina pain.
9.
Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, 
metabolic, immunologic, hepatic, cardiovascular disease, or any other medical 
condition that in the opinion of the investigator would adversely affect his/her 
participating in this study.
10.
Subject has chronic respiratory disease that requires continuous oxygen use.
11.
Subject has a malabsorption syndrome or other condition that precludes enteral 
route of administration.
12.
Subject exhibits evidence of other clinically significant uncontrolled condition(s) 
including, but not limited to:
●
Uncontrolled systemic infection requiring IV 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 breast or cervix uteri;
●
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 is 
permitted to meet this criterion.


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15.
Subject is a candidate for a bone marrow or stem cell transplant within 12 weeks 
after study enrollment.
16.
Subject has a history of myeloproliferative neoplasm (MPN) including 
polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic 
myelogenous leukemia.
Rationale for Exclusion Criteria
(1 – 5, 13 – 16) 
To select the appropriate subject population for the evaluation
(7 – 12) 
For the safety of the subjects
5.2.3
Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements or if administration of any medication becomes necessary, 
from the Screening Visit through the end of the study, the name of the medication, dosage 
information including dose, route and frequency, date(s) of administration including start 
and end dates, and reason for use must be recorded on the appropriate electronic case 
report form (eCRF).
The AbbVie medical monitor identified in Section 6.1.6 should be contacted if there are 
any questions regarding concomitant or prior therapy(ies).
General guidelines regarding excluded and cautionary medications are summarized in 
Table 1.


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Table 1.
Excluded and Cautionary Medications and Dietary Restrictions 
(See Appendix C for Examples of the Medications)
Excluded Foods During Ramp-Up and Throughout Study

Grapefruit and grapefruit products

Seville Oranges (including marmalade containing Seville oranges)

Starfruit
Excluded Medications During Venetoclax Ramp-Up Phase and Throughout Study:

Strong CYP3A inducers
Cautionary

Moderate or Strong CYP3A inhibitors
- Consider therapeutic alternative medications whenever appropriate.
-If a subject requires use of these medications, limit the duration to the minimal duration medically 
required and reduce the venetoclax dose by at least 2-fold for moderate inhibitors and by at least 
8-fold for strong inhibitors (see Table 2).  After discontinuation of a moderate or strong CYP3A 
inhibitor, wait for 2 to 3 days before venetoclax dose is increased back to the initial target dose.

Moderate CYP3A inducers
-Exclude during the ramp-up phase and consider alternative medications.
-If a subject requires use of these medications at the cohort designated dose, use with caution and 
contact the AbbVie medical monitor for guidance.

Warfarin* 

P-gp substrates

BCRP substrates

OATP1B1/1B3 substrates

P-gp inhibitors

BCRP inhibitors
*
Closely monitor the international normalized ratio (INR).


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Table 2.
Dose Modifications for Venetoclax:  Moderate and Strong CYP3A 
Inhibitor Use
Assigned Venetoclax Dose
Dose if Co-Administered with 
a Moderate CYP3A Inhibitor
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
A sample list of excluded medications and cautionary medications that fall into the 
categories within Section 5.2.3 can be found in Appendix C.  It is not possible to produce 
a 100% exhaustive list of medications that fall into these categories, so if in question, 
please notify the AbbVie medical monitor and discuss the investigator's use of these 
medications and the investigator's plans to medically monitor the potential study subject 
under consideration.
5.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenetic, 
Safety and Efficacy, Assessments/Variables
5.3.1
Safety and Efficacy Measurements Assessed and Flow 
Chart
This study is designed to assess pharmacokinetic, pharmacodynamic, pharmacogenetic, 
efficacy, and safety data.  Study procedures described in this protocol are summarized in 
Table 3.


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Table 3.
Study Activities (Phases 1 and 2 {Including Cohort C})
Procedures
Scra
Day 
–1
Cycle 1
Day 1 of Cycle 2 and 
Day 1 of Every Cycle 
Thereafter (± 3 Days)
Cycle 2 Day 1, Cycle 4 
Day 1, and Every 
3 Cycles Thereafter 
(± 7 Days)
Final 
Visitn
30-Day 
Safety 
F/U
PT 
F/Uu
(± 1 
Week)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Informed Consent
Xb
Medical/Oncology History 
Assessment
X
Xc
Cytogenetic Assessmentd
X
AE/Concomitant Medication 
Assessmentv
X
X
X
X
X
X
X
X
X
X
Tumor Lysis Syndrome Prophylaxise
X
X
X
X
X
X
Physical Exam (including weight)f,v
Xh
X
Xi
Xj
Xj
Xj
Vital Signsf,v
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusf,v
X
X
X
X
X
Hematologyf,g,v
X
X
X
X
X
X
X
X
X
X
Chemistrye,f,v
Xk
X
X
X
X
X
Xk
Xk
X
Coagulationf,v
X
X
Xl
X
X
Urinalysisf,v
X
12-lead ECGm,v
X
Xo
MUGA (preferred)/2D 
Echocardiogram w/Dopplerm,p
X
Clinical Disease Progression 
Assessment
X
X
X
Bone Marrow Aspirate and Biopsy 
for Response Assessment
Xq
Xr
X


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Table 3.
Study Activities (Phases 1 and 2 {Including Cohort C}) (Continued)
Procedures
Scra
Day 
–1
Cycle 1
Day 1 of Cycle 2 and 
Day 1 of Every Cycle 
Thereafter (± 3 Days)
Cycle 2 Day 1, Cycle 4 
Day 1, and Every 
3 Cycles Thereafter 
(± 7 Days)
Final 
Visitn
30-Day 
Safety 
F/U
PT 
F/Uu
(± 1 
Week)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Dispense Subject Calendar/Diary
Xs
X
Collect Study Drug and Subject 
Calendar/Diaryw
X
X
Survival Assessmentst
X
Scr = Screening; F/U = Follow-Up; PT = Post-Treatment
a.
Screening procedures must be performed within 21 days prior to initial study drug administration.
b.
Obtain informed consent prior to performing any screening or study-specific procedures.
c.
On Cycle 1 Day 1, any additional medical history that is observed after signing of the informed consent but prior to initial study drug administration and not considered 
related to study-required procedures will be recorded in the subject's medical history.
d.
Cytogenetic testing should be performed if not completed within 3 months prior to Screening.
e.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to Section 6.1.8.2 Management 
of Tumor Lysis Syndrome (TLS) and Appendix E – Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome (TLS) for 
further information.
f.
For all study visits beginning with Cycle 3, physical examination, vital signs, ECOG performance status, hematology, chemistry, coagulation and urinalysis may be performed 
within 72 hours before Day 1 of treatment for that cycle.
g.
Hematology will be performed weekly (at the minimum, hematology should be performed weekly during Cycle 1 and Cycle 2).
h.
Height will be measured only at Screening.
i.
Only applies to Dose Level (–)2.  Subjects should have Physical exam upon discharge from the hospital.  Subjects should remain hospitalized no less than 24 hours post 
dosing of their designated cohort dose.  Also, Dose Levels 4 and 5 would stay in hospital until Day 8, needing a Physical exam at Day 8.
j.
A symptom-directed physical exam may be performed.
k.
Amylase and lipase are required at Screening, Cycle 2 Day 1, and the Final Visit.


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Table 3.
Study Activities (Phases 1 and 2 {Including Cohort C}) (Continued)
l.
Coagulation to be performed on Cycle 2 Day 1 and not required subsequently unless clinically indicated.
m.
Additional ECGs and a MUGAs/Echos should be performed as clinically necessary per the discretion of the investigator.
n.
Final Visit procedures should be performed when a subject discontinues from the study.
o.
May be obtained ± 2 days of the visit.
p.
Should be performed provided that such assessment would not inappropriately delay therapy per discretion of the investigator.
q.
Historical bone marrow aspirates at screening will not be sufficient; a bone marrow aspirate must be performed for study entry to collect mandatory biomarker assessments.
r.
May be performed ± 7 days of the anticipated Day 1 of the subsequent cycle visit, for visits beginning with Cycle 2 Day 1.  Assessments beginning with Cycle 4 Day 1 should 
be performed and resulted prior to the dispensation of the next cycle of drug.
s.
Diaries will be dispensed upon discharge from the hospital.
t.
Survival assessments should be performed every 12 weeks (± 1 week) for 1 year after last subject's last dose or possibly sooner if all patients have discontinued and most 
patients have expired.
u.
Post Treatment visits will be performed every 12 weeks (± 1 week) for up to 1 year after last subject's last dose or possibly sooner if all patients have discontinued and most 
patients have expired.  Survival assessments will be performed every 12 weeks, beginning when subjects develop progressive disease, for 1 year after the last subject's last 
dose or possibly sooner if all patients have discontinued and most patients have expired.
v.
Procedure may be performed in the subject's home or local hospital/clinic by adequately trained personnel if required due to COVID-19 restrictions.
w.
Venetoclax may be shipped directly to a subject's home only if required due to COVID-19 restrictions.
Note:
Refer to Table 4 for treatment schedule.


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Table 4.
Treatment Schedule (Phase 1 and Initial Phase 2)
Cycle 1a
Cycle 2a and Subsequent Cyclesa
Continuation of Venetoclax
Monotherapy Onlya,b
Day 1
Day 2 – 10
Days 11 – 28
Days 1 – 10
Days 11 – 28
Days 1 – 28
Venetoclax
X
X
X
X
X
Cytarabine
X
X
X
a.
Cycle length = 28 Days.
b.
Subjects enrolled in either Phase 1 or Phase 2 portions may discontinue LDC but continue receiving venetoclax once daily as monotherapy for up to 4 years following the 
first dose of the last subject enrolled on study provided they continue to tolerate venetoclax, have no evidence of disease progression, and do not meet any criteria for subject 
discontinuation (Section 5.4.1).


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Table 5.
Treatment Schedule (Phase 2 Cohort C)
All Cyclesa
Day 1 – 10
Days 11 – 28
Venetoclaxb
X
X
Cytarabineb
X
a.
Cycle length = 28 Days.
b.
Subjects enrolled in the Cohort C portion may discontinue LDC but continue receiving venetoclax once daily as 
monotherapy for up to 4 years following the first dose of the last subject enrolled on study provided they continue 
to tolerate venetoclax, have no evidence of disease progression, and do not meet any criteria for subject 
discontinuation (Section 5.4.1).  Additionally, should a subject discontinue venetoclax or LDC due to reasons other 
than progression or unacceptable toxicity, subjects may be allowed to subsequently resume treatment with 
venetoclax and/or LDC upon discussion between the AbbVie medical monitor and the investigator.


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Table 6.
Schedule of Biomarker/Pharmacogenetic/Pharmacodynamic Sample Collection (Phase 1 and 2 {Including 
Cohort C})
Sample Collections
Screening/ 
Cycle 1 
Day 1a
Cycle 2
Day 1
Cycle 4 Day 1, Every 
3 Cycles Thereafter, 
and as Clinically 
Indicated (± 7 Days)c
Final 
Visit/Time 
of Relapse
Comments
Mandatory Samples
Bone Marrow Aspirate for Disease Assessment (MRD)b
X
X
X
X
1 – 2 mL bone marrow aspirate
Bone Marrow Aspirate for Mutational Profiling
X
X
1 – 2 mL bone marrow aspirate
Bone Marrow Aspirate for Ex Vivo sensitivity and 
translational research
X
X
X
3 mL bone marrow aspirate
Bone Marrow Aspirate for Bcl-2 Family Protein 
Analysis
X
X
X
1 mL bone marrow aspirate
Blood for Mutational Profiling
X
X
2.5 mL blood
Blood for Plasma
X
X
Xf
X
4d mL blood
OR
12d mL blood
Blood for Serum
X
X
Xf
X
3.5 mL blood
Blood for Ex Vivo Sensitivity and Translational 
Research
X
X
X
8 mL blood
Blood for Bcl-2 Family Protein Analysis
X
X
X
2 mL blood
Pharmacogenetics
Xe
Xe
X
4 mL blood
Bone Marrow Core Biopsy for BCL-2 IHC
X
X
4 – 10 slides
a.
Sample may be performed at Screening or Cycle 1 Day 1 prior to dosing.


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Table 6.
Schedule of Biomarker/Pharmacogenetic/Pharmacodynamic Sample Collection (Phase 1 and 2 {Including 
Cohort C}) (Continued)
b.
This sample should be taken from the first bone marrow aspirate draw.
c.
Only until 2 consecutive samples show a CR.
d.
Blood for Plasma:  4 mL blood at Screening/Cycle 1 Day 1, Cycle 2 Day 1, and Final Visit/Time of Relapse; 12 mL blood at Cycle 4 Day 1 and every 3 Cycles Thereafter.
e.
Pharmacogenetics should be collected on Cycle 1 Day 1, Cycle 4 Day 1, and Final Visit.
f.
Subjects who achieve 2 consecutive CR assessments and no longer require a bone marrow aspirate/biopsy for disease assessment, will still have plasma and serum collections 
at every 3 cycles thereafter.


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Table 7.
Schedule of Blood Collection for Venetoclax and Cytarabine Assay (Pharmacokinetic Sampling) – Phase 1 
Only
Procedures
Cycle 1
Cycle 2, Cycle 4 and Every 
3 Cycles Thereafter (± 7 Days)
Day 1
Days 2 – 6
Day 10
Day 18
Day 1
Venetoclax
8 hours post-dosea
0 (pre-dose), 2, 4, 6, 
8 and 24 hours 
post-dose
0 (pre-dose), 2, 4, 6, 8 
and 24 hours 
post-dose
0-hour (pre-dose)
Cytarabineb
0 hour (pre-dose) and at 
15 and 30 min and 1, 3, 
6 hours following the 
SC dose
0 hour (pre-dose) at 
and 15 and 30 min 
and 1, 3, 6 hours 
following the SC 
dose
a.
The 8-hour post-dose PK sample on Days 2 – 6 of Cycle 1 will be collected if venetoclax is initiated or escalated to a new dose level.  If there is a delay in the escalation step, 
the 8-hour post-dose PK sample will be delayed accordingly.  The PK collection performed 8 hours post-dose after each dose escalation may be taken up to 1 hour prior or up 
to 20 minutes after the scheduled time to allow for processing, if necessary.  If the Day 2 – 6 PK draws fall on a weekend, collection is optional but strongly encouraged.
b.
These samples are not optional, however, due to the complexity of the sample collection and processing for the cytarabine PK, AbbVie recognizes some centers may not have 
the capability to perform the PK samples.  In those instances, the cytarabine PK samples will not be collected.  Sites with these capabilities will be predetermined.
Table 8.
Schedule of Blood Collection for Venetoclax Assay (Pharmacokinetic Sampling) – Initial Phase 2 Only
Procedures
Cycle 1 Day 2
Cycle 2 Day 1
Cycle 4 Day 1, and Every 3 Cycles Thereafter (± 7 Days)
Venetoclax
0 hour (pre-dose)
0 hour (pre-dose)
0 hour (pre-dose)


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Table 9.
Schedule of Blood Collection for Venetoclax Assay (Pharmacokinetic Sampling) – Phase 2 Cohort C
Procedures
Cycle 2 Day 1
Cycle 4 Day 1, and Every 3 Cycles Thereafter (± 7 Days)
Venetoclax
0 hour (pre-dose)
0 hour (pre-dose)


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5.3.1.1
Study Procedures
All study procedures outlined in Table 3 are discussed in detail in this section, with the 
exception of adverse event information (discussed in Section 6.0).  All study data will be 
recorded on eCRFs.
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
in the subsequent section.  Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow Table 3 on how 
to proceed.
Procedures performed at Screening will serve as baseline, unless repeated on Cycle 1 
Day 1 prior to dosing, in which case the latter will serve as baseline.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative in order to participate in this study.  The IEC/IRB approved 
informed consent 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.  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 and updated prior to the 
first dose of study drug on Cycle 1 Day 1:
●
Complete medical history, including documentation of any clinically 
significant medical condition
●
History of tobacco and alcohol use


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●
Detailed oncology history including:
○
Histology
○
Date of diagnosis of AML
○
Any surgical procedures
○
Treatments administered (including dates and type of modality)
●
Detailed prior and concomitant medication usage including dates of usage and 
dosing information for all medications and supplements taken.
On Cycle 1 Day 1, any additional medical history that is observed after signing of the 
informed consent but prior to initial study drug administration and not considered related 
to study-required procedures will be recorded in the subject's medical history.
Adverse Event and Prior/Concomitant Medication Assessment
On Cycle 1 Day 1, any events observed from the time of signing of the informed consent 
but prior to initial study drug administration will be recorded as a serious or nonserious 
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 changes from baseline will 
be recorded on the adverse event eCRF.
All medications (prescription or over-the-counter, including vitamins and/or herbal 
supplements) will be recorded beginning with the Screening Visit and continuing until 
30 days following the last dose of study drug.
Physical Examination
A complete physical examination (PE) will be performed at Screening.  A 
symptom-directed PE including weight changes will be performed at visits as outlined in 
Table 3.  Height will be measured only at Screening.  The subject should wear lightweight 
clothing and no shoes during weighing.


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Physical exams may be performed up to 72 hours prior to or after a scheduled study visit 
beginning with Cycle 3, if necessary.  If the Screening PE is performed within 7 days of 
Cycle 1 Day 1, PE is not required on Cycle 1 Day 1, unless clinically indicated.  
Clinically significant changes from baseline will be documented in the source 
documentation and eCRFs as adverse events.
Vital Signs
Body temperature (oral), weight, blood pressure, pulse, and respiratory rate will be 
measured at the study visits as outlined in Table 3.  Vital Signs may be performed up to 
72 hours prior to or after a scheduled study visit beginning with Cycle 3, if necessary.
Blood pressure and pulse rate should be measured after the subject has been sitting for at 
least 5 minutes.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, weight, blood pressure, vitals and respiratory rate 
measurements may be performed by the subject or caregiver as needed.
ECOG Performance Status
The ECOG performance status37 will be assessed at the study visits outlined in Table 3 as 
follows:
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.


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ECOG performance status may be assessed up to 72 hours prior to or after a scheduled 
study visit beginning with Cycle 3, if necessary.
12-Lead Electrocardiogram (ECG)
A single 12-lead resting ECG will be obtained at Screening, Final Visit, and as clinically 
needed.  The Final Visit ECG may be obtained within ± 2 days of the visit.
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.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event this may not be performed due to study modifications related to the 
COVID-19 pandemic, perform the 12-lead ECG at the next earliest feasible visit or 
arrange to have an alternative acceptable local facility perform the ECG for the subject.
ECG Safety Review
Each ECG will be printed and 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 decision on whether a subject will be discontinued 
from the study.
The local reader will sign and date the safety ECG and provide a global interpretation 
using the following categories:
●
Normal ECG


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●
Abnormal ECG – Not clinically significant (NCS)
●
Abnormal ECG – Clinically significant (CS)
●
Unable to evaluate
All local reader evaluations of the ECGs will be entered into the electronic case report 
form (eCRF).  If the global interpretation is Abnormal (NCS or CS), the local reader will 
provide further information (e.g., sinus bradycardia, arrhythmia).  The QT interval 
measurement will be documented in the eCRF only if a "prolonged QT" is observed.  
Correction by the Fridericia formula (QTcF) is preferred; however, correction by other 
methods may be acceptable based on discussion with the AbbVie medical monitor.  The 
original ECG tracing will be retained as source documentation in the subject's records at 
the study site.
Multiple Gated Acquisition Scan (MUGA)/2D Echocardiogram with Doppler
Assessment of ejection fraction will be made at Screening by either a MUGA (preferred 
method) or 2D echocardiogram with Doppler provided that such assessment would not 
inappropriately delay therapy per discretion of the investigator.  Subsequent evaluation 
will be made as clinically indicated for subjects who develop signs of cardiac compromise.  
It is preferred that the same method of assessment is used for a given subject.
Bone Marrow Aspirate and Biopsy
A bone marrow aspirate and biopsy will be done at Screening, at Cycle 2 Day 1, Cycle 4 
Day 1, and every 3 cycles thereafter for response assessment until two successive bone 
marrow biopsies demonstrate CR then will be repeated if clinical evidence for recurrence 
occurs.  Historical bone marrow aspirates at screening will not be sufficient, a bone 
marrow aspirate and biopsy must be performed for study entry to collect mandatory 
biomarker assessments.  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 status may be determined, based on the phenotypic markers 


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detected in the screening sample.  Bone marrow aspirates and/or biopsies performed as 
standard of care throughout the study should also be captured on an eCRF.
Note:  For all study visits after Screening, bone marrow aspirates and/or biopsies may be 
performed within 7 days of the anticipated Day 1 visit of the subsequent cycle.  Bone 
marrow aspirates and/or biopsies should be performed and resulted prior to drug 
dispensation beginning with Cycle 4 Day 1 visit.
A sufficient bone marrow aspirate (biopsy) must be collected for clinical assessment and 
predictive biomarker assessments.
Bone marrow aspirates and biopsies performed as standard of care throughout the study, 
typically because the investigator has suspicion for improved response or progression, 
should also acquire bone marrow aspirate for MRD detection and blood for serum and 
blood for mutational profiling (per Table 6) and also be captured on an eCRF.
Due to differences in standard of care bone marrow core biopsy collection and analyses 
procedures amongst countries and individual sites, the core biopsy collection will be 
considered an optional procedure for subjects enrolled at sites where aspirate evaluation 
with cytometric and/or molecular diagnostics is considered standard of care.  The aspirate 
samples should be collected for all subjects.
A sufficient bone marrow aspirate and/or biopsy must be collected for clinical assessment 
(pathology) performed by local laboratory as well as for shipment of a portion to AbbVie 
(or designee) for biomarker analyses as described in Section 5.3.1.5.  The biopsy 
collection for biomarker analyses is only applicable to countries/individual sites where the 
procedure is performed as part of standard of care.
Clinical Laboratory Tests
Samples will be obtained at all study visits as outlined in Table 3 for, at minimum, the 
clinical laboratory tests outlined in Table 10.


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Local laboratories will be utilized to process and provide results for the clinical laboratory 
tests.  The principal investigator or sub-investigator, if delegated, will review, initial, and 
date all laboratory results.  The laboratory test results will be collected on an eCRF.  
Laboratory normal ranges will be provided to the AbbVie Clinical Team, as requested.
All local laboratory measurements will be entered on the eCRF within 5 days of report 
availability, unless the report reflects a Grade 3 or 4 test result in which case the results 
will be entered immediately on the eCRF within 24 hours of report availability.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  Local lab results should be obtained along with reference ranges and 
kept within the subjects' source documentation.  Local lab results should be reviewed by 
the investigator as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued 
provided the investigator has reviewed all prior laboratory results and confirms and 
discusses with the subject that there is no safety concern for the subject to continue use of 
the study drug in the absence of current labs.  The subject should be scheduled for 
laboratory draws as soon as feasible from the scheduled visit.


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Table 10.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not 
acceptable)
Mean corpuscular hemoglobin 
(MCH)
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin 
concentration (MCHC) 
Blasts
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 acida
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH) 
Magnesium
Chloride
Bicarbonate
Amylase (Screening, Cycle 2 
Day 1 and Final Visit only)
Lipase (Screening, Cycle 2 
Day 1 and Final Visit only)
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination (as 
indicated)
Coagulation
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
a.
At room temperature, rasburicase causes enzymatic degradation of the uric acid in blood/plasma/serum samples 
potentially resulting in spuriously low plasma uric acid assay readings.  The following special sample handling 
procedure must be followed to avoid ex vivo uric acid degradation.
Uric acid must be analyzed in plasma.  Blood must be collected into pre-chilled tubes containing heparin 
anticoagulant.  Immediately immerse plasma samples for uric acid measurement in an ice water bath.  Plasma 
samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C).  Finally, the plasma must be 
maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
For any laboratory test value outside the reference range that the investigator considers 
clinically significant:
●
The investigator may repeat the test to verify the out-of-range value.


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●
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 6.1.8 regarding 
toxicity management), and/or if the investigator considers them to be adverse event.
Chemistry and Hematology
Chemistry and hematology will be collected at the following time points and as outlined 
in Table 3.
Starting with Cycle 3 Day 1, chemistry and hematology may be performed within 
72 hours before or after the scheduled visit.  However, there is no 72-hour window 
permitted for post-dose chemistry and hematology samples collected during Cycle 1 
Day 1, Cycle 2 Day 1, or at the time of any dose escalation.  Amylase and lipase are only 
required at Screening, Cycle 2 Day 1, and at the Final Visit.  Refer to Section 6.1.8.2.  If 
subject is taking rasburicase, the special sample handling procedure outlined in Table 10
must be followed to avoid ex vivo uric acid degradation in the presence of rasburicase.
Refer to Section 6.1.8.2, Prophylaxis and Management of Tumor Lysis Syndrome, for 
monitoring required.  If laboratory abnormalities consistent with TLS are observed, see 
Appendix E, Recommendations for Initial Management of Electrolyte Imbalances and 
Prevention of Tumor Lysis Syndrome (TLS) for procedures to follow.
Coagulation
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) samples will be 
collected as outlined in Table 3 and as needed throughout the study.  Beginning at Cycle 3, 
coagulation may be performed within 72 hours before or after the scheduled visit.


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Urinalysis
Urinalysis samples will be collected as outlined in Table 3 and as needed throughout the 
study.  Beginning at Cycle 3, urinalysis may be performed within 72 hours before or after 
the scheduled visit.
Clinical Disease Progression Assessment
Assessment of clinical disease progression will be made at visits as outlined in Table 3
and as deemed appropriate by the investigator at an interval of no greater than every 
3 cycles.  Subjects exhibiting disease progression should be discontinued from the study 
per Section 5.4.
Cytogenetic Assessment
Cytogenetic assessment will be done locally within 3 months prior to beginning therapy.
Molecular Markers
Profiling of common genetic abnormalities in AML may be explored at screening on a 
mandatory screening bone marrow sample and sent to a central laboratory designated by 
AbbVie.  Although this is not a complete list, the following genes are commonly altered 
in AML subjects:
●
fms-related tyrosine kinase-3 (FLT3), nucleophosmin1 (NPM1), 
CCAAT/enhancer-binding protein alpha (CEBPA), Isocitrate Dehydrogenase 1 
(IDH1), Isocitrate Dehydrogenase 2 (IDH2), ten-eleven translocation 2, 
(TET2) and DNA methyltransferase 3A(DNMT3A).
Tumor Lysis Syndrome Prophylaxis
Tumor lysis syndrome prophylaxis will be initiated in all subjects starting at least the day 
before the first dose of venetoclax and continued through 24 hours post the first dose at 
the highest administered dose level of venetoclax per the guidelines in Section 6.1.8.2.


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Subject Calendars/Diaries
Subject calendars/diaries will be provided.  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).
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.
Enrollment and Assignment of Subject Numbers
An Interactive Response Technology (IRT) system will be utilized to register subjects.  
Once the subject has signed the informed consent the site will obtain a screening (subject) 
number via the IRT system.  Once the screening number is assigned, if the subject is not 
enrolled into the study, the reason for screen failure will be documented in the source 
document and will be captured in the eCRF.
The results of all screening evaluations must be within clinically acceptable limits, upon 
review by the investigator before a subject can be administered study drug.  Subjects will 
not be enrolled in the study if laboratory or other screening results are unacceptable.
Subjects who complete all screening procedures and meet the eligibility criteria in 
Section 5.2.1 and none of the exclusion criteria in Section 5.2.2 will proceed to enrollment.


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Post-Treatment Follow-Up Visit(s)
For subjects who discontinue study treatment for reasons other than disease progression, 
the following post-treatment assessments will be performed every 12 weeks (± 1 week) 
until criteria are met for discontinuation from the study (e.g., disease progression, death or 
a subject's refusal of the Post-Treatment visits) for a period of 1 year after last subject's 
last dose or possibly sooner if all patients have discontinued and most patients have 
expired:
●
Hematology
●
Disease Assessment
Survival Assessment(s)
Survival information (e.g., date and cause of death, post-treatment cancer therapies, 
including transplantation) will be collected once the subject's disease has progressed via 
telephone calls (e.g., to subject or family member) and/or clinical visits at 12 weeks 
intervals (± 1 week) after the subject's last study visit for a period of 1 year after last 
subject's last dose or possibly sooner if all patients have discontinued and most patients 
have expired.
5.3.1.2
Confinement
Subjects will be hospitalized during dose escalation of venetoclax.  Confinement is 
recommended to begin by Study Day –1 and must occur by at least Day 1 through at least 
24 hours after completion of the ramp-up period for subjects in both Phase 1 and Phase 2 
including Cohort C.
5.3.1.3
Meals and Dietary Requirements
Each dose of venetoclax will be taken with approximately 240 mL of water within 
30 minutes after the completion of a meal, preferably breakfast.


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Subjects may not consume grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or Starfruit 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.
5.3.1.4
Blood Samples for Pharmacogenetic Analysis
A 4 mL whole blood sample for DNA isolation will be collected on Cycle 1 Day 1, 
Cycle 4 Day 1, and the Final Visit.  The sample collection tubes will minimally be labeled 
with "PG-DNA," protocol number, visit, and subject number.  Pharmacogenetic collection 
should occur unless precluded by local or national regulations or policies.  AbbVie will 
store the DNA samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on venetoclax (or drugs of 
this class) continues but no longer than 20 years.  Sample collection and shipping 
information are detailed in the most current version of Study M14-387 Laboratory Manual.
5.3.1.5
Pharmacodynamic and Predictive Biomarker Testing
Blood Collections
Whole blood will be collected into appropriately labeled tubes and processed as outlined 
in the most current version of Study M14-387 Laboratory Manual.
Blood Collection for Mutational Profiling:
Approximately 2.5 mL for blood will be collected prior to dose at:
●
Screening (preferred) or prior to the first dose of study drug
●
Final Visit/Time of Relapse
Blood Collection for Plasma
Approximately 4 mL of blood or 12 mL of blood will be collected prior to dose at
●
Screening (preferred) or prior to the first dose of study drug (4 mL blood)


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●
Cycle 2 Day 1 (4 mL blood)
●
Response assessments:
Cycle 4 Day 1, and every 3 cycles thereafter (12 mL blood)
Subjects who achieve 2 consecutive CR assessments and no longer require a 
bone marrow aspirate/biopsy for disease assessment, will still have plasma and 
serum collections at every 3 cycles thereafter.
●
Final Visit/Time of Relapse (4 mL blood)
Blood Collection for Serum
Approximately 3.5 mL of blood will be collected prior to dose at
●
Screening (preferred) or prior to the first dose of study drug
●
Cycle 2 Day 1
●
Response assessments:
Cycle 4 Day 1, and every 3 cycles thereafter
Subjects who achieve 2 consecutive CR assessments and no longer require a 
bone marrow aspirate/biopsy for disease assessment, will still have plasma and 
serum collections at every 3 cycles thereafter.
●
Final Visit/Time of Relapse
Blood Collection for Ex Vivo Sensitivity and Translational Research 
(e.g., mutational analysis, BH3 profiling):
Approximately 8 mL of blood will be collected prior to dose at:
●
Screening (preferred) or prior to the first dose of study drug
●
Cycle 2 Day 1
●
Final Visit/Time of Relapse
Blood Collection for Bcl-2 Family Protein Analysis
Approximately 2 ml of blood will be collected prior to dose at:


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●
Screening (preferred) or prior to the first dose of study drug
●
Cycle 2 Day 1
●
Final Visit/Time of Relapse
Bone Marrow Aspirate and Biopsy Collections
Bone marrow aspirates should be drawn into appropriately labeled tubes in conjunction 
with the clinical assessments.  A portion of the aspirate must be processed according to 
the institutional standard procedures for diagnostic evaluation; however, approximately 
6 to 8 mL of the bone marrow aspirate should be collected for biomarker assessments.  
Subjects, who achieve 2 consecutive CR assessments and no longer require a bone 
marrow aspirate/biopsy for disease assessment, will also not require bone marrow 
aspirates for biomarker collections.  Detailed processing will be as outlined in the most 
current version of the Study M14-387 Laboratory Manual for the following:
Minimal Residual Disease Assessment
Minimal Residual Disease Assessment aspirate samples will be collected, processed and 
shipped to the central laboratory per the most current version of the Study M14-387 
Laboratory Manual.
NOTE:  This should be the first tube drawn from the bone marrow aspirate collection.
●
Screening (preferred) or prior to the first dose of study drug
●
Cycle 2 Day 1
●
Response assessments:  Cycle 4 Day 1, and every 3 cycles thereafter
●
Final Visit/Time of Relapse
Mutational Profiling
Mutational Profiling will be collected at:
●
Screening (preferred) or prior to the first dose of study drug
●
Final Visit/Time of Relapse


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Bcl-2 Family Protein Analysis
Bcl-2 Family Protein Analysis will be collected at:
●
Screening (preferred) or prior to the first dose of study drug
●
Cycle 2 Day 1
●
Final Visit/Time of Relapse
Ex vivo sensitivity and Translational Research (e.g., BH3 profiling)
Ex vivo sensitivity and Translational research will be collected at:
●
Screening (preferred) or prior to the first dose of study drug
●
Cycle 2 Day 1
●
Final Visit/Time of Relapse
Bone Marrow Core Biopsy for Bcl-2 IHC
A portion of the core biopsy (applicable only to counties/individual sites were this 
procedure is included as standard of care) must be processed for according to the 
institutional standard procedures for diagnostic evaluation:  however, if tissue remains 
approximately 4 to 10 slides from the biopsy should be collected for 
immunohistochemistry analysis at:  
●
Screening (preferred) or prior to the first dose of study drug
●
Final Visit/Time of Relapse
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
The timing of PK blood collections will take priority over all other scheduled study 
activities except for dosing.  The order of blood collections will be maintained to the 
minute such that the time intervals relative to the preceding dosing will be the same for all 


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subjects.  The date and time of each blood sample collection will be recorded to the 
nearest minute on the source documents.
Blood Samples for Venetoclax Assay
Blood samples (3 mL) for venetoclax (and possible metabolite[s]) assay will be collected 
by central venous catheter into evacuated potassium (K2) EDTA tubes at the following 
times:
Phase 1 Cohorts
●
Cycle 1 Day 2:  8 hours post-dose
●
Cycle 1 Days 3 – 6 or 7:  8 hours post-dose (if escalation to a new dose level)
●
Cycle 1 Day 10:  0 hour (pre-dose) and at 2, 4, 6, 8 and 24 hours post-dose
●
Cycle 1 Day 18:  0 hour (pre-dose) and at 2, 4, 6, 8 and 24 hours post-dose
●
Cycle 2 Day 1, Cycle 4 Day 1, and every 3 cycles thereafter (± 7 Days):  
0 hour (pre-dose)
Initial Phase 2 Cohort
●
Cycle 1 Day 2, Cycle 2 Day 1, Cycle 4 Day 1, and every 3 cycles thereafter 
(± 7 Days):  0 hour (pre-dose)
Phase 2 Cohort C
●
Cycle 2 Day 1, Cycle 4 Day 1, and every 3 cycles thereafter (± 7 Days):  
0 hour (pre-dose)
A total of approximately 17 blood samples (51 mL) will be collected per subject during 
Cycle 1 in Phase 1 portion.  For a schedule of the blood collection for venetoclax assay, 
refer to Table 7 and Table 8.  All 0 hour (pre-dose) samples are relative to the start of 
venetoclax administration.  The PK collection performed 8 hours post-dose after each 
dose escalation may be taken up to 1 hour prior or up to 20 minutes after to allow for 
processing, if necessary.


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The date and time (to the nearest minute) of each venetoclax dose and whether or not the 
venetoclax dose was taken within 30 minutes after the completion of a meal (preferably 
breakfast) will be recorded on the eCRF for each scheduled venetoclax PK day and for the 
2 days prior to each scheduled venetoclax PK day (if applicable).  Sites will ensure all 
information is captured through source documents (site or subject calendar/diary provided 
by AbbVie).
Blood Samples for Cytarabine Assay
Blood samples (4 mL) for cytarabine assay will be collected by central venous catheter in 
the Phase 1 cohorts at the following times:
●
Day 1 and Day 10 of Cycle 1:  0 hour (pre-dose) and at 15 and 30 minutes and 
1, 3, 6 hours following the SC dose.
For a schedule of the blood collection for cytarabine assay, refer to Table 7.
The start time of each cytarabine SC injection will be recorded to the nearest minute on 
the eCRF as applicable.
A total of 12 blood samples (72 mL) for cytarabine concentration determination are 
planned to be collected per subject.
The necessary anticoagulant and sample pre-treatment will be provided in the lab manual 
for the study.  These samples are not optional, however, due to the expected complexity of 
the sample collection and processing for the cytarabine PK, AbbVie recognizes some 
centers may not have the capability to perform the PK samples.  In those instances, the 
cytarabine PK samples will not be collected.  Sites with these capabilities will be 
predetermined. 


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5.3.2.2
Handling/Processing of Samples
Blood Samples for Venetoclax PK Assay
Detailed sample collection and processing instructions for the venetoclax PK samples will 
be provided in the lab manual for this study.
Blood Samples for Cytarabine PK Assay
Detailed sample collection and processing instructions for the cytarabine PK samples will 
be provided in the lab manual for this study.
5.3.2.3
Disposition of Samples
The frozen plasma PK samples for venetoclax and cytarabine will be packed in dry ice 
sufficient to last during transport and shipped from the study site to the central lab 
according to instructions in the laboratory manual.  An inventory of the samples included 
will accompany the package.  The central lab will ship the samples to reference 
laboratories for analysis.
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 concentrations of possible venetoclax 
metabolite(s) may be determined with either validated or non-validated methods.  Plasma 
concentrations of cytarabine will be determined at an external lab using a validated 
method under the supervision of the Drug Analysis Department at AbbVie. 
5.3.3
Efficacy Variables
Efficacy Assessments
Responses will be evaluated based on the revised guidelines by the International Working 
Group (IWG) for AML.38  As a significant number of the subjects in this study might 
have antecedent hematologic illnesses, hematologic response will also be evaluated.  
Transfusion dependence is defined as having received ≥ 2 units of RBCs and or platelets 


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within 8 weeks prior to study treatment.  Duration of Response will be measured from the 
time when all response criteria are first met until recurrent or progressive disease is 
documented.
Criteria for Evaluation is as follows:
●
CR:  Absolute neutrophil count ≥ 103/µL, platelets ≥ 105/µL, red cell 
transfusion independence, and bone marrow with < 5% blasts.
●
CRi:  bone marrow with < 5% blasts, and peripheral neutrophils of <103/µL or 
platelets < 105/µL.
●
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 and/or bone marrow core sample. 
There should be no blasts with Auer rods or persistence of extramedullary 
disease. The presence of a unique phenotype (by flow cytometry) identical to 
what was found in the pretreatment specimen (e.g., CD34, CD7 coexpression) 
should be viewed as persistence of leukemia.
●
RD:  failure to achieve CR, CRi, PR; only including subjects surviving at least 
7 days following completion of initial treatment cycle, with evidence of 
persistent leukemia by blood and/or bone marrow examination.
●
PD:  one or more of the following:  ≥ 50% decrement from maximum response 
levels in neutrophils or platelets, a reduction in hemoglobin by at least 2 g/dL, 
or transfusion dependence,* not due to other toxicities and bone marrow blast 
≥5%.
In addition to the response determination using the above IWG AML response criteria, 
each subject will also be evaluated for hematologic response and complete remission with 
partial hematologic recovery (CRh).
●
HR:  improvement in peripheral blood counts with all of the following:  fewer 
absolute peripheral blood blasts than prior to initiating study treatment for 
subjects presenting with peripheral blood blasts, ANC ≥ 500 (cells/μL), 


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platelets ≥ 0.25 × 105 (platelets/μL), and no more than 2 units of packed red 
blood cells within a 28-day period.
●
CRh:  all of the following criteria are met:  Bone marrow with < 5% blasts, 
peripheral neutrophils of ≥ 0.5 × 103/µL, and peripheral platelets 
≥0.5 × 105/µL**
*
Transfusion independence is defined as the absence of any RBC or platelet transfusion during any consecutive 
8 weeks during the treatment period.39
**
For a bone marrow sample collected before the last cycle of study treatment, the hematology lab results collected 
from the date of bone marrow sample collection up to 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.
Reporting of Results
All dosed subjects will be assessed for response to treatment based on the published 
guidelines.  Assessments will be performed at Cycle 2 Day 1, Cycle 4 Day 1, and every 
3 cycles thereafter for response assessment until two successive bone marrow samples 
document a CR.  When additional bone marrow evaluations are routinely indicated for 
clinical management, additional collection of bone marrow aspirate and peripheral blood 
are strongly encouraged as these findings have the potential to define either remission 
status or potential progression of leukemia.  NOTE:  For subjects who achieve CR or CRi, 
MRD status may be determined.
Subjects will be assigned to one disease state for best IWG response assessment, 
achievement of protocol defined hematologic response, and minimal residual disease 
positivity at the time of the best response.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse event 
monitoring and vital signs, physical examination, ECG and laboratory tests assessments.


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5.3.5
Pharmacokinetic Variables
For the intensive PK days of venetoclax, values for the PK parameters including the 
maximum observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the 
area under the plasma concentration-time curve (AUC) from 0 to the time of the last 
measurable concentration (AUCt) and AUC over a 24-hour dose interval (AUC0-24) will 
be determined using noncompartmental methods.  For the intensive PK days of cytarabine, 
values for the PK parameters including Cmax, Tmax, half-life (t1/2), AUCt, AUC from 0 to 
the time of infinity (AUC∞) and clearance (CL/F) will be determined using 
noncompartmental methods. Additional analyses may be performed if useful in the 
interpretation of the data.
5.3.6
Pharmacogenetic Variables
DNA samples may be sequenced, and data analyzed for genetic factors contributing to the 
disease or to the subject's response to venetoclax (or other study treatment) in terms of PK, 
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 
pharmacogenetic analyses may not be reported with the study summary.
5.3.7
Pharmacodynamic Variables
Several putative biomarkers of efficacy and response may be evaluated in this protocol 
with the goal of defining the relationship between drug concentration and disease status.  
Samples taken may be used for the assessment of specific biologic markers, including 
proteins and/or nucleic acids not currently known to be prognostic, in order to better 
understand the biology of AML and disease prognosis, to predict response to treatment 


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with venetoclax, or to assess venetoclax activity.  Biospecimens collected during the 
course of this study may be banked and used in the future to investigate new scientific 
questions related to this study.  These analyses are exploratory in nature and may not be 
conducted in GLP laboratories and may not be included in the clinical study report.  The 
samples may also be used for diagnostic test development.  AbbVie (or a designated 
laboratory) will store the samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on venetoclax (or 
drugs of this class) continues but no longer than 20 years.
Reduction in subject leukocytosis or blast counts may be evaluated as a measure of 
pharmacodynamics activity to venetoclax.  Measurement of relevant nucleic acids and 
proteins (including but not limited to the Bcl-2 family members) in tumor cells in the 
blood, pre-treatment, and at time of disease progression, may be examined for putative 
stratification markers for correlation with efficacy.
For the study to be comprehensive, a determination of whether the cellular context 
influences response to this drug will need to be made; therefore both subject bone marrow 
and peripheral blood collections may be evaluated for a subset of the biomarker analyses 
which are planned.  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 subject populations (based on subject 
characteristics at baseline and relapse).
Venetoclax inhibits the ability of cancer cells to evade cell death, or apoptosis, by 
blocking the activity of the anti-apoptotic protein Bcl-2.  Preclinical studies have 
demonstrated a pattern of response to venetoclax based on the levels of Bcl-2 family 
proteins.  High levels of Bcl-2 and low levels of Mcl-1 and Bcl-XL are generally 
predictive of response to this drug in vitro.  The measurement of relevant DNA, RNA and 
proteins (including those in the Bcl-2 family and those related to AML disease biology) in 
leukemic blood and bone marrow as well as serum and protein may be examined 
pre-treatment, on therapy, and at the time of progression for putative stratification markers 
and correlation with efficacy.  In addition, blood and bone marrow samples will be


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collected and may be used to determine ex vivo sensitivity of leukemic cells by BH3 
profiling and/or by treatment with venetoclax (IC50 values) to evaluate if response to 
venetoclax can be predicted in vitro.  These methods may be further used along with 
subject cytogenetics and mutational profile to enrich for subjects likely to respond to 
venetoclax in the second portion of the study.  Based on the ongoing assessment of data, 
the criteria for subject enrichment will be defined.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
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;
●
The subject experiences toxicities related to study drug that require more than 
a 4-week (one cycle) dose interruption of venetoclax;
●
The subject requires more than two dose reductions, in two consecutive cycles, 
of venetoclax, in the absence of clinical benefit from the study treatment;
●
The subject requires radiotherapy or alternate anti-neoplastic agents during the 
study period (with the exception of hydroxyurea [allowed in first month 
only]);
●
The occurrence of an adverse event that precludes further investigational drug 
administration;
●
Noncompliance with the protocol.
In the event that a subject withdraws or is discontinued from the study, the reason(s) for 
the discontinuation from the study and the primary reason will be recorded and a Final 
Visit and procedures listed in Table 3 will be performed as soon as possible after 
discontinuation from the study.


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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.
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 any 
adverse event is achieved.
A separate 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.
Post-treatment assessment will be performed every 12 weeks (± 1 week) until 
discontinuation from the study (e.g., disease progression death or a subject's refusal of the 
Post-Treatment visits) for a period of 1 year after last subject's last dose or possibly 
sooner if all patients have discontinued and most patients have expired.
Survival information (e.g., date and cause of death, post-treatment cancer therapies, 
including transplantation) will be collected once the subject's disease has progressed via 
telephone calls (e.g., to subject or family member) and/or clinical visits at 12 weeks 
intervals (± 1 week) after the subject's last study visit for a period of 1 year after last 
subject's last dose or possibly sooner if all patients have discontinued and most patients 
have expired.
Additionally, in the event a subject withdraws from the study, PD and predictive samples 
stored for long term (up to 20 years) biomarker research will also be destroyed.  In the 
event that destruction is not possible, they will no longer be linked to the subject.  If the 
subject changes his/her mind, and the samples have already been tested, those results will 
still remain as part of the overall research data.  In the event of a subject's death or loss of 


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competence, the samples and data will continue to be part of AbbVie's research, but will 
not be stored more than 20 years.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID 19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.  Refer to the 
Section 5.3.1.1, Study Procedures and Table 3 for details on how to handle study 
activities/procedures accordingly.  Study drug interruptions due to COVID-19 restrictions 
should be captured in EDC.
The investigator should contact the sponsor medical contact before discontinuing a subject 
from the study for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
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.


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●
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.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
Decisions to delay or interrupt any study treatment based on the current situation and any 
concern for active infection should be made by the treating investigator after considering 
the subject's current oncologic status and treatment tolerance, as well as their general 
medical condition. As a potentially serious infection, consideration for treatment 
interruption is advised.  If needed, any questions can be discussed with the Therapeutic 
Area Medical Director (TAMD).
5.5
Treatments
5.5.1
Treatments Administered
Study drug will be administered daily as follows:
Each dose of venetoclax will be taken with approximately 240 mL of water.  Subjects will 
be trained to self-administer venetoclax orally QD within 30 minutes after the completion 
of a meal, preferably breakfast.
If vomiting occurs within 15 minutes of taking venetoclax and all expelled tablets are still
intact, another dose may be taken and the second dose noted in the drug log.  Otherwise, 
no replacement dose is to be taken.  In cases where a dose of venetoclax is missed or 
forgotten, the subject should take the dose as soon as possible, ensuring the dose is taken 
within 8 hours of the missed dose with food.  Otherwise, the dose should not be taken.


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Low-dose cytarabine (20 mg/m2) should be prepared per package insert and administered 
subcutaneously by a trained provider meeting local qualifications for administration of 
subcutaneous chemotherapy.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If a subject is unable to come to the study site to pick up their study drug due to 
COVID-19, a direct-to-patient (DTP) venetoclax shipment can be made from the study 
site to the subject if allowed by local regulations.  Cytarabine DTP are is not allowed by 
AbbVie.  AbbVie will submit any required notifications to the regulatory authority as 
applicable.
Venetoclax may be shipped from the study site directly to the study subject's home if all 
the following criteria are met:
●
Direct-to-patient (DTP) shipment of venetoclax is allowed by local regulations 
and the relevant ethics committee
●
Venetoclax can be administered by the subject (or subject's caregiver) at home
●
Subject agrees to have the venetoclax shipped directly to their home
○
Shipments may also include other study supplies (e.g., drug dosing diaries).  
Instructions will be provided by AbbVie as to how a study site can initiate 
a DTP shipment using Marken, a global vendor selected by AbbVie to 
provide this service when necessary.  Shipments of venetoclax from the 
study site to a subject's home will be appropriately temperature controlled 
(qualified shipper or temperature monitoring) within the labeled storage 
conditions.  Signature is required upon delivery; due to COVID-19 related 
social distancing, this may be provided by the courier after delivery.  
Documentation of the shipment is to be retained by the clinical site.
○
AbbVie will not receive subject identifying information related to these 
shipments, as the site will work directly with the courier.


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The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, and for obtaining consent to provide delivery information to the 
courier and documenting this consent in source documents.
5.5.2
Identity of Investigational Products
Information about the venetoclax and cytarabine formulations to be used in this study is 
presented in Table 11.
Table 11.
Identity of Investigational Products
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Venetoclax
N/A
10 mg Tablet
Oral
AbbVie
Venetoclax
N/A
50 mg Tablet
Oral
AbbVie
Venetoclax
N/A
100 mg Tablet
Oral
AbbVie
Cytarabine
generic
20 mg/mL solution for injection
SC
generic
AbbVie or designee will supply cytarabine.
5.5.2.1
Packaging and Labeling
The venetoclax tablets will be packaged in high density polyethylene (HDPE) plastic 
bottles.  Each bottle will be labeled per local regulatory requirements.  Cytarabine will be 
provided as one vial per carton.  Each vial and carton will be labeled per local regulatory 
requirements.
5.5.2.2
Storage and Disposition of Study Drug
The venetoclax study drug must be stored at 15° to 25°C (59° to 77°F).  Cytarabine must 
be stored at 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
There is no randomization schedule for this study.  Subjects will be assigned at screening 
a unique subject number via IRT system beginning with 30101 for the Phase 1 portion of 
the study.  For the Phase 2 portions of the study, subjects will be assigned at screening a 
unique consecutive subject number by an IRT system beginning with 30201.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the dose for this study is discussed in Section 5.6.4.  Venetoclax will be 
administered orally once daily (QD) on Days 2 through Day 28 of Cycle 1 (28-day cycle) 
for subjects enrolled into Phase 1 and the initial Phase 2 portion.
Venetoclax will administered orally once daily (QD) on Day 1 through Day 28 of Cycle 1 
(28-day cycle) for subjects enrolled into Phase 2 Cohort C.
Each dose of venetoclax should be taken with approximately 240 mL of water within 
30 minutes after the completion of a meal, preferably breakfast.
5.5.5
Blinding
This is an open-label 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 of venetoclax to be 
dispensed to a subject during the study.  Prior to each scheduled visit, site personnel must 
contact IRT for the next bottle number(s) for assignment.  AbbVie or its designee will 
provide specific instructions on the use of IRT.


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To document compliance with the treatment regimen, subjects will be instructed to return 
all unused tablets and/or bottles, even if empty, and any other study related items as 
necessary, to the study coordinator at scheduled study visits.  Compliance will be 
monitored and documented by the study coordinator on the appropriate form.  The study 
coordinator 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 study drug) 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 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
Low-dose cytarabine is a commonly prescribed treatment within the United States for 
subjects who fulfill the entry criteria of this study.  Venetoclax is undergoing testing in 
other clinical trials as a single-agent treatment for AML and in combination with other 
standard AML treatments.  The ongoing single-agent study, Study M14-212, has 


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demonstrated that venetoclax has anti-leukemia activity for subjects with relapsed or 
refractory AML and therefore may be efficacious for subjects with previously untreated 
AML.  This study consists of a Phase 1 portion to define the MTD and generate data to 
support a RPTD for the Phase 2 portion.  The Phase 1 portion of the study is a dose 
escalation phase which will consist of up to 42 subjects who initiate therapy with 
venetoclax combined with cytarabine.  In each cohort, a minimum of 3 and/or up to 
6 subjects will be evaluated before making venetoclax designated cohort dose escalation 
decision.  A subsequent Phase 2 portion will enroll approximately 50 subjects who will be
administered venetoclax at the RPTD and schedule defined in the Phase 1 portion of the 
study.  An additional Phase 2 cohort, Cohort C, will evaluate if the ORR for subjects 
enrolled with modified entry criteria and allowing additional supportive medications 
(strong CYP3A inhibitors) is substantially different than the ORR observed for subjects 
enrolled under the prior entry criteria in Phases 1 and 2.  There are no direct control 
groups in this study although a recent historical control cohort of treatment naïve subjects 
age 65 and older with AML receiving LDC reported an 11% ORR utilizing the same 
response definitions.30
5.6.2
Appropriateness of Measurements
Standard PK, statistical, clinical and laboratory procedures will be utilized in this study.  
The efficacy measurements in this study are standard and validated.
5.6.3
Suitability of Subject Population
Subjects who have histological confirmation of acute myelogenous leukemia who are 
treatment-naïve, greater than or equal to 60 years of age, and who are not eligible for 
standard induction therapy due to co-morbidity or other factors will be selected to 
participate in this study.
5.6.4
Selection of Doses in the Study
In the initial Phase 1 trial (Study M12-175) evaluating venetoclax monotherapy in 
subjects with CLL and NHL, the most significant toxicity was TLS in CLL subjects 


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during the initiation of dosing.  Reductions in circulating CLL cells and electrolyte 
changes consistent with tumor lysis have been observed within 6 to 8 hours after initiation 
of therapy, a time consistent with the Tmax for venetoclax.  To minimize the risk of TLS36
in Study M12-175, a dose titration scheme is being employed, starting at doses 
significantly lower than the final target dose.  The response in CLL is dose-dependent, 
with incremental reductions in circulating CLL cells observed at the titration steps.  Final 
target doses of up to 800 mg have been shown to be tolerable in subjects with CLL.  
Subjects with NHL have received target doses of 1200 mg without dose limiting toxicities.
Few DLTs for subjects at venetoclax target doses (≥ 600 mg) have been seen and include 
2 events of neutropenia and 1 event of febrile neutropenia.
Preclinical studies evaluating the activity of venetoclax ex vivo in primary AML subject 
samples have shown sensitivities similar to those seen in primary CLL samples.  Ex vivo 
sensitivity even greater than that in CLL cells has been observed in a small fraction of the 
primary AML cells with IC50 values < 1 nM.8 Based on these data, rapid tumor lysis of 
AML may occur upon initiation of dosing with venetoclax.  Therefore, a dose titration 
scheme based on that being used in CLL studies will be utilized in this study.  The 
escalation steps are similar, but the timeline has been condensed due to more acute nature 
of AML versus CLL.  No serious or nonserious AE of clinical TLS have been reported in 
the Phase 2 study of venetoclax monotherapy in AML.  Phosphate and potassium 
laboratory changes have been observed and managed using the TLS electrolyte 
management guideline as described in Appendix E.
This combination regimen is designed to escalate the dose of venetoclax rapidly with 
LDC to optimize the opportunity for achieving a response and enable close subject 
monitoring.  The dosing regimen will also enable interruptions and slower intra-subject 
dose escalations to the assigned target dose if rapid tumor lysis is observed.  Based on the 
ex vivo testing of primary subject AML samples that has shown significant variability 
among subjects, it is expected that initial signs of tumor response will occur at different 
doses for different subjects.  However, the Cycle 1 Day 2 dose and the final target dose 


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are anticipated to be the same for all subjects with modifications to the regimen permitted 
to respond to signals consistent with antitumor activity/tumor lysis.
Potential target daily doses of venetoclax are 200 mg, 400 mg, 600 mg, 800 mg, 1200 mg, 
1600 mg and 2000 mg for dose levels (–)2 through 5 respectively.  Based on potential 
dose limiting impurities, the dose of venetoclax for this protocol will not exceed 
2000 mg/day.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.1.6).  For adverse events, please refer to Sections 6.1
through 6.1.8.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.


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6.1.1
Definitions
6.1.1.1
Adverse Event
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 6.1.8 regarding toxicity 
management), and/or if the investigator considers them to be adverse events.
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 reported by a subject 
with onset or worsening from the time that the first dose of study drug is administered 
until 30 days have elapsed following discontinuation of study drug administration.


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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.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability 
is not intended to include experiences of relatively minor 
medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or stillbirth 
is considered an important medical event.  Examples of such 
events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse


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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 serious adverse events (see Section 6.1.3.1).
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 (e.g., abnormal post-dose TLS laboratories that 
necessitate therapeutic medical intervention, etc.).  Additional criteria for defining TLS 
are in Appendix H.
6.1.1.3
Adverse Events Commonly Associated with Acute 
Myelogenous Leukemia Study Population and/or 
Progression of Acute Myelogenous Leukemia
Certain adverse events are anticipated to occur in the study population (AML) at some 
frequency independent of drug exposure.  Such events include known consequences of the 
underlying disease or condition under investigation (e.g., symptoms, disease progression) 
and events unlikely to be related to the underlying disease or condition under investigation 
but common in the study population independent of drug therapy (e.g., cardiovascular 
events in an elderly population).
These events are listed in Appendix F (Adverse Events Commonly Associated with AML 
Study Population or Progression of AML).
These adverse events may occur alone or in various combinations and are considered 
expected for reporting purposes for this protocol.
Cytopenias (anemia, neutropenia, or thrombocytopenia) are part of the natural history of 
AML.  Persistent cytopenias at the same CTCAE grade as at baseline are not to be 
reported as adverse events, unless they fulfill a seriousness criteria, result in permanent 
discontinuation of a study drug, or the investigator had an identifiable cause other than the 


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underlying disease.  However, all laboratory data should be entered regardless of whether 
an adverse event is reported.
Although exempted from expedited reporting to Health Authorities and IRBs as 
individual cases, if an event commonly associated with AML or progression of AML 
meets seriousness criteria (as defined in Section 6.1.1.2) it must be reported to AbbVie 
within 24 hours of the site being made aware of the serious adverse event.  For deaths 
related to disease progression, the date and cause of death will be recorded on the 
appropriate case report form, but the death will not be expedited as an individual case 
safety report (ICSR) to regulatory authorities.
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 4.0).40  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.  The dates on the adverse events cannot overlap.  For all reported 
serious adverse events that increase in severity, the supplemental eCRFs also need to be 
updated to reflect any changes due to the increase in severity.
For adverse events not captured by the Common Terminology Criteria, the following 
should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (moderate to severe).
Grade 4
The adverse event is life threatening requiring urgent intervention 
(severe).
Grade 5
The adverse event resulted in death of the subject (severe).


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6.1.3
Adverse Events Expected Due to Study Related Endpoints
6.1.3.1
Deaths
For this protocol, overall survival is an efficacy endpoint.
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section 6.1.5) that are attributed by the investigator solely to progression of AML should 
be recorded only on the Study Completion and Death eCRF.  All other on-study deaths, 
regardless of relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 6.1.6).
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 1 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.
6.1.3.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
subject to expedited reporting.
6.1.4
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:


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Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is insufficient evidence (information) to suggest a causal 
relationship.
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.
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.
6.1.5
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 study drug 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 solicited or spontaneously reported by the subject.
Adverse event information will be collected as shown in Figure 11.


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Figure 11.
Adverse Event Collection
*
Only if considered by the investigator to be causally related to study required procedures.
6.1.6
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 the site or investigator being made aware of the 
serious adverse event.
FAX to:
+1 (847) 938-0660
Email:
PPDINDPharmacovigilance@abbvie.com




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countries will be the most current version of the Investigator's Brochure or Summary of 
Product Characteristics (SmPC) for cytarabine.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed (for both serious and non-serious events):
●
COVID -19 Supplemental Signs/ Symptoms
●
COVID-19 Status Form
6.1.7
Pregnancy
Pregnancy in a study subject must be reported to an AbbVie representative (Section 6.1.6
or Section 7.0) within 1 working day of the site becoming aware of the pregnancy.  
Subjects who become pregnant during the study must be discontinued (Section 5.4.1).
All subjects should be informed that contraceptive measures should be taken throughout 
the study and for 180 days after discontinuing study drug.  Male subjects should be 
informed that contraceptive measures should be taken by their female partner.  
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  In the event of pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information from the 
partner must be obtained prior to the collection of any pregnancy-specific information and 
the pregnancy will be followed to outcome.


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Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.8
Toxicity Management
6.1.8.1
Definition – Dose Limiting Toxicity
Dose limiting toxicities (DLTs) for dose-escalation purposes will be determined during 
Cycle 1 (4 weeks) of study treatment.  Adverse events that occur after the first cycle will 
also be evaluated by the investigator and the AbbVie medical monitor and may be 
considered as dose limiting.
Any of the following events, which cannot be attributed by the investigator to a clearly 
identifiable cause such as tumor progression, underlying illness, concurrent illness, or 
concomitant medication, will be considered a DLT:
●
Grade 4 or 5 non-hematologic toxicity considered at least possibly related to 
the study drug, except those listed in Appendix F.
●
Grade 4 or 5 pancytopenia with a hypocellular bone marrow and no greater 
than or equal to 5% marrow blasts lasting for 42 days or more.
Any DLT will require an interruption and possible discontinuation of venetoclax or LDC.  
Venetoclax and LDC therapy may be reintroduced at a reduced dose, if the toxicity grade 
returns to ≤ Grade 1 or to baseline if Grade 2 at study entry.
Any reduced dose level will be jointly defined by the investigator and the AbbVie medical 
monitor.  The dose may be increased thereafter upon joint determination of the 
investigator and the AbbVie medical monitor.  This dose is not to exceed the highest 
tolerated dose level.  All decisions regarding continued dosing for individual subjects will 


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be medically managed by the investigator, per discussion with the AbbVie medical 
monitor, as appropriate.  These decisions will be driven by the definition of DLTs as 
described above.
6.1.8.2
Prophylaxis and Management of Tumor Lysis Syndrome 
(TLS)
There is a potential for TLS for patients with AML receiving induction therapy, especially 
for those with elevated pretreatment LDH levels, elevated leukocyte count, renal 
dysfunction, and dehydration.  To mitigate the risk for TLS,36 subjects will receive tumor 
lysis prophylaxis, including hydration (e.g., oral, intravenous) and treatment with an agent 
to reduce the uric acid level (e.g., allopurinol, rasburicase).36,41
TLS prophylaxis must be initiated in all such subjects prior to the first venetoclax dose or 
first new escalated dose.
Tumor Lysis Syndrome Prophylaxis and Management for Subjects Dose Escalated 
in Protocol Version 1 and Amendment 1
●
Hospitalization recommended on Day –1 and mandated by Day 1 and for a 
minimum of 24 hours after any venetoclax dose escalation.
●
Nephrology (or other acute dialysis service) should be available on each 
admission per institutional standards to ensure emergency dialysis is available.
●
An agent to reduce the uric acid level (e.g., allopurinol) to be initiated at least 
24 hours prior to venetoclax dosing.  Treatment may need to be continued for 
up to 28 days based on the ongoing risk of TLS development.  Subjects 
allergic to allopurinol must use another uric acid reducer starting at least 
24 hours prior to venetoclax dosing or rasburicase on the day of treatment 
(prior to venetoclax dosing).
●
Oral hydration (at least 1 to 2 liters) starting from at least 24 hours prior to 
first venetoclax dose or any dose escalation.
●
Intravenous hydration (target 150 to 200 mL/hr, as tolerable) must be started 
upon admission and continued during hospitalization as appropriate.  Urine 
output must be monitored.


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●
Chemistries on the first day of venetoclax dosing at 0 (within 4 hours prior to 
dosing), 4, 8 and 12 hours and each day of a new dose at 0 (within 4 hours 
prior to dosing), 4, 8 and 12 hours.*
●
Chemistries at 24, 48, 72 hours after receiving the first designated target dose.*
●
Collection of samples for venetoclax PK assay 8 hours after dosing on each 
day of new dose.  The 8-hour post-dose PK sample may be collected up to 
1 hour earlier or up to 20 minutes after the scheduled time, if necessary to 
facilitate sample processing.
*
Chemistry samples (calcium, inorganic phosphorus, potassium, uric acid, and creatinine) must be reviewed by the 
investigator real time and prior to the subject's next dose to ensure appropriate subject management.  Based upon 
the results, subjects may need further monitoring or may need additional post-dose labs.  Refer to Appendix E
(Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome 
[TLS]) and Appendix H (Tumor Lysis Syndrome Classification) for toxicity management guidelines and 
procedures to follow for TLS prevention.  If a subject meets criteria for clinically significant laboratory or clinical 
TLS, no additional venetoclax doses should be administered until resolution.
Refer to Table 10 (footnote "a") for a special sample handling procedure that must be 
followed to avoid ex vivo uric acid degradation in the presence of rasburicase.
Drug interruption for up to 72 hours following transient (i.e., lasting < 48 hours) chemical 
changes and laboratory TLS may be allowed and will not require a dose reduction.  If the 
TLS has not resolved within 72 hours, then a dose reduction should be considered.
If TLS requires a dose hold or dose modifications, after resolution of electrolyte 
imbalances (Appendix E), venetoclax may be continued at the same dose per discussion 
between the investigator and the AbbVie medical monitor.
Tumor Lysis Syndrome Prophylaxis and Management in Phase 2 Cohort C –
Applies to Subjects Enrolled in Amendment 2
Safety data from the 94 subjects treated in 3 AML studies demonstrated no events of 
clinical TLS; 40 subjects treated in the escalation phase of this study; 32 subjects in 
monotherapy study (Study M14-212) and 22 subjects in a combination study 
(Study M14-387) using low dose cytarabine.  Based on this data, simplification of TLS 
prophylaxis and management will be followed for subjects enrolled into Cohort C.


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All subjects enrolled into Phase 2 Cohort C will need TLS prophylaxis and monitoring.  
Below are the minimum requirements for TLS prophylaxis and management for subjects 
enrolled into the expansion phase.  All other prophylaxis and monitoring procedures for 
TLS will be done as per institutional/regional 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 
at least for 24 hours after reaching the final dose of venetoclax. TLS chemistry 
tests should be confirmed 24 hours after reaching the maximal dose of 
venetoclax.
●
Administration of uric acid reducing agent, adequate oral and intravenous 
hydration while monitoring the fluid status of the subject prior to and during 
the ramp-up of venetoclax will be based on regional standards or institutional 
guidelines.
●
Tumor Lysis Syndrome chemistry tests to be drawn (calcium, inorganic 
phosphorus, potassium, uric acid, and creatinine) on the first day of venetoclax 
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 should be corrected promptly.
●
If a subject meets criteria for clinically significant laboratory or clinical TLS, 
no additional venetoclax dose should be administered until resolution.
○
Prophylactic reductions of potassium, inorganic phosphorus and/or uric 
acid above normal range are recommended prior to beginning study 
treatment and continue based on the ongoing risk of TLS.
*
Chemistry samples (calcium, inorganic phosphorus, potassium, uric acid, and creatinine) must be reviewed by the 
investigator real time and prior to the subject's next dose to ensure appropriate subject management.  Based upon 
the results, subjects may need further monitoring or may need additional post-dose labs.  Refer to Appendix E
(Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome 
[TLS]) and Appendix H (Tumor Lysis Syndrome Classification) for toxicity management guidelines and 
procedures to follow for TLS prevention.  If a subject meets criteria for clinically significant laboratory or clinical 
TLS, no additional venetoclax doses should be administered until resolution.


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For continued dosing of venetoclax, monitor for evidence of TLS during treatment, and 
manage abnormalities in serum creatinine, uric acid and electrolytes promptly.  For 
subjects at higher risk (e.g., circulating blasts), more intensive measures should be 
considered.
Refer to Table 10 (footnote "a") for a special sample handling procedure that must be 
followed to avoid ex vivo uric acid degradation in the presence of rasburicase.
Drug interruption for up to 72 hours following transient (i.e., lasting < 48 hours) chemical 
changes and laboratory TLS may be allowed and will not require a dose reduction.  If the 
TLS has not resolved within 72 hours, then a dose reduction should be considered.
6.1.8.3
Management of Myelosuppresion (Cytopenias)
Venetoclax
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 CR or CRi or is found to have a 
morphologically leukemia free bone marrow, and has Grade 4 neutropenia or 
thrombocytopenia, venetoclax should be held from Day 28 until ANC ≥500 – 1000/µL 
and platelets ≥ 25 – 100 × 105/μL.  At the investigator's discretion, subjects may resume a 
subsequent cycle of therapy after a 2-week interruption if the investigator believes the risk 
of AML progression outweighs the risk of further treatment before cytopenia recovery.  
Typically, if morphologic AML remains in the bone marrow, concurrent cytopenias are 
thought to be attributable to the disease processes of AML.  In subsequent cycles, if a 
subject in CR presents with new onset Grade 4 neutropenia or thrombocytopenia for more 
than 1 week, unless it is due to the underlying disease, venetoclax dosing may be 
interrupted until ANC recovery to ≥500 – 1000/µL or platelets ≥ 25 – 100 × 105/μL per 
investigator discretion in consultation with the AbbVie medical monitor.  Venetoclax may 
be re-initiated at a lower dose per discussion with the AbbVie medical monitor.


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Administration of venetoclax in subjects with lymphoproliferative disorders has been 
associated with clinically significant lymphopenia (B and T lymphocyte subtypes).  If 
clinically indicated in AML subjects treated in this study, anti-infective prophylaxis 
should be implemented at the investigator's discretion, including appropriate prophylaxis 
for viral, fungal, bacterial or Pneumocystis infections.  Potential for drug-drug interactions 
should be considered.  Please refer to Table 1 and Appendix C for a description of 
excluded and cautionary medications.
If a subject is continuing to respond based on the bone marrow assessment beyond 
Cycle 2 of treatment but has persistent neutropenia or thrombocytopenia venetoclax dose 
may be reduced as follows:
Table 12.
Dose Reduction Guidelines for Management of Persistent 
Neutropenia or Thrombocytopenia
Venetoclax Dose/Duration
Reduced 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
Standard Therapy:  Low – Dose Cytarabine
In a recent international clinical trial, subjects receiving LDC 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%, leukopenia 
10%.35  It is unknown whether the aforementioned adverse events are attributable to 
receiving treatment with LDC or were attributable to the underlying health condition of 
AML.  Complications of myelosuppression, including infections and bleeding, may be 
exacerbated by treatment with LDC.  During Cycle 2 and subsequent cycles, LDC 
treatment 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)


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●
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 LDC 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 LDC is reversible.  Complete blood and platelet counts 
should be performed regularly, as clinically indicated and prior to each treatment cycle.  
In the presence of myelosuppression or its complications, treatment with LDC may be 
interrupted or supportive measures instituted.
LDC dose reductions are not typically recommended.  If a dose reduction is believed to be 
necessary a discussion with the AbbVie medical monitor is required.
6.1.8.4
Management of Decreased Spermatogenesis
Based on findings in a preclinical study of venetoclax, there is a potential for decreased 
spermatogenesis.  Male subjects should consider sperm banking before treatment with 
venetoclax if they are considering preservation of fertility.
6.1.8.5
Management of Other Toxicities
If other events occur that are related to venetoclax or LDC the investigator, in consultation 
with the AbbVie medical monitor, may interrupt or dose reduce venetoclax and/or 
reference therapy, as appropriate.  Grade 3 or greater nonhematologic toxicity 
(e.g., nausea, vomiting, and diarrhea when additional supportive care fails), that is related 
to venetoclax or LDC will require interruption and possible discontinuation of dosing.  
Venetoclax or LDC may be reintroduced, but only at a reduced dose, (in consultation with 
the AbbVie medical monitor) if the toxicity returns to ≤ Grade 1 or to baseline if Grade 2 
at study entry.


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Subjects should be monitored for new onset hematologic toxicity and renal toxicities, with 
dose delay or reduction as appropriate.  Please follow local, approved product label or 
applicable SmPC for monitoring guidelines.
6.1.8.6
Determination of the MTD
If a single subject within a cohort experiences a DLT, a total of 6 subjects will be enrolled 
and dosed at the same dose level.  If these additional subjects do not exhibit a DLT, dose 
escalation may proceed.  If any of the additional subjects exhibits a DLT, then dose 
de-escalation may occur to interrogate lower dose levels.  The MTD, if identified, will be 
defined at the highest dose level at which less than 2 of 6 subjects or < 33% of (if cohort 
is expanded beyond 6) subjects experience a DLT.
6.1.8.7
Determination of the RPTD
If an MTD is reached, the RPTD will not be a dose higher than the MTD and will be 
selected by the sponsor based on the types of DLTs which occur and the MTD identified.  
If an MTD is not reached, then the RPTD will be defined based on the safety and PK data.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  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, including those that may be due to COVID-19 pandemic) 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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8.1.1
Baseline Characteristics
All baseline summary statistics and analyses will be based on characteristics obtained 
prior to the initiation of study drug.  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 study 
drug.
8.1.1.1
Demographics
Age, height, weight and gender will be summarized with means, standard deviation and 
range.  Frequencies and percentages will be computed for the following parameters:  race, 
smoking history, and performance status.
8.1.1.2
Medical History
Frequencies and percentages will be computed for each medical history parameter.
8.1.2
Pharmacokinetics
8.1.2.1
Tabulations and Summary Statistics
Plasma concentrations and PK parameter values of venetoclax and cytarabine will be 
tabulated for each subject, visit, and dose regimen, and summary statistics will be 
computed for each sampling time and each parameter.
8.1.2.2
Model and Tests
All analyses will be performed on the Phase 1 portion subjects only.
Dose Proportionality and Covariate Selection of Venetoclax 
The following analysis will be performed separately on Cycle 1 Day 10 and Cycle 1 
Day 18 venetoclax PK parameters.
An analysis will be performed for dose-normalized Cmax, AUC24, and other PK parameters 
provided that they can be adequately determined from the data.  The model used for the 
statistical analyses will include designated cohort dose level.  This may be done by 


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classifying subjects by dose level or, if appropriate, using dose level as a continuous 
variable.  Covariates such as age, body weight, body surface area, gender, and perhaps 
others that might explain some of the variability in the population will be included in the 
model initially.  However, a covariate may be dropped from the model if the regression 
coefficient is not significant at alpha level 0.10.  The natural logarithmic transformation 
will be employed for Cmax and the AUC's unless the data clearly indicate that other 
transformation or the untransformed variable provides more nearly symmetric probability 
distributions and/or more nearly homogenous variances across dose levels.  Within the 
framework of the model, tests that have good power for a trend with dose will be 
performed on the effect of designated cohort dose level.
Venetoclax Effect on Cytarabine Pharmacokinetics Parameters
A linear mixed effects analysis will be performed for Cmax, AUCt and AUC∞, to compare 
cytarabine PK parameters when co-administered with venetoclax (Cycle 1 Day 10) 
relative to cytarabine administered alone (Cycle 1 Day 1).  For Cmax and AUC, the 
logarithmic transformation will be used unless the data indicate that the logarithm has 
significant non-normality.  The model will include effects for visit (Cycle 1 Day 1, 
Cycle 1 Day 10).  To account for the correlation among visits, the repeated statement for 
the visit effect will be specified under SAS procedure mixed.  The relative bioavailability 
of cytarabine co-administered with venetoclax relative to cytarabine alone will be 
estimated and a 90% confidence interval will be provided for each of Cmax and AUC.  The 
confidence intervals will be obtained by the antilogarithm of the endpoints of confidence 
intervals for the difference of mean logarithms obtained within the mixed modeling 
framework.
Cytarabine Effect on Venetoclax Pharmacokinetics Parameters
A similar analysis to venetoclax effect on cytarabine PK parameters will be performed on 
Cycle 1 Day 10 and Cycle 1 Day 18 venetoclax PK parameters.


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8.1.2.3
Missing Values and Model Violations
All available data will be included the mixed effect analyses.  Data exclusion, if any, will 
be documented and justification provided.
Normally distributed values of PK variables (Cmax, AUC, etc.) will be determined without 
replacing missing individual concentration values, simply using the available data, and if 
necessary doing the analysis with some missing values for a PK variable.  However, if a 
missing individual concentration results in a value of a PK parameter that may be too low 
or too high to a meaningful degree, the value of the PK parameter will tentatively be 
considered missing.  In this case, a value for the missing individual concentration may be 
imputed so that an appropriate value of the PK parameter can be included in the analysis.  
The imputed value will be obtained using appropriate methodology that takes into account 
the individual characteristics of the subject.
If an outlier is identified and/or a pronounced non-normal probability distribution is 
observed (after logarithmic transformation for Cmax and AUC), then a non-parametric 
analysis may also be performed.  Such a model violation may be identified by graphical 
methods, measures of non-normality (e.g., skewness, kurtosis) or other appropriate 
methods.  If the regimens have unequal variances to the extent that conclusions might be 
affected, then approximate methods that allow for unequal variances will be used.
8.1.3
Efficacy Summaries
Efficacy will include analyses of ORR as defined by CR + CRi + PR, CR rate, CRi rate, 
CRh rate, CR + CRi rate, CR + CRh rate, DOR, EFS, OS, the exploratory analysis of the 
proportion of for all subjects who achieve MRD negativity, the proportion of subjects who 
are transfusion independent post baseline, and the proportion of subjects who undergo 
subsequent stem cell transplant.  Transfusion support needs will be recorded to define 
ongoing transfusion dependence.


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8.1.3.1.1
Overall Response Rates
CRh (Complete remission with partial hematologic recovery) is a derived response based 
on bone marrow blast count and hematology lab values.  A response of CRh is achieved 
when the following criteria are met:
●
Bone marrow with < 5% blasts and 
●
peripheral blood neutrophil count of ≥ 0.5 × 103/µL* and
●
peripheral blood platelet count ≥ 0.5 × 105/µL.*
*For a bone marrow sample collected before the last cycle of study treatment, the 
hematology lab results collected from the date of bone marrow sample collection up to 
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 CR or CRh at 
any time point during the study.  Subjects who never achieve CR or CRh or have not had 
IWG disease assessment will be considered to be non-responders in the calculation of 
CR + CRh rate.
Overall response rate will be defined as the proportion of subjects who achieve a CR, CRi, 
or PR at any time point during the study per the IWG criteria for AML.  Subjects who do 
not achieve a response of CR, CRi, or PR will be considered to be non-responders 
participating in the calculation of the ORR rate.
In addition, the proportion of subjects who achieve CR, the proportion of subjects who 
achieve a CRi, the proportion of subjects who achieve a CRh, and the proportion of 
subjects who achieve CR + CRi will be summarized.  The 95% confidence interval based 
on the binomial distribution will be provided for CR + CRh rate, ORR, CR rate, CRi rate, 
CRh rate, and CR + CRi rate.  


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8.1.3.1.2
Duration of Response
Duration of response will be defined as the number of days from the date of first response 
(CR, CRi, or PR) per the IWG criteria for AML to the earliest recurrence or PD.  If a 
subject is still responding, then the subject's data will be censored at the date of the 
subject's last available disease assessment.  For subjects who never experience response, 
the subject's data will not be included unless otherwise indicated.  Duration of response 
will be analyzed by Kaplan-Meier methodology using data for all enrolled subjects who 
responded.  Median DOR will be calculated and the corresponding 95% confidence 
interval will be presented.
8.1.3.1.3
Event-Free Survival
Event-free survival (EFS) will be defined as the number of days from the date of first dose 
to the date of earliest evidence of progression or relapse, subsequent treatment other than 
stem cell transplant while in composite complete response (CR + CRi), or death.  If the 
specified event (relapse, start of subsequent treatment, or death) does not occur, patients 
will be censored at the date of last disease assessment.  Data for subjects without any 
disease assessments performed after the baseline visit will be censored at the date of first 
dose plus 1 day.  Event-free survival (EFS) will be analyzed by Kaplan-Meier 
methodology.  Median EFS will be calculated and 95% confidence interval for median 
EFS will be presented.
8.1.3.1.4
Overall Survival
Overall survival will be defined as number of days from the date of first dose to the date 
of death.  For subjects who did not die, their data will be censored at the date of last study 
visit or the last known date to be alive, whichever is later. Overall survival will be 
analyzed by Kaplan-Meier methodology using data from all enrolled subjects.  Median 
time survival will be estimated and 95% confidence interval for the median time survival 
will be presented.


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8.1.3.1.5
MRD Negativity Rate
The proportion of subjects who reach MRD negativity in this exploratory measurement 
and the duration of this status will be summarized.
8.1.3.1.6
Proportion of Subjects Who Undergo Transplant
The proportion of subjects who undergo a subsequent transplant will be summarized.
8.1.3.1.7
Post Baseline Transfusion Independence (RBC/Platelet)
Post baseline transfusion independence is defined as a period of at least 56 days with no 
RBC or platelet transfusion between the first dose of study drug and the last dose of study 
drug + 30 days.  Post baseline transfusion independence rate will be estimated as the 
portion of subjects who achieve transfusion independence post baseline.  The 
corresponding 95% CI for transfusion independence rate will be provided based on the 
binomial distribution (Clopper-Pearson exact method).
In addition, the baseline transfusion dependence rate, which is defined as the portion of 
subjects who received either RBC or platelet transfusion within 56 days prior to the 
first dose of study drug, will be summarized.
8.1.4
Safety
The safety of Venetoclax and cytarabine will be assessed by evaluation study drug 
exposure, adverse events, serious adverse events, all deaths, as well as changes in 
laboratory determinations and vital sign parameters.
Safety analyses will be performed for all subjects who take at least one dose of study drug.
8.1.4.1
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug.


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Analyses of adverse events will not include those that have an onset greater than 30 days 
after the last dose of study drug.
Treatment-emergent adverse events will be summarized by preferred terms within a 
System and Organ Class according to the most current MedDRA dictionary.42  In addition, 
the percentage of subjects experiencing an adverse event at a NCI CTCAE Version 4.040
toxicity grade, and relationship to study drug will be provided.
8.1.4.2
Serious Adverse Events
Serious adverse events will be summarized using the same methods as adverse events 
described above.
8.1.4.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, (2) for deaths occurring more than 30 days of the last dose 
of study drug and (3) for all deaths in this study regardless of the number of days after the 
last dose of study drug.
8.1.4.4
Longitudinal Analyses of Laboratory and Vital Signs Data
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 urinalysis and 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.
8.1.4.5
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry, hematology and lymphocyte enumeration 
determinations will be categorized according to NCI CTCAE Version 4.040 grades, and 


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shifts from baseline NCI CTCAE40 grades to maximum and final post-baseline grades will 
be assessed.
The baseline and final grades will be defined respectively as the grade of the last 
measurement collected prior to the first dose of study drug, and as the last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.  The 
percentage of subjects experiencing a shift from baseline grades of 0 to 2 to maximum 
post-baseline grades of 3 to 4, and from baseline grades of 0 to 2 to final post-baseline 
grades of 3 to 4 will be summarized.
Detailed listings of data for subjects experiencing NCI CTCAE40 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.
8.2
Determination of Sample Size
This is a Phase 1/2 study where the Phase 1 portion is a dose escalation study and the 
Phase 2 portion is a dose expansion study.
For the Phase 1 portion of the study, the sample size is dependent upon the dose levels 
utilized and whether toxicities require and allow enrollment of 3 or 6 subjects to dose 
levels.
For the initial Phase 2 portion, approximately 50 subjects will be enrolled.  With 
50 subjects, the 95% confidence intervals for estimation of ORR would have a margin of 
error not exceeding ± 15%.  Clopper and Pearson 95% confidence intervals for expected 
observed rates for a sample size of 50 subjects are shown in Table 13.  With 50 subjects, 
an ORR rate of approximately 15% lower than the observed rate would be ruled out.


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Table 13.
95% Confidence Intervals for Assumed Observed Rates Based on 
Sample Size of 50 Subjects
ORR Rate
No. of Subjects with Objective Response (95% CI for rate)
60%
30 (45%, 74%)
50%
25 (35%, 64%)
40%
20 (26%, 55%)
30%
15 (18%, 45%)
For Cohort C, approximately 20 subjects will be enrolled to assess the experience of 
dosing venetoclax with LDC to evaluate if the efficacy of the combination is still 
consistent with that observed in previously treated subjects.  These factors include more 
objectively defined criteria with a lower age limit, modification to the venetoclax dose to 
account for strong CYP3A inhibitors, and potential reduction in liver/kidney function 
allowed for enrollment.  With 20 subjects, the ORR and Clopper and Pearson 95% 
confidence interval are specified in Table 14.
Table 14.
95% Confidence Intervals for Assumed Observed Rates Based on 
Sample Size of 20 Subjects
ORR Rate
No. of Subjects with Objective Response (95% CI for rate)
70%
14 (46%, 88%)
60%
12 (36%, 81%)
50%
10 (27%, 73%)
40%
8 (19%, 64%)
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 


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ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Serious adverse events that meet the reporting criteria, as dictated by local regulations, 
will be reported to both responsible Ethics Committees and Regulatory Agencies as 
required by local regulations.  During the conduct of the study, the investigator should 
promptly provide written reports (e.g., ICH Expedited Reports or any additional reports 
required by local regulations) to the IEC/IRB of any changes that affect the conduct of the 
study and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) GCP guidelines, applicable regulations and guidelines governing 
clinical study conduct and ethical principles that have their origin in the Declaration of 
Helsinki.  
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, 
conflict/combat) occurs leading to difficulties in performing protocol-specified procedures, 
AbbVie may engage with study site personnel in efforts to ensure the safety of subjects, 
maintain protocol compliance, and minimize risks to the integrity of the study while 
trying to best manage subject continuity of care.  This may include alternative methods for 
assessments (e.g., phone contacts or virtual site visits), alternative locations for data 
collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  


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In all cases, these alternative measures must be allowed by local regulations and permitted 
by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures are taken 
to protect the subjects against any immediate hazard.
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.
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 
pharmacogenetic and pharmacodynamic 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 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.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 


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study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data, and records.  These may 
include hospital records, clinical and office charts, laboratory data/information, subject 
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.  Source document data may be transcribed onto case report forms 
(CRFs) as required.  Data collected during this study must be recorded on the appropriate 
source document.
The investigator/institution 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 (CRF) 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 electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 


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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.
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
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.
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 


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will be performed to ensure that the investigator is complying with the protocol and 
regulations.  In addition, after the case report forms are retrieved, a review of the data will 
be conducted by a physician or representative at AbbVie.
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.
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.  A review of all laboratory results will be conducted by the 
AbbVie or contract monitors, the investigator and other appropriate personnel from 
AbbVie.
12.0
Use of Information
All information concerning venetoclax and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
venetoclax.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.


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The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or subject management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different from the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic 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.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic 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 and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator 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.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.


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AbbVie will select the signatory coordinating investigator from the investigators who 
participate in each multicenter 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 
(ABT-199/GDC-0199) and the product label for cytarabine.
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 Phase 1/2 Study of Venetoclax in Combination with Low-Dose 
Cytarabine in Treatment-Naïve Subjects with Acute Myelogenous 
Leukemia Who Are ≥ 60 Years of Age and Who Are Not Eligible 
for Standard Anthracycline-Based Induction Therapy
Protocol Date:
22 October 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
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Yamamura K, Kamada S, Ito S, et al.  Accelerated disappearance of melanocytes in 
bcl-2-deficient mice.  Cancer Res.  1996;56(15):3546-50.
16.
Marsden VS, Strasser A.  Control of apoptosis in the immune system:  Bcl-2, BH3 
only proteins and more.  Annu Rev Immunol. 2003;21:71-105.
17.
Sugiyama N, Obinata M, Matsui Y.  Bcl-2 Inhibits Apoptosis of Spermatogonia 
and Growth of Spermatogonial Stem Cells in a Cell-Intrinsic Manner.  Mol Reprod 
Dev.  2001;58(1):30-8.
18.
Oldereid NB, De Angelis P, Wiger R, et al.  Expression of Bcl-2 family proteins 
and spontaneous apoptosis in normal human testis.  Mol Hum Reprod.  
2001;7(5):403-8.
19.
Yamamura K, Kamada S, Ito S, et al.  Accelerated Disappearance of Melanocytes 
in bcl-2-deficient Mice.  Cancer Research.  1996;56:3546-50.
20.
Elmore S.  Apoptosis:  A Review of Programmed Cell Death.  Toxicol Pathol.  
2007;35(4):495-516.


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21.
Yao XH, Sugihara H, Hattori T, et al.  Regulation of apoptotic cell death in the 
pyloric glands of the canine stomach.  Virchows Arch.  1998;433(3):275-80.
22.
Jones BA, Gores GJ.  Physiology and pathophysiology of apoptosis in epithelia 
cells of the liver, pancreas, and intestine.  Am J Physiol.  
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23.
Morgan SJ, Besenhofer LM, Buck W, et al.  Copovidone-related Cutaneous 
Response in the Dog.  Toxicol Pathol.  2016;45(1):84-9.
24.
Wilson H, O'Connor A, Czuczman S, et al.  Phase 1/2a study of navitoclax 
(ABT-263) in relapsed or refractory lymphoid malignancies.  Haematologica.  
2010;95(s2):116-7.
25.
AbbVie.  ABT-199 Investigator's Brochure Edition 12.  15 January 2020.
26.
American Cancer Society.  Cancer Facts & Figures 2014.  Atlanta:  American 
Cancer Society; 2014.  Abstract 0292.
27.
Juliusson G, Antunovic P, Derolf A, et al.  Age and acute myeloid leukemia:  real 
world data on decision to treat and outcomes from the Swedish Acute Leukemia 
Registry.  Blood.  2009;113(18):4179-87.
28.
Thein MS, Ershler WB, Jemal A, et al.  Outcome of older patients with acute 
myeloid leukemia:  an analysis of SEER data over 3 decades.  Cancer.  
2013;119(15):2720-7.
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Foon, K, Zighelboim J, Yale C, et al.  Intensive chemotherapy is the treatment of 
choice for elderly patients with acute myelogenous leukemia.  Blood.  
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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.
Hamaker ME, Augschoell J, Stauder R.  Clinical judgement and geriatric 
assessment for predicting prognosis and chemotherapy completion in older patients 
with a hematological malignancy.  Leuk Lymphoma.  Epub 2016 Apr 6.  Available 
from:  http://www.tandfonline.com/doi/full/10.3109/10428194.2016.1163345.
32.
Ferrara F, Barosi G, Venditti A, et al.  Consensus-based definition of unfitness to 
intensive and non-intensive chemotherapy in acute myeloid leukemia:  a project of 
SIE, SIES and GITMO group on a new tool for therapy decision making.  
Leukemia. 2013;27(5):997-9.
33.
Ferrara F.  Conventional chemotherapy or hypomethylating agents for older 
patients with acute myeloid leukaemia?  Hematol Oncol.  2014;32(1):1-9.
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treatment of acute leukemia in adults.  Blood.  1968; 32(4):507-23.
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and Myelodysplastic Syndromes:  A Review of 20 Years' Experience.  Semin 
Oncol.  1987; 14 (2 Suppl 1):126-33.
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Coiffier B, Altman A, Pui CH, et al.  Guidelines for the management of pediatric 
and adult tumor lysis syndrome:  an evidence-based review.  J Clin Oncol.  
2008;26(16):2767-78.
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Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the 
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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 of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia.  J Clin Oncol.  
2003;21(24):4642-9.
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Silverman LR.  Hypomethylating agents in myelodysplastic syndromes changing 
the inevitable:  the value of azacitidine as maintenance therapy, effects on 
transfusion and combination with other agents.  Leuk Res.
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Cairo MS, Bishop M.  Tumour lysis syndrome:  new therapeutic strategies and 
classification.  Br J Haematol.  2004;127(1):3-11.
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Pharmaceutical Research and Development (GPRD), Global Pharmacovigilance 
and Clinical Project Team.  Current version on file at AbbVie.
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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
Clinical
Clinical
Pharmacokinetics


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Appendix C.
Sample List of Excluded and Cautionary Medications
Excluded During Ramp-Up Phase and Throughout Study:
Strong CYP3A inducers – avasimibe, carbamazepine (Tegretol®), phenytoin (Dilantin®), enzalutamine, mitotane 
rifampin (Rifadin®), St. John's wort
Cautionary (Additional Guidance Noted in Table 1):
Moderate CYP3A inducers – bosentan, efavirenz, etravirine, modafinil, nafcillin
Strong CYP3A inhibitors – boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, 
elvitegravir/ritonavir, idelalisib,* indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, paritaprevir/ritonavir combinations posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
tipranavir/ritonavir, voriconazole
Moderate CYP3A inhibitors – amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, clotrimazole, 
crizotinib,* cyclosporine,* darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, 
fosamprenavir, imatinib,* isavuconazole, tofisopam, verapamil
Cautionary:
Warfarin and Courmarin derivatives** 
P-gp substrates
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus,* fexofenadine, lapatinib,* loperamide, 
maraviroc, nilotinib,* ranolazine, saxagliptin, sirolimus,* sitagliptin, talinolol, tolvaptan, topotecan*
BCRP substrates
Methotrexate,* mitoxantrone,* irinotecan,* lapatinib,* rosuvastatin, sulfasalazine, topotecan*
OATP1B1/1B3 substrates
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, rosuvastatin, pitavastatin, pravastatin, repaglinide, 
simvastatin acid, telmisartan, valsartan, olmesartan
P-gp inhibitors
Amiodarone, captopril, carvedilol, felodipine, quercetin, quinidine, ronalzine, ticagrelor
BCRP inhibitors
geftinib*
Note that this is not an exhaustive list.  For an updated list, see the following link:  
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08049
9 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.
*
These are anticancer agents; consult contact the AbbVie medical monitor before use.
**
Closely monitor the international normalized ratio (INR).


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Appendix D.
NCCN Risk Categorization:  Guidelines for AML Version 2.2014
Risk Category
Cytogenetic
Better Risk
inv(16) or t(16;16)
t(8;21)
t(15;17)
Intermediate Risk
Normal cytogenetics
+8 alone
t(9;11)
Other non-defined
Poor Risk
Complex(> 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 E.
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 within normal 
limits (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.
o
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, 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).
o
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.
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.


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Appendix F.
Adverse Events Commonly Associated with Acute Myelogenous 
Leukemia Study Population and/or Progression of Acute 
Myelogenous leukemia
Fever
Fatigue 
Dyspnea
Pain, all types
Thrombocytopenia
Anemia
Neutropenia
Infection (bacterial, viral, fungal)
Neutropenic infection
Neutropenic sepsis
Oral candidiasis
Stomatitis
Periodontal infection
Tooth infection, abscess
Upper respiratory tract infection
Sinusitis, Rhinitis 
Bronchitis (bacterial, viral)
Bronchitis chronic
Pneumonia (bacterial, viral, fungal)
Catheter site cellulitis
Herpes zoster disseminated, multi-dermatomal
Herpes zoster
Herpes simplex (oral, genital)
Skin candida
Urinary tract infection bacterial, fungal
Genitourinary tract infection (viral, bacterial, fungal)


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Gastroenteritis
Enterocolitis
Malignant disease progression, including death
Hyperleukocytosis, including the symptomatic form (leukostasis) 
Leukaemic infiltration brain
Malignant pleural effusion
Chloroma/granulocytic sarcoma
Second primary cancers, all types
Bleeding
Gingival bleeding 
Mouth haemorrhage 
Epistaxis 
Haematuria
Injection site haemorrhage
Petechiae
Skin haemorrhage
Retinal hemorrhage
Population-Related Comorbidities
Hypertension
Rheumatoid arthritis/osteoarthritis
Hyperlipidemia
Peptic ulcer
Inflammatory bowel disease
Coronary artery disease
Peripheral vascular disease


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Cardiomyopathy 
Valvular disease
Atrial fibrillation
Diabetes mellitus
Chronic obstructive pulmonary disease
Cerebrovascular accident
Transient ischemia attack


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Appendix G.
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
< 0.100
MLL- and FLT3-mutant
GDM-1
< 0.100
nd
EOL-1
< 0.100
MLL-mutant
HL-60
< 0.100
N-Ras-mutant
MV4-11
< 0.100
MLL- and FLT3-mutant
ML-2
< 0.100
MLL-mutant
SIG-M5
< 0.100
nd
OCI-AML2
< 0.100
nd
MOLM-16
0.040
nd
OCI-AML5
0.110
nd
THP-1
0.820
MLL- and N-Ras-mutant
Kasumi-1
1.000
t(8;21) translocation
KG-1
1.200
nd
HNT-34
1.700
nd
PL-21
1.810
FLT3-mutant
SKM-1
2.530
nd
UKE-1
3.060
JAK2-mutant
SET-2
3.330
JAK2-mutant
HEL
3.370
JAK2-mutant
OCI-M2
4.050
nd
OCI-AML3
5.450
N-Ras-mutant
OCI-M1
5.610
nd
NOMO-1
6.950
MLL-mutant
ME-1
> 10
N-Ras-mutant and inv16
nd = not determined


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Appendix H.
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.
Cross reference:  Howard SC 201143


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Appendix I.
Protocol Amendment:  List of Changes
A summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
COVID-19
Coronavirus Disease-2019
DTP
Direct-to-patient
Section 3.3  Benefits and Risks
Add:  new last paragraph
Considering the coronavirus (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated. Subjects receiving venetoclax may be at 
an increased risk for COVID-19 infection or experience serious illness if infected. 
Management of these adverse events will be made on a case-by-case basis with 
consideration of benefit/risk. However, based on the population and disease being studied 
and the anticipation that COVID-19 related risks are not expected to differ substantially 
between study subjects and the broader population of subjects receiving treatment for 
AML, no change to the benefit/risk balance for subjects in this study is expected.


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Table 3.  Study Activities (Phases 1 and 2 {Including Cohort C})
Previously read:
Procedures
Scra
Day 
–1
Cycle 1
Day 1 of Cycle 2 and 
Day 1 of Every Cycle 
Thereafter (± 3 Days)
Cycle 2 Day 1, Cycle 4 
Day 1, and Every 
3 Cycles Thereafter 
(± 7 Days)
Final 
Visitn
30-Day 
Safety 
F/U
PT 
F/Uu
(± 1 
Week)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Informed Consent
Xb
Medical/Oncology History 
Assessment
X
Xc
Cytogenetic Assessmentd
X
AE/Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
X
X
Tumor Lysis Syndrome Prophylaxise
X
X
X
X
X
X
Physical Exam (including weight)f
Xh
X
Xi
Xj
Xj
Xj
Vital Signsf
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusf
X
X
X
X
X
Hematologyf,g
X
X
X
X
X
X
X
X
X
X
Chemistrye,f
Xk
X
X
X
X
X
Xk
Xk
X
Coagulationf
X
X
Xl
X
X
Urinalysisf
X
12-lead ECGm
X
Xo
MUGA (preferred)/2D 
Echocardiogram w/Dopplerm,p
X
Clinical Disease Progression 
Assessment
X
X
X


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Procedures
Scra
Day 
–1
Cycle 1
Day 1 of Cycle 2 and 
Day 1 of Every Cycle 
Thereafter (± 3 Days)
Cycle 2 Day 1, Cycle 4 
Day 1, and Every 
3 Cycles Thereafter 
(± 7 Days)
Final 
Visitn
30-Day 
Safety 
F/U
PT 
F/Uu
(± 1 
Week)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Bone Marrow Aspirate and Biopsy 
for Response Assessment
Xq
Xr
X
Dispense Subject Calendar/Diary
Xs
X
Collect Study Drug and Subject 
Calendar/Diary
X
X
Survival Assessmentst
X
Scr = Screening; F/U = Follow-Up; PT = Post-Treatment
a.
Screening procedures must be performed within 21 days prior to initial study drug administration.
b.
Obtain informed consent prior to performing any screening or study-specific procedures.
c.
On Cycle 1 Day 1, any additional medical history that is observed after signing of the informed consent but prior to initial study drug administration and not considered 
related to study-required procedures will be recorded in the subject's medical history.
d.
Cytogenetic testing should be performed if not completed within 3 months prior to Screening.
e.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to Section 6.1.8.2 Management 
of Tumor Lysis Syndrome (TLS) and Appendix E– Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome (TLS) for 
further information.
f.
For all study visits beginning with Cycle 3, physical examination, vital signs, ECOG performance status, hematology, chemistry, coagulation and urinalysis may be performed 
within 72 hours before Day 1 of treatment for that cycle.
g.
Hematology will be performed weekly (at the minimum, hematology should be performed weekly during Cycle 1 and Cycle 2).
h.
Height will be measured only at Screening.
i.
Only applies to Dose Level (–)2.  Subjects should have Physical exam upon discharge from the hospital.  Subjects should remain hospitalized no less than 24 hours post 
dosing of their designated cohort dose.  Also, Dose Levels 4 and 5 would stay in hospital until Day 8, needing a Physical exam at Day 8.
j.
A symptom-directed physical exam may be performed.
k.
Amylase and lipase are required at Screening, Cycle 2 Day 1, and the Final Visit.
l.
Coagulation to be performed on Cycle 2 Day 1 and not required subsequently unless clinically indicated.


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m.
Additional ECGs and a MUGAs/Echos should be performed as clinically necessary per the discretion of the investigator.
n.
Final Visit procedures should be performed when a subject discontinues from the study.
o.
May be obtained ± 2 days of the visit.
p.
Should be performed provided that such assessment would not inappropriately delay therapy per discretion of the investigator.
q.
Historical bone marrow aspirates at screening will not be sufficient; a bone marrow aspirate must be performed for study entry to collect mandatory biomarker assessments.
r.
May be performed ± 7 days of the anticipated Day 1 of the subsequent cycle visit, for visits beginning with Cycle 2 Day 1.  Assessments beginning with Cycle 4 Day 1 should 
be performed and resulted prior to the dispensation of the next cycle of drug.
s.
Diaries will be dispensed upon discharge from the hospital.
t.
Survival assessments should be performed every 12 weeks (± 1 week) for 1 year after last subject's last dose.
u.
Post Treatment visits will be performed every 12 weeks (± 1 week) for up to 1 year after last subject's last dose.  Survival assessments will be performed every 12 weeks, 
beginning when subjects develop progressive disease, for 1 year after the last subject's last dose.
Note:
Refer to Table 4 for treatment schedule.
Has been changed to read:
Procedures
Scra
Day 
–1
Cycle 1
Day 1 of Cycle 2 and 
Day 1 of Every Cycle 
Thereafter (± 3 Days)
Cycle 2 Day 1, Cycle 4 
Day 1, and Every 
3 Cycles Thereafter 
(± 7 Days)
Final 
Visitn
30-Day 
Safety 
F/U
PT 
F/Uu
(± 1 
Week)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Informed Consent
Xb
Medical/Oncology History 
Assessment
X
Xc
Cytogenetic Assessmentd
X
AE/Concomitant Medication 
Assessmentv
X
X
X
X
X
X
X
X
X
X
Tumor Lysis Syndrome Prophylaxise
X
X
X
X
X
X
Physical Exam (including weight)f,v
Xh
X
Xi
Xj
Xj
Xj


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Procedures
Scra
Day 
–1
Cycle 1
Day 1 of Cycle 2 and 
Day 1 of Every Cycle 
Thereafter (± 3 Days)
Cycle 2 Day 1, Cycle 4 
Day 1, and Every 
3 Cycles Thereafter 
(± 7 Days)
Final 
Visitn
30-Day 
Safety 
F/U
PT 
F/Uu
(± 1 
Week)
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Vital Signsf,v
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusf,v
X
X
X
X
X
Hematologyf,g,v
X
X
X
X
X
X
X
X
X
X
Chemistrye,f,v
Xk
X
X
X
X
X
Xk
Xk
X
Coagulationf,v
X
X
Xl
X
X
Urinalysisf,v
X
12-lead ECGm,v
X
Xo
MUGA (preferred)/2D 
Echocardiogram w/Dopplerm,p
X
Clinical Disease Progression 
Assessment
X
X
X
Bone Marrow Aspirate and Biopsy 
for Response Assessment
Xq
Xr
X
Dispense Subject Calendar/Diary
Xs
X
Collect Study Drug and Subject 
Calendar/Diaryw
X
X
Survival Assessmentst
X
Scr = Screening; F/U = Follow-Up; PT = Post-Treatment
a.
Screening procedures must be performed within 21 days prior to initial study drug administration.
b.
Obtain informed consent prior to performing any screening or study-specific procedures.
c.
On Cycle 1 Day 1, any additional medical history that is observed after signing of the informed consent but prior to initial study drug administration and not considered 
related to study-required procedures will be recorded in the subject's medical history.
d.
Cytogenetic testing should be performed if not completed within 3 months prior to Screening.


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e.
All subjects must receive tumor lysis prophylaxis prior to and during treatment.  For details on tumor lysis prophylaxis and management, refer to Section 6.1.8.2 Management 
of Tumor Lysis Syndrome (TLS) and Appendix E – Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome (TLS) for 
further information.
f.
For all study visits beginning with Cycle 3, physical examination, vital signs, ECOG performance status, hematology, chemistry, coagulation and urinalysis may be performed 
within 72 hours before Day 1 of treatment for that cycle.
g.
Hematology will be performed weekly (at the minimum, hematology should be performed weekly during Cycle 1 and Cycle 2).
h.
Height will be measured only at Screening.
i.
Only applies to Dose Level (–)2.  Subjects should have Physical exam upon discharge from the hospital.  Subjects should remain hospitalized no less than 24 hours post 
dosing of their designated cohort dose.  Also, Dose Levels 4 and 5 would stay in hospital until Day 8, needing a Physical exam at Day 8.
j.
A symptom-directed physical exam may be performed.
k.
Amylase and lipase are required at Screening, Cycle 2 Day 1, and the Final Visit.
l.
Coagulation to be performed on Cycle 2 Day 1 and not required subsequently unless clinically indicated.
m.
Additional ECGs and a MUGAs/Echos should be performed as clinically necessary per the discretion of the investigator.
n.
Final Visit procedures should be performed when a subject discontinues from the study.
o.
May be obtained ± 2 days of the visit.
p.
Should be performed provided that such assessment would not inappropriately delay therapy per discretion of the investigator.
q.
Historical bone marrow aspirates at screening will not be sufficient; a bone marrow aspirate must be performed for study entry to collect mandatory biomarker assessments.
r.
May be performed ± 7 days of the anticipated Day 1 of the subsequent cycle visit, for visits beginning with Cycle 2 Day 1.  Assessments beginning with Cycle 4 Day 1 should 
be performed and resulted prior to the dispensation of the next cycle of drug.
s.
Diaries will be dispensed upon discharge from the hospital.
t.
Survival assessments should be performed every 12 weeks (± 1 week) for 1 year after last subject's last dose or possibly sooner if all patients have discontinued and most 
patients have expired.
u.
Post Treatment visits will be performed every 12 weeks (± 1 week) for up to 1 year after last subject's last dose or possibly sooner if all patients have discontinued and most 
patients have expired.  Survival assessments will be performed every 12 weeks, beginning when subjects develop progressive disease, for 1 year after the last subject's last 
dose or possibly sooner if all patients have discontinued and most patients have expired.
v.
Procedure may be performed in the subject's home or local hospital/clinic by adequately trained personnel if required due to COVID-19 restrictions.
w.
Venetoclax may be shipped directly to a subject's home only if required due to COVID-19 restrictions.
Note:
Refer to Table 4 for treatment schedule.


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Section 5.3.1.1  Study Procedures
Add:  new second paragraph
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes 
such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others.  Additional details are provided 
in the subsequent section.  Every effort should be made to ensure the safety of subjects 
and site staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, follow Table 3 on how 
to proceed.
Section 5.3.1.1  Study Procedures
Subsection Vital Signs
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Due to the COVID-19 pandemic, subject visits may be conducted via phone or video 
conference.  In these situations, weight, blood pressure, vitals and respiratory rate
measurements may be performed by the subject or caregiver as needed.
Section 5.3.1.1  Study Procedures
Subsection 12-Lead Electrocardiogram (ECG)
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event this may not be performed due to study modifications related to the 
COVID-19 pandemic, perform the 12-lead ECG at the next earliest feasible visit or 
arrange to have an alternative acceptable local facility perform the ECG for the subject.


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Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations in light of the COVID-19 
pandemic prevent the subject from having blood drawn for laboratory testing at the study 
site, if possible, arrange for subjects to have laboratory work done at a local lab, hospital, 
or other facility.  Local lab results should be obtained along with reference ranges and 
kept within the subjects' source documentation.  Local lab results should be reviewed by 
the investigator as soon as possible.
If laboratory samples cannot be obtained, study drug administration may be continued 
provided the investigator has reviewed all prior laboratory results and confirms and 
discusses with the subject that there is no safety concern for the subject to continue use of 
the study drug in the absence of current labs.  The subject should be scheduled for 
laboratory draws as soon as feasible from the scheduled visit.
Section 5.3.1.1  Study Procedures
Subsection Post-Treatment Follow-Up Visit(s)
First sentence previously read:
For subjects who discontinue study treatment for reasons other than disease progression, 
the following post-treatment assessments will be performed every 12 weeks (± 1 week) 
until criteria are met for discontinuation from the study (e.g., disease progression, death or 
a subject's refusal of the Post-Treatment visits) for a period of 1 year after last subject's 
last dose:
Has been changed to read:
For subjects who discontinue study treatment for reasons other than disease progression, 
the following post-treatment assessments will be performed every 12 weeks (± 1 week) 
until criteria are met for discontinuation from the study (e.g., disease progression, death or 


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a subject's refusal of the Post-Treatment visits) for a period of 1 year after last subject's 
last dose or possibly sooner if all patients have discontinued and most patients have 
expired:
Section 5.3.1.1  Study Procedures
Subsection Survival Assessment(s)
Previously read:
Survival information (e.g., date and cause of death, post-treatment cancer therapies, 
including transplantation) will be collected once the subject's disease has progressed via 
telephone calls (e.g., to subject or family member) and/or clinical visits at 12 weeks 
intervals (± 1 week) after the subject's last study visit for a period of 1 year after last 
subject's last dose.
Has been changed to read:
Survival information (e.g., date and cause of death, post-treatment cancer therapies, 
including transplantation) will be collected once the subject's disease has progressed via 
telephone calls (e.g., to subject or family member) and/or clinical visits at 12 weeks 
intervals (± 1 week) after the subject's last study visit for a period of 1 year after last 
subject's last dose or possibly sooner if all patients have discontinued and most patients 
have expired.
Section 5.4.1  Discontinuation of Individual Subjects
Sixth paragraph previously read:
Post-treatment assessment will be performed every 12 weeks (± 1 week) until 
discontinuation from the study (e.g., disease progression death or a subject's refusal of the 
Post-Treatment visits) for a period of 1 year after last subject's last dose.
Has been changed to read:
Post-treatment assessment will be performed every 12 weeks (± 1 week) until 
discontinuation from the study (e.g., disease progression death or a subject's refusal of the 


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Post-Treatment visits) for a period of 1 year after last subject's last dose or possibly 
sooner if all patients have discontinued and most patients have expired.
Section 5.4.1  Discontinuation of Individual Subjects
Seventh paragraph previously read:
Survival information (e.g., date and cause of death, post-treatment cancer therapies, 
including transplantation) will be collected once the subject's disease has progressed via 
telephone calls (e.g., to subject or family member) and/or clinical visits at 12 weeks 
intervals (± 1 week) after the subject's last study visit for a period of 1 year after last 
subject's last dose.
Has been changed to read:
Survival information (e.g., date and cause of death, post-treatment cancer therapies, 
including transplantation) will be collected once the subject's disease has progressed via 
telephone calls (e.g., to subject or family member) and/or clinical visits at 12 weeks 
intervals (± 1 week) after the subject's last study visit for a period of 1 year after last 
subject's last dose or possibly sooner if all patients have discontinued and most patients 
have expired.
Section 5.4.1  Discontinuation of Individual Subjects
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modification
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID 19 pandemic, it has been necessary to employ mitigation strategies to 
enable the investigator to ensure subject safety and continuity of care.  Refer to the 
Section 5.3.1.1, Study Procedures and Table 3 for details on how to handle study 
activities/procedures accordingly.  Study drug interruptions due to COVID-19 restrictions 
should be captured in EDC.


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The investigator should contact the sponsor medical contact before discontinuing a subject 
from the study for a reason other than "planned per protocol," to ensure all acceptable 
mitigation steps have been explored.
Section 5.4.2  Discontinuation of Entire Study
Subsection Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
Add:  new subsection title and text
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
Decisions to delay or interrupt any study treatment based on the current situation and any 
concern for active infection should be made by the treating investigator after considering 
the subject's current oncologic status and treatment tolerance, as well as their general 
medical condition. As a potentially serious infection, consideration for treatment 
interruption is advised.  If needed, any questions can be discussed with the Therapeutic 
Area Medical Director (TAMD).
Section 5.5.1  Treatments Administered
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If a subject is unable to come to the study site to pick up their study drug due to 
COVID-19, a direct-to-patient (DTP) venetoclax shipment can be made from the study 
site to the subject if allowed by local regulations.  Cytarabine DTP are is not allowed by 
AbbVie.  AbbVie will submit any required notifications to the regulatory authority as 
applicable.
Venetoclax may be shipped from the study site directly to the study subject's home if all 
the following criteria are met:
●
Direct-to-patient (DTP) shipment of venetoclax is allowed by local regulations 
and the relevant ethics committee
●
Venetoclax can be administered by the subject (or subject's caregiver) at home


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●
Subject agrees to have the venetoclax shipped directly to their home
○
Shipments may also include other study supplies (e.g., drug dosing diaries).  
Instructions will be provided by AbbVie as to how a study site can initiate 
a DTP shipment using Marken, a global vendor selected by AbbVie to 
provide this service when necessary.  Shipments of venetoclax from the 
study site to a subject's home will be appropriately temperature controlled 
(qualified shipper or temperature monitoring) within the labeled storage 
conditions.  Signature is required upon delivery; due to COVID-19 related 
social distancing, this may be provided by the courier after delivery.  
Documentation of the shipment is to be retained by the clinical site.
○
AbbVie will not receive subject identifying information related to these 
shipments, as the site will work directly with the courier.
The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, and for obtaining consent to provide delivery information to the 
courier and documenting this consent in source documents.
Section 6.1.6  Adverse Event Reporting
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or adverse 
events (including capture of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  The following COVID-19 related supplemental eCRFs should be 
completed (for both serious and non-serious events):
●
COVID -19 Supplemental Signs/ Symptoms
●
COVID-19 Status Form


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Section 7.0  Protocol Deviations
First paragraph, last sentence previously read:
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):
Has been changed to read:
If a protocol deviation occurs (or is identified, including those that may be due to 
COVID-19 pandemic) 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):
Section 9.2  Ethical Conduct of the Study
Last sentence previously read:
Responsibilities of the clinical investigator are specified in Appendix A.
Has been changed to read:
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, 
conflict/combat) occurs leading to difficulties in performing protocol-specified procedures, 
AbbVie may engage with study site personnel in efforts to ensure the safety of subjects, 
maintain protocol compliance, and minimize risks to the integrity of the study while 
trying to best manage subject continuity of care.  This may include alternative methods for 
assessments (e.g., phone contacts or virtual site visits), alternative locations for data 
collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  
In all cases, these alternative measures must be allowed by local regulations and permitted 
by IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures are taken 
to protect the subjects against any immediate hazard.


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Responsibilities of the clinical investigator are specified in Appendix A.
Section 9.3  Subject Information and Consent
Add:  new last paragraph
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not 
outlined in this protocol may become necessary.  If this situation arises, in addition to the 
study informed consent, additional verbal consent may be obtained prior to these 
adaptations or substantial changes in study conduct in accordance with local regulations.
Section 10.2  Case Report Forms
Add:  new fourth paragraph
During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.

SAP_001.pdf: 
Venetoclax (ABT-199/GDC-0199)
Efficacy Statistical Analysis Plan
Version 4.0 – 02 Oct 2019
1
1.0
Title Page
Efficacy Statistical Analysis Plan
Study M14-212
Study M14-358
Study M14-387
Venetoclax (ABT-199/GDC-0199) in Combination with 
LDAC (Low Dose Cytarabine) (LDAC) or HMA 
(Azacitidine or Decitabine) for the Treatment 
Subjects with Acute Myeloid Leukemia
Date:  02 Oct 2019
Version 4.0
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02287233


Venetoclax (ABT-199/GDC-0199)
Efficacy Statistical Analysis Plan
Version 4.0 – 02 Oct 2019
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
2.1
Summary of Versions ................................................................................4
2.2
List of Abbreviations and Definitions of Terms........................................5
3.0
Introduction .............................................................................6
4.0
Objectives for Statistical Analysis Plan.................................6
5.0
Studies/Protocols......................................................................6
6.0
Analysis Sets.............................................................................8
6.1
Definition of Analysis Sets and Rationale .................................................8
6.2
Planned Efficacy Analyses for Each Analysis Dataset............................10
7.0
Analysis Conventions ............................................................11
8.0
Statistical Methods ................................................................12
8.1
Efficacy Analyses ....................................................................................12
8.1.1
Complete Remission (CR) Rate...............................................................13
8.1.2
CRh Rate..................................................................................................13
8.1.3
CR + CRh Rate ........................................................................................14
8.1.4
CR + CRh Rate by Initiation of Cycle 2 ..................................................14
8.1.5
Duration of CR.........................................................................................15
8.1.6
Duration of CR + CRh .............................................................................16
8.1.7
Overall Survival (OS) ..............................................................................17
8.1.8
Post Baseline Transfusion Independence Rate (RBC/Platelet) and 
Duration of Post Baseline Transfusion Independence.............................17
8.1.9
Time to the First Event ............................................................................18
8.1.9.1
Transfusion ..............................................................................................19
8.1.9.2
Time to the First Hospitalization due to SAE..........................................21
8.1.9.3
Time to First Event of Grade 3 or Above TEAE of Haemorrhages 
(Narrow SMQ).........................................................................................23
8.1.9.4
Time to First Event of Grade 3 or Above TEAE of 
Infections/Infestations (SOC) ..................................................................26
8.1.10
Time to the 1st Recurrent Transfusion Event from the 
1st Transfusion Event ...............................................................................29
8.1.11
Additional Sensitivity Analyses of Efficacy Variables............................30


Venetoclax (ABT-199/GDC-0199)
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Version 4.0 – 02 Oct 2019
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8.1.12
Exploratory Analysis of MRD Data ........................................................32
8.1.13
Subgroup Assessment of Efficacy Variables...........................................33
9.0
Sample Size.............................................................................34
10.0
References...............................................................................35
List of Tables
Table 1.
Studies to be Included in Efficacy Summary.............................................7
Table 2.
Regimens Investigated in Venetoclax AML Studies.................................8
Table 3.
Definition of the Analysis Sets ..................................................................9
Table 4.
Event/Censor and Corresponding Event/Censor Time for Duration 
of CR or CR + CRh..................................................................................16
Table 5.
Censoring Methods for Analyses of CR + CRh, CR, and CRh ...............31
Table 6.
Censoring Methods for Analyses of OS ..................................................32
Table 7.
Sample Size Justification .........................................................................35


Venetoclax (ABT-199/GDC-0199)
Efficacy Statistical Analysis Plan
Version 4.0 – 02 Oct 2019
4
2.1
Summary of Versions
Version
Date of Completion
Summary
1.0
19 Dec 2017
First version (Appendix of Briefing Book of FDA Type C 
Meeting)
2.0
04 May 2018
Implemented comments from FDA
3.0
27 Nov 2018
Update the version date for 2nd interim CSR
4.0
02 Oct 2019
Update the version date for 3rd interim CSR


Venetoclax (ABT-199/GDC-0199)
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Version 4.0 – 02 Oct 2019
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2.2
List of Abbreviations and Definitions of Terms
AE
Adverse event
AESI
Adverse Event of Special Interest
AML
Acute Myeloid leukemia
AST
Aspartate aminotransferase
HMA
Azacitidine or Decitabine
LDAC
Low dose cytarabine
MedDRA
Medical dictionary for regulatory activities 
MPN
Myeloproliferative neoplasm
NCI
National Cancer Institute
NCI CTC
National Cancer Institute Common Terminology Criteria
PT
Preferred term
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SMQ
Standardized MedDRA query
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WBC
White blood cells
WHO
World Health Organization


Venetoclax (ABT-199/GDC-0199)
Efficacy Statistical Analysis Plan
Version 4.0 – 02 Oct 2019
6
3.0
Introduction
This efficacy SAP covers the statistical procedure for the efficacy analyses of the data 
from Studies M14-358 (R&D/17/1341) and M14-387 (R&D/17/1340).  These analyses 
will support the efficacy assessment of venetoclax for AML.  Analyses will be performed 
by personnel from Data and Statistical Sciences at AbbVie or their designees using SAS 
Version 9.3 or later (SAS Institute Inc., Cary, NC  27513) under the UNIX operating 
system.
4.0
Objectives for Statistical Analysis Plan
This SAP provides the details of the statistical analyses planned to be performed for the 
efficacy assessment of Studies M14-358 and M14-387.  The analyses will include all 
AML subjects who had at least one dose of venetoclax.
5.0
Studies/Protocols
A complete list of relevant clinical studies associated with venetoclax that will be 
contributed to the product efficacy assessment is listed in Table 1.


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Table 1.
Studies to be Included in Efficacy Summary
Study ID 
Phase 
(Status)
Number of 
Enrolled 
Subjects 
(Actual/Planned)
Location
Study Design
Primary Objective
M14-358 
Phase 1b 
(Enrollment 
complete 
and 
follow-up 
is ongoing)
212/260
Australia, 
Germany, 
France, 
and US
Open-label study of 
venetoclax + azacitidine 
or decitabine in treatment 
naïve elderly (≥ 60 years) 
subjects with AML who 
are not eligible for 
standard induction 
therapy; 2 stages:  dose 
escalation and dose 
expansion (both HMAs)
Evaluate the safety, PK, 
and efficacy of 
venetoclax + decitabine or 
azacitidine in the target 
population.
The objective of the safety 
expansion is to confirm 
efficacy and safety of the 
intended dose for Phase 3 
study.
M14-387 
Phase 1/2 
(Enrollment
complete 
and 
follow-up 
is ongoing)
92/92
Australia, 
Germany, 
Italy, US
Open-label study of 
venetoclax + LDAC in 
treatment naïve subjects 
with AML who are 
≥60 years of age and who 
are not eligible for 
standard anthracycline-
based induction therapy; 
2 stages:  dose escalation 
and safety expansion
Phase 1:  Evaluate the 
safety, PK and determine 
the MTD and RPTD of 
venetoclax + LDAC.
Phase 2:  Estimate 
efficacy, including ORR, 
and characterize the 
toxicity of the 
combination at the RPTD.
Cohort C:  Evaluate the 
ORR for subjects allowed 
additional supportive 
medications (strong 
CYP3A inhibitors) if 
medically indicated.
The venetoclax doses and regimens in the Studies listed in Table 1 are described in 
Table 2 below.


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Table 2.
Regimens Investigated in Venetoclax AML Studies
Study ID
Venetoclax Dose and Frequency
Treatment Regimen
M14-358
Venetoclax 400 mg QD, 800 mg QD, 
1200 mg QD 
Venetoclax in combination with HMA 
(Azacitidine or Decitabine)
M14-387
Venetoclax 600 mg QD, 800 mg QD
Venetoclax in combination with LDAC 
(Low dose cytarabine)
6.0
Analysis Sets
6.1
Definition of Analysis Sets and Rationale
This efficacy SAP provides details of statistical analyses that are to be performed for the 
efficacy assessment of Studies M14-358 and M14-387.  The analyses for 
Studies M14-358 and M14-387 will not be pooled and three analysis sets will be prepared 
for summaries of efficacy as detailed in Table 3.  The reason for not pooling the 
Studies M14-358 and M14-387 is that the different treatment regimens (venetoclax 
monotherapy, venetoclax in combination with azacitidine, venetoclax in combination with 
decitabine, and venetoclax in combination with LDAC) are expected to have different 
efficacy profiles.  Thus, it is not appropriate to pool data across these studies to assess the 
efficacy of venetoclax.


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Table 3.
Definition of the Analysis Sets
Analysis Data 
Sets
Studies 
Included
Study 
Population
Treatment Groups
1.  Venetoclax 
in combination 
with HMA
M14-358
Subjects who 
received at 
least one dose 
of venetoclax 

venetoclax 400 mg QD + azacitidine (N = 84)

venetoclax 800 mg QD + azacitidine (N = 37)

overall of venetoclax + azacitidine (N = 127) 

venetoclax 400 mg QD + decitabine (N = 31) 

venetoclax 800 mg QD + decitabine (N = 37) 

overall of venetoclax + decitabine (N = 73)

DDI venetoclax 400 mg QD (N = 12)
2.  Venetoclax 
in combination 
with LDAC
M14-387
Subjects who 
received at 
least one dose 
of venetoclax 

venetoclax 600 mg QD + LDAC (N = 82)

venetoclax 600 mg QD + LDAC without MPN 
(N = 78) 

All Subjects (venetoclax 600 mg 
QD + LDAC or Venetoclax 800 mg 
QD + LDAC) (N = 92)
1) Venetoclax in combination with HMA Analysis Set
This analysis set includes subjects who received at least one dose of venetoclax in 
Study M14-358.  This analysis dataset will be used to provide a comprehensive summary 
of efficacy of venetoclax in combination with HMA (azacitidine 75 mg/m2 daily 
administered intravenously or subcutaneously [Days 1 - 7] or decitabine 20 mg/m2 daily 
administered intravenously [Days 1 - 5] during each 28 day cycle).
2) Venetoclax in combination with LDAC Analysis Set
This analysis set includes subjects who received at least one dose of venetoclax in 
Study M14-387.
This analysis dataset will be used to provide a comprehensive summary of efficacy of 
venetoclax in combination with LDAC (20 mg/m2 daily administered subcutaneously 
[Days 1 - 10]).  Patients with an antecedent history of myeloproliferative neoplasm 
(MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or 
chronic myelogenous leukemia were excluded from the study in Study M14-387 Protocol 


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Amendment 2 because emerging evidence suggested that patients with JAK2 mutated 
MPN may not benefit from treatment with venetoclax in combination with LDAC.  To 
explore the efficacy of venetoclax in combination with LDAC both including and 
excluding those patients with a history of MPN will be presented.
Unless otherwise stated, data included in efficacy analyses is subjected to the cutoff date 
which is determined at each interim analysis.
6.2
Planned Efficacy Analyses for Each Analysis Dataset
A list of contents of efficacy analyses described in the Statistical Methods section 
(Section 8.0) is provided below.  The list of analyses will be performed for all 
three analysis datasets separately.  Data will not be pooled across studies.
●
Complete remission (CR) rate (Analysis datasets 1 - 3)
●
Complete remission with partial hematologic recovery (CRh) rate (Analysis 
datasets 1 - 3)
●
CR + CRh rate (Analysis datasets 1 - 3)
●
CR + CRh rate by the initiation of Cycle 2 (Analysis datasets 1 - 3)
●
Time to the first response of CR + CRh (Analysis datasets 1 - 3)
●
Time to best response of CR + CRh (Analysis datasets 1 - 3)
●
Duration of CR (Analysis datasets 2 - 3)
●
Duration of CR + CRh (Analysis datasets 1 - 3)
●
CR + CRi rate (Analysis datasets 2 - 3)
●
CR + CRi rate by the initiation of Cycle 2 (Analysis datasets 2 - 3)
●
Time to the first response of CR + CRi (Analysis datasets 2 - 3)
●
Time to best response of CR + CRi (Analysis datasets 2 - 3)
●
Duration of CRi (Analysis datasets 2 - 3)
●
Duration of CR + CRi (Analysis datasets 2 - 3)
●
Objective Response Rate (CR + CRi + PR) (Analysis datasets 2 - 3)
●
Overall survival (OS) (Analysis datasets 2 - 3)


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●
Post baseline RBC/Platelet transfusion independence and duration of post 
baseline RBC/Platelet transfusion independence (Analysis datasets 1 - 3)
●
Time to first RBC/platelet transfusion (Analysis datasets 2 - 3)
●
Time to the first recurrent RBC/platelet transfusion (Analysis dataset 2 - 3)
●
Time to first Grade 3 or above TEAE hemorrhage event (SMQ narrow) 
(Analysis datasets 2 - 3)
●
Time to first Grade 3 or above TEAE SOC of "infections and infestations" 
event (Analysis datasets 2 - 3)
●
Time to first hospitalization due to SAE (Analysis datasets 2 - 3)
7.0
Analysis Conventions
Definition of Study Drug
Unless otherwise specified, the study drug in this document refers to
●
Venetoclax and HMA (Study M14-358)
●
Venetoclax and LDAC (Study M14-387)
Definition of Last Dose of Study Drug + 30 Days
Last dose of study drug + 30 days is defined as the last of dose of venetoclax, HMA, or 
LDAC + 30 days on or prior to data extraction dates.
Definition of Baseline
Unless otherwise stated, baseline for a given variable will be defined as the last non-
missing value for that variable obtained prior to the first dose of any component of study 
drug.


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Definition of Study Day
Study Day is defined as the number of days since (positive numbers) or prior to (negative 
numbers) the first dose of study drug.  The day of the first dose of study drug is defined as 
Study Day 1, while the day prior to the first dose of study drug is defined as 
Study Day –1; there is no Study Day 0.
Definition of Final Observation
The final observation is defined as the last non-missing observation collected.
Full Analysis Set
The full analysis set includes all subjects who received at least one dose of venetoclax.
Safety Analysis Set
The safety analysis set includes all subjects who received at least one dose of venetoclax.
8.0
Statistical Methods
Unless otherwise specified, all summaries/analyses of three analysis datasets will be 
presented separately.  Disposition, demographic, prior and concomitant medication, prior 
disease history including AML, and study drug exposure summary will be performed as 
described in the safety SAP.
8.1
Efficacy Analyses
Unless otherwise specified, all summaries/analyses of efficacy data will be presented for 
all treatment groups of the analysis datasets 1 – 3 specified in Table 3 separately.  There 
will be no pooled analyses across the three analysis datasets.  All subjects who have 
received at least one dose of venetoclax will be included in the efficacy analyses.  Unless 
otherwise stated, the data cutoff date will be applied to efficacy analyses for 
Study M14-358 and Study M14-387 (Analysis dataset 2 - 3).


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8.1.1
Complete Remission (CR) Rate 
Complete Remission (CR) is a response based on investigator report using modified IWG 
criteria for AML.
Complete Remission (CR) rate will be defined as the proportion of subjects who achieve a 
complete remission at any time point during the study per the modified IWG criteria for 
AML.  Subjects who never achieve CR or have no IWG disease assessment will be 
considered to be non-responders in the calculation of CR rate.  In addition to the CR rate, 
the 95% confidence interval for CR rate based on the binomial distribution 
(Clopper-Pearson exact method) will be provided.  The disease assessment collected after 
the post-treatment therapy will be excluded.
8.1.2
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.


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CRh rate will be defined as the proportion of subjects who achieve CRh as the best 
response at any time point during the study.  Subjects who never achieve CRh or have not 
had disease assessment or hematology data will be considered to be non-responders in the 
calculation of CRh rate.  In addition to the CRh rate, the 95% confidence interval for CRh 
rate based on the binomial distribution (Clopper-Pearson exact method) will be provided.  
The disease assessment collected after the post-treatment therapy will be excluded for 
above analyses.
8.1.3
CR + CRh Rate
CR + CRh rate will be defined as the proportion of subjects who achieve CR or CRh at 
any time point during the study.  Subjects who never achieve CR/CRh or have no disease 
assessment will be considered to be non-responders in the calculation of CR + CRh rate.  
In addition to the CR + CRh rate, the 95% confidence interval for CR + CRh rate based 
on the binomial distribution (Clopper-Pearson exact method) will be provided.
The time to the 1st response of CR + CRh is defined as number of days from the 1st date of 
study drug to the 1st response of CR + CRh.  The time to the best response of CR + CRh is 
defined as number of days from the 1st date of study drug to the 1st date of best response 
of CR + CRh.
The medians and ranges of time to the 1st response of CR + CRh and time to the best 
response of CR + CRh for all subjects, as well as for subjects with best response CR or 
best response of CRh will be summarized.
The disease assessment collected after the post-treatment therapy will be excluded for 
above analyses.
8.1.4
CR + CRh Rate by Initiation of Cycle 2
CR + CRh rate by initiation of Cycle 2 will be defined as the proportion of subjects who 
achieve CR or CRh by initiation of Cycle 2 of study treatment.  Subjects who never 
achieve CR or CRh or have not had disease assessment by initiation of Cycle 2 will be 


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considered to be non-responders in the calculation of CR + CRh rate by initiation of 
Cycle 2.  In addition to the CR + CRh rate by initiation of Cycle 2, the 95% confidence 
interval for CR + CRh rate by initiation of Cycle 2 based on the binomial distribution 
(Clopper-Pearson exact method) will be provided.
The disease assessment collected after the post-treatment therapy will be excluded for 
above analysis.
8.1.5
Duration of CR
Duration of CR is defined as number of days from date that subject achieved CR to the 
first date of relapse, clinical disease progression or death due to disease progression, 
whichever occurred earliest.  If a subject is still responding at the data cutoff date, then the 
subject's data will be censored.  The disease assessment data after the onset of any post-
treatment therapy will not be included in the duration of CR analysis.  The detailed 
censoring rule is described in Table 4.  For each analysis dataset, the distribution of 
duration of CR will be estimated using Kaplan-Meier methodology.  Median duration of 
CR with the corresponding 95% CI will be provided from Kaplan-Meier estimation.


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Table 4.
Event/Censor and Corresponding Event/Censor Time for Duration 
of CR or CR + CRh
Situation
Event/Censor
Event Time/Censor Time
IWG disease progression (PD) or 
Clinical disease progression (CPD) 
on or prior to any post-treatment
therapy and data cutoff date, 
whichever is earliest
Event
Earliest PD date
Death due to disease progression on 
or prior to data cutoff date regardless 
whether it occurred after any new 
post-treatment
Event
Death date
Neither PD nor CPD nor Death due 
to disease progression and without 
post-treatment therapy 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
Neither PD nor CPD nor Death due 
to disease progression but having 
post-treatment therapy on or prior to 
the data cutoff date
Censor
Start of post-treatment therapy
8.1.6
Duration of CR + CRh
Duration of CR + CRh is defined as number of days from date that subject achieved 
CR + CRh to the first date of relapse, clinical disease progression or death due to disease 
progression, whichever occurred earliest.  If a subject is still responding at the data cutoff 
date, then the subject's data will be censored.  The disease assessment data after the onset 
of any post-treatment therapy will not be included in the duration of CR + CRh analysis.  
The detailed censoring rule is described in Table 4.  For each analysis dataset, the 
distribution of duration of CR + CRh will be estimated using Kaplan-Meier methodology.  
Median duration of CR + CRh with the corresponding 95% CI will be provided from 
Kaplan-Meier estimation.  Duration of CR + CRh will be summarized for all subjects, 
subjects achieving CR, and subjects achieving CRh.


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8.1.7
Overall Survival (OS)
Time to death for a given subject will be defined as the number of days from the date of 
first dose of study drug to the date of the subject's 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 on or before 
the "Cutoff" date, and there is any data (survival follow-up, study visit, death date, etc.) 
confirming that the subject is still alive or dies after the "Cutoff" date, the data will be 
censored at the "Cutoff" date; otherwise the data will be censored at the date when the 
subject was last known to be alive.
For each analysis datasets, the distribution of OS will be estimated using Kaplan-Meier 
methodology.  Median survival time with the corresponding 95% CI will be provided 
from Kaplan-Meier estimation.
OS will be summarized for all subjects, subjects achieving CR, subjects achieving CRh, 
and non-CR/non-CRh subjects.
8.1.8
Post Baseline Transfusion Independence Rate 
(RBC/Platelet) and Duration of Post Baseline Transfusion 
Independence
The transfusion data was designed to be collected during the treatment period and until 
the 30 day follow-up visit.  Therefore, the evaluation period for the post baseline 
transfusion independence is from the first dose of study drug to the last dose of study drug 
+ 30 days, disease progression (including clinical progression), or death, whichever is 
earlier. Thus, post baseline transfusion independence is defined as a period of at least 
56 days (≥ 56 days) with no RBC or platelet transfusion during the evaluation period.
Post baseline transfusion independence rate will be estimated as the proportion of subjects 
known to achieve transfusion independence during the evaluation period.  The 
corresponding 95% CI for transfusion independence rate will be provided based on the 
binomial distribution (Clopper-Pearson exact method).


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In addition, the baseline transfusion independence rate, which is defined as the proportion 
of subjects who received no transfusion within 56 days prior to the first dose of study drug 
(Studies M14-358 and M14-387) or 28 days (Study M14-212) prior to the first dose of 
study drug, will also be summarized.  An analysis based on the definition of baseline 
transfusion independence as 28 days on or prior to the first dose of study drug will also be 
performed for all studies.
Number and percentage of subjects who were transfusion dependent at baseline and then 
become transfusion independent during the evaluation period will be provided.  Number 
and percentage of subjects who were transfusion-independent at baseline and remain 
transfusion-independent during the evaluation period will also be provided.
In addition to the transfusion independence rate, the duration of transfusion independence 
will also be summarized.  The duration of transfusion independence is defined as the 
1st time period that a subject receives no RBC/platelet transfusions for at least 56 days 
during the evaluation period.  The descriptive statistics (median and range) will be 
provided for duration of transfusion independence.
All transfusion data available in the extracted database will be used in the analyses of 
transfusion independence rate and duration of transfusion independence.  The above 
analyses will also be performed separately for
●
RBC transfusion
●
Platelet transfusion.
8.1.9
Time to the First Event
For each analysis set, the distribution of time to event for each parameter described in 
below sections will be estimated using Kaplan-Meier methodology.  Median time to the 
first event for each parameter listed below with the corresponding 95% CI will be 
provided from Kaplan-Meier estimation.  All data available in the extracted database will 
be used for the analyses described in Section 8.1.9.


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8.1.9.1
Transfusion
The transfusion data was designed to be collected during the treatment period and until 
the 30 day follow-up visit.  Thus, the data included in this section is from the first dose 
date of study drug to the last dose of study drug + 30 days.  Transfusion data will be 
summarized as RBC transfusion and platelet transfusion separately.
Time to 1st RBC/Platelet Transfusion After Achieving CR
Time to 1st RBC/platelet transfusion after achieving CR will be defined as number of days 
from achieving CR to the first RBC/platelet transfusion.  If a subject did not have any 
RBC/platelet transfusion events, the subject's data will be censored at 30 days after the 
last dose date of study drug or death of any cause, whichever occurs earlier.  Subjects who 
achieve CR will be included in the analysis.
Time to 1st RBC/Platelet Transfusion After Achieving CRh
Time to 1st RBC/platelet transfusion after achieving CRh will be defined as number of 
days from achieving CRh to the first RBC/platelet transfusion.  If a subject did not have 
any RBC/platelet transfusion events, the subject's data will be censored at 30 days after 
the last dose date of study drug or death of any cause, whichever occurs earlier.  Subjects 
who achieve CRh will be included in the analysis.
Time to 1st RBC/Platelet Transfusion After Achieving CR/CRh
Time to 1st RBC/platelet transfusion after achieving CR/CRh will be defined as number of 
days from achieving CR/CRh to the first RBC/platelet transfusion.  If a subject did not 
have any RBC/platelet transfusion, the subject's data will be censored at 30 days after the 
last dose date of study drug or death of any cause, whichever occurs earlier.  Subjects who 
achieve CR/CRh will be included in the analysis.


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Time to the 1st RBC/Platelet Transfusion Before Achieving CR
Time to the 1st RBC/platelet transfusion before achieving CR will be defined as number of 
days from the 1st date of study drug to the 1st RBC/platelet transfusion before achieving 
CR.  If a subject did not have any RBC/platelet transfusion before achieving CR, the 
subject's data will be censored at the date that CR is first achieved.  Only subjects who 
achieve CR will be included in the analysis.
Time to the 1st RBC/Platelet Transfusion Before Achieving CRh
Time to the 1st RBC/platelet transfusion before achieving CRh will be defined as number 
of days from the 1st date of study drug to the 1st RBC/platelet transfusion before achieving 
CRh.  If a subject did not have any RBC/platelet transfusion before achieving CRh, the 
subject's data will be censored at the date that CRh is first achieved.  Only subjects who 
achieve CRh will be included in the analysis.
Time to the 1st RBC/Platelet Transfusion Before Achieving CR/CRh
Time to the 1st RBC/platelet transfusion before achieving CR/CRh will be defined as 
number of days from the 1st date of study drug to the 1st RBC/platelet transfusion before 
achieving CR/CRh.  If a subject did not have any RBC/platelet transfusion before 
achieving CR/CRh, the subject's data will be censored at the date that CR/CRh is 
first achieved.  Only subjects who achieve CR/CRh will be included in the analysis.
Time to 1st RBC/Platelet Transfusion from 60 Days After the First Dose of Study Drug
Time to 1st RBC/platelet transfusion from 60 days after the first dose of study drug will be 
defined as number of days from 60 days after first dose date of study drug to the 
first RBC/platelet transfusion.  If a subject did not have any RBC/platelet transfusion, the 
subject's data will be censored at 30 days after the last dose date of study drug or death of 
any cause, whichever occurs earlier.  This analysis will be performed for subjects who 
achieve CR, achieve CR/CRh, and don't achieve CR or CRh separately.


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Time to First RBC/Platelet Transfusion from 1st Date of Study Drug
Time to 1st RBC/platelet transfusion from 1st date of study drug will be defined as number 
of days from first dose date of study drug to the first RBC/platelet transfusion.  If a 
subject did not have any RBC/platelet transfusion, the subject's data will be censored at 
30 days after the last dose date of study drug or death of any cause, whichever occurs 
earlier.  This analysis will be performed for subjects who achieve CR, achieve CR/CRh, 
and don't achieve CR or CRh separately.
8.1.9.2
Time to the First Hospitalization due to SAE
Analyses of adverse events will include only "treatment-emergent" events.  "Treatment 
emergent adverse events" are defined as any adverse events that first occur on or after the 
date of first dose of study drug and with an onset date no more than 30 days after the last 
dose date of study drug.  Thus, the data included in this section is from first dosing of 
study drug to last dose date of study drug + 30 days.
Time to 1st Hospitalization After Achieving CR
Time to the 1st hospitalization after achieving CR will be defined as number of days from 
achieving CR to the first hospitalization.  If a subject did not have any hospitalization, the 
subject's data will be censored at 30 days after the last dose date of study drug or death of 
any cause, whichever occurs earlier.  Subjects who achieve CR will be included in the 
analysis.
Time to 1st Hospitalization After Achieving CRh
Time to the 1st hospitalization after achieving CRh will be defined as number of days from 
achieving CRh to the first hospitalization. If a subject did not have any hospitalization, 
the subject's data will be censored at 30 days after the last dose date of study drug or death 
of any cause, whichever occurs earlier.  Subjects who achieve CRh will be included in the 
analysis.


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Time to the 1st Hospitalization After Achieving CR/CRh
Time to the 1st hospitalization from achieving CR/CRh will be defined as number of days 
from achieving CR/CRh to the 1st hospitalization.  If a subject did not have any 
hospitalization, the subject's data will be censored at 30 days after the last dose date of 
study drug or death of any cause, whichever occurs earlier.  Subjects who achieve 
CR/CRh will be included in the analysis.
Time to the 1st Hospitalization Before Achieving CR
Time to the 1st hospitalization before achieving CR will be defined as number of days 
from the 1st date of study drug to the 1st hospitalization before achieving CR.  If a subject 
did not have any hospitalization event, the subject's data will be censored at date that CR
is first achieved.  Subjects who achieve CR will be included in the analysis.
Time to the 1st Hospitalization Before Achieving CRh
Time to the 1st hospitalization before achieving CRh will be defined as number of days 
from the 1st date of study drug to the 1st hospitalization before achieving CRh.  If a subject 
did not have any hospitalization event, the subject's data will be censored at date that CRh 
is first achieved.  Subjects who achieve CRh will be included in the analysis.
Time to the 1st Hospitalization Before Achieving CR/CRh
Time to the 1st hospitalization before achieving CR/CRh will be defined as number of 
days from the 1st date of study drug to the 1st hospitalization before achieving CR/CRh.  If 
a subject did not have any hospitalization event, the subject's data will be censored at date 
that CR/CRh is first achieved.  Subjects who achieve CR/CRh will be included in the 
analysis.
Time to the 1st Hospitalization from 60 Days After the First Dose of Study Drug
Time to the 1st hospitalization from 60 days after the first dose of study drug will be 
defined as number of days from 60 days after first dose date of study drug to the 


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1st hospitalization.  If a subject did not have any hospitalizations, the subject's data will be 
censored at 30 days after the last dose date of study drug or death of any cause, whichever 
occurs earlier.  This analysis will be performed for subjects who achieve CR, achieve 
CR/CRh, and don't achieve CR or CRh separately.
Time to the 1st Hospitalization After 1st Date of Study Drug
Time to the 1st hospitalization after 1st date of study drug will be defined as number of 
days from first dose date of study drug to the 1st hospitalization.  If a subject did not have 
any hospitalizations, the subject's data will be censored at 30 days after the last dose date 
of study drug or death of any cause, whichever occurs earlier.  This analysis will be 
performed for subjects who achieve CR, achieve CR/CRh, and don't achieve CR or CRh 
separately.
8.1.9.3
Time to First Event of Grade 3 or Above TEAE of 
Haemorrhages (Narrow SMQ) 
Analyses of adverse events will include only "treatment-emergent" events.  "Treatment 
emergent adverse events" are defined as any adverse events that first occur on or after the 
date of first dose of study drug and with an onset date no more than 30 days after the last 
dose date of study drug.  Thus, the data included in this section is from first dosing of 
study drug to last dose date of study drug + 30 days.
Time to First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) from 
Achieving CR
Time to the first event of Grade 3 or above TEAE of Haemorrhages from achieving CR 
will be defined as number of days from achieving CR to the first event of Grade 3 or 
above TEAE of Haemorrhages.  If a subject did not have any Grade 3 or above TEAE of 
Haemorrhages, the subject's data will be censored at 30 days after the last dose date of 
study drug or death of any cause, whichever occurs earlier.  Subjects who achieve CR will 
be included in the analysis.


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Time to First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) from 
Achieving CRh
Time to the first event of Grade 3 or above TEAE of Haemorrhages from achieving CRh 
will be defined as number of days from achieving CRh to the first event of Grade 3 or 
above TEAE of Haemorrhages.  If a subject did not have any Grade 3 or above TEAE of 
Haemorrhages, the subject's data will be censored at 30 days after the last dose date of 
study drug or death of any cause, whichever occurs earlier.  Subjects who achieve CRh 
will be included in the analysis.
Time to the First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) 
from Achieving CR/CRh
Time to the first event of Grade 3 or above TEAE of Haemorrhages from achieving 
CR/CRh will be defined as number of days from achieving CR/CRh to the first event of 
Grade 3 or above TEAE of Haemorrhages.  If a subject did not have any Grade 3 or above 
TEAE of Haemorrhages, the subject's data will be censored at 30 days after the last dose 
date of study drug or death of any cause, whichever occurs earlier.  Subjects who achieve 
CR/CRh will be included in the analysis.
Time to the First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) 
Before Achieving CR
Time to the 1st first event of Grade 3 or above TEAE of Haemorrhages (narrow SMQ) 
before achieving CR will be defined as number of days from the 1st date of study drug to 
the 1st Grade 3 or above haemorrhages event before achieving CR.  If a subject did not 
have any Grade 3 or above TEAE of Haemorrhages (narrow SMQ), the subject's data will 
be censored at date that CR is first achieved.  Subjects who achieve CR will be included 
in the analysis.


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Time to the First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) 
Before Achieving CRh
Time to the 1st event of Grade 3 or above TEAE of Haemorrhages (narrow SMQ) before 
achieving CRh will be defined as number of days from the 1st date of study drug to the 
1st Grade 3 or above haemorrhages event before achieving CRh.  If a subject did not have 
any Grade 3 or above TEAE of Haemorrhages (narrow SMQ), the subject's data will be 
censored at date that CRh is first achieved.  Subjects who achieve CRh will be included in 
the analysis.
Time to the First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) 
Before Achieving CR/CRh
Time to the 1st event of Grade 3 or above TEAE of Haemorrhages (narrow SMQ) before 
achieving CR/CRh will be defined as number of days from the 1st date of study drug to 
the 1st Grade 3 or above Haemorrhage event before achieving CR/CRh.  If a subject did 
not have any Grade 3 or above TEAE of Haemorrhages (narrow SMQ), the subject's data 
will be censored at date that CR/CRh is first achieved.  Subjects who achieve CR/CRh 
will be included in the analysis.
Time to the First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) 
from 60 Days After the First Dose of Study Drug
Time to the first event of Grade 3 or above TEAE of Haemorrhages (narrow SMQ) from 
60 days after the first dose of study drug will be defined as number of days from 60 days 
after first dose date of study drug to the first event of Grade 3 or above TEAE of 
Haemorrhages (narrow SMQ).  If a subject did not have any events of Grade 3 or above 
TEAE of Haemorrhages (narrow SMQ), the subject's data will be censored at 30 days 
after the last dose date of study drug or death of any cause, whichever occurs earlier.  This 
analysis will be performed for subjects who achieve CR, achieve CR/CRh, and don't 
achieve CR or CRh separately.


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Time to the First Event of Grade 3 or Above TEAE of Haemorrhages (Narrow SMQ) 
from the First Dose of Study Drug
Time to the first event of Grade 3 or above TEAE of Haemorrhages (narrow SMQ) from 
first dose of study drug will be defined as number of days from first dose date of study 
drug to the first event of Grade 3 or above TEAE of Haemorrhages (narrow SMQ).  If a 
subject did not have any events of Grade 3 or above TEAE of Haemorrhages (narrow 
SMQ), the subject's data will be censored at 30 days after the last dose date of study drug 
or death of any cause, whichever occurs earlier.  This analysis will be performed for 
subjects who achieve CR, achieve CR/CRh, and don't achieve CR or CRh separately.
Time to 1st serious Haemorrhages (narrow SMQ) will be performed using the same 
method if data is available.
8.1.9.4
Time to First Event of Grade 3 or Above TEAE of 
Infections/Infestations (SOC) 
Time to First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) from 
Achieving CR
Time to the first event of Grade 3 or above TEAE of infections/infestations (SOC) from 
achieving CR will be defined as number of days from achieving CR to the first event of 
Grade 3 or above TEAE of infections/infestations (SOC).  If a subject did not have any 
Grade 3 or above TEAE of infections/infestations (SOC), the subject's data will be 
censored at 30 days after the last dose date of study drug or death of any cause, whichever 
occurs earlier.  Subjects who achieve CR will be included in the analysis.
Time to First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) from 
Achieving CRh
Time to the first event of Grade 3 or above TEAE of infections/infestations (SOC) from 
achieving CRh will be defined as number of days from achieving CRh to the first event of 
Grade 3 or above TEAE of infections/infestations (SOC).  If a subject did not have any 


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Grade 3 or above TEAE of infections/infestations (SOC), the subject's data will be 
censored at 30 days after the last dose date of study drug or death of any cause, whichever 
occurs earlier.  Subjects who achieve CRh will be included in the analysis.
Time to First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) from 
Achieving CR/CRh
Time to the first event of Grade 3 or above TEAE of infections/infestations (SOC) from 
achieving CR/CRh will be defined as number of days from achieving CR/CRh to the 
first event of Grade 3 or above TEAE of infections/infestations (SOC).  If a subject did 
not have any Grade 3 or above TEAE of infections/infestations (SOC), the subject's data 
will be censored at 30 days after the last dose date of study drug or death of any cause, 
whichever occurs earlier.  Subjects who achieve CR/CRh will be included in the analysis.
Time to the First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) 
Before Achieving CR
Time to the 1st first event of Grade 3 or above TEAE of infections/infestations (SOC) 
before achieving CR will be defined as number of days from the 1st date of study drug to 
the 1st event of Grade 3 or above TEAE of infections/infestations (SOC) before achieving 
CR.  If a subject did not have any Grade 3 or above TEAE of infections/infestations 
(SOC), the subject's data will be censored at date that CR is first achieved.  Subjects who 
achieve CR will be included in the analysis.
Time to the First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) 
Before Achieving CRh
Time to the 1st event of Grade 3 or above TEAE of infections/infestations (SOC) before 
achieving CR will be defined as number of days from the 1st date of study drug to the 
1st event of Grade 3 or above TEAE of infections/infestations (SOC) before achieving 
CRh.  If a subject did not have any Grade 3 or above TEAE of infections/infestations 
(SOC), the subject's data will be censored at date that CRh is first achieved. Subjects who 
achieve CRh will be included in the analysis.


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Time to the First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) 
Before Achieving CR/CRh
Time to the 1st event of Grade 3 or above TEAE of infections/infestations (SOC) before 
achieving CR/CRh will be defined as number of days from the 1st date of study drug to 
the 1st event of Grade 3 or above TEAE of infections/infestations (SOC) before achieving 
CR/CRh.  If a subject did not have any Grade 3 or above TEAE of infections/infestations 
(SOC), the subject's data will be censored at date that CR/CRh is first achieved.  Subjects 
who achieve CR/CRh will be included in the analysis.
Time to First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) from 
60 Days After the First Dose of Study Drug
Time to the first event of Grade 3 or above TEAE of infections/infestations (SOC) from 
60 days after the first dose of study drug will be defined as number of days from 60 days 
after first dose date of study drug to the first event of Grade 3 or above TEAE of 
infections/infestations (SOC) during the treatment period.  If a subject did not have any 
events of Grade 3 or above TEAE of infections/infestations (SOC), the subject's data will 
be censored at 30 days after the last dose date of study drug or death of any cause, 
whichever occurs earlier.  This analysis will be performed for subjects who achieve CR, 
achieve CR/CRh, and don't achieve CR or CRh separately.
Time to First Event of Grade 3 or Above TEAE of Infections/Infestations (SOC) from the 
First Dose of Study Drug
Time to the first event of Grade 3 or above TEAE of infections/infestations (SOC) from 
first dose of study drug will be defined as number of days from first dose date of study 
drug to the first event of Grade 3 or above TEAE of infections/infestations (SOC).  If a 
subject did not have any events of Grade 3 or above TEAE of infections/infestations 
(SOC), the subject's data will be censored at 30 days after the last dose date of study drug 
or death of any cause, whichever occurs earlier.  This analysis will be performed for 
subjects who achieve CR, achieve CR/CRh, and don't achieve CR or CRh separately.


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Time to 1st serious infections/infestations (SOC) will be performed using the same method 
if data is available.
8.1.10
Time to the 1st Recurrent Transfusion Event from the
1st Transfusion Event
Transfusion data will be summarized by RBC transfusion and platelet transfusion 
separately.
Time to 1st Recurrent RBC/Platelet Transfusion from the 1st Transfusion After Achieving 
CR
Time to 1st recurrent RBC/platelet transfusion from the 1st transfusion after achieving CR 
will be defined as number of days from the 1st transfusion after achieving CR to the 
first recurrent RBC/platelet transfusion.  If a subject only has one RBC/platelet 
transfusion after achieving CR, the subject's data will be censored at 30 days after the last 
dose date of study drug or death of any cause, whichever occurs earlier.  Only subjects 
with best response CR with at least one subsequent transfusion will be included in the 
analysis.
Time to 1st Recurrent RBC/Platelet Transfusion from the 1st Transfusion After Achieving 
CRh
Time to 1st recurrent RBC/platelet transfusion from the 1st transfusion after achieving CRh 
will be defined as number of days from the 1st transfusion after achieving CRh to the 
first recurrent RBC/platelet transfusion.  If a subject only has one RBC/platelet 
transfusion after achieving CRh, the subject's data will be censored at 30 days after the 
last dose date of study drug or death of any cause, whichever occurs earlier.  Only 
subjects with best response CRh with at least one subsequent transfusion will be included 
in the analysis.


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Time to 1st Recurrent RBC/Platelet Transfusion from the 1st Transfusion After Achieving 
CR/CRh
Time to 1st recurrent RBC/platelet transfusion from the 1st transfusion after achieving 
CR/CRh will be defined as number of days from the 1st transfusion after achieving 
CR/CRh to the first recurrent RBC/platelet transfusion.  If a subject only has 
one RBC/platelet transfusion after achieving CR/CRh, the subject's data will be censored 
at 30 days after the last dose date of study drug or death of any cause, whichever occurs 
earlier.  Only subjects with best response CR/CRh with at least one subsequent 
transfusion will be included in the analysis.
Time to 1st Recurrent RBC/Platelet Transfusion from the 1st Transfusion for non-CR/CRh 
Subjects
Time to 1st recurrent RBC/platelet transfusion from the 1st transfusion will be defined as 
number of days from the 1st RBC/platelet transfusion to the first recurrent RBC/platelet 
transfusion.  If a subject only has one RBC/platelet transfusion, the subject's data will be 
censored at last dose of study drug + 30 days or death of any cause, whichever occurs 
earlier.  Only subjects with best response of non-CR/CRh and with at least one subsequent 
transfusion will be included in the analysis.
8.1.11
Additional Sensitivity Analyses of Efficacy Variables
Duration of Response
Sensitivity analyses for duration of CR + CRh, duration of CRh, and duration of CR will 
be provided based on different censoring methods.
1.
For subjects who had post treatment therapy before disease progression events or 
death due to disease progression, two methods will be performed:
●
Method 1:  this subject data will be censored at the date of last disease 
assessment before starting post treatment therapy;


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●
Method 2:  this subject's data will be considered as an event at the date of last 
disease assessment before starting post treatment therapy.
2.
For subjects who are lost to follow-up without disease progression or death due to 
disease progression documented, last disease assessment (bone marrow and 
hematology lab collations) will be considered as an event.
3.
If a disease progression or death due to disease progression event occurred more 
than 91 days (3 cycles) from the last disease assessment (bone marrow collection or 
hematology lab collection), this subject will be censored at the date of last disease 
assessment prior to the disease progression or death due to disease progression 
event.
Details of the censoring method for sensitivity analyses of duration of response are 
provided below in Table 5.
Table 5.
Censoring Methods for Analyses of CR + CRh, CR, and CRh
Situation
Date of Progression/Date of Censor
Outcome
Post-treatment therapy initiated 
with no disease progression 
documented
Date of last disease assessment before 
initiating post-treatment therapy (bone 
marrow or hematology lab)
Method 1) Censored
Post-treatment therapy initiated 
with no disease progression 
documented
Date of last disease assessment before 
initiating post-treatment therapy (bone 
marrow or hematology lab)
Method 2) Event
Loss to follow-up without disease 
progression or death due to disease 
progression documented 
Date of last disease assessment (bone 
marrow or hematology lab)
Event
Death or disease progression 
occurred after missing a scheduled 
disease assessments (disease 
progression or Death due to disease 
progression occurred > 91 days of 
last disease assessment)
Date of last disease assessment (bone 
marrow or hematology lab)
Censored


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Overall Survival
Sensitivity analyses for OS will be provided based on different censoring methods as 
shown in Table 6.  OS analysis including all deaths collected in the extracted database 
will also be performed.
Table 6.
Censoring Methods for Analyses of OS
Situation
Date of Progression/Date of Censor
Outcome
Withdrawal consent for survival 
follow-up 
Last known alive date
Event
Post-treatment therapy
Start date of post-treatment therapy
Censored
8.1.12
Exploratory Analysis of MRD Data
The MRD data is collected at baseline, the end of Cycle 1, and every 3 cycles thereafter 
when bone marrow is collected in Study M14-358 and Study M14-387.  The MRD data 
collected after the first dose of study drug to the last dose of study drug + 7 days, disease 
progression, clinical progression, the start of new post-treatment therapy, death, or cutoff 
date, whichever occurs earlier, will be included in the post-baseline MRD analyses.
The MRD analyses include MRD records meeting the following criteria:
1.
CD45 value ≥ 100,000 and MRD value < 0.1%; or
2.
MRD value ≥ 0.1%.
Zero is imputed if MRD value is 'less than LLoQ.'  Missing MRD is assigned if MRD 
value is 'too few CD45+ cell.'
The best post-baseline MRD (the lowest) value will be defined as the smallest MRD 
collected after the first dose of study drug to the last dose of study drug + 7 days, disease 
progression, clinical progression, the start of new post-treatment therapy, death, or cutoff 
date, whichever occurs earlier.  The median and range will be presented for subjects who 


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achieved CR, CR + CRh or CR + CRi.  The best MRD value will also be categorized to 
three groups < 0.1%, ≥ 0.1%, and Unknown/Missing MRD value.  The summary of the 
best MRD value will be performed among subjects who achieved CR, CR + CRh, or 
CR + CRi.
OS will also be summarized by the best MRD value (< 0.1%, ≥ 0.1%, Unknown/Missing 
if any) for subjects achieved CR + CRh or CR + CRi.  Median survival time with the 
corresponding 95% CI will be provided from Kaplan-Meier estimation.
OS will also be summarized by the best MRD value (< 1%, ≥ 1%, Unknown/Missing if 
any) for subjects achieved CR + CRh or CR + CRi.  Median survival time with the 
corresponding 95% CI will be provided from Kaplan-Meier estimation.
Duration of CR + CRh will also be summarized by the best MRD value (< 0.1%, ≥ 0.1%, 
Unknown/Missing if any) for subjects achieved CR + CRh.  Median duration of 
CR + CRh with the corresponding 95% CI will be provided from Kaplan-Meier 
estimation.
Duration of CR + CRi will also be summarized by the best MRD value (< 0.1%, ≥ 0.1%, 
Unknown/Missing if any) for subjects achieved CR + CRi.  Median duration of CR + CRi 
with the corresponding 95% CI will be provided from Kaplan-Meier estimation.
8.1.13
Subgroup Assessment of Efficacy Variables
The subgroup analyses will be performed for Studies M14-358 and M14-387 including 
the following treatment groups.
Study M14-358:
1.
overall of venetoclax + azacitidine (N = 127)
2.
venetoclax 400 mg + azacitidine (N = 84)
3.
overall of venetoclax + decitabine (N = 73)


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Study M14-387: 
1.
venetoclax 600 mg QD + LDAC or venetoclax 800 mg QD + LDAC (N = 92)
2.
venetoclax 600 mg QD + LDAC (N = 82)
3.
venetoclax 600 mg QD + LDAC and without MPN (N = 78).
No subgroup analyses will be performed for Study M14-212 due to relative small number 
of patients in this study.
CR rate, CR + CRh rate, post-baseline transfusion independence rate, duration of CR, 
duration of CR + CRh, and OS will be assessed for the subgroups within each treatment 
group as defined below.
●
Gender (Male, Female)
●
Age (< 75 years, ≥ 75 years)
●
By modified Ferrara Criteria (Y, N)
●
By Cytogenetics (Intermediate risk, poor risk)
●
Type of AML (primary, secondary)
●
AML MDS related changes (Yes, No)
●
Prior HMA use (Yes, No) (only for Study M14-387)
●
Biomarker mutation (TP53, FLT3, IDR1/2, NPM1)
●
Moderate/Strong CYP3A inhibitors (Y, N)
In addition, number of percentage of CR/CRh subjects went on post-treatment therapy 
will be summarized.
9.0
Sample Size 
For the non-randomized Phase 1/2 Studies M14-358 and M14-387, there is no formal 
statistical testing and study-wise sample size justification planned.  Sample size 
justification for the Expansion 1 and Expansion 2 cohorts of Study M14-358 based on 


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CR + CRi rate and the Phase 2 portion of Study M14-387 based on ORR rate can be 
found in each study protocol.  The full analysis set of Study M14-358 and Study M14-387 
includes both dose escalation and dose expansion.  The sample size justification using CR 
rates at the recommended Phase 2 venetoclax dose level for Study M14-358 and Study 
M14-387 and historical CR rates are summarized in Table 7.
Table 7.
Sample Size Justification
N
Targeted CR 
Rate (95% CI)
Historical CR 
Rate of LDAC 
Alone (%)1
Historical CR 
Rate of AZA 
Alone (%)1
Historical CR 
Rate of DEC 
Alone (%)2
Study M14-387 
venetoclax 600 mg 
QD + LDAC 
82
21% (13%, 31%)
7.9%
NA
NA
Study M14-358 
venetoclax 400 mg 
QD + AZA 
84
36% (27%, 48%)
NA
19.5%
NA
Study M14-358 
venetoclax 400 mg 
QD + DEC
31
39% (22%, 58%)
NA
NA
15.7%
Based on the enrolled sample sizes in Studies M14-358 and M14-387, the lower limit of 
the 95% confidence intervals for the target CR rates are higher than the historical CR rates 
from previously conducted clinical trials of azacitidine, decitabine and LDAC, and 
represent a clinically meaningful improvement for subjects.
10.0
References
1.
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.
2.
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 


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with newly diagnosed acute myeloid leukaemia.  J Clin Oncol.  
2012;30(21):2670-7.


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1.0
Title Page
Safety Statistical Analysis Plan
Study M14-212
Study M14-358
Study M14-387
Venetoclax (ABT-199/GDC-0199) in Combination with 
LDAC (low dose Cytarabine) or HMA (Azacitidine and 
Decitabine) for the Treatment Subjects with Acute 
Myeloid Leukemia
Date:  21 Dec 2018
Version 3.0
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
2.1
Summary of Versions............................................................................. 4
2.2
List of Abbreviations and Definitions of Terms ...................................... 5
3.0
Introduction...........................................................................6
4.0
Study Background.................................................................6
5.0
Studies Included ....................................................................6
6.0
Analysis Sets ..........................................................................8
6.1
Definition of Analysis Sets..................................................................... 8
6.2
Rationale for Analysis Sets..................................................................... 8
7.0
Statistical Methods ..............................................................10
7.1
Analysis Conventions........................................................................... 10
7.2
Subject Disposition............................................................................... 11
7.3
Study Drug Exposure ........................................................................... 11
7.4
Demographics and Baseline Disease Related Characteristics ................ 12
7.5
Prior and Concomitant Medications...................................................... 14
7.6
Adverse Events..................................................................................... 14
7.6.1
Analysis of Treatment Emergent Adverse Events ................................. 15
7.6.2
Selected Treatment-Emergent Adverse Events...................................... 16
7.6.3
Hospitalization Due to Serious Adverse Events .................................... 16
7.6.4
Transfusion During the Treatment Period............................................. 17
7.6.5
Subgroup Assessment of Adverse Events for Overall Treatment 
Groups ................................................................................................. 17
7.7
Laboratory Parameters.......................................................................... 18
7.7.1
Assessment of Shifts from Baseline in Clinical Laboratory 
Parameters............................................................................................ 18
7.7.2
Laboratory Abnormalities..................................................................... 19
7.7.3
Subgroup Assessment of Shifts from Baseline in Clinical 
Laboratory............................................................................................ 19
7.8
Vital Signs Parameter........................................................................... 20
7.8.1
Assessment of Potentially Clinically Significant Vital Signs 
Parameters............................................................................................ 20


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List of Tables
Table 1.
List of Venetoclax Studies to be Included in the Safety Summary........... 7
Table 2.
Regimens Investigated in Venetoclax AML Studies ............................... 8
Table 3.
Definition of the Analysis Sets ............................................................... 8
Table 4.
Selected Adverse Events....................................................................... 16
Table 5.
Laboratory Abnormalities..................................................................... 19
Table 6.
Criteria for Potentially Clinically Significant Vital Signs 
Parameters............................................................................................ 21


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2.1
Summary of Versions
Version
Date of Completion
Summary
1.0
13 Dec 2017
First version (Appendix of Briefing Book of
FDA Type C Meeting)
2.0
04 May 2018
Final version for Interim 1 CSR
3.0
27 Nov 2018
Update MEDDRA version for Interim 2 CSR


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2.2
List of Abbreviations and Definitions of Terms
AE
Adverse event
AESI
Adverse Event of Special Interest
ALC
Absolute lymphocyte count
ALT
Alanine aminotransferase
AML
Acute Myeloid leukemia 
AST
Aspartate aminotransferase
HMA
Azacitidine or Decitabine
ISS
Integrated summary of safety
LDAC
Low dose cytarabine
MedDRA
Medical dictionary for regulatory activities 
MPN
Myeloproliferative neoplasm
NCI
National Cancer Institute
NCI CTC
National Cancer Institute Common Terminology Criteria
PT
Preferred term
RBC
Red blood cells
SAE
Serious adverse event
SAP
Statistical analysis plan
SMQ
Standardized MedDRA query
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WBC
White blood cells
WHO
World Health Organization


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3.0
Introduction
This safety statistical analysis plan (SAP) covers analyses of safety data from 
Studies M14-358 (R&D/17/1341), M14-387 (R&D/17/1340), and M14-212 
(R&D/15/0200).  These analyses will support the safety assessment of venetoclax for 
AML.  Analyses will be performed by personnel from Data and Statistical Sciences at 
AbbVie or their designees using SAS Version 9.3 or later (SAS Institute Inc., Cary, 
NC  27513) under the UNIX operating system.
4.0
Study Background
This SAP provides details of statistical analyses that are to be performed for the safety 
assessment of venetoclax treatment for AML.  Safety analyses will be performed to assess 
the potential effect of venetoclax monotherapy or in combination with hypomethylating 
agents (HMA) or low dose cytarabine (LDAC) on adverse events (AEs), as well as 
clinical laboratory measurements and vital signs.
5.0
Studies Included
All AbbVie sponsored venetoclax AML studies to be included are described below in 
Table 1.  All studies' results will be presented separately.  Data will not be pooled across 
studies.


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Table 1.
List of Venetoclax Studies to be Included in the Safety Summary
Study ID 
Phase 
(Status)
Number of 
Enrolled 
Subjects 
(Actual/Planned)
Location
Study Design
Primary Objective
M14-212 
Phase 2 
(completed)
32/54
US
Open-label study of 
venetoclax in adults 
with relapsed or 
refractory AML, or 
untreated AML unfit 
for intensive therapy
Evaluate the 
preliminary efficacy 
of single agent 
venetoclax.
M14-358 
Phase 1b 
(Enrollment 
complete and 
follow-up is 
ongoing)
212/260
Australia, 
Germany, 
France, and 
US
Open-label study of 
venetoclax + 
azacitidine or 
decitabine in treatment 
naïve elderly 
(≥60 years) subjects 
with AML who are not 
eligible for standard 
induction therapy; 
2 stages:  dose 
escalation and dose 
expansion
Evaluate the safety, 
PK, and efficacy of 
venetoclax + 
decitabine or 
azacitidine in the 
target population.
The objective of the 
safety expansion is to 
confirm efficacy and 
safety of the intended 
dose for Phase 3 
study.
M14-387 
Phase 1/2 
(Enrollment 
complete and 
follow-up is 
ongoing)
92/94
Australia, 
Germany, 
Italy, US
Open-label study of 
venetoclax + LDAC in 
treatment naïve subjects 
with AML who are 
≥60 years of age and 
who are not eligible for 
standard anthracycline-
based induction 
therapy; 2 stages:  dose 
escalation and safety 
expansion
Phase 1:  Evaluate the 
safety, PK and 
determine the MTD 
and RPTD of 
venetoclax + LDAC.
Phase 2:  Estimate 
efficacy, including 
ORR, and 
characterize the 
toxicity of the 
combination at the 
RPTD.
Cohort C:  Evaluate 
the ORR for subjects 
allowed additional 
supportive 
medications (strong 
CYP3A inhibitors) if 
medically indicated.


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The venetoclax doses and regimens in the studies listed in Table 1 are described in 
Table 2 below.
Table 2.
Regimens Investigated in Venetoclax AML Studies
Study ID
Venetoclax Dose and Frequency
Treatment Regimen
M14-212
Venetoclax 400 mg QD, 800 mg QD, 
1200 mg QD
Venetoclax monotherapy
M14-358
Venetoclax 400 mg QD, 800 mg QD, 
1200 mg QD
Venetoclax in combination with HMA 
(Azacitidine or Decitabine)
M14-387
Venetoclax 600 mg QD, 800 mg QD
Venetoclax in combination LDAC
(Low dose cytarabine)
6.0
Analysis Sets
6.1
Definition of Analysis Sets
Each of the three studies will represent a separate analysis set as detailed in Table 3
below.  No pooled analysis sets are defined.
Table 3.
Definition of the Analysis Sets
Analysis Data Sets
Study Included
Study Population
1.
Monotherapy
M14-212
Subjects who received at least 
one dose of venetoclax
2.
Venetoclax in combination with HMA
M14-358
Subjects who received at least 
one dose of venetoclax
3.
Venetoclax in combination with LDAC
M14-387
Subjects who received at least 
one dose of venetoclax
6.2
Rationale for Analysis Sets
The reason for not pooling the Studies M14-212, M14-358, and M14-387 is that the 
different treatment regimens (venetoclax monotherapy, venetoclax in combination with 
HMA, venetoclax in combination with LDAC) are expected to have different safety 


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profiles.  Thus, it is not appropriate to pool data across these studies to assess the safety of 
venetoclax in combination with HMA or venetoclax in combination with LDAC.
1) Monotherapy Analysis Set
This analysis set includes AML subjects who have been treated with venetoclax in 
Study M14-212.  This analysis dataset will be used to provide a comprehensive summary 
of safety of venetoclax monotherapy in AML subjects.  Safety summaries will be 
presented for all subjects (N = 32).
2) Venetoclax in Combination with HMA Analysis Set
This analysis set includes subjects who received at least one dose of venetoclax in 
Study M14-358.  This analysis dataset will be used to provide a comprehensive summary 
of safety of venetoclax in combination with HMA (azacitidine 75 mg/m2 or decitabine 
20 mg/m2).  Safety summaries will be presented for the following nine groups:
1.
venetoclax 400 mg QD + azacitidine (N = 84);
2.
venetoclax 800 mg QD + azacitidine (N = 37);
3.
venetoclax 1200 mg QD + azacitidine (N = 6); 
4.
overall of venetoclax + azacitidine (N = 127);
5.
venetoclax 400 mg QD + decitabine (N = 31);
6.
venetoclax 800 mg QD + decitabine (N = 37);
7.
venetoclax 1200 mg QD + decitabine (N = 5);
8.
overall of venetoclax + decitabine (N = 73);
9.
DDI (drug-drug interaction) venetoclax 400 mg QD (N = 12).


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3) Venetoclax in Combination with LDAC Analysis Set
This analysis set includes subjects who received at least one dose of venetoclax in 
Study M14-387.  This analysis dataset will be used to provide a comprehensive summary 
of safety of venetoclax in combination with LDAC (20 mg/m2 subcutaneously given 
Days 1 – 10).  Patients with an antecedent history of myeloproliferative neoplasm (MPN) 
including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic 
myelogenous leukemia were excluded from the study in Study M14-387 Protocol 
Amendment 2 because emerging evidence suggested that patients with JAK2 mutated 
MPN may not benefit from treatment with venetoclax in combination with LDAC.  To 
explore the safety of venetoclax in combination with LDAC both including and excluding 
those patients with a history of MPN, safety summaries will be presented for the 
following three groups:
1.
All subjects (N = 92)
2.
venetoclax 600 mg QD (N = 82)
3.
venetoclax 600 mg QD without MPN (N = 78).
7.0
Statistical Methods
The methods described here apply to the analysis on the analysis sets described in 
Section 6.2.
7.1
Analysis Conventions
All data available in the extracted database will be used in the safety analyses.
Definition of Study Drug
Unless otherwise specified, the study drug in this document refers to
●
Venetoclax (Study M14-212)
●
Venetoclax and HMA (Study M14-358)


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●
Venetoclax and LDAC (Study M14-387)
Definition of Baseline
All baseline summary statistics and analyses will be based on characteristics prior to the 
initiation of any component of study drug.  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.
Definition of Study Day
Study Day is defined as the number of days since (positive numbers) or prior to (negative 
numbers) the first dose of study drug.  The day of the first dose of study drug is defined as 
Study Day 1, while the day prior to the first dose of study drug is defined as Study
Day –1; there is no Study Day 0.
Definition of Final Observation
The final observation 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.
7.2
Subject Disposition
The number and percentage of subjects will be provided for analysis data sets 2 – 3 
specified in Table 3 for the following summaries.  The summary of subject disposition for 
Study M14-212 is in study CSR.
●
Subjects by country
●
Subjects discontinued for each reported primary reason (e.g., due to AE, due to 
disease progression, due to withdrew consent, etc.).
7.3
Study Drug Exposure
Exposure to venetoclax will be characterized in the following ways for summarization:


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●
Treatment duration:  time from the first dose to the last dose of study drug 
(days)
●
Treatment cycle:  number of cycles that subjects are exposed to venetoclax
●
Dose Intensity due to reduction:  the ratio of actual total venetoclax dose and 
the planned total venetoclax.  Days without venetoclax are not included in the 
planned total venetoclax dose.
●
Dose Intensity due to reduction and interruption:  the ratio of actual total 
venetoclax dose and the planned total venetoclax dose in the time period 
between first dose of venetoclax to the last dose of venetoclax.  Days without 
venetoclax are included in the planned total venetoclax dose.
Dose intensity is also summarized for subjects who are moderate or strong CYP3A 
inhibitor users.  The moderate or strong CYP3A inhibitor users are defined as subjects 
who take moderate or strong CYP3A inhibitors with venetoclax for a period with at least 
7 days.
Exposure to LDAC and HMA will be characterized in the following ways for 
summarization:
●
Treatment cycle:  The number of cycles that subjects are exposed to LDAC or 
HMA
7.4
Demographics and Baseline Disease Related 
Characteristics
The following demographics and baseline disease related characteristics will be 
summarized for Analysis Data Sets 1 – 3 specified in Table 3.
Demographics:
●
Gender (Male, Female)
●
Age (< 75 years, ≥ 75 years)
●
Race (White, Non-white)


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●
Weight (< 75 kg, ≥ kg)
●
Region (US and Non-US)
Baseline and Disease-Related Characteristics:
Study M14-212
Study M14-358
Study M14-387
Baseline Bone Marrow Blast (%) (mean, 
SD, median, range)
√
√
√
Baseline Bone Marrow Blast (< 30%, 
30 – 50%, ≥ 50%)
√
√
√
ECOG Performance Status (0, 1, 2, 3)
√
√
√
Subjects with secondary AML (Yes, No)
√
√
Cytogenetics (Intermediate, Poor)
√
√
AML Disease Type (Primary, Secondary)
√
√
Subjects receiving prior HMA for MDS 
(Yes, No)
N/A
√
Antecedent hematologic history (Yes, No)
√
√
History of oncological surgery (Yes, No)
√
√
Prior oncological therapy (Yes, No)
√
√
History of radiation therapy (Yes, No)
√
√
Transfusion independence at baseline 
(Yes, No)
√
√
Prior MPN (Yes, No)
√
√
Prior Hydoxyurea Use (Yes, No)
√
√
Fulfilling Modified Ferrara Criteria 
(Yes, No)
√
√
Comorbidities (Yes, No) if data is available
√
√
For demographic and baseline characteristics:  categorical data will be summarized with 
the number of subjects and corresponding percentage – the number and percentage of 
subjects with missing information will also be summarized; continuous data will be 
summarized with sample size, mean, standard deviation, median, and range.


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7.5
Prior and Concomitant Medications
Prior medications include all medications administered prior to the first dose of study 
drug.  Concomitant medications include all medications administered (started treatment or 
continued treatment) during the treatment period defined as the day of the first dose of 
study drug through the day of the final dose of study drug.
The number and percentage of subjects that received at least one concomitant medication 
("Any Concomitant Medication") will be summarized.  Additionally, the number and 
percentage of subjects who received concomitant medications will be summarized by the 
World Health Organization (WHO) generic drug names according to the WHO-DRUG 
dictionary.  Similar summaries will be presented for prior medications.
For summaries of concomitant medications, if an incomplete start date was collected for a 
medication, the medication will be assumed to be a concomitant medication 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 WHO 
generic drug name.  Similar rules apply to prior medications as well.
Concomitant medications will be summarized for analysis data sets 2 – 3 specified in 
Table 3.  The summary for prior and concomitant medications of Study M14-212 is in 
study CSR.
In addition, post-treatment therapy will be summarized for analysis data sets 2 – 3.
7.6
Adverse Events
All summaries/analyses involving AEs will include treatment-emergent AEs (TEAE) 
only, unless otherwise specified.  TEAEs are defined as any event with onset or 
worsening after the first dose of study drug and no more than 30 days after the last dose of 


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study drug.  If an incomplete 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).
All adverse event summaries will be summarized for analysis sets 2 – 3 specified in 
Table 3.
7.6.1
Analysis of Treatment Emergent Adverse Events
Adverse event data will be summarized using system organ classes (SOCs) and preferred 
terms (PTs) from the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.0 or later for Studies M14-358 and M14-387.  Adverse events were coded and 
summarized in MedDRA Version 18.1 for the Study M14-212 CSR.
For each AE summary, the number and percentage of subjects experiencing at least 
one AE will be presented (overall) for each dosing group.  Subjects reporting more than 
one AE within a SOC will be counted only once for that SOC.  Subjects reporting more 
than one AE for a PT will be counted only once for that PT.
For summaries of AEs by the National Cancer Institute Common Toxicity Criteria (NCI 
CTC) grade, at each level of summation (overall, SOC, and PT) each subject is counted 
only once at the maximum grade level.  The number and percentage of subjects 
experiencing at least one event for each of the following events will be summarized (but 
not limited to):
●
Any TEAE.
●
Any TEAE with reasonable possibility related to venetoclax by the 
investigator.
●
Any TEAE with NCI toxicity (CTCAE V4.0) Grade 3, 4, or 5 adverse events.
●
Any TEAE with NCI toxicity (CTCAE V4.0) Grade 3 or 4 adverse event.
●
Any treatment-emergent serious AE (SAE).
●
Any TEAE leading to discontinuation of venetoclax.


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●
Any TEAE leading to venetoclax dose interruption.
●
Any TEAE leading to venetoclax dose reduction.
●
Any TEAE leading to hospitalizations.
●
Any TEAE of special interest (AESI) (Section 7.6.2).
●
Any TEAE leading to death.
●
Any TEAE with reasonable possibility related to HMA (Study M14-358) or 
LDAC (Study M14-387) by the investigator.
●
Any TEAE leading to discontinuation of HMA (Study M14-358) or LDAC 
(Study M14-387).
●
Any TEAE leading to HMA (Study M14-358) or LDAC (Study M14-387) 
dose interruption.
●
Any TEAE leading to HMA (Study M14-358) or LDAC (Study M14-387) 
dose reduction.
7.6.2
Selected Treatment-Emergent Adverse Events
The selected TEAEs will be summarized by following the search criteria Table 4.
Table 4.
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)
SMQ – "Haemorrhages" (narrow)
AE = adverse events; PT = preferred term; SMQ = Standardised MedDRA Query; SOC = system organ class
7.6.3
Hospitalization Due to Serious Adverse Events
Hospitalization due to serious adverse events will be summarized for analysis data
set 2 – 3.  The number of days of hospitalization during the treatment period will be 


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summarized with descriptive statistics.  The treatment period is defined as from the 
first date of study drug to 30 days after last date of study drug.  This analysis will be 
performed for analysis dataset 2 – 3.
7.6.4
Transfusion During the Treatment Period
Transfusion during the treatment period will be summarized for analysis dataset 1 – 3.  
The number of transfusions for each type of transfusion (RBC and Platelet) during the 
treatment period will be summarized with descriptive statistics.
7.6.5
Subgroup Assessment of Adverse Events for Overall 
Treatment Groups
TEAE, grade 3 or above TEAEs, and SAEs, will be assessed for the subgroups defined 
below in analysis datasets 2 – 3.
●
Gender (Male, Female)
●
Age (< 75 years, ≥ 75 years)
●
Race (White, Non-white)
●
Geographic region (US, Non-US)
●
Best response (CR, CRh, CR/CRh, non-CR/CRh)
●
Baseline Weight (< 75 kg, ≥ 75 kg)
●
Baseline Renal Function (Normal, Mild impairment, Moderate impairment, 
sever impairment)
●
Baseline Hepatic Function (Normal, Mild impairment, Moderate impairment, 
sever impairment)
●
Moderate or Strong CYP3A inhibitors Users during treatment period
Study M14-358:
1.
overall of venetoclax + azacitidine (N = 127);
2.
venetoclax 400 mg QD + azacitidine (N = 84);
3.
overall of venetoclax + decitabine (N = 73);


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Study M14-387:
1.
All subjects venetoclax 600 mg QD + LDAC or venetoclax 800 mg QD + LDAC 
(N = 92)
2.
venetoclax 600 mg QD + LDAC (N = 82)
3.
venetoclax 600 mg QD + LDAC and without MPN (N = 78).
7.7
Laboratory Parameters
Data collected from the central and local laboratories, including additional laboratory 
testing due to an SAE, will be used in all analyses.  All values will be assessed based on 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE 4.0).  The highest grade will be used if lab results are collected on the same date.
All laboratory parameters will be summarized for analysis sets 2 – 3 specified in Table 3.  
The laboratory parameters summaries for Study M14-212 are available in the CSR.
7.7.1
Assessment of Shifts from Baseline in Clinical Laboratory 
Parameters
For shifts relative to NCI CTCAE grading, 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 4.0.  For each parameter, 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 final observations of Grade 0, Grade 1, 
Grade 2, Grade 3, or Grade 4.  Additionally, for each parameter, the number and 
percentage of subjects that have a baseline observation that is categorized as a Grade 0 to 
Grade 2 and have a Grade 3 or 4 final observations will be presented.  In addition to the 
final observation, a similar summary will be produced for the maximum post-baseline 
NCI CTCAE grade.


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7.7.2
Laboratory Abnormalities
Abnormal laboratory values will be summarized by following the search criteria in 
Table 5.
Table 5.
Laboratory Abnormalities
Laboratory Abnormalities
Search Criteria
Tumor Lysis Syndrome (Howard 
Criteria) (Howard SC et al.  2011)
≥ 2 of the following metabolic abnormalities within 24 hours of 
each other (applicable to post-dose laboratory values only):  Uric 
Acid > 476 μmol/L or 8.0 mg/dL; Potassium > 6.0 mmol/L; 
Inorganic Phosphorus > 1.5 mmol/L or 4.5 mg/dl; corrected 
Calcium < 1.75 mmol/L or 7.0 mg/dl
Potential Drug-Induced Liver Injury
Post-dose laboratory ALT or AST > 3 × ULN in combination 
with total bilirubin > 2 × ULN that occur within 72 hours of each 
other
ALT = alanine aminotransferase; AST = aspartate aminotransferase; L = litre; μmol = micromole; 
mg/dL = milligram/deciliter; mmol = millimole; mEq = milliequivalent; ULN = upper limit of normal
7.7.3
Subgroup Assessment of Shifts from Baseline in Clinical 
Laboratory
Shifts from baseline Grade 0 – 2 to post baseline Grade 3 – 4 for the maximum grade in 
clinical laboratory variables will be assessed for the subgroups defined below:
●
Gender (Male, Female)
●
Age (< 75 years, ≥ 75 years)
●
Race (White, Non-White)
●
Region (US, Non-US)
Study M14-358:
1.
overall of venetoclax + azacitidine (N = 127);
2.
venetoclax 400 mg QD + azacitidine (N = 84);
3.
overall of venetoclax + decitabine (N = 73).


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Study M14-387:
1.
All subjects venetoclax 600 mg QD + LDAC or venetoclax 800 mg QD + LDAC 
(N = 92)
2.
venetoclax 600 mg QD + LDAC (N = 82)
3.
venetoclax 600 mg QD + LDAC and without MPN (N = 78).
7.8
Vital Signs Parameter
The vital sign variables that will be assessed are systolic blood pressure, diastolic blood 
pressure, pulse and temperature.  All vital sign summaries will be summarized for analysis 
sets 2 – 3 specified in Table 3.  The vital signs variables summary for Study M14-212 is 
in study CSR.
7.8.1
Assessment of Potentially Clinically Significant Vital Signs 
Parameters
For selected vital signs parameters, a listing of all observations collected will be generated 
for subjects that had at least one post-baseline observation meeting pre-defined criteria for 
potentially clinically significant values.  The number and percentage of subjects in each 
treatment group who have at least one post-baseline observation meeting the pre-defined 
criteria for potentially clinically significant values will be provided for each variable.
Pre-defined criteria for potentially clinically significant vital signs parameters are given in 
Table 6 below:


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Table 6.
Criteria for Potentially Clinically Significant Vital Signs 
Parameters
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant
Systolic blood pressure
High
Value ≥ 160 mmHg
Diastolic blood pressure
High
Value ≥ 100 mmHg
Heart Rate
Low
Value ≤ 50 bpm
High
Value ≥ 120 bpm
Temperature
Low
Value ≤ 36°C
High
Value ≥ 38.5°C