Conditions: Acute Myeloid Leukemia (AML) Cancer
Keywords: Acute Myeloid Leukemia (AML) Cancer Treatment-naïve Venetoclax Azacitidine Decitabine Outpatient setting
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
A study evaluating the effectiveness and safety of venetoclax, in combination with azacitidine or decitabine, in an outpatient setting for treatment-naïve participants with AML who are ineligible for intensive chemotherapy.

Detailed description:

Arms:
arm 1: Participants received venetoclax orally daily for 28-day cycles, for a maximum of 6 cycles, beginning on Cycle 1 Day 1. The venetoclax dosing ramp-up schedule was 100 mg on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, and 400 mg on Cycle 1 Days 3 -28 and 400 mg daily for each 28-day cycle thereafter. Azacitidine (75 mg/m\^2) was administered subcutaneously or intravenously per investigator's choice and institutional practice for 7 days beginning on Day 1 of each 28-day cycle. arm 2: Participants received venetoclax orally daily for 28-day cycles, for a maximum of 6 cycles, beginning on Cycle 1 Day 1. The venetoclax dosing ramp-up schedule was 100 mg on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, and 400 mg on Cycle 1 Days 3 -28 and 400 mg daily for each 28-day cycle thereafter. Decitabine (20 mg/m\^2) was administered intravenously per investigator's choice and institutional practice for 5 days beginning on Day 1 of each cycle.

Interventions: intervention 1: Venetoclax intervention 2: Azacitidine intervention 3: Decitabine
Intervention descriptions: intervention 1: Venetoclax tablets were to be taken orally once daily with a meal and water in the morning at approximately the same time each day. Tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing. On the days that the participant received either azacitidine or decitabine, venetoclax was dosed in clinic and administered prior to these agents. intervention 2: The azacitidine infusion was prepared and administered per the package insert and given either subcutaneously or intravenously, per institutional practice. intervention 3: The decitabine infusion was prepared and administered per the package insert and given intravenously, per institutional practice.

Protocol document:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
11
3
OBJECTIVES AND ENDPOINTS
12
3.1
OBJECTIVES
12
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
SAFETY ENDPOINTS
13
3.5
EXPLORATORY RESEARCH AND VALIDATION ENDPOINTS
13
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
15
5
STUDY ACTIVITIES
16
5.1
ELIGIBILITY CRITERIA
16
5.2
CONTRACEPTION RECOMMENDATIONS
19
5.3
PROHIBITED MEDICATIONS AND THERAPY
21
5.4
PRIOR AND CONCOMITANT THERAPY
21
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
22
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
24
5.7
STUDY DRUG
24
5.8
RANDOMIZATION/DRUG ASSIGNMENT
25
5.9
PROTOCOL DEVIATIONS
25
6
SAFETY CONSIDERATIONS
26
6.1
COMPLAINTS AND ADVERSE EVENTS
26
6.2
TOXICITY MANAGEMENT
30
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
33
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7.1
STATISTICAL AND ANALYTICAL PLANS
33
7.2
DEFINITION FOR ANALYSIS POPULATIONS
33
7.3
STATISTICAL ANALYSES FOR EFFECTIVENESS
33
7.4
STATISTICAL ANALYSES FOR SAFETY
34
8
ETHICS
34
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
34
8.2
ETHICAL CONDUCT OF THE STUDY
34
8.3
SUBJECT CONFIDENTIALITY
35
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
35
10
DATA QUALITY ASSURANCE
35
11
COMPLETION OF THE STUDY
35
12
REFERENCES
36
LIST OF TABLES
TABLE 1.
DOSE MODIFICATION FOR VENETOCLAX WHEN CO-ADMINISTERED WITH P-GP INHIBITORS OR 
MODERATE OR STRONG CYP3A INHIBITORS
22
TABLE 2.
STUDY DRUG INFORMATION
25
TABLE 3.
AZACITIDINE DOSE MODIFICATION
32
LIST OF FIGURES
FIGURE 1.
CYCLE 1 DOSING RAMP-UP SCHEMATIC
14
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
38
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
40
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
41
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APPENDIX D.
SAMPLE LIST OF EXCLUDED AND CAUTIONARY MEDICATIONS, WITH ADDITIONAL GUIDANCE 
NOTED
42
APPENDIX E.
DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS SYNDROME
43
APPENDIX F.
RECOMMENDATIONS FOR INITIAL MANAGEMENT OF ELECTROLYTE ABNORMALITIES AND 
PREVENTION OF TUMOR LYSIS SYNDROME
44
APPENDIX G.
RECOMMENDED DOSE REDUCTIONS RELATED TO DRUG TOXICITIES IN AML
47
APPENDIX H.
ACTIVITY SCHEDULE
48
APPENDIX I.
PROTOCOL SUMMARY OF CHANGES
51
APPENDIX J.
OPERATIONS MANUAL
52
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy defined by the World Health 
Organization (WHO) as a myeloid neoplasm with 20% or more blasts in the peripheral blood or bone 
marrow.1  In AML, the clonal expansion of myeloid blasts in bone marrow, peripheral blood, and 
occasionally extramedullary tissues leads to disruption of normal hematopoiesis.2,3  It is the most 
common form of acute leukemia in adults, with a projected estimate of 19,520 new cases and 
10,670 deaths in the United States (US) in 2018.4  Of all types of leukemia, AML has the lowest survival 
rate and accounts for the largest number of deaths, as patients are often elderly and ineligible to receive 
intensive therapy.3
Elderly AML is a biologically and clinically distinct disease with a diminished response to chemotherapy 
with low remission rates and short disease-free and overall survival.  Higher proportion of unfavorable 
cytogenetics, higher frequency of antecedent hematologic disorders or prior therapy for previous 
malignancies, and more frequent expression of the multidrug resistance phenotype account 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.5  While some elderly patients 
are able to receive standard induction or intensive chemotherapy, the majority are treated with less 
intensive therapies such as hypomethylating agents (HMAs, such as azacitidine or decitabine), low-dose 
cytarabine or best supportive care.  Similarly, younger patients with significant cardiac, pulmonary or 
other comorbidities may not be eligible to receive standard induction therapy.  Several studies have 
demonstrated the benefits of induction therapy over supportive care only, with respect to survival and 
quality of life, suggesting that treatment should be offered to all patients diagnosed with AML.6,7
In Europe, azacitidine and decitabine are approved as single agents for patients with treatment naïve 
AML.  However, the reported overall response rate (complete remission [CR] + complete remission with 
incomplete hematologic recovery [CRi]) in a randomized trial was 25.6% and a with median overall 
survival of 7.7 months with decitabine compared with 7.8% and 5.0 months in treatment arms 
consisting of either subcutaneous (SC) cytarabine (88.5% of patients) or supportive care (11.5% of 
patients).7  In another study of azacitidine, the reported overall response (CR + CRi) rate and median 
overall survival were 27.8% and 10.4 months with azacitidine versus 25.1% and 6.5 months, respectively, 
in the conventional care regimens arm consisting of best supportive care, low-dose cytarabine or 
intensive chemotherapy.8  Both of these trials in AML patients who were ≥ 65 years of age demonstrate 
lower response rates and survival than standard induction therapy.  These data highlight the need for 
novel approaches that offer greater improvements in survival for those patients who are not eligible for 
treatment with standard induction therapy.
B-cell lymphoma (BCL)-2 overexpression 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 AML.9,10
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AbbVie is developing a potent, selective, and orally bioavailable small molecule inhibitor of BCL-2, 
venetoclax (also referred to as ABT-199, A-1195425.0, GDC-0199, RO5537382, Venclexta®, and 
Venclyxto®), that may address some of the needs for patients with AML.  In addition, venetoclax is being 
evaluated for the treatment of patients with Non-Hodgkin's lymphoma (NHL), chronic lymphocytic 
leukemia (CLL), acute lymphoblastic leukemia, and multiple myeloma (MM).
Venetoclax binds with high affinity (inhibition rate constant [Ki] < 0.010 nM) to anti-apoptotic protein 
BCL-2 and with lower affinity to other anti-apoptotic BCL-2 family proteins, like B-cell lymphoma extra-
large (BCL-XL) and B-cell lymphoma-Walter and Eliza Hall Institute (BCL-w) (> 4,000-fold and > 2,000- to 
> 20,000-fold lower affinity than to BCL-2, respectively).  The anticipated and observed venetoclax-
associated toxicities are also mechanism based; in particular, BCL-2-mediated effects on lymphocytes.9,11  
Venetoclax, as a BCL-2-selective (BCL-XL-sparing) inhibitor, is projected to yield an improved therapeutic 
profile compared to dual BCL-2/BCL-XL inhibitors.  Because survival of platelets depends on BCL-XL,12
thrombocytopenia, a major dose-limiting toxicity (DLT) caused by inhibition of BCL-XL in the clinic,13 is 
not expected to be dose-limiting for venetoclax.
Based on the mechanism of action, as well as the nonclinical and clinical data available to date, the 
safety profile of venetoclax is well described.  The most common adverse drug reactions across all 
indications are nausea, diarrhea, hematological effects, and serious and/or opportunistic infections.  
Hematologic effects include neutropenia/febrile neutropenia, thrombocytopenia, anemia, and 
lymphopenia.  Upper respiratory tract infections are among the most common infections.  Tumor lysis 
syndrome (TLS) is an important identified risk and is predominantly seen in the CLL population with high 
tumor burden.  Based on pre-clinical data, decreased spermatogenesis has been identified as a potential 
risk for subjects treated with venetoclax.
Venetoclax has been evaluated as a single agent (Study M14-212)14 in patients with relapsed/refractory 
AML or frontline in patients with AML who were unfit to receive intensive chemotherapy and in 
combination with azacitidine or decitabine (Study M14-358)15 or low-dose cytarabine (Study M14-387)16
for treatment naïve patients ineligible for intensive chemotherapy.
In Study M14-212, a total of 32 subjects were dosed with venetoclax.14  The most common adverse 
events observed in ≥30% of the subjects were nausea (59.4%); diarrhea (56.3%); hypokalemia, vomiting 
(40.6% each); fatigue, headache (34.4% each); hypomagnesemia (37.5%); febrile neutropenia (31.3%); 
abdominal pain, cough, hypophosphatemia (28.1% each); epistaxis, hyperphosphatemia, hypocalcemia, 
malignant neoplasm progression (25.0% each); dyspnea, hypotension, peripheral edema, pyrexia, and 
pneumonia (21.9% each).  Serious adverse events were reported in 27 subjects (84.4%), the most 
common being febrile neutropenia (28.1%), malignant neoplasm progression (25.0%), and pneumonia 
(15.6%).  No cases of TLS occurred during venetoclax treatment.  Efficacy data for Study M14-212 are 
available for all 32 subjects.  The majority (30, 94%) of the subjects had relapsed/refractory AML and a 
few (2 subjects, 6%) were deemed unfit for intensive therapy.  The objective response rate (ORR) was 
19% (6 of 32 subjects), with CR in 2 subjects (6%) and CRi in 4 subjects (13%).  Anti-leukemic activity was 
observed in an additional 7 subjects (22%), with ≥50% bone marrow reduction with hematologic 
recovery in 4 of these subjects.
In Study M14-358, venetoclax was administered daily in a three day ramp-up from 100 to 200 to 400 mg 
and coadministered with either azacitidine 75 mg/m2 IV or SC on Days 1 - 7 or decitabine 20 mg/m2 IV 
on Days 1 - 5 within each 28 day cycle.15  Dose adjustments for venetoclax were implemented for 
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concomitant medications routinely used for prophylaxis with known drug-drug interactions.  Safety and 
efficacy were evaluated.  Of 115 subjects treated with the 400 mg dose of venetoclax, 84 subjects were 
treated with venetoclax and azacitidine, and 31 subjects received venetoclax and decitabine.  The 
median age for subjects treated with azacitidine or decitabine were 75 (range:  61 – 90) and 72 
(range:  65 – 86), respectively.  Key adverse events of Grade ≥3, across all subjects, were febrile 
neutropenia (44%), anemia (28%), pneumonia (25%), thrombocytopenia (22%), and neutropenia (18%).  
For subjects treated with azacitidine or decitabine, 70% and 74% of subjects achieved CR/CRi, 
respectively, and the median time to first response was 1.2 and 1.9 months, respectively.  The median 
overall survival was 14.9 months for subjects treated with azacitidine and 16.2 months for subjects 
treated with decitabine.  Subjects who received venetoclax dose reduction for cytochrome (CYP) P450 
3A inhibitors had similar responses compared to those without dose reduction.
Study M14-387 evaluated the safety and efficacy of venetoclax in combination with low-dose cytarabine 
in patients with previously untreated AML who were ineligible for intensive chemotherapy due to 
comorbidities or age.16  Venetoclax was initiated at 50 or 100 mg daily and dose escalated over 4 -
5 days to reach 600 mg.  In subsequent 28-day cycles, venetoclax was administered at 600 mg on all 
days.  Low-dose cytarabine (20 mg/m2 daily) was administered SC on Days 1 – 10 of each cycle.  At the 
beginning of the study, concomitant strong and moderate cytochrome P450 3A isoform subfamily 
(CYP3A) inhibitor use was prohibited; however, as additional safety and pharmacokinetic data became 
available, their use was allowed with appropriate venetoclax dose adjustments.  The most common 
adverse events of Grade ≥3 across all subjects were febrile neutropenia (43%), thrombocytopenia 
(38%), neutropenia (27%), and anemia (27%).  Laboratory evidence of Grade 3 TLS was observed in 
2 subjects; both subjects achieved the target dose of venetoclax.  Forty seven percent of subjects 
received moderate (40%) or strong (7%) CYP3A inhibitors for at least 7 days (predominantly azole 
antifungals); no relevant differences in serious adverse event rates were observed.  Median time to first 
response was 1.4 months, and 54% and 46% of subjects achieved CR/CRi and CR/complete remission 
with partial hematologic recovery (CRh), respectively.  The rates of CR/CRi for subjects with secondary 
and de novo AML were 35% and 71%, respectively; median duration of response for those with 
secondary and de novo AML was 8.1 and 11.6 months, respectively.
Supported by these results, 2 randomized trials (Studies M15-656 and M16-043) have been initiated 
evaluating venetoclax in combination with the common frontline treatments of azacitidine or low-dose 
cytarabine in subjects with treatment-naïve AML who are ineligible for intensive chemotherapy.
With the general improvement seen in AML treatment over the last decades, an interest to move AML 
treatment towards outpatient care has emerged.  Potential benefits with outpatient care that have been 
cited include reduction of healthcare costs, improvement in quality of life, and decreased risk of 
hospital-acquired infections.17  Given the severity of the disease, there are potential safety issues related 
to outpatient management that need to be addressed:  one of these issues is the introduction of new 
treatment options and how they can be safely and effectively administered in an outpatient setting.
In Studies M14-358 and M14-387, hospitalization was a requirement during treatment initiation and 
drug ramp-up.  There is a need to confirm the safety and effectiveness of the administration and ramp-
up of venetoclax in patients treated in an outpatient setting.
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The clinical trial described in this Protocol is designed to ascertain whether venetoclax, in combination 
with azacitidine or decitabine, can be safely initiated in an outpatient setting and to assess clinical 
effectiveness in a community setting.
The clinical hypothesis for this study is that venetoclax, in combination with azacitidine or decitabine, 
can safely be given in an outpatient setting during the ramp-up phase for AML patients who are 
ineligible to receive intensive chemotherapy as demonstrated by a composite complete remission rate 
(CR + CRi) of approximately 60% in a community setting and consistent with Phase 1/2 results conducted 
in a controlled scenario.
2.2 Benefits and Risks to Subjects
As described above, data from previous clinical trials with venetoclax demonstrate favorable safety 
profiles and promising clinical activity in subjects with untreated AML, including subjects who are unfit 
to receive intensive chemotherapy.
Benefits for subjects participating in this study include receiving outpatient care which could have 
quality of life implications, as well as making the treatment accessible to larger numbers of patients.  
Furthermore, treatment in an outpatient setting would reduce the risk of infections acquired due to 
hospitalization.
Rapid tumor lysis of AML may occur upon initiation of venetoclax dosing in combination with azacitidine 
or decitabine.  To mitigate the risk of TLS in AML patients the regimen is designed to escalate the dose 
of venetoclax rapidly and safely with standard doses and schedules of azacitidine or decitabine to 
optimize the opportunity for achieving a response and enable close subject monitoring.  The dosing 
regimen will also enable interruptions and extensions at dose levels if rapid tumor lysis is observed.
For further details, please see findings from completed and ongoing studies, including safety data in the 
current Venetoclax Investigator's Brochure.18
Considering the coronavirus disease - 2019 (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study has been re-evaluated.  Subjects receiving venetoclax, azacitidine, or 
decitabine 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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3 OBJECTIVES AND ENDPOINTS
3.1 Objectives
This study will evaluate the safety and effectiveness of venetoclax in combination with azacitidine or 
decitabine for those AML subjects appropriately treated in the outpatient setting and ineligible to 
receive intensive chemotherapy.
Primary
The primary objective of this study is:

To determine composite complete remission rate (CR + CRi), during the initial 6 cycles of 
treatment, as determined by the modified International Working Group (IWG) criteria, of 
venetoclax in combination with azacitidine or decitabine given in an outpatient setting to 
treatment-naïve subjects with AML who are ineligible for intensive chemotherapy
Secondary
The secondary objectives of this study are:

To determine the incidence and severity of adverse events including, but not limited to, rates of 
TLS and neutropenia

To assess the rate of red blood cell (RBC) and platelet independence upon treatment with 
venetoclax and azacitidine or decitabine
3.2 Primary Endpoint
The primary endpoint is the Composite Complete Remission Rate (CR + CRi):  complete remission (CR) 
plus complete remission with incomplete hematologic recovery (CRi) as described by the modified IWG 
criteria.
3.3 Secondary Endpoints
The secondary endpoints are:

Overall Response Rates (CR, CRi):  complete remission (CR) or complete remission with 
incomplete hematologic recovery (CRi) as described by the modified IWG criteria.

Transfusion Independence:  evaluate the rate of RBC and platelet transfusion dependence 
(defined as having received ≥2 units of RBCs and/or platelets within 56 days prior to study) at 
baseline and assess transfusion independence, defined as at least 56 consecutive days without a 
RBC or platelet transfusion during the treatment period.
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3.4 Safety Endpoints
Safety evaluations include adverse event monitoring, physical examinations, vital sign measurements, 
clinical laboratory testing (chemistry, hematology, and coagulation), and rate of hospitalizations 
observed as measures of safety and tolerability for the entire study duration.
3.5 Exploratory Research and Validation Endpoints
The exploratory endpoints are to:

Evaluate the time to blood count improvements and duration of blood count improvements for 
subjects who experience cytopenias and anemia.

Evaluate effectiveness (CR/CRi) in molecular subtypes identified per institutional practices.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3b, open label, single-arm, multicenter study evaluating the composite complete 
remission rate and safety of venetoclax in combination with azacitidine or decitabine in an outpatient 
setting for treatment-naïve subjects with AML who are ineligible for intensive chemotherapy.
The study will enroll approximately 60 subjects with a venetoclax dose ramp-up over 3 days and 
adjusted as appropriate with concomitant use of CYP3A inhibitors.  Ramp-up activities for subjects, in 
this study, will be performed in an outpatient, community setting.  The choice of azacitidine or 
decitabine for each subject will be determined by the investigator, and the subject is to remain on their 
assigned therapy for the duration of the study.
The schematic for the venetoclax dosing ramp-up is shown in Figure 1.  Further details regarding study 
procedures are located in the Operations Manual.
See Section 5 for information regarding eligibility criteria.
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Figure 1.
Cycle 1 Dosing Ramp-Up Schematic
IV = intravenous; SC = subcutaneous
Screening
Screening procedures must be performed within 21 days prior to first dose of study drug administration.  
Longer intervals require discussion with the Medical Monitor.  Once screening procedures are complete 
and eligibility is confirmed, subjects will be enrolled.
Study Treatment
All subjects will receive venetoclax (daily for 28 days), in combination with azacitidine or decitabine, 
beginning on Cycle 1 Day 1.  Depending on investigator's choice, subjects will receive either azacitidine 
for 7 days beginning on Day 1 of each 28-day cycle or decitabine for 5 days beginning on Day 1 of each 
28-day cycle, as per institutional practice.  The subject is to remain on their assigned therapy for the 
duration of the study.  All subjects will receive a maximum of 6 cycles of venetoclax during the study 
period.  After the study period ends, subjects may continue receiving AML-directed therapy including 
commercially-acquired standard-of-care treatments for venetoclax and azacitidine or decitabine.
Cycle Length – (28 Days)

Venetoclax orally daily:  100 mg on Cycle 1 Day 1, 200 mg on Cycle 1 Day 2, and 400 mg on 
Cycle 1 Days 3 – 28; 400 mg daily for each 28-day cycle thereafter.

Azacitidine 75 mg/m2 subcutaneous (SC) or intravenous (IV) for 7 days beginning on Day 1 of 
each cycle, as per institutional practice.

Decitabine 20 mg/m2 intravenous (IV) for 5 days beginning on Day 1 of each cycle, as per 
institutional practice.
Subjects with progressive disease for whom the treating physician feels are still deriving clinical benefit 
can be continued on treatment after discussion with the medical monitor or until no longer achieving 
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clinical benefit per investigator assessment, unacceptable toxicity, withdrawal of consent, or the subject 
meets other protocol criteria for discontinuation (whichever occurs first).  All subjects will have a Final 
Visit performed when treatment is discontinued or when the end of the 6th cycle has been achieved 
unless the subject has withdrawn consent to participate in the study.  Baseline laboratory assessments 
will be obtained at Cycle 1 Day 1 prior to first dose of study drug administration.  Disease assessments 
by modified IWG criteria (Operations Manual, Section 3.16) will be performed at the timepoints 
described in Section 3.14 of the Operations Manual.
4.2 Discussion of Study Design
Choice of Control Group
Not applicable.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All effectiveness 
measurements in this study are standard for assessing disease activity in subjects with AML.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
Subjects who have histological confirmation of AML, who are treatment naïve, greater than or equal to 
12 years of age, and who are not eligible to receive intensive chemotherapy due to co-morbidity or 
other factors will be selected to participate in this study.
Preliminary studies have demonstrated that venetoclax in combination with azacitidine or decitabine 
can induce responses for patients with AML and be dosed safely.  Additionally, these clinical studies 
indicate that the combination may be more efficacious than either agent alone (Study M14-358).  
Therefore, given the prognosis, current limited effective options, safety of venetoclax and HMAs to date, 
and the preclinical signals of efficacy, the subject population is suitable.
Selection of Doses in the Study
The currently approved venetoclax dose is 400 mg in combination with either azacitidine or decitabine 
and 600 mg in combination with low-dose cytarabine.  This study will adhere to the US label in terms of 
dosing and, thus, the target venetoclax dose is 400 mg in combination with either azacitidine or 
decitabine.  The regimen is designed to ramp up the dose of venetoclax rapidly with azacitidine or 
decitabine thereby optimizing the opportunity for achieving a response and enabling close subject 
monitoring.  The dosing regimen will also enable interruptions and extensions at dose levels if rapid 
tumor lysis is observed.  To date, this strategy has been effective at minimizing the risk of clinical TLS 
with a rate across the AML program at < 1%.
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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects or their legally authorized representative must voluntarily sign and date an informed 
consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), 
prior to the initiation of any screening or study-specific procedures.
Demographic and Laboratory Assessments
2. Subjects must be at least 12 years old.
3. Subjects must have a projected life expectancy of at least 12 weeks.
4. Laboratory values meeting the following criteria within the screening period prior to the 
first dose of study drug:

Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN)*

Serum aspartate aminotransferase (AST) ≤3 × ULN*

Bilirubin ≤1.5 × ULN*
* Unless considered to be due to leukemic organ involvement or if a patient has confirmed 
Gilbert's disease.

Creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured 
by 24-hour urine collection
eCCr =  (140 – Age) × (Weight in kg) × [0.85 if Female]
72 × Serum Creatinine (mg/dL)
Or, if serum creatinine is in µmol/L:
eCCr =  (140 – Age) × (Weight in kg) × [1.23 if Male, 1.04 if Female]
Serum Creatinine (µmol/L)

White blood cell (WBC) count < 25 × 109/L (hydroxyurea is permitted to meet this criterion)
5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance status of 
0 to 3.
6. Are willing or able to comply with procedures required in this Protocol.
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Disease Activity
7. Subject must have confirmation of AML by WHO criteria and, as determined by the 
investigator, must be ineligible for treatment with a standard cytarabine and anthracycline 
induction regimen and deemed by the investigator as an appropriate candidate for outpatient 
ramp-up of venetoclax.
8. Subject meets the following disease activity criteria:

Subject must not have received any prior treatment for AML with the exception of 
hydroxyurea.

Subject has no evidence of spontaneous TLS at Screening.

Subject can have progressed from myelodysplastic syndrome (MDS) or be considered to 
have secondary AML and could have been treated with growth factors or other agents with 
the exception of HMAs.
Subject History
9. Subject has no history of the following conditions:

Acute promyelocytic leukemia.

Known active central nervous system (CNS) involvement with AML.

Positive for HIV (HIV testing is not required).

Positive for hepatitis B or C infection, with the exception of those with an undetectable viral 
load within 3 months (Hepatitis B or C testing is not required).  Subjects with serologic 
evidence of prior vaccination to hepatitis B virus [i.e., HBs Ag–, and anti-HBs+] may 
participate.

Cardiovascular disability status of New York Heart Association Class > 2.  Class 2 is defined as 
cardiac disease in which patients are comfortable at rest but ordinary physical activity 
results in fatigue, palpitations, dyspnea, or anginal pain.

Chronic respiratory disease that requires continuous oxygen, or 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.

Malabsorption syndrome or other condition that precludes enteral route of administration.
10. No history of other malignancies within 2 years prior to study entry, with the exception of:

Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast.

Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.

Previous malignancy confined and surgically resected (or treated with other modalities) with 
curative intent.
11. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months.
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12. No conditions that could interfere with drug absorption including but not limited to short 
bowel syndrome.
13. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug.
14. No history of an allergic reaction or significant sensitivity to constituents of the study drug
(and its excipients) and/or other products in the same class.
15. No clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG 
with QT interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) > 450 msec 
(males) or > 470 msec (females) at Screening.
Contraception
16. Female subjects must be either postmenopausal defined per one of the following criteria:

Age > 55 years with no menses for 12 or more months without an alternative medical cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND a follicle-stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).
OR,
17. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Cycle 1 Day 1 through at least 90 days after the last dose 
of study drug.
18. For all female subjects of childbearing potential, negative results should be obtained for 
pregnancy tests performed:

At Screening, with a serum sample obtained within 14 days prior to the first dose of study 
drug administration, and

Prior to dosing obtained on Cycle 1 Day 1, with urine sample if it has been > 7 days since 
obtaining serum pregnancy test results.
19. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study, from Screening through at least 90 days after the last dose of study drug.
20. Male who is not considering fathering a child or donating sperm during the study from 
Cycle 1 Day 1 through at least 90 days after the last dose of study drug.  For subjects receiving 
azacitidine, this period is 6 months following the last dose of azacitidine.
21. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Cycle 1 Day 1 through at least 90 days after the last dose of study drug, to 
practice the protocol-specified contraception.  For subjects receiving azacitidine, this period is 
6 months following the last dose of azacitidine.
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Concomitant Medications
22. Subject has not received treatment with the following:

CAR-T cell therapy

Prior therapy or experimental therapies for AML
23. Subject has not consumed grapefruit, grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit within 3 days prior to the initiation of study 
treatment.
24. Subject must not have received any investigational drug within the 30 days prior to the first 
dose of study drug or must not be currently enrolled in another clinical study.
25. Subject must not have systemically used known strong or moderate CYP3A inducers within 
7 days prior to the initiation of study treatment.
26. Subject must not have received any live vaccine within 4 weeks prior to the first dose of 
study drug, or expected need of live vaccination during study participation including at least 
4 weeks after the last dose of study drug.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND an FSH level > 40 IU/L

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy)

Females who have not experienced menarche (at least one menstrual period)

Females, of Childbearing Potential

Females of childbearing potential must give consent to abide by contraception requirements

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 90 days after the last dose of study drug

Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at 
least 30 days prior to Cycle 1 Day 1
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
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to Cycle 1 Day 1

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure)

Intrauterine device (IUD)

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with 
spermicide AND a condom)

Intrauterine hormone-releasing system (IUS)

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject)

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when 
this is in line with the usual and preferred lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable)
Contraception Requirements for Males
Male subjects who are sexually active with a female partner of childbearing potential, must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Cycle 1 Day 1 through 
at least 90 days after the last dose of study drug.  For subjects receiving azacitidine, this period is 
6 months following the last dose of azacitidine.

His female partner(s) must also use at least 1 of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days 
prior to Cycle 1 Day 1

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to Cycle 1 Day 1

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure)

Intrauterine device (IUD)

Contraceptive sponge, diaphragm or cervical cap with spermicide

Intrauterine hormone-releasing system (IUS)
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5.3 Prohibited Medications and Therapy
In addition to the medications and therapy listed in the eligibility criteria (Section 5.1, concomitant 
medications), the following is not allowed during the study (refer to the Operations Manual,
Appendix J):

Grapefruit, grapefruit products, Seville oranges, or star fruits are not allowed during the study

Strong or moderate CYP3A inducers are prohibited 7 days prior to the first dose of study drug

Strong CYP3A inducers are prohibited through the end of the study
Subjects must be consented for the study before discontinuing any prohibited medications for the 
purpose of meeting study eligibility.
A sample list of excluded and cautionary medications, with additional guidance noted, is provided in 
Appendix D.
5.4 Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medications, vitamins, and/or herbal 
supplements, or if administration of any medication becomes necessary, beginning with the screening 
visit through the end of the study, the name of the medication, dosage information including dose, 
route and frequency, date(s) of administration including start and end dates, and reason for use must be 
recorded.  Although cautionary, use of strong or moderate CYP3A inhibitors or moderate inducers, or 
P-gp substrates or inhibitors are allowed if no appropriate therapeutic alternative exists (refer to the 
Operations Manual, Section 3.3).  Concomitant use of a moderate CYP3A inducer should be avoided.  
Alternative treatments with less CYP3A induction or inhibition should be considered.  Concomitant use 
of a P-gp substrate should be avoided.  Alternative treatments should be considered.  If use of P-gp 
substrate is unavoidable, P-gp substrate should be separately dosed at least 6 hours before venetoclax.  
Herbal supplements known to inhibit or induce CYP3A or P-glycoprotein (P-gp) should be excluded and 
use of other supplements should be discouraged.  Transfusion of blood and blood products, antibiotics, 
anti-fungals, anti-emetics, granulocyte-colony stimulating factor (G-CSF), and other standard supportive 
care medications are permitted as needed, per institutional practices.  Anti-uric acid agents (such as 
hydroxyurea or allopurinol) or leukapheresis are also permitted per institutional guidelines and to 
decrease WBC counts to < 25 × 109/L at the time of study entry or during the study, as needed.  
Filgrastrim may be administered, per clinical practice.
Venetoclax dose modifications for co-administration with strong or moderate CYP3A inhibitors and P-gp 
inhibitors during Cycle 1 and after ramp-up are noted below and in Table 1.  Two to three days post the 
removal of the strong or moderate CYP3A inhibitor or P-gp inhibitor, venetoclax treatment will be given 
at the target dose of 400 mg without the need to ramp-up.

For subjects who are on a strong CYP3A inhibitor, at the time of initiation, the dose of 
venetoclax will be reduced (Table 1) for the duration of treatment with the strong CYP3A 
inhibitor.
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
For subjects who are on posaconazole, at the time of initiation, the dose of venetoclax will be 
reduced (Table 1) for the duration of treatment with posaconazole.

For subjects who are on a moderate CYP3A inhibitor (such as ciprofloxacin, fluconazole or 
isavuconazole) or a P-gp inhibitor (such as amiodarone or captopril), the venetoclax dose will be 
reduced by 50% (Table 1) for the duration of treatment with the moderate CYP3A inhibitor or 
P-gp inhibitor.
Table 1.
Dose Modification for Venetoclax When Co-administered with P-gp Inhibitors 
or Moderate or Strong CYP3A Inhibitors
Venetoclax Dose (mg)a
Venetoclax Dose if 
Co-Administered with 
1 or more Strong 
CYP3A Inhibitor
Venetoclax Dose if 
Co-Administered 
with posaconazole
Venetoclax Dose if 
Co-Administered with 1 or 
more Moderate CYP3A 
Inhibitor or P-gp Inhibitor
100 mg (Cycle 1 Day 1 only)
10 mg
10 mg
50 mg
200 mg (Cycle 1 Day 2 only)
20 mg
20 mg
100 mg
400 mg (Cycle 1 Day 3)
50 mg
50 mg
200 mg
400 mg (Cycle 1 Day 4 and daily 
thereafter)
100 mg
70 mg
200 mg
400 mg (Target Dose after Ramp-
up)
100 mg
70 mg
200 mg
CYP3A = Cytochrome P450 3A; P-gp = P glycoprotein
a.
If a subject requires co-administration of venetoclax with both a strong and a moderate CYP3A inhibitor or a P-gp inhibitor, 
venetoclax dose modification recommended for strong CYP3A inhibitors should be followed.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact.  Information regarding potential drug interactions with venetoclax (ABT-199) can be located in 
the Venetoclax Investigator's Brochure.18  A sample list of excluded and cautionary medications is 
provided in Appendix D.
If a CYP3A inhibitor or P-gp inhibitor is discontinued, resume the venetoclax target dose 2 to 3 days after 
discontinuation of the inhibitor.
Subjects must be able to safely discontinue any prohibited medications 4 weeks prior to first dose of 
study drug administration.  Subjects must be consented for the study prior to discontinuing any 
prohibited medications for the purpose of meeting study eligibility.
5.5 Withdrawal of Subjects and Discontinuation of Study
Subjects will continue their treatment assignment until documented disease progression, unacceptable 
toxicity, withdrawal of consent, or the subject meets other protocol criteria for discontinuation 
(whichever occurs first).  All subjects will have a Final Visit performed when treatment is discontinued 
unless the subject has withdrawn consent to participate in the study.  A 30-day safety follow-up visit will 
also be conducted after the last dose of study drug.  After the study period ends, subjects may continue 
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receiving AML-directed therapy including commercially acquired standard-of-care treatments for 
venetoclax and azacitidine or decitabine.
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:

Clinically significant abnormal laboratory results or adverse events, which rule out continuation 
of the study drug, as determined by the investigator or the AbbVie Therapeutic Area Medical 
Director.

The investigator believes discontinuation is in the best interest of the subject.

The subject requests withdrawal from the study.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The occurrence of an adverse event that precludes further azacitidine or decitabine drug 
administration.

The subject experiences toxicities related to study drug requiring more than a 4-week (1 cycle) 
dose interruption of venetoclax, azacitidine, or decitabine, in the absence of clinical benefit.

The subject requires radiotherapy or alternate anti-neoplastic agents for a new primary cancer 
diagnosis or AML during the study period (with the exception of hydroxyurea for AML during 
Cycle 1 only)

The subject becomes pregnant while on study drug.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix J.
The investigator should contact the 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.
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Refer to the Operations Manual in Appendix J for details on how to handle study activities/procedures.
5.6 Follow-Up for Subject Withdrawal from Study
To minimize missing data for effectiveness and safety assessments, subjects who prematurely 
discontinue study drug treatment should continue to be followed for all regularly scheduled visits, 
unless subjects have decided to discontinue the study participation entirely (withdrawal of informed 
consent).  Subjects should be advised on the continued scientific importance of their data even if they 
discontinue treatment with study drug early.
If a subject prematurely discontinues study participation, the procedures outlined for the Final Visit 
should be completed as soon as possible, preferably within 2 weeks.  In addition, if a subject is willing, a 
30-day follow-up visit after the last dose of study drug should be completed to capture all treatment-
emergent adverse events/serious adverse events have been resolved to ≤ Grade 1, baseline level, or 
initiation of a new treatment, whichever is earlier, or, in the opinion of the investigator, the event is 
unlikely to resolve.
5.7 Study Drug
Venetoclax, manufactured by AbbVie, will be taken orally daily beginning on Cycle 1 Day 1, through 
Cycle 6 Day 28, and should be taken at approximately the same time every day for each 28-day cycle.  
Each dose of venetoclax should be administered with approximately 240 mL of water and within 
30 minutes after the completion of breakfast or the subject's first meal of the day.  On the days the 
subject is given either azacitidine or decitabine, venetoclax must be dosed in clinic and administered 
prior to these agents.
All subjects will receive a maximum of 6 cycles of venetoclax during the study period.  After the study 
period ends, the subject may continue receiving AML-directed therapy including commercially-acquired 
standard-of-care treatments for venetoclax and azacitidine or decitabine.
Depending on investigator's choice, subjects will receive azacitidine or decitabine on Cycle 1 Day 1.  The 
subject is to remain on their assigned therapy for the duration of this study.  Azacitidine (75 mg/m2) 
infusions or injections and decitabine (20 mg/m2) infusions should be prepared and administered per 
the respective package inserts.  Azacitidine will be administered SC or IV beginning on Day 1 for 7 days 
of each 28-day cycle, as per institutional practice.  Decitabine will be administered IV beginning on Day 1 
for 5 days of each 28-day cycle, as per institutional practice.
Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.  
If a subject should forget to take his/her venetoclax dose at his/her regularly scheduled dosing time, the 
subject should take the forgotten dose as soon as he/she remembers, provided that the dose will be 
taken within 8 hours of the missed dose.  Otherwise, the subject should take the next dose at the next 
scheduled dosing time.  If the subject vomits following dosing, no additional dose should be taken that 
day.  The next prescribed dose should be taken at the usual time.
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Subject dosing will be recorded on a subject dosing diary (as described in the Operations Manual, 
Section 3.13).  The subject will be instructed to return all study drug containers (even if empty) to the 
study site personnel at each study visit.  The study site personnel will document compliance.
AbbVie will provide venetoclax.  AbbVie provided study drug should not be substituted or alternately 
sourced unless otherwise directed by AbbVie.  The site will be responsible for obtaining azacitidine or 
decitabine.
Venetoclax will be packaged in blisters or bottles with quantities sufficient to accommodate study 
design.  Each kit will be labeled per local requirements and this label must remain affixed to the kit.  
Upon receipt, study drug should be stored as specified on the label and kept in a secure location.  Each 
kit will contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  Site staff will complete all blank spaces on the label before dispensing to subjects.  Study 
drug will only be used for the conduct of this study.
Study drug information is presented in Table 2.
Table 2.
Study Drug Information
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
Venetoclax (ABT-199)
AbbVie
Oral
Film-coated tablet
10, 50, and 100 mg
5.8 Randomization/Drug Assignment
This is an open-label study.  There is no randomization for this study.
All subjects will be assigned a unique identification number by the IRT at the screening visit (refer to the 
Operations Manual, Section 6.3).  For subjects who rescreen, the screening number assigned by the IRT 
at the initial screening visit should be used.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable), and AbbVie.
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6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An 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 
"special situations," which must be reported whether associated with an adverse event or not.
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study.  All adverse events will be followed to a satisfactory conclusion.
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/or 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.
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If an adverse event, whether associated with study drug or not, meets any of the following criteria, it is 
to be reported to AbbVie clinical pharmacovigilance or CRO (as appropriate) as a serious adverse event 
within 24 hours of the site being made aware of the serious adverse event (refer to Section 4.3 of the 
Operations Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken.  This does 
not include an event that would have been fatal if it had occurred in a 
more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length of 
time or prolongs the subject's hospital stay.  This does not include an 
emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in fetal 
loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with the 
activities of daily living of a study subject.  Disability is not intended to 
include experiences of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately life-threatening 
or result in death or hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of subject, life 
threatening, hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  Additionally, 
any elective or spontaneous abortion or stillbirth is considered an 
important medical event.
All adverse events reported from the time of study drug administration until 30 days after 
discontinuation of study drug administration will be collected, whether solicited or spontaneously 
reported by the subject.  In addition, protocol-related serious adverse events and protocol-related 
nonserious adverse events will be collected from the time the subject signs the study-specific informed 
consent.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
Worsening of disease or underlying cancer (serious or nonserious events) will be collected as an adverse 
event due to disease progression on the electronic case report form (eCRF).  For serious adverse events 
with the outcome of death, the date and cause of death will be recorded in the appropriate case report 
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form (CRF).  Deaths due to disease progression that occur within the adverse event reporting period will 
be collected as an adverse event on the eCRF.
Adverse Events of Special Interest
The following adverse events of special interest will be monitored during the study:

Cytopenias

TLS
Subjects will be monitored for blood counts through resolution of cytopenias.  Myelosuppression and 
the related adverse events (thrombocytopenia, anemia, neutropenia, and febrile neutropenia) are 
common in subjects with AML.  Subjects with baseline neutropenia or those with secondary AML might 
be particularly at high risk for associated adverse events.  Additional details are provided in Section 6.2.
If additional dose reductions are thought to be necessary by the investigator, a discussion with the 
AbbVie medical monitor is required.  Subjects experiencing delays for a medical event unrelated to study 
treatment may delay study treatment up to 4 weeks.  Delays greater than 21 days must be discussed 
with the AbbVie Primary TA MD or a designee.
Anti-infective prophylaxis should be implemented per regional guidelines or institutional standards 
including appropriate prophylaxis for bacterial, viral, and fungal infections.  Potential for drug-drug 
interactions should be considered and appropriate dose adjustments made if required.
Subjects with resistant disease, based on modified IWG criteria (as described in the Operations Manual, 
Section 3.16), after End of Cycle 1 will need a bone marrow aspirate to evaluate response after End of 
Cycle 2.  Subjects with resistant disease after end of Cycle 2, based on modified IWG criteria (as 
described in the Operations Manual, Section 3.16) will need a bone marrow aspirate to evaluate 
response after end of Cycle 4.  Subjects who have not recovered absolute neutrophil count 
(ANC) ≥500/μL within 14 days of drug interruption or require longer duration of interruption between 
treatment cycles, bone marrow aspirate may be performed, as determined by the investigator, to assess 
disease status before resuming treatment with next cycle.
Guidelines for TLS management are provided in Section 6.2.  Chemistry labs (including creatinine, 
potassium, calcium, inorganic phosphorus, lactate dehydrogenase, and uric acid) will be performed 
real-time pre-dose, 4 - 6 hours post-dose, and 24 hours post-dose for each venetoclax dose escalation, 
and also as deemed necessary per investigator to monitor TLS.
Adverse Event Severity and Relationship to Study Drug
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 5.0).  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.
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For adverse events not captured by the Common Terminology Criteria, the following should be used:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the subject's usual activities 
(moderate).
Grade 3
The adverse event causes considerable interference with the subject's usual activities and 
may be incapacitating (moderate to severe).
Grade 4
The adverse event is life-threatening and requires urgent intervention (severe).
Grade 5
The adverse event resulted in death of the subject (severe).
The investigator will use the following definitions to assess the relationship of the adverse event to the 
use of study drug:
Reasonable Possibility
After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
Pregnancy
While not an adverse event, pregnancy in a study subject must be reported to AbbVie within 24 hours 
after the site becomes aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.5).
All subjects should be informed of the contraceptive measure requirements.  If a pregnancy occurs in a 
study subject or in the partner of a study subject, information regarding the pregnancy and the outcome 
will be collected.
In the event of pregnancy occurring in a subject's partner during the study, written informed consent for 
release of medical information from the partner must be obtained prior to collection of any 
pregnancy-specific information, and the pregnancy will be followed to outcome.
AbbVie will provide a separate consent form for this purpose.  Pregnancy in a subject's partners will be 
collected from the date of the first dose through 30 days following the last dose of study drug or at least 
90 days after the last dose of the selected combination.
The pregnancy outcome, for either mother or infant, 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 after the site becomes aware of the event.
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6.2 Toxicity Management
The management of specific adverse events and laboratory parameters is described below.  This 
includes adverse events of TLS and neutropenia for venetoclax.  Subjects will be monitored for these 
events throughout the study and treatment may be discontinued or adjusted as appropriate.
Prophylaxis and Management of Tumor Lysis Syndrome
There is a potential risk for TLS in subjects with AML, especially in those with elevated leukocyte count, 
circulating blasts, elevated pretreatment LDH levels, dehydration, or renal dysfunction.
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS.  Changes in electrolytes 
consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the 
first dose of treatment (Appendix F).  Definitions of laboratory TLS and clinical TLS are provided in 
Appendix E (Howard grading classification).  If a subject experiences blood chemistry changes suggestive 
of TLS, the dose of venetoclax may be withheld and/or reductions may be required.
Tumor lysis syndrome prophylaxis must be initiated in all subjects before the first dose of study drug or 
first new escalated dose.  For subjects who had dose delay or interruptions TLS prophylactic measures 
may need to be implemented based on the disease status prior to resuming treatment.  Below are the 
minimum requirements for TLS prophylaxis and management.  Additional prophylaxis and monitoring 
procedures for TLS should be implemented as per institutional/regional standards.

An oral agent to reduce the uric acid level (e.g., allopurinol) to be initiated at least 72 hours prior 
to dosing.  Treatment may need to be continued for up to 28 days based on the ongoing risk of 
TLS development.  Subjects allergic to or otherwise unable to receive allopurinol must use 
another uric acid reducer starting at least 72 hours prior to dosing or rasburicase on the day of 
treatment (prior to venetoclax dosing).

Adequate hydration per day starting from at least 24 hours prior to first dose or any dose 
escalation.

TLS Chemistry panel (creatinine, potassium, calcium, inorganic phosphorus, lactate 
dehydrogenase, and uric acid) will be performed real-time pre-dose, 4 - 6 hours post-dose and 
24-hours post-dose for each venetoclax dose escalation, and as deemed necessary per 
investigator to monitor TLS.

TLS Chemistry panel results (creatinine, potassium, calcium, inorganic phosphorus, lactate 
dehydrogenase, and uric acid) must be reviewed by the investigator in real time and prior to the 
subject's next dose to ensure appropriate subject management.

If any clinically significant laboratory changes are observed within the first 24 hours after 
initiation of dosing or after a dose escalation, see Appendix F for management guidelines.  Refer 
to table in Appendix E for definitions of laboratory and clinical TLS.

If subjects develop TLS and the treatment is withheld, they should be admitted and managed as 
inpatient until the ramp-up is complete and TLS labs have normalized.
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Subjects with reduced renal function (CLcr < 80 mL/min, Cockcroft-Gault formula) require more 
intensive prophylaxis and monitoring to reduce the risk of TLS when initiating treatment with 
venetoclax.  For subjects with a higher risk for TLS and lower creatinine clearance, additional measures 
with more intensive lab monitoring and intervention should be implemented (Appendix F).
If a subject meets criteria for clinically significant laboratory or clinical TLS please follow institutional 
guidelines or recommendations in Appendix G; no additional venetoclax dose should be administered 
until resolution.
For continued dosing of venetoclax, monitor for evidence of TLS during study treatment, and manage 
abnormalities of serum creatinine, and electrolytes promptly.  After resolution of electrolyte imbalances 
(Appendix F), venetoclax may be continued at the original dose after discussion between the 
investigator and the AbbVie TA MD. 
Management of Cytopenias
Myelosuppression and the related adverse events (thrombocytopenia, anemia, neutropenia, and febrile 
neutropenia) are common in both treated and untreated patients with AML.  Subjects with baseline 
neutropenia or those who have significant bone marrow involvement may be particularly at high risk.
If a subject achieves CRi or has a morphologic leukemia free bone marrow (MLFS) (i.e., bone marrow 
blasts < 5%) after completion of Cycle 1, venetoclax should be interrupted to allow for ANC recovery 
from Day 29 until ANC ≥500/μL or up to 14 days.
Cycle 2 administration of azacitidine or decitabine will also be delayed until ANC ≥ 500/μL.  Both 
venetoclax and azacitidine or decitabine will resume on the same day after the interruption.  If a subject 
presents with new onset Grade 4 neutropenia for more than 1 week during subsequent cycles, unless it 
is thought to be due to the underlying disease, dosing with venetoclax and azacitidine or decitabine may 
be interrupted until ANC is ≥ 500/μL.
After Cycle 3, for subjects in CR/CRi who required interruption or delay of study drug administration for 
cytopenias (neutropenia [≤500/μL] or thrombocytopenia [≤50 × 103/μL]) venetoclax should be 
administered for 21 days out of 28 days during each of the subsequent cycles.  The treatment cycle 
should also be delayed to allow for count recovery until ANC ≥ 500/μL, platelet count ≥50 × 103/μL, or 
for up to 14 days, whichever occurs earlier.
Subjects with resistant disease, based on modified IWG criteria (as described in the Operations Manual, 
Section 3.16) after Cycle 1 should receive subsequent cycles of study treatment with no dose 
interruption/delay until a repeat bone marrow assessment demonstrates CRi or MLFS.  Transfuse blood 
products, administer prophylactics, and administer treatment anti-infectives as clinically indicated and 
as per institutional practice.  Once CRi or MLFS is achieved, dose interruptions and reduction in duration 
of venetoclax administration for neutropenia should be implemented as described above, beginning 
from the cycle where a CRi or MLFS is demonstrated.  If hematologic recovery (ANC or platelets) is 
achieved within 14 days after completion of the cycle (where the CRi or MLFS is demonstrated), the 
duration of venetoclax is reduced to 21 days of the subsequent 28-day cycle.
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Azacitidine
During subsequent cycles, if hematologic recovery with > 25% increase above the nadir is not seen by 
Day 28, reassess counts every 7 days.  If a 25% increase has not been achieved within 14 days after the 
completion of a cycle, based on the bone marrow biopsy cellularity, azacitidine dose adjustment can be 
made per Table 3, or according to institutional standards.
Table 3.
Azacitidine Dose Modification
Bone Marrow Cellularity
% Dose in the Next Cycle
if Recovery is Not Achieved Within 14 Days
Recovery ≤ 21 days
Recovery > 21 days
15 – 50%
100%
50%
< 15%
100%
33%
Decitabine
If a dose reduction for decitabine is believed to be necessary, a discussion with the AbbVie medical 
monitor is required.
Management of Non-TLS Serum Electrolytes and Renal Impairment
If unexplained reductions in serum bicarbonate levels to < 20 mEq/L occur, azacitidine dosage should be 
reduced by 50% on the next course.  Similarly, if unexplained elevations of blood urea nitrogen (BUN) or 
serum creatinine occur, the next cycle should be delayed until values return to normal or baseline and 
the dose should be reduced by 50% on the next treatment course.
Management of Decrease in Spermatogenesis
Venetoclax may cause a decrease in spermatogenesis.  Male subjects considering preservation of 
fertility should bank sperm before initiating treatment with venetoclax.
Management of Other Toxicities
If other events occur that are related to venetoclax, azacitidine, or decitabine, the investigator, in 
consultation with the AbbVie medical monitor, may interrupt or reduce the dose of venetoclax and/or 
azacitidine or decitabine, as appropriate.  Grade 3 or greater nonhematologic toxicity (e.g., nausea, 
vomiting, and diarrhea when additional supportive care fails or neurotoxicity, AST, ALT, or bilirubin 
increased), that is related to venetoclax, azacitidine, or decitabine will require interruption and possible 
discontinuation of dosing.  Venetoclax, azacitidine, or decitabine 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.
Management of Infections
Anti-infective prophylaxis should be implemented per regional guidelines or institutional standards 
including appropriate prophylaxis for bacterial, viral and fungal infections.  Potential for drug-drug 
interactions should be considered.
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All 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 Summary of 
Product Characteristics (SmPC) for monitoring guidelines.
Dose Modifications Based on Toxicities
Subjects who discontinue 1 study drug because of study drug-related toxicities may continue to receive 
the other study drug for up to a maximum of 21 days, as determined by the investigator.
Dose Modifications for Venetoclax
See Appendix G for dose modifications for toxicities related to venetoclax.  Venetoclax dose 
modifications for possible drug-drug interactions are provided in the Section 5.4.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
Effectiveness and safety analyses will be performed on all subjects who receive at least one dose of 
venetoclax and azacitidine or decitabine.  Subjects in the trial will have AML, will be treatment-naïve, 
and will be ineligible for intensive chemotherapy.
7.3 Statistical Analyses for Effectiveness
Endpoints
The primary objective for the study is to determine the composite complete remission rate (CR + CRi), 
during the initial 6 cycles of treatment, in AML subjects treated with venetoclax and either azacitidine or 
decitabine in an outpatient setting.  The composite complete remission rate will be achieved if IWG 
criteria for complete remission or complete remission with incomplete hematologic recovery (CR + CRi) 
have been met.
Secondary effectiveness endpoints include:

Overall Response (CR, CRi).

RBC and platelet transfusion independence.
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Exploratory effectiveness endpoints include:

Time to blood count improvements and duration of blood count improvements

Remissions (CR/CRi) in molecular subtypes.
Details on the primary and other effectiveness analyses are provided in the SAP.
Sample Size Estimation
The planned study will enroll approximately 60 subjects.  A sample size of 60 subjects would ensure that 
the true CR + CRi rate will be within 13% of the observed CR + CRi rate with 95% confidence.
7.4 Statistical Analyses for Safety
The safety of venetoclax in combination with azacitidine or decitabine will be assessed by evaluation of 
study drug exposure, adverse events, serious adverse events, and deaths, as well as changes in 
laboratory and vital sign parameters.
Safety and tolerability will be assessed for all treated subjects and for azacitidine or decitabine 
separately.
Details on the statistical analyses for safety will be provided in the SAP.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The Protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the Protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the Protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the Protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B.
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 
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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.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved Protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  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.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the Protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit or date of the last follow-up 
contact, whichever is later.
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12
REFERENCES
1.
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405.
2.
Showel MM, Levis M. Advances in treating acute myeloid leukemia. F1000Prime Rep. 2014;6:96.
3.
Deschler B, Lubbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer. 
2006;107(9):2099-107.
4.
American Cancer Society. Cancer Facts and Figures 2018. 2018.
5.
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.
6.
Foon KA, Zighelboim J, Yale C, et al. Intensive chemotherapy is the treatment of choice for elderly 
patients with acute myelogenous leukemia. Blood. 1981;58(3):467-70.
7.
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 leukemia. J Clin 
Oncol. 2012;30(21):2670-7.
8.
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.
9.
Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the 
BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375-88.
10. Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein 
function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann 
Hematol. 2012;91(12):1861-70.
11. Gribben JG. Salvage therapy for CLL and the role of stem cell transplantation. Hematology Am Soc 
Hematol Educ Program. 2005:292-8.
12. Nakayama K, Nakayama K, Negishi I, et al. Targeted disruption of Bcl-2 alpha beta in mice: 
occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci U S A. 
1994;91(9):3700-4.
13. Yamamura K, Kamada S, Ito S, et al. Accelerated disappearance of melanocytes in bcl-2-deficient 
mice. Cancer Res. 1996;56(15):3546-50.
14. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II 
study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 
2016;6(10):1106-17.
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15. Pollyea DA, Pratz KW, Jonas BA, et al. Venetoclax in Combination with Hypomethylating Agents 
Induces Rapid, Deep, and Durable Responses in Patients with AML Ineligible for Intensive Therapy. 
Blood. 2018;132(Supplement 1):285-.
16. Wei A, Strickland SA, Hou J-Z, et al. Venetoclax with Low-Dose Cytarabine Induces Rapid, Deep, and 
Durable Responses in Previously Untreated Older Adults with AML Ineligible for Intensive 
Chemotherapy. Blood. 2018;132(Supplement 1):284-.
17. Vaughn JE, Buckley SA, Walter RB. Outpatient care of patients with acute myeloid leukemia: 
Benefits, barriers, and future considerations. Leuk Res. 2016;45:53-8.
18. AbbVie. Venetoclax (ABT-199) Investigator's Brochure. Current Edition.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BCL
B cell lymphoma
BCL-w
B-cell lymphoma - Walter and Eliza Hall Institute
CL/F
Apparent clearance
CLL
chronic lymphocytic leukemia
COVID-19
Coronavirus Disease – 2019
CR
complete remission
CRF
Case Report Form
CRh
complete remission with partial hematologic recovery
CRi
complete remission with incomplete blood count recovery
CS
clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A
cytochrome P450 3A isoform subfamily
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FSH
follicle-stimulating hormone
GCP
Good clinical practice
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
Independent ethics committee
IMP
Investigational medicinal product
IRB
Institutional review board
IRT
Interactive response technology
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IV
intravenous
IWG
International Working Group
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MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MLFS
morphologic leukemia free bone marrow
NCI
National Cancer Institute
NCS
not clinically significant
P-gp
P-glycoprotein
PT
Preferred term
QD
once daily
RBC
red blood cell
RSI
Reference Safety Information
SAP
Statistical analysis plan
SC
subcutaneous(ly)
SOC
System organ class
SUSAR
Suspected unexpected serious adverse reaction
TLS
tumor lysis syndrome
ULN
upper limit of normal
US
United States
WBC
white blood cell
WHO
World Health Organization
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-072:  A Phase 3b, Single-Arm, Multicenter Open-Label Study of Venetoclax in Combination 
with Azacitidine or Decitabine in an Outpatient Setting in AML Patients Ineligible for Intensive 
Chemotherapy
Protocol Date:  29 October 2020
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and 
local regulations and guidelines governing the study at the site location.  In signing the Investigator 
Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting 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. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Therapeutic Area Medical Director
Medical Affairs
Group Medical Director
Clinical Development
Study Project Manager
Clinical Program Development
Associate Director
Statistics
Director
Clinical Pharmacology and Pharmacometrics
Director
Medical Writing
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APPENDIX E. DEFINITIONS OF LABORATORY AND CLINICAL 
TUMOR LYSIS SYNDROME
Metabolic Abnormality
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome
Criteria for Classification of Clinical Tumor 
Lysis Syndrome
Hyperuricemia
Uric acid > 8.0 mg/dL (475.8 μmol/L) 
in adults
Hyperphosphatemia
Phosphorus > 4.5 mg/dL (1.5 mmol/L) 
in adults
Hyperkalemia
Potassium > 6.0 mmol/L
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/L) or ionized calcium 
< 1.12 mg/dL (0.3 mmol/L)a
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 injuryb
Not applicable
Increase in the serum creatinine level of 
0.3 mg/dL (26.5 µmol/L) (or a single value 
> 1.5 × the upper limit of the age-
appropriate normal range if no baseline 
creatinine measurement is available) or the 
presence of oliguria, defined as an average 
urine output < 0.5 mL/kg/hr for 6 hrs
a.
The corrected calcium level in mg/dL = measured calcium level in mg/dL + 0.8 × (4-albumin in g/dL).
b.
Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg/dL (26.5 μmol/L) or a period of oliguia 
lasting 6 hours or more.  By definition, if acute kidney injury is present, the subject has clinical tumor lysis syndrome.
Note:
In laboratory tumor lysis syndrome, 2 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 afterward. Clinical tumor lysis syndrome requires the 
presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or 
death.
Source:  Howard SC, Jones DP, Pui CH.  The tumor lysis syndrome.  N Engl J Med.  2011;364(19):1844-54.
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APPENDIX F. RECOMMENDATIONS FOR INITIAL 
MANAGEMENT OF ELECTROLYTE 
ABNORMALITIES AND PREVENTION OF TUMOR 
LYSIS SYNDROME
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.

As determined by the investigator, may recheck prior to 
hospitalization.  If stable or decreased, and still WNL, 
hospitalization is at the decision 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 to 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.
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Abnormality
Management Recommendations
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 to 2 mEq IV push.

If sodium bicarbonate is used, rasburicase should not be 
used as this may exacerbate calcium phosphate 
precipitation.

Administer calcium gluconate 100 to 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.
Hyperuricemia
Uric acid ≥ 8.0 mg/dL (476 µmol/L)

Consider rasburicase (dose based on local guidelines and/or 
institutional standards).

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 predose 
level

Administer rasburicase (dose based on local guidelines 
and/or institutional standards).

When 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.
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Abnormality
Management Recommendations
Calcium ≤ 7.0 mg/dL (1.75 mmol/L) AND 
Subject symptomatic (e.g., muscle cramps, 
hypotension, tetany, cardiac arrhythmias)

Administer calcium gluconate 50 to 100 mg/kg IV slowly 
with ECG monitoring.

Telemetry.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT.

If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 
4 hours, later, if no other evidence of tumor lysis.

Calculate corrected calcium and check ionized calcium if 
albumin low.
Hyperphosphatemia
Phosphorus ≥ 5.0 mg/dL (1.615 mmol/L) 
with ≥ 0.5 mg/dL (0.16 mmol/L) increase

Administer a phosphate binder (e.g., aluminum hydroxide, 
calcium carbonate, sevelamer hydroxide, or lanthanum 
carbonate).

Nephrology (or other acute dialysis service) notification 
(dialysis required for phosphorus ≥ 10 mg/dL).

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1-hour STAT.

If phosphorus < 5.0 mg/dL 1 hour later, repeat 
potassium, phosphorus, uric acid, calcium and 
creatinine 2 and 4 hours, later, if no other evidence of 
tumor lysis.
Creatinine
Increase ≥ 25% from baseline

Start or increase rate of IV fluids.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 to 2 hours STAT.
ECG = electrocardiogram; IV = intravenous; ULN = upper limit of normal; WNL = within normal limit
Page 46 of 80
 


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APPENDIX G. RECOMMENDED DOSE REDUCTIONS RELATED 
TO DRUG TOXICITIES IN AML
Recommended Venetoclax Dose Modifications for Toxicities
Event
Occurrence
Action
Hematologic Toxicities
Grade 4 neutropenia with 
or without fever or 
infection; or Grade 4 
thrombocytopenia (see 
Warnings and 
Precautions in 
Management of 
Cytopenias, Section 6.2)
Occurrence prior to 
achieving remission
Transfuse blood products, administer prophylactic and 
treatment anti-infectives as clinically indicated.
In most instances, venetoclax and azacitidine or decitabine 
cycles should not be interrupted due to cytopenias prior to 
achieving remission.
First occurrence after 
achieving remission 
and lasting at least 
7 days
Delay subsequent treatment cycle of venetoclax and 
azacitidine or decitabine and monitor blood counts.
Administer granulocyte-colony stimulating factor (G-CSF) if 
clinically indicated for neutropenia.  Once the toxicity has 
resolved to Grade 1 or 2, resume venetoclax therapy at the 
same dose in combination with azacitidine or decitabine or 
low-dose cytarabine.
Subsequent 
occurrences in cycles 
after achieving 
remission and lasting 
7 days or longer
Delay subsequent treatment cycle of venetoclax and 
azacitidine or decitabine and monitor blood counts.
Administer G-CSF if clinically indicated for neutropenia.  
Once the toxicity has resolved to Grade 1 or 2, resume 
venetoclax therapy at the same dose and the duration 
reduced by 7 days for each subsequent cycle.
AML = acute myeloid leukemia; G-CSF = granulocyte-colony stimulating factor.
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APPENDIX H. ACTIVITY SCHEDULE
The following table shows the required activities across the subject encounters, as well as the period of 
continued venetoclax supply.  The individual activities are described in detail in the Operations Manual.
Allowed modifications due to COVID-19 are detailed within the Operations Manual.
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STUDY M19-072  |  Version 3.0
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APPENDIX I.
PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
28 January 2019
Version 2.0
17 June 2019
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol 
and incorporate necessary protocol modifications due to the COVID-19 pandemic as follows:

Section 2.2 - included information on the re-evaluation of the benefit and risk to subjects 
participating in the study.  There is no additional risk to subjects or state what the additional 
risks are that may change the benefit-risk balance to participating subjects.

Section 5.1 and Section 5.2 – added language that male subjects receiving azacitidine must 
practice protocol-specified contraception and must refrain from fathering children or donating 
sperm for 6 months following the last dose of azacitidine, as per updated safety risk language.

Section 5.5 - added instructions to refer to Operations Manual for necessary changes to 
activities or procedures in the event of temporary study drug interruption/halt.

Section 5.9 - clarified that protocol deviations may include modifications due to COVID-19.

Section 8.2 - noted that AbbVie will modify the study protocol as necessary due to the 
pandemic, referring to the Operations Manual in Appendix J for additional details.  Investigators 
must also notify AbbVie if any urgent safety measures are taken.

Section 9 - noted that remote monitoring may be employed as needed based on COVID-19.

Appendix H - added reference to Operations Manual for allowed modification.

Appendix J - Operations Manual updated to include details on how to perform specific 
activities/procedures that may be impacted by changes in global/local regulations due to the 
pandemic.

Appendix J - Operations Manual, Table 2, updated to capture the numerical corrections to the 
IWG disease assessment criteria of CR and CRi based on regulatory feedback.
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APPENDIX J.
OPERATIONS MANUAL
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p. 2 of 26
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical Contact
 MBBS, MS
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
EMERGENCY 24 hour Number:  
+1 (973) 784-6402
Office:
Mobile:
Fax:
Email:
Safety Concerns
Oncology Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Phone:
+1 (833) 942-2226
Email:
SafetyManagement_Oncology@abbvie.com
SAE Reporting 
outside of RAVE
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 (847) 348-2303
Protocol 
Deviations and 
Product 
Complaints
Study Project Manager
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Email:
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p. 3 of 26
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
11
3
STUDY PROCEDURES
11
3.1
STUDY SUBJECT INFORMATION AND INFORMED CONSENT
11
3.2
MEDICAL AND ONCOLOGICAL HISTORY
12
3.3
CONCOMITANT MEDICATIONS
12
3.4
ADVERSE EVENT ASSESSMENT
13
3.5
EASTERN COOPERATIVE ONCOLOGY GROUP
13
3.6
HEIGHT AND WEIGHT
13
3.7
PHYSICAL EXAMINATION
13
3.8
VITAL SIGNS
14
3.9
12-LEAD ELECTROCARDIOGRAM
14
3.10
CYTOGENETIC ASSESSMENT
15
3.11
MOLECULAR SUBTYPES TESTING
15
3.12
DISPENSE STUDY DRUG
15
3.13
SUBJECT DIARIES
15
3.14
CLINICAL LABORATORY TESTS
15
3.15
BONE MARROW ASPIRATE AND/OR BIOPSY
18
3.16
DISEASE ASSESSMENTS
19
3.17
POST TREATMENT FOLLOW-UP
20
3.18
SUBJECT WITHDRAWAL FROM STUDY
20
3.19
UNSCHEDULED VISITS
21
4
SAFETY MANUAL
21
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
21
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
22
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
22
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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5
COUNTRY-SPECIFIC REQUIREMENTS
24
5.1
SUSAR REPORTING
24
6
STUDY DRUG
24
6.1
TREATMENTS ADMINISTERED
24
6.2
PACKAGING AND LABELING
25
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
25
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
25
7
REFERENCES
26
LIST OF TABLES
TABLE 1.
CLINICAL LABORATORY TESTS
17
TABLE 2.
MODIFIED IWG CRITERIA
20
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p. 12 of 26
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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3.2 Medical and Oncological History
A complete medical history including demographics, history of tobacco, alcohol, and drug use will be 
taken at Screening.  The subject's medical history will be updated before the first dose of study drug 
(Cycle 1, Day 1).  This updated medical history will serve as the baseline for clinical assessment.  A 
detailed oncology history will also be collected including:  histology, date of diagnosis of acute myeloid 
leukemia (AML), any surgical procedures, transfusion of blood products within 8 weeks, and treatments 
administered (including dates and type of modality).
On Cycle 1 Day 1, any additional medical history observed after signing of the informed consent but 
prior to first dose of study drug administration and not considered related to study-required procedures 
will be recorded in the subject's medical history.
3.3 Concomitant Medications
All reported concomitant medications, over-the-counter or prescription medications, vitamins and/or 
herbal supplements or if administration of any medication becomes necessary beginning with the 
Screening visit through 30 days after last dose of study drug, 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).
Subjects should receive full supportive care during study participation including transfusion of blood 
products, fluid and electrolyte replacement, and antibiotics when appropriate.  Subjects who use oral 
contraceptives, hormone-replacement therapy, or other maintenance therapy should continue their 
use.
General guidelines regarding prohibited and cautionary concomitant medications and dietary 
restrictions are provided in Protocol Section 5.1, Section 5.3, and Section 5.4.  Although cautionary, use 
of strong or moderate cytochrome P450 3A isoform subfamily (CYP3A) inhibitors or moderate inducers 
are allowed if no appropriate therapeutic alternative exists (refer to the Protocol Section 5.4).  Dose 
reductions of venetoclax are required with concomitant administration of a P-gp inhibitor or strong or 
moderate CYP3A inhibitor (refer to the Protocol Section 5.4).  Concomitant administration of a 
moderate CYP3A inducer should be avoided.  Alternative treatments with less CYP3A induction or 
inhibition should be considered.  If concomitant use of P-gp substrate is unavoidable, separate dosing of 
the P-gp substrate at least 6 hours before venetoclax.
A sample list of prohibited medications and cautionary medications that may interact with study drug is 
provided in the Protocol, Appendix D.  It is not possible to produce a complete list of medications that 
fall into these categories; if in question, please refer to the appropriate product label.
For guidance regarding medications for management of tumor lysis syndrome (TLS) and neutropenia, 
refer to the Protocol Section 6.2.  The AbbVie Therapeutic Area Medical Director (TA MD) identified in 
Section 1 should be contacted if there are any questions regarding concomitant or prior therapy(ies).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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3.4 Adverse Event Assessment
Please refer to Section 4.2 and Section 4.3.
3.5 Eastern Cooperative Oncology Group
For all subjects, the Eastern Cooperative Oncology Group (ECOG) performance status will be performed 
as outlined in Section 2.1 and Section 2.2.
It is recommended, when possible, that a subject's performance status be assessed by the same person 
throughout the study.  ECOG performance status will be assessed as follows:
Grade
Description
0
Fully active, able to carry on all predisease 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.
5
Dead
3.6 Height and Weight
Height will be measured at Screening only.  Body weight will be measured for all subjects at scheduled 
visits as specified in the Activity Schedule and Section 2.1.  The subject will wear lightweight clothing and 
no shoes during weighing.
3.7 Physical Examination
A physical examination (complete and targeted) will be performed at the designated study visits as 
specified in Section 2.1 and Section 2.2.  The complete physical examination performed at Screening will 
serve as the baseline physical examination for the entire study.  If the screening physical examination is 
performed within 7 days of Cycle 1 Day 1, it is not required to repeat the physical examination on 
Cycle 1 Day 1 unless clinically indicated.  Targeted physical examinations will be performed at all other 
specified visits after Screening and may be performed within 72 hours before the scheduled visit.
Physical examination abnormalities noted at the Baseline Visit prior to the first dose of study drug 
should be recorded in the subject's medical history.  Any significant physical examination findings after 
the first dose of study drug administration will be recorded as adverse events.  All findings, whether 
related to an adverse event or part of each subject's medical history, will be captured on the 
appropriate eCRF page.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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The targeted physical examination includes an assessment of heart, lungs, abdomen, as well as any 
system of the body, guided by the examiner's observations or subject complaints on new or changed 
conditions, symptoms, or concerns.  Targeted exams can be performed by the principal investigator or 
delegated to qualified medical staff (e.g., sub-investigator, nurse practitioner, etc.).  At any time, a 
symptom-directed physical examination can be performed as deemed necessary by the investigator.
3.8 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature will 
be obtained at visits as specified in Section 2.1 and Section 2.2.  Blood pressure and pulse rate should be 
measured after the subject has been sitting for at least 3 minutes.
3.9 12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at the Screening visit as specified in Section 2, and 
when clinically indicated per Investigator's determination.  
ECGs 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 electrical interference in the room.
Each ECG will be printed and evaluated by an appropriately qualified physician (preferably a cardiologist)
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 all safety ECGs and provide a global interpretation for each ECG using 
the following categories:

Normal ECG

Abnormal ECG – Not clinically significant (NCS)

Abnormal ECG – Clinically significant (CS)

Unable to evaluate
All local reader evaluations of ECGs will be entered into the electronic source documents, electronic 
case report forms (CRFs), or paper CRFs.  If the global interpretation is Abnormal (NCS or CS), the local 
reader will provide further information (e.g., sinus bradycardia, arrhythmia).
All ECG source documentation will be retained at the study site.  The automatic cardiograph reading 
(i.e., cardiograph-generated measurements and interpretations) will not be collected for analysis.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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3.10 Cytogenetic Assessment
Local, certified laboratories will be utilized to process and provide results for cytogenetic assessment as 
per institutional practice.  Cytogenetic testing should be performed at Screening, if it is not completed 
within 3 months prior to the first dose of study drug administration.
3.11 Molecular Subtypes Testing
Local, certified laboratories will be utilized to process and provide results for molecular subtype testing 
of bone marrow aspirates as per institutional practice.  If done per institutional practice, then testing 
should be performed at Screening (if it is not completed within 3 months prior to the first dose of study 
drug) administration.  This will be obtained at visits as specified in Section 2.1.
3.12 Dispense Study Drug
Venetoclax will be dispensed to subjects beginning at Cycle 1 Day 1 and as specified in Section 2.1.  The 
first dose of study drug will be administered after all other Day 1 procedures are completed.  At the 
visits specified in Section 2.1, the site personnel will review and retain a copy of the dosing diary, review 
returned study drug kits, and empty study drug packaging to verify compliance.
Each dose of venetoclax should be taken with approximately 240 mL of water and within 30 minutes 
after the completion of breakfast or the subject's first meal of the day.  Venetoclax tablets should be 
taken together and swallowed whole (i.e., not chewed, crushed, or broken prior to swallowing).  
Azacitidine (75 mg/m2) injections or infusions and decitabine (20 mg/m2) infusions should be prepared 
and administered per the respective package inserts.  On the days the subject is given either azacitidine 
or decitabine, venetoclax must be dosed in clinic and administered prior to these agents.
3.13 Subject Diaries
Subject diaries will be dispensed at Cycle 1 Day 1 and at Day 1 of every cycle thereafter.  Subjects will be 
instructed to bring their 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 venetoclax, (indicating if any doses are missed).
The diaries are to be reviewed at each visit.  The completed diaries are to be collected and a new diary 
dispensed at Day 1 of every cycle.  Diaries are to be appropriately filed with the subject's source 
documents for this study.
3.14 Clinical Laboratory Tests
Local, certified laboratories will be utilized to process and provide results for all the clinical laboratory 
tests.  Laboratory reference ranges will be obtained prior to the initiation of the study.  The blood 
samples for serum chemistry tests will be collected as specified in Section 2.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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Chemistry, hematology, and coagulation will be analyzed by certified local laboratories.  The baseline 
laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the first dose of study drug administration.
The baseline laboratory tests will be reviewed for eligibility before study drug administration.  Beginning 
with Cycle 3 Day 1, chemistry, hematology, and coagulation may be performed within 72 hours prior to 
the scheduled visit.  For cycles with bone marrow assessments, hematology laboratory tests should be 
performed on the same day as the bone marrow assessment.  If the assessment occurs outside of the 
chemistry and hematology visit window, then the laboratory tests should be repeated prior to dosing.  
All Day 1 chemistry and hematology assessments should be performed pre-dose and the results should 
be available prior to the administration of treatment.
For chemistry labs performed for TLS prophylaxis and monitoring during the dose ramp-up period in 
Cycle 1, refer to the Protocol, Section 6.2 (Toxicity Management) and the Protocol, Appendix F 
(Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis 
Syndrome) for specific requirements.
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator:

may repeat the test to verify the out-of-range value;

will follow the out-of-range value to a satisfactory clinical resolution; or

may discontinue the subject from the study or require the subject to receive treatment; in this 
case, the laboratory result will be recorded as an adverse event.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
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Table 1.
Clinical Laboratory Tests
Hematology
Clinical Chemistrya
Other Tests
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell count 
(WBC)
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not 
acceptable)
Blast count
Blood urea nitrogen (BUN)
Creatinine
Calculated or measured creatinine 
clearance
Total bilirubin
Albumin
Alanine transaminase (SGPT/ALT)
Aspartate transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acidb
Total protein
Glucose
Bicarbonate/CO2
Chloride
Lactate dehydrogenase
Urine and serum
- human chorionic gonadotropinc,d,e
- Follicle-stimulating hormonec,d,f
TLS Chemistry Panela,g
Creatinine
Potassium
Calcium
Inorganic phosphorus
Lactate dehydrogenase
Uric acidb
Coagulation
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
TLS = tumor lysis syndrome
a.
All chemistries should be performed at as specified in Section 2.1 and Section 2.2.
b.
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 prechilled 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 precooled centrifuge (4°C).  Finally, the 
plasma must be maintained in an ice water bath and analyzed for uric acid within 4 hours of collection.
c.
Performed only at Screening or Cycle 1 Day 1, as specified in the activity schedule and Section 2.1.
d.
Females only.
e.
Pregnancy testing is not required for females of non-childbearing potential.
f.
If needed to determine postmenopausal status.
g.
TLS chemistry samples for TLS monitoring will occur at pre-dose, 4 to 6 hours post-dose, and 24 hours post-dose for each 
venetoclax dose escalation.
Pregnancy Tests (Serum and Urine)
Pregnancy testing should not be performed for postmenopausal women.
A qualitative serum pregnancy test will be performed at Screening.  A urine pregnancy test will be 
performed at Cycle 1 Day 1 if it has been > 7 days since obtaining the serum pregnancy test results for all 
female subjects of childbearing potential.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The serum pregnancy test will be sent to and performed by the local laboratory.  If the serum pregnancy 
test is positive the subject is considered a screen failure. If the serum pregnancy test is borderline, it 
should be repeated ≥ 3 days later to determine eligibility.
If the repeat serum pregnancy test is:

Positive, the subject is considered a screen failure;

Negative, and performed < 14 days prior to Cycle 1 Day 1, the subject can be enrolled into the 
trial;

Still borderline, ≥ 3 days later, this will be considered documentation of continued lack of a 
positive result and the subject can be enrolled into the study (unless prohibited per local 
requirements) in the absence of clinical suspicion of pregnancy and other pathological causes of 
borderline results.
Urine pregnancy tests will be performed at Cycle 1 Day 1, as indicated in the Activity Schedule and 
Section 2.1.

If the urine pregnancy test is negative, then dosing with study drug may begin.

If the urine pregnancy test is positive, dosing with study drug must be withheld and a serum 
pregnancy test is required (as stated above).

Unless a woman is suspected to have become pregnant, additional pregnancy testing during the 
clinical trial is not necessary.
Tumor Lysis Syndrome Monitoring
For chemistry laboratory tests performed for TLS prophylaxis and monitoring during ramp-up period, 
refer to Table 1.
3.15 Bone Marrow Aspirate and/or Biopsy
Bone marrow aspirate will be performed at time points described in Section 2.1.  Bone marrow aspirates 
performed throughout the study should be captured on an eCRF, including those performed to confirm 
or rule out disease progression.  Bone marrow will be assessed at:

Screening

the end of Cycle 1 (must be performed within ± 3 days of Cycle 1 Day 28 and resulted prior to 
the administration of treatment for Cycle 2),

the end of Cycle 2 (must be performed within ± 3 days of Cycle 2 Day 28 and resulted prior to 
administration of treatment for Cycle 3) [only if complete remission (CR)/complete remission 
with incomplete blood count recovery (CRi) not achieved at end of Cycle 1],

the end of Cycle 4 (must be performed within ± 3 days of Cycle 4 Day 28 and resulted prior to 
administration of treatment for Cycle 5) [only if CR/CRi not achieved at end of Cycle 2], and

upon concern for relapse, and
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

the Final Visit/end of Cycle 6 (must be performed within ± 3 days of Cycle 6 Day 28).
Historical bone marrow aspirates and biopsies assessed locally to confirm the diagnosis can be used as 
baseline assessments to satisfy eligibility criteria and for screening as long as the samples were taken 
30 days prior to first study drug administration.  Bone marrow aspirates and/or biopsies performed in 
addition to those required per protocol, as standard of care throughout the study as per institutional 
practice, should also be captured on an eCRF.
3.16 Disease Assessments
For all subjects, disease assessments at Screening will be performed as listed in Section 2.1.  Disease 
response assessments while on treatment may be performed within approximately –3 days of the 
scheduled visit.  All measurable disease must be documented at Screening for all subjects based on the 
analysis of bone marrow testing (AML), clinical laboratory tests (hematology), and physical 
examinations.
Disease assessments for AML will be evaluated based on the revised guidelines by the International 
Working Group (IWG) criteria.1  Subject's response is based on most recent bone marrow results and 
recent hematology values.  For subjects who require a delay in study treatment for peripheral blood 
count recovery after a bone marrow evaluation, hematology values for up to 2 weeks from the bone 
marrow analysis can be used to determine the IWG response.  As a significant number of the subjects in 
this study might have antecedent hematologic illnesses, hematologic response will also be evaluated.
Each subject should receive only 1 response assessment at each time point where such data is being 
collected.  This response assessment should represent the single best and most specific response 
achieved at that time.  For example, any subject meeting CR criteria will also, by definition, meet criteria 
for CRi; such subjects should be categorized as CR.  Response assessment categories are as follows in 
order of best response.  The modified IWG criteria are presented in Table 2.

CR

CRi

Partial Remission (PR)

Morphologic Leukemia-Free State (MLFS)

Resistant Disease (RD)

Progressive Disease (PD)
Subjects with nonevaluable bone marrow will be reported as indeterminate and a repeat bone marrow 
should be completed within 1 week.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 2.
Modified IWG Criteria
CR:
Absolute neutrophil count > 103/µL, platelets > 105/µL, red cell transfusion independence, and 
bone marrow with < 5% blasts.
CRi:
Bone marrow with less than 5% blasts, and absolute neutrophils of ≤103/µL (1000/µL) or platelets 
≤ 105/µL (100,000/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 sample with marrow spicules and with a count of at least 
200 nucleated cells.
RD:
Failure to achieve CR, CRi, PR; only for subjects surviving at least 7 days following completion of 
Cycle 1 treatment, with evidence of persistent leukemia by blood and/or bone marrow 
examination.
PD:

50% increase in marrow blasts over baseline (a minimum 15% point increase is required in 
cases with < 30% blasts at baseline); or persistent marrow blast percentage of > 70% over at 
least 3 months; without at least a 100% improvement in ANC to an absolute level 
(> 0.5 × 109/L [500/mL], and/or platelet count to > 50 × 109/L [50,000/mL] non-transfused); or

50% increase in peripheral blasts (WBC × % blasts) to > 25 × 109/L (> 25,000/μL); or

New extramedullary disease
ANC = absolute neutrophil count; CR = complete remission; CRi = CR with incomplete blood count recovery; IWG = International 
Working Group; PD = progressive disease, as defined by ELN criteria; PR = partial remission; MLFS = morphologically leukemia 
free state; RD = resistant disease; WBC = white blood cells
Note:
Subjects should be classified at each response assessment based on BEST response to therapy using the assessments 
adapted from the IWG criteria in the table.
3.17 Post Treatment Follow-Up
Post-treatment follow-up (i.e., all cancer therapies including stem cell transplantation, regimens, dates 
of initiation and completion, etc.) will be collected at the 30-day safety follow-up visit.
3.18 Subject Withdrawal from Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate eCRF page.  If a subject discontinues study participation, the procedures outlined for the 
Final Visit should be completed as soon as possible, preferably within 2 weeks.  A 30-day safety follow-
up visit will also be conducted after the last dose of study drug.  If the subject refuses or is unable to 
attend the safety follow-up visit, this should be noted in the subject's source documentation.
However, these procedures should not interfere with the initiation of any new treatments or 
therapeutic modalities that the investigator feels are necessary to treat the subject's condition.  
Following discontinuation of study drug, the subject will be treated in accordance with the investigator's 
best clinical judgment, irrespective of whether or not the subject decides to continue participation in the 
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p. 21 of 26
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
study.  Post-treatment follow-up (i.e., all cancer therapies including stem cell transplantation, regimens, 
dates of initiation and completion, etc.) will be collected at the 30-day safety follow-up visit.
3.19 Unscheduled Visits
An Unscheduled Visit should be performed when the subject comes in for a medical visit for evaluation 
and assessment.  During Unscheduled Visits, blood and urine samples may be obtained for the 
laboratory tests listed in Section 3, or for other tests, as determined by the investigator.
Visits for dispensing new study drug in case of temperature excursion, loss or damage are not 
considered an Unscheduled Visit.  In addition, visits to only retest a lab will not be considered an 
Unscheduled Visit.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All serious and nonserious adverse events which could be related to study procedures (e.g., infection at 
liver biopsy site, done during Screening), will be collected from the time the subject signed the study-
specific informed consent until study drug administration.  From the time of study drug administration 
until 30 days after discontinuation of study treatment, all adverse events and serious adverse events will 
be collected whether solicited or spontaneously reported by the subject.  After 30 days following 
completion of study treatment and throughout the Post-Treatment Period, all spontaneously reported 
serious adverse events will be collected (nonserious adverse events will not be collected), except for 
those subjects that are able to receive commercial venetoclax treatment after the end of study 
participation.  Any new adverse events should be reported through the mechanism used for all post 
marketing adverse experiences.
AE = adverse event; SAE = serious adverse event
*
Only if considered by the investigator to be causally related to study required procedures.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 SUSAR Reporting
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the IMP in accordance with global and local guidelines and Appendix A of the Investigator Brochure will 
serve as the Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting period 
serves as the RSI during the reporting period.  For follow-up reports, the RSI in place at the time of 
occurrence of the 'suspected' Serious Adverse Reaction will be used to assess expectedness.
6 STUDY DRUG
6.1 Treatments Administered
Venetoclax will be dispensed in the form of 10-, 50-, and 100-mg film-coated tablets at the visits listed in 
Section 2.1 (refer to the Protocol Section 5.7).  Each dose of venetoclax will be taken with approximately 
240 mL of water.  Subjects will be trained to self-administer venetoclax orally once daily (QD) within 
30 minutes after the completion of breakfast or the subject's first meal of the day.  On the days the 
subject is given either azacitidine or decitabine, venetoclax must be dosed in clinic and administered 
prior to these agents.
Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing.  
If a subject should forget to take his/her venetoclax dose at his/her regularly scheduled dosing time, the 
subject should take the forgotten dose as soon as he/she remembers, provided that the dose will be 
taken within 8 hours of the missed dose.  Otherwise, the subject should take the next dose at the next 
scheduled dosing time.  If the subject vomits with 15 minutes of taking venetoclax, no additional dose 
should be taken that day.  The next prescribed dose should be taken at the usual time.
Depending on the investigator's choice, subjects will receive azacitidine or decitabine on Cycle 1 Day 1.  
The subject is to remain on their assigned therapy for the duration of this study.  Azacitidine (75 mg/m2) 
infusions or injection and decitabine (20 mg/m2) infusions should be prepared and administered per the 
respective package inserts.  Azacitidine will be administered subcutaneously or intravenously beginning 
on Day 1 for 7 days of each 28-day cycle, as per institutional practice.  Decitabine will be administered 
intravenously beginning on Day 1 for 5 days of each 28-day cycle, as per institutional practice.
AbbVie will provide venetoclax.  AbbVie provided study drug should not be substituted or alternately 
sourced unless otherwise directed by AbbVie.
Study drug must not be dispensed without contacting the Interactive Response Technology (IRT) system.  
Study drug may only be dispensed to subjects enrolled in the study through the IRT system.  At the end 
of the Treatment Period or at the final visit (Cycle 6 Day 28), the site will contact the IRT system to 
provide visit date information and study drug return information for each kit.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.2 Packaging and Labeling
The venetoclax tablets will be packaged in high density polyethylene (HDPE) plastic bottles or blister 
cards to accommodate the study design.  Each bottle or blister card will be labeled per local regulatory 
requirements.  The labels must remain affixed to the bottles.  All blank spaces should be completed by 
site staff prior to dispensing to subject.
The site will be responsible for obtaining azacitidine or decitabine.
Storage and Disposition of Study Drug
Venetoclax must be stored at controlled room temperature (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, destroyed on site, or 
returned to AbbVie, as appropriate.
6.3 Method of Assigning Subjects to Treatment Groups
This is a non-randomized, open-label study.  All eligible subjects will receive venetoclax QD in 
combination with azacitidine or decitabine as described in Section 2.1.  The choice of azacitidine or 
decitabine will be as determined by the investigator.  The subject is to remain on their assigned therapy 
for the duration of the study.
At the Screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the Screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in the study protocol, Section 4.2.
All tablets of venetoclax will be dosed together, QD for 28-day cycles.  Azacitidine will be administered 
either SC or intravenously (IV), and decitabine will be administered IV.  All subjects should take all doses 
of study drug with food around the same time each day, as described in Section 6.1.  On the days the 
subject is given either azacitidine or decitabine, venetoclax must be dosed in clinic and administered 
prior to these agents.
All subjects will be treated with venetoclax and azacitidine or decitabine for a maximum of six cycles 
(28 days each).  Subjects will undergo a final visit when treatment is discontinued or at the end of the 
sixth cycle.  After the study period ends, subjects may continue receiving AML-directed therapy 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M19-072 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
including commercially-acquired standard-of-care treatments for venetoclax and azacitidine or 
decitabine.
7 REFERENCES
1.
Cheson BD, Bennett JM, Kopecky KJ, et al. 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.
Page 78 of 80
 

SAP_001.pdf: 
Venetoclax (ABT-199)
M19-072 – Statistical Analysis Plan
Version 2.0 – 11 May 2022
1
1.0
Title Page
Statistical Analysis Plan
Study M19-072
A Phase 3b, Single-Arm, Multicenter Open-Label 
Study of Venetoclax in Combination with Azacitidine 
or Decitabine in an Outpatient Setting in AML 
Patients Ineligible for Intensive Chemotherapy
Date:  11 May 2022
Version 2.0
 
NCT03941964


Venetoclax (ABT-199)
M19-072 – Statistical Analysis Plan
Version 2.0 – 11 May 2022
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Background.................................................................5
4.1
Objectives .............................................................................................. 5
4.2
Study Design.......................................................................................... 5
4.3
Endpoints ............................................................................................... 6
4.3.1
Primary Efficacy Endpoint ..................................................................... 6
4.3.2
Secondary Efficacy Endpoints................................................................ 6
4.3.3
Exploratory Efficacy Endpoints.............................................................. 7
4.3.4
Safety Endpoint...................................................................................... 7
4.4
Sample Size Justification........................................................................ 7
4.5
Interim Analysis ..................................................................................... 7
5.0
Analysis Populations .............................................................8
5.1
Definition of Analysis Populations ......................................................... 8
5.2
Definition of Treatment Groups.............................................................. 8
6.0
Analysis Conventions ............................................................8
6.1
Definition of Study Drug........................................................................ 8
6.2
Definition of Baseline............................................................................. 8
6.3
Definition of Final Observation .............................................................. 8
6.4
Definition of Rx Days ............................................................................ 8
7.0
Demographics, Baseline Characteristics, Medical 
History, Prior and Post-treatment Systemic 
Therapies, and Concomitant Medications ...........................9
7.1
Demographic and Baseline Characteristics ............................................. 9
7.2
Medical History.................................................................................... 11
7.3
Prior and Post-treatment Systemic Therapies and Concomitant 
Medications.......................................................................................... 11
8.0
Patient Disposition and Study Drug Exposure ..................12
8.1
Patient Disposition ............................................................................... 12
8.2
Study Drug Exposure ........................................................................... 12
 


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9.0
Efficacy Analysis .................................................................13
9.1
General Considerations......................................................................... 13
9.1.1
Analysis of Efficacy Endpoints by Variable Type................................. 14
9.1.2
Missing Data Imputation for Efficacy Endpoints .................................. 14
9.2
Primary Efficacy Analysis.................................................................... 14
9.3
Secondary Efficacy Analyses ............................................................... 14
9.3.1
Remissions........................................................................................... 14
9.3.2
Transfusion Independence .................................................................... 15
9.4
Exploratory Efficacy Analysis.............................................................. 15
9.4.1
Time to Blood Count Improvement ...................................................... 16
9.4.1.1
Time to Improvement of Grade 4 Neutropenia...................................... 16
9.4.1.1.1
Time to Improvement of Grade 4 Neutropenia Present at the Time 
of Blast Clearance ................................................................................ 16
9.4.1.1.2
Time to Improvement of First Grade 4 Neutropenia Onset Post 
Blast Clearance..................................................................................... 16
9.4.1.2
Time to Improvement of Grade 4 Thrombocytopenia ........................... 16
9.4.1.3
Time to Improvement of Grade 3 Anemia ............................................ 16
9.4.2
Duration of Blood Count Improvement................................................. 16
9.4.2.1
Duration of Improvement of Grade 4 Neutropenia Present at the 
Time of Blast Clearance ....................................................................... 17
9.4.2.2
Duration of Improvement of Grade 4 Thrombocytopenia Present 
at the Time of Blast Clearance.............................................................. 17
9.4.2.3
Duration of Improvement of Grade 3 Anemia Present at the Time 
of Blast Clearance ................................................................................ 17
9.4.3
Rates of CR or CRi in molecular subtypes............................................ 17
9.5
Efficacy Subgroup Analysis ................................................................. 17
10.0
Safety Analysis.....................................................................18
10.1
General Considerations......................................................................... 18
10.2
Analysis of Adverse Events.................................................................. 18
10.2.1
Treatment-Emergent Adverse Events.................................................... 18
10.2.2
SAEs (Including Deaths) ...................................................................... 20
10.2.3
Selected AEs ........................................................................................ 20
10.2.4
Listing of SAEs and Deaths.................................................................. 21
 


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10.3
Analysis of Laboratory Data................................................................. 21
10.3.1
Variables and Criteria Defining Abnormality........................................ 21
10.3.2
Statistical Methods ............................................................................... 21
11.0
Summary of Changes Between the Previous Version 
of SAP and the Current SAP ..............................................22
List of Tables
Table 1.
Selected Adverse Events....................................................................... 20
 


Venetoclax (ABT-199)
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3.0
Introduction
The statistical analysis plan describes the analyses of safety and efficacy data collected for 
Study M19-072.  Analysis conventions to guide statistical programming conventions are 
provided.
Analyses will be performed using SAS Version 9.4 or higher.
4.0
Study Background
4.1
Objectives
Primary:
●
To determine the composite complete remission rate (CR + CRi), during the 
initial 6 cycles of treatment, as determined by the modified International 
Working Group (IWG) criteria, of venetoclax in combination with azacitidine 
or decitabine given in an outpatient setting to treatment-naïve subjects with 
AML who are ineligible for intensive chemotherapy.
Secondary:
●
To determine the incidence and severity of adverse events including, but not 
limited to, rates of TLS and neutropenia
●
To assess the rate of transfusion independence upon treatment with venetoclax 
and azacitidine or decitabine.
4.2
Study Design
The study is a Phase 3b, open-label, single-arm, multicenter study evaluating the 
composite complete remission rate and safety of venetoclax in combination with 
azacitidine or decitabine in an outpatient setting for treatment-naïve subjects with AML 
who are ineligible for intensive chemotherapy.
 


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Approximately 60 subjects will be enrolled in the trial.  Treatment will be initiated with a 
venetoclax dose ramp-up over three days and adjusted as appropriate with concomitant 
use of CYP3A inhibitors.  Ramp-up activities for subjects in this study will be done in an 
outpatient setting.  The choice of azacitidine or decitabine will be made at the discretion 
of the investigator:  the subject is to remain on their assigned therapy for the duration of 
the study.
All subjects will receive venetoclax daily.  Subjects will receive either azacitidine for 
seven days or decitabine for five days of each 28 day cycle up to 6 cycles.  After the 
sixth cycle, subjects may continue to receive AML-directed therapy, including 
commercially acquired venetoclax with azacitidine or decitabine, outside of this study 
protocol.
Subjects with progressive disease for whom the treating physician feels are still deriving 
clinical benefit can be continued on treatment until no longer achieving clinical benefit, 
unacceptable toxicity, withdrawal of consent, or other protocol criteria for discontinuation 
are met.  All subjects will have a final visit performed when treatment is discontinued and 
a 30-day safety follow-up assessment.
4.3
Endpoints
4.3.1
Primary Efficacy Endpoint
The primary endpoint is the composite complete remission rate (CR + CRi): complete 
remission (CR) plus complete remission with incomplete hematologic recovery (CRi) as 
described by the modified IWG criteria (Operations Manual, Section 3.15).
4.3.2
Secondary Efficacy Endpoints
The secondary endpoints are:
●
Response of CR or CRi:  complete remission (CR) or complete remission with 
incomplete hematologic recovery (CRi) as described by the modified IWG 
criteria.
 


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●
Transfusion independence rate is defined as the proportion of subjects who 
achieved post-baseline transfusion independence, which is defined as a period 
of at least 56 days with no transfusion after the first dose of study drug and 
within 30 days of the last dose of study drug, death, initiation of post-treatment 
therapy, whichever is earliest.  Transfusion independence rate will be 
calculated for both RBC transfusion and platelet transfusion separately and 
together.
4.3.3
Exploratory Efficacy Endpoints
The exploratory endpoints are:
●
Time to the first improvement of absolute neutrophil count (ANC), platelets, 
and hemoglobin as well as duration of the first improvement of absolute 
neutrophil count, platelets and hemoglobin.  See Section 9.4.1 for definitions of 
both endpoints.
●
Rates of CR/CRi in molecular subtypes identified per institutional practices.
4.3.4
Safety Endpoint
Safety evaluations will include adverse event monitoring, clinical lab testing, vital signs 
measurements, and rate of hospitalization.
4.4
Sample Size Justification
A sample size of 60 subjects would ensure that the true CR + CRi rate will be within 13% 
of the observed rate with 95% confidence.
4.5
Interim Analysis
None are planned.
 


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5.0
Analysis Populations
5.1
Definition of Analysis Populations
Subjects who receive at least one dose of venetoclax, azacitidine, or decitabine will be 
included in all analyses unless specified otherwise.
5.2
Definition of Treatment Groups
Subjects will receive venetoclax in combination with one hypomethylating agent, either 
azacitidine or decitabine. Study results will be presented for 3 groups: Venetoclax in 
combination with either azacitidine or decitabine and for all treated subjects combined.
6.0
Analysis Conventions
6.1
Definition of Study Drug
Study drug in this document refers to venetoclax and hypomethylating agents azacitidine 
and decitabine.
6.2
Definition of Baseline
Baseline for a given variable will be the last value obtained on or prior to the first dose of 
any component of study drug.
6.3
Definition of Final Observation
The final observation is defined as the last non-missing observation collected after the 
first dose of any component of study drug to the last dose of any component of study 
drug + 30 days.
6.4
Definition of Rx Days
Study Day is defined as the number of days since or prior to the first dose of any 
component of study drugs.  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 study Day –1.
 


Venetoclax (ABT-199)
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7.0
Demographics, Baseline Characteristics, Medical 
History, Prior and Post-treatment Systemic 
Therapies, and Concomitant Medications
All analysis in this session will be summarized for the 3 treatment groups:  venetoclax in 
combination with either azacitidine or decitabine, and all treated subjects combined.  The 
number of subjects with missing information will also be summarized.  There will be no 
statistical comparison for the variables summarized in this section.
7.1
Demographic and Baseline Characteristics
All baseline characteristic summary statistics and analyses are based on characteristics 
prior to the first dose of study drug.
Summaries of continuous characteristics will consist of the number of non-missing 
observations, mean, standard deviation, and range.  Categorical characteristics will be 
summarized by the frequencies and percentages of subjects within each category.
The following demographic, baseline, and disease-related characteristics will be 
summarized:  
Demographics:
Age (years) and age categories (12 – < 18, 18 – < 65, 65 – < 75 years, ≥ 75 years)
Gender (male, female)
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander)
Ethnicity (Hispanic or Latino vs. Not Hispanic or Latino)
Height (cm)
Weight (kg)
 


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Baseline and Disease-Related Characteristics:
ECOG performance status (Grade 0, 1, 2, 3)
Cytogenetic risk (favorable, intermediate, poor)
Bone marrow blast count (< 30%, ≥ 30% – < 50%, ≥ 50%)
Bone marrow blast count (%)
White blood cell count (× 109/L)
CTC grade of neutropenia
Neutrophil value (× 109/L)
CTC grade of anemia
Hemoglobin value (G/L)
CTC grade of thrombocytopenia
Platelet count (× 109/L)
Type of AML (de novo, secondary, therapy-related AML)
Reasons for being ineligible for standard induction therapy 
Antecedent hematologic history of MDS or MPN (Yes, No)
Baseline packed RBC transfusion dependence (Yes, No)
Baseline platelet transfusion dependence (Yes, No)
Molecular marker (FLT3-ITD, FLT3-TKD, IDH1, IDH2, IDH1/2, TP53, NPM1, 
CEBPA, TET2, ASXL1, DNMT3A, Other)
 


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Hepatic impairment (Yes [Mild Impairment, Moderate Impairment, Severe 
Impairment], No)
Renal impairment (Yes [Mild Impairment, Moderate Impairment, Severe 
Impairment], No)
7.2
Medical History
Medical history will be summarized according to the MedDRA dictionary, with 
presentation organized by system organ class (SOC) and preferred term (PT). The SOCs 
will be presented in alphabetical order and the PTs will be presented in alphabetical order 
within each body system. The number and percentage of subject with a particular PT will 
be summarized. Subjects reporting more than one PT within a SOC will be counted only 
once for that SOC.
7.3
Prior and Post-treatment Systemic Therapies and 
Concomitant Medications
A prior medication is defined as any medication taken prior to the first dose of study drug.  
A concomitant medication is defined as any medication that started prior to the first dose 
of study drug and continued to be taken after the first dose of study drug, or any 
medication that started after the first dose of study drug, but not after the last dose of 
study drug.  
The number and percentage of subjects who took at least one dose of concomitant 
medication other than study drug will be summarized by the generic medication name 
coded by WHO dictionary.  A subject who reports the use of two or more medications 
with same start date 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.
The number and percentage of subjects who have prior or post-treatment systemic 
therapies will be summarized by generic medication name coded by WHO dictionary.  
 


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The number and percentage of subjects who have taken TLS prophylaxis agents including 
intravenous hydration on or prior to the first dose of study drug and concomitant to the 
study treatment will be summarized separately.
The number and percentage of subjects who have received transfusions on or prior to 
first dose of study drug will be summarized by transfusion type.
8.0
Patient Disposition and Study Drug Exposure
All analysis in this session will be summarized for the 3 treatment groups:  venetoclax in 
combination with either azacitidine or decitabine, and all treated subjects combined.  The 
number of subjects with missing information will also be summarized.  There will be no 
statistical comparison for the variables summarized in this session.
8.1
Patient Disposition
The number of screen failures and screen failure reasons will be tabulated.  The numbers 
and percentages of subjects will be summarized by treatment groups for each of the 
following categories for all enrolled subjects:
●
Subjects enrolled into the study
●
Subjects who received at least one dose of study drug
●
Subjects who were enrolled but not treated with any component of study drug
●
Subjects who discontinued venetoclax due to all reasons and primary reason
●
Subjects who discontinued azacitidine due to all reasons and primary reason
●
Subjects who discontinued decitabine due to all reasons and primary reason
8.2
Study Drug Exposure
Exposure to each of the three study drugs will be summarized in days using sample size 
(N), mean, standard deviation, median, and range for each of the following variable:
●
The duration of exposure which is defined for each subject as (last dose 
date – first dose date) + 1;
 


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The number of cycles that subjects were exposed to study drug.
●
Average dosed days per cycle which is defined for each subject as (total 
number of days subject received study drug)/(the number of cycles subject was 
exposed to study drug).
●
Dose intensity accounting for dose reduction.
●
Dose intensity accounting for dose reduction and interruption.
The number and percentage of subjects with dose reduction or dose interruption will be 
summarized by the number of occurrences of dose reduction or interruption as no, 1 time, 
2 times, or > 2 times.
In addition, the number and percentage of subjects exposed to each of the three study 
drugs will be summarized for the following categories of exposure duration:
●
0 to 4 weeks (0 to 28 days),
●
4 weeks to 8 weeks (28 to 56 days),
●
8 weeks to 12 weeks (57 to 84 days),
●
12 weeks to 16 weeks (85 to 112 days),
●
16 weeks to 20 weeks (113 to 140 days),
●
20 weeks to 24 weeks (141 to 168 days).
The number and percentage of subjects who received CYP3A inhibitors and/or P-gp 
inhibitors during the period from first exposure to study drug to last exposure of study 
drug will be summarized by the type: moderate/strong CYP3A inhibitor, moderate P-gp 
inhibitors.
9.0
Efficacy Analysis
9.1
General Considerations
All analyses in this session will be presented for the 3 treatment groups:  venetoclax in 
combination with either azacitidine or decitabine, and all treated subjects combined.
 


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9.1.1
Analysis of Efficacy Endpoints by Variable Type
The primary endpoint is composite complete remission (CR + CRi), a complete remission 
(CR) with or without complete hematologic recovery (CRi).  The secondary endpoints are 
rates of complete remission (CR), complete remission with incomplete hematologic 
recovery (CRi), and transfusion-independence rates for red blood cells and platelets 
separately and combined.  The observed rates for each endpoint will be presented with a 
95% confidence interval.  Rates of composite complete remission (CR + CRi) in 
molecular subtypes will be similarly presented.
Time to the first absolute neutrophil count improvement and hemoglobin improvement as 
well as duration of the first absolute neutrophil count improvement and hemoglobin 
improvement will also be analyzed using Kaplan-Meier curve, where median time to 
improvement and duration of improvement with their corresponding 95% CI will be 
provided.
9.1.2
Missing Data Imputation for Efficacy Endpoints
Subjects who do not have any post-baseline IWG assessments will be considered as non-
responders in the remission rate analyses.
9.2
Primary Efficacy Analysis
The primary endpoint is the composite complete remission rate (CR + CRi) as identified 
by the investigators during the study.  An exact 95% confidence interval based on the 
binomial distribution will be provided along with the rate.
9.3
Secondary Efficacy Analyses
9.3.1
Remissions
Rates of complete remission and complete remission with incomplete hematologic 
recovery (as the best response) as identified by the investigator will be tabulated 
separately.  Exact 95% confidence intervals will also be provided.
 


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9.3.2
Transfusion Independence
Post baseline transfusion independence rate will be calculated as the proportion of 
subjects who achieved transfusion independence post baseline regardless of their baseline 
transfusion status.  Transfusion independence is defined as a period of at least 56 days (≥ 
56 days) with no transfusion after the first dose of study drug and on or before the last 
dose of study drug + 30 days, relapse, death, or before the initiation of post-treatment 
therapy, whichever is earliest.  The transfusion independence rate will be evaluated for 1) 
red blood cells (RBC), 2) platelets, and 3) RBC and platelets.  Exact 95% confidence 
intervals will also be provided.
9.4
Exploratory Efficacy Analysis
Time to blood counts improvement as well as duration of the improvement will be 
summarized by descriptive statistics (mean, median, and range) and analyzed by Kaplan-
Meier (KM) methodology.  KM plots will be presented.  Median improvement time and 
median duration of improvement and their corresponding 95% confidence intervals will 
be provided. 
Blood count improvement is defined separately for ANC, platelet count and hemoglobin.
●
Improvement of Grade 4 Neutropenia defined as ANC lab values < 0.5 
× 10^9/L lasting for at least 7 days: when ANC lab values improve to 
≥0.5× 10^9/L sustaining for a minimum of 5 days.
●
Improvement of Grade 4 Thrombocytopenia defined as platelet count lab 
values <25 × 10^9/L lasting for at least 7 days: when platelet count lab values 
improve to ≥25 × 10^9/L sustaining for a minimum of 5 days.
●
Improvement of Grade 3 Anemia defined as hemoglobin lab values <80 G/L 
lasting for at least 7 days: when hemoglobin lab values improve to ≥80 G/L 
sustaining for a minimum of 5 days.
 


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9.4.1
Time to Blood Count Improvement
Time to blood count improvement will be analyzed for subjects who achieved bone 
marrow blast clearance (CR/CRi/MLFS).
9.4.1.1
Time to Improvement of Grade 4 Neutropenia 
9.4.1.1.1
Time to Improvement of Grade 4 Neutropenia Present at the 
Time of Blast Clearance
For subjects whose ANC lab value is <0.5× 10^9/L at the time of blast clearance, their 
time to improvement of Grade 4 neutropenia present at the time of blast clearance is 
defined as number of days from the blast clearance to the first date of ANC lab 
value recovered to ≥0.5 × 10^9/L.
9.4.1.1.2
Time to Improvement of First Grade 4 Neutropenia Onset 
Post Blast Clearance 
For 1) subjects whose ANC lab value is ≥0.5× 10^9/L at the time of blast clearance and 
for 2) subjects whose ANC lab value is <0.5× 10^9/L at the time of blast clearance and is 
recovered to ≥0.5× 10^9/L post blast clearance, their time to improvement of first Grade 4 
neutropenia onset post blast clearance is defined as number of days from the first date 
when ANC lab value drop to <0.5× 10^9/L post blast clearance to the first date when 
ANC lab recovered to ≥0.5 × 10^9/L.
9.4.1.2
Time to Improvement of Grade 4 Thrombocytopenia
Analyses will be performed similar to Time to Improvement of Grade 4 Neutropenia.
9.4.1.3
Time to Improvement of Grade 3 Anemia 
Analyses will be performed similar to Time to Improvement of Grade 4 Neutropenia.
9.4.2
Duration of Blood Count Improvement 
Duration of blood count improvement will be analyzed for subjects who achieved bone 
marrow blast clearance (CR/CRi/MLFS).
 


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9.4.2.1
Duration of Improvement of Grade 4 Neutropenia Present at 
the Time of Blast Clearance 
For subjects whose ANC lab value is <0.5× 10^9/L at the time of blast clearance with a 
subsequent improvement, the duration of improvement of Grade 4 Neutropenia present at 
the time of blast clearance is defined as number of days from the first date of ANC lab 
value recovered to ≥0.5 × 10^9/L following blast clearance to the first date when ANC lab 
value dropped back to <0.5 × 10^9/L.
9.4.2.2
Duration of Improvement of Grade 4 Thrombocytopenia 
Present at the Time of Blast Clearance 
Analyses will be performed similar to Duration of Improvement of Grade 4 Neutropenia.
9.4.2.3
Duration of Improvement of Grade 3 Anemia Present at the 
Time of Blast Clearance 
Analyses will be performed similar to Duration of Improvement of Grade 4 Neutropenia.
9.4.3
Rates of CR or CRi in molecular subtypes
Rates of CR/CRi in molecular subtypes (FLT3-ITD/TKD, IDH1, IDH2, IDH1/2, TP53, 
NPM1, CEBPA, TET2, ASXL1, DNMT3A, Other) identified per institutional practices 
will be summarized using summary statistics (N, mean, standard deviation, median, 
range) for each of the treatment groups.  
9.5
Efficacy Subgroup Analysis
Rates of composite complete remission rates (CR + CRi) will be presented along with 
their exact 95% CI.
The subgroups defined below, not limited to, will be used for these analyses:
1.
Gender (Male, Female)
2.
Age (12– < 65 years, 65 – < 75 years, ≥ 75 years) 
 


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3.
Baseline ECOG (Grade < 2, ≥ 2)
4.
Type of AML (De Novo, Secondary, Therapy-related AML)
5.
Cytogenetic risk (Intermediate, Poor, Favorable)
6.
CYP3A inhibitors use leading to venetoclax dose reduction (Yes, No)
7.
Antecedent hematologic history of MDS or MPN (Yes, No)
10.0
Safety Analysis
10.1
General Considerations
All analyses in this session will be presented for:  venetoclax in combination with 
azacitidine, venetoclax in combination with decitabine, and all treated subjects combined.
10.2
Analysis of Adverse Events
10.2.1
Treatment-Emergent Adverse Events
Adverse events (AE) with onset or worsening on or after the first dose of study drug and 
no more than 30 days after the last dose of study drug are treatment emergent.  All 
summaries of adverse events will include treatment-emergent events (TEAE) only unless 
specified otherwise.
Adverse event data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The version of the MedDRA dictionary that is current at the time of 
summarization will be applied to the codes prior to summarization.  AE rates will then be 
summarized by system organ class (SOC) and preferred term (PT).
Within each summary the following AE rates will be presented:
●
Overall rates:  subjects who had at least one AE,
●
SOC rates:  subjects who had a least one event falling in a given system organ 
class,
 


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●
PT rates:  subjects who had at least one event with the given preferred term.
For summaries of AE by National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE v4.03) grade, at each level of summarization (overall, 
SOC, and PT) each subject is counted only once at the maximum grade level.
Summaries of SAE are described in Section 10.2.3.  
The number and percentage of subjects experiencing at least one event for each of the 
following categories will also be summarized:
●
Any TEAE
●
TEAE with reasonable possibility of relationship to venetoclax per the 
investigator.
●
TEAE with NCI grade 3 or higher
●
TEAE with NCI grade 3 or 4
●
TEAE leading to discontinuation of venetoclax
●
TEAE leading to venetoclax dose interruption
●
TEAE leading to venetoclax dose reduction
●
TEAE with reasonable possibility of relationship to the HMA per the 
investigator
●
TEAE leading to discontinuation of the HMA
●
TEAE leading to HMA dose interruption
●
TEAE leading to HMA dose reduction.
Overview tables with overall rates of each of the above AE types plus treatment-emergent 
death rates will be prepared for TEAE.
 


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10.2.2
SAEs (Including Deaths)
Treatment-emergent serious adverse event rates will be summarized by MedDRA system 
organ class and preferred term as done for adverse events in general.  The summaries of 
SAE data will include tabulations of the following rates:
●
All treatment-emergent SAE
●
Adverse events resulting in hospitalization
●
Adverse events resulting in death.
Treatment Emergent Deaths
Rates of deaths that occur within 30 days of start of treatment and within 30 days 
following the last dose of study drug will also be summarized. 
10.2.3
Selected AEs 
Selected AEs will be identified through the search criteria provided in table below and 
summarized by MedDRA system organ class and preferred term.
Table 1.
Selected Adverse Events
Selected Adverse Events
Search Criteria
Tumor Lysis Syndrome* (AE) 
occurring within 7 days from the 
first dose study drug
SMQ – "Tumor Lysis Syndrome" (narrow)
Neutropenia*
PT terms – "neutropenia," "neutrophil count decreased," "febrile 
neutropenia*," "agranulocytosis," "neutropenic infection," and 
"neutropenic sepsis"
Thrombocytopenia*
PT terms – 'Thrombocytopenia' and 'platelet count decreased'
Anemia*
PT terms – 'Anaemia' and 'Haemoglobin decreased'
Grade ≥3 infections
SOC of 'infections and infestations'
Hemorrhages
SMQ - 'Haemorrhages' (narrow)
*Considered as AESI in the protocol.
 


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10.2.4
Listing of SAEs and Deaths
A listing of serious adverse events will be provided.  All data from the adverse event 
records will be compiled into the data listing.  A listing of reports of treatment-emergent 
deaths will also be provided.
10.3
Analysis of Laboratory Data
10.3.1
Variables and Criteria Defining Abnormality
Where applicable, lab test data will be graded according to National Cancer Institute 
Common Terminology Criteria (NCI CTCAE) version 4.03.
The NCI criteria are ranges of test values that are to be graded from one to four.  Lab test 
results that do not fall into the grade one to four ranges, generally those that are in the 
normal range for the lab or else are abnormal in the direction opposite the test, will be 
assigned a grade of zero.
10.3.2
Statistical Methods
For each lab test for which NCI criteria exist, shift tables will be generated that cross 
tabulate the number of subjects with baseline values of Grade 0, Grade 1, Grade 2, 
Grade 3, or Grade 4 versus maximum post-baseline of Grade 0, Grade 1, Grade 2, 
Grade 3, or Grade 4.  All treated subjects will be included in the cross tabulation 
regardless whether baseline or post-baseline measurements are collected.
Separate laboratory shifts tables based on the two criteria below will be generated for each 
laboratory tests related to CTCAE:
●
Shifts from Grade 0 (Normal) at baseline to Grade 1 - 4 Post-baseline 
(maximum) and worsening from an abnormal baseline value of at least 
one grade up post-baseline (maximum)
●
Shifts from Grade 0 - 2 at baseline to Grade 3 or 4 Post-baseline (maximum) 
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The maximum NCI grade value is the value with highest NCI grade collected after the 
first dose of study drug and within 30 days following the last dose of study drug.  In cases 
where multiple values are collected on the same day, the maximum grade value and 
minimum grade value will be selected as the value for that day for the post-baseline grade 
value and for the baseline grade value, respectively.
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
The number and percentage of subjects with liver Enzyme value meeting the criteria for 
potential drug-induced liver injury (ALT > 3 × ULN or AST > 3 × ULN and TBILI > 2 × 
ULN within 72 hours [3 days if time stamp is not collected] of each other) will be 
presented.
The number and percentage of subjects meeting the Howard criteria for TLS will be 
presented.  The Howard Criteria for TLS is defined as two or more of the following 
treatment-emergent lab changes within a 24-hour period.  The evaluation period for TLS 
is after 1st dose of study drug to 7 days from the 1st dose of study drug.
●
uric acid > 475.8 mcmol/l,
●
potassium > 6 mmol/l,
●
inorganic phosphorus > 1.5 mmol/l
●
calcium < 1.75 mmol/l.
11.0
Summary of Changes Between the Previous 
Version of SAP and the Current SAP
1. From version 1 to version 2, clarify transfusion independence and conversion rate 
in Section 4.3.2.
 


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2. From version 1 to version 2, clarify molecular marker in Section 7.1 and 
Section 9.3.
3. From version 1 to version 2, updated selected AE in Section 10.2.3.
4. From version 1 to version 2, updated Section 9.4.