Azacitidine and Venetoclax (ABT-199) as Induction Therapy With Venetoclax Maintenance in Previously Untreated Elderly Patients With Acute Myeloid Leukemia (AML)
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Sponsor: University of Colorado, Denver

Confidential 
 
 
 
 
 
Azacitidine and Venetoclax (ABT-199) as Induction Therapy with  
Venetoclax Maintenance in Previously Untreated Elderly Patients with 
Acute Myeloid Leukemia  
 
 
Study Sponsor / 
Principal Investigator 
Daniel A. Pollyea, MD, MS 
University of Colorado Cancer Center 
1665 Aurora Court 
Mail Stop F754 
Aurora, CO 80045 
Phone: 720-848-8084 
Fax: 720-848-1786 
Daniel.pollyea@cuanschutz.edu 
 
Study Location 
University of Colorado Cancer Center 
Protocol / COMIRB# 
17-7821 
Version Date 
September 15, 2025 
Indication to be 
studied 
Previously untreated elderly patients with 
acute myeloid leukemia (AML) 
Study Agents: 
1.  Venetoclax (ABT-199, Abbvie), is not 
currently FDA approved for AML. 
2. Azacitidine (Vidaza™, Celgene) is not 
currently approved for AML, but it is 
routinely used as the standard of care 
treatment. 
 
 

 
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CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
STATEMENT OF COMPLIANCE 
This is an investigator-initiated study.  The principal investigator (PI), Daniel 
A. Pollyea, is conducting the study and acting as the sponsor.  As the sponsor-
investigator, both the legal/ethical obligations of a PI and those of a sponsor will 
be followed. 
The trial will be carried out in accordance with Good Clinical Practice (GCP) 
as required by applicable United States (US) laws and applications, including but 
not limited to United States (US) Code of Federal Regulations (CFR) applicable to 
clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 
312, and/or 21 CFR Part 812)  
The PI will assure that no changes to the protocol will take place without 
documented approval from the Institutional Review Board (IRB). All personnel 
involved in the conduct of this study have completed Human Subjects Protection 
Training.  
I agree to ensure that all staff members involved in the conduct of this study 
are informed about their obligations in meeting the above commitments.  
 
 
Daniel A. Pollyea, MD 
 
 
 
  
Print/Type Name  
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
  
Date 
 
 

 
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.  
LIST OF ABBREVIATIONS 
 
ACRONYM 
DESCRIPTION 
IIT 
Investigator-Initiated Trial 
LSC 
Leukemia stem cell 
AML 
Acute myeloid leukemia 
MDS 
Myelodysplastic syndrome 
MRD 
Minimal residual disease 
TLS 
Tumor lysis syndrome 
CR 
Complete remission 
CRi 
Complete remission with incomplete blood count recovery 
MLFS 
Morphologic leukemia free state 
AE 
Adverse event 
SAE 
Serious adverse event 
UGT 
UDP-glucuronosyltransferases 
OATP 
Organic anion transporting polypeptide 
BCRP 
Breast cancer resistance protein 
CYP 
Cytochrome P 
RBC 
Red blood cell 
AUC 
Area under the curve 
CLL 
Chronic lymphocytic leukemia 
NHL 
Non-Hodgkin lymphoma 
eCRF 
Electronic case report form 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
LDH 
Lactate dehydrogenase 
PT 
Prothrombin time 
INR 
International normalized ratio 
PTT 
Partial thromboplastin time 
 
 
 

 
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Table of Contents 
LIST OF ABBREVIATIONS ........................................................................................................ iii 
1 PROTOCOL SYNOPSIS .......................................................................................................... 6 
2 SCHEDULE OF STUDY ASSESSMENTS ............................................................................... 8 
3 INTRODUCTION .................................................................................................................... 9 
3.1 
Background and Rationale ............................................................................................... 9 
3.2 
Venetoclax ..................................................................................................................... 12 
3.2.1 
Preclinical Pharmacokinetic Profile ....................................................................... 12 
3.2.2 
Preclinical Toxicology ........................................................................................... 12 
3.2.3 
Clinical Data .......................................................................................................... 16 
3.3 
Azacitidine ..................................................................................................................... 19 
3.3.1 
Preclinical Pharmacokinetic Profile ....................................................................... 19 
3.3.2 
Clinical Data .......................................................................................................... 20 
3.4 
Differences Statement .................................................................................................... 20 
4 STUDY OBJECTIVES ............................................................................................................ 21 
4.1 
Primary Objective .......................................................................................................... 21 
4.2 
Secondary Objectives ..................................................................................................... 21 
5 INVESTIGATIONAL PLAN ................................................................................................... 21 
5.1 
Overall Study Design ..................................................................................................... 21 
5.1.1 
Study Schema ......................................................................................................... 21 
5.1.2 
Response Assessments ........................................................................................... 23 
5.1.3 
Continuation and Interruptions .............................................................................. 24 
5.2 
Study Endpoints ............................................................................................................. 24 
5.2.1 
Primary Endpoint ................................................................................................... 24 
5.2.2 
Secondary Endpoints ............................................................................................. 24 
5.3 
Selection of Study Population and Enrollment Procedures ........................................... 25 
5.3.1 
Inclusion Criteria ................................................................................................... 25 
5.3.2 
Exclusion Criteria .................................................................................................. 26 
5.4 
Duration of Study ........................................................................................................... 28 
5.5 
Drug Administration ...................................................................................................... 28 
5.5.1 
Venetoclax Administration .................................................................................... 28 
5.5.2 
Azacitidine Administration .................................................................................... 30 
5.6 
Assuring Patient Compliance ......................................................................................... 30 
5.7 
Drug Accountability ....................................................................................................... 31 
5.8 
Concomitant Therapy ..................................................................................................... 31 
5.8.1 
Permitted Concomitant Therapy ............................................................................ 31 
5.8.2 
Prohibited Concomitant Therapy ........................................................................... 32 
5.9 
Contraception Recommendations .................................................................................. 33 
5.10 
Study Procedures ........................................................................................................... 34 
5.11 
Response Assessments ................................................................................................... 38 
5.12 
Reporting of Results ...................................................................................................... 40 
5.13 
Stopping Rules ............................................................................................................... 41 
5.13.1 
Individual Patient Stopping Rules .......................................................................... 41 
5.13.2 
Study Stopping Rules ............................................................................................. 41 
5.14 
Dosing Delays and Modifications .................................................................................. 42 
5.14.1 
Missed Doses ......................................................................................................... 42 
5.14.2 
Additional Doses .................................................................................................... 42 
5.14.2.1 
Dose Delays ................................................................................................... 42 

 
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5.14.3 
Dose De-Escalation and Re-Escalation .................................................................. 43 
6 SAFETY PLAN ....................................................................................................................... 45 
6.1 
Adverse Event ................................................................................................................ 45 
6.2 
Serious Adverse Events ................................................................................................. 45 
6.3 
Adverse Events Commonly Associated with AML ....................................................... 47 
6.4 
Adverse Event Severity .................................................................................................. 47 
6.5 
Relationship to Study Drug ............................................................................................ 48 
6.6 
Deaths ............................................................................................................................ 49 
6.7 
Recording Adverse Events ............................................................................................. 49 
6.8 
Investigator Reporting Responsibilities ......................................................................... 49 
6.8.1 
Adverse Event Reporting ....................................................................................... 49 
6.8.2 
Reporting to Abbvie ............................................................................................... 50 
6.8.3 
Reporting From Abbvie ......................................................................................... 51 
6.9 
Pregnancy ....................................................................................................................... 51 
6.10 
Prophylaxis and Management of Tumor Lysis Syndrome ............................................. 51 
6.11 
Decreased Spermatogenesis ........................................................................................... 53 
6.12 
Management of Infection ............................................................................................... 53 
6.13 
Management of Other Toxicities ................................................................................... 53 
7 PROTOCOL DEVIATIONS ................................................................................................... 53 
8 STATISTICAL METHODS ..................................................................................................... 54 
8.1 
Demographics ................................................................................................................ 54 
8.2 
Efficacy Analysis ........................................................................................................... 54 
8.3 
Safety Analysis .............................................................................................................. 54 
8.4 
Deaths ............................................................................................................................ 54 
8.5 
Sample Size Determination ............................................................................................ 54 
9 ETHICS .................................................................................................................................. 55 
9.1 
Institutional Review Board ............................................................................................ 55 
9.2 
Ethical Standards ........................................................................................................... 56 
9.3 
Informed Consent Process ............................................................................................. 56 
10 SOURCE DOCUMENTS AND CASE REPORT FORMS ...................................................... 57 
11 STUDY OVERSIGHT – Quality Assurance and Quality Control .......................................... 57 
11.1 
Data Safety and Study Oversight ................................................................................... 57 
11.2 
Clinical Monitoring ........................................................................................................ 58 
11.3 
Study Auditing ............................................................................................................... 59 
12 REFERENCES ....................................................................................................................... 59 
 
 
 
 

 
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1 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE:  Azacitidine and Venetoclax (ABT-199) as Induction Therapy with 
Venetoclax Maintenance in Previously Untreated Elderly Patients with Acute Myeloid 
Leukemia  
INDICATION:  Previously untreated elderly patients with acute myeloid leukemia (AML) 
STUDY PHASE: II 
BACKGROUND AND RATIONALE:  The majority of patients with AML are elderly, but 
standard approaches to this disease involve treatment with intensive chemotherapy which 
is prohibitively toxic with sub-optimal response rates. Less toxic and more effective 
therapies are needed. Venetoclax is a specific BCL-2 inhibitor that has been highly 
effective in a large-scale phase 2 study when paired with the hypomethylator azacitidine 
and given continuously in this population. However, both of these therapies result in 
cytopenias, and the degree and severity of this complication can be limiting for patients 
who are otherwise deriving anti-leukemia benefit. Therefore, a clinical trial using this 
combination that is designed to allow for a deep response followed by a more tolerable 
maintenance strategy, guided by the presence or absence of minimal residual disease, is 
proposed. 
STUDY OBJECTIVES: 
Primary:  To determine the remission duration experienced by elderly previously 
untreated AML patients with azacitidine plus venetoclax followed by venetoclax alone as 
a maintenance therapy for patients who achieve a minimal residual disease (MRD) 
negative remission. 
Secondary:   
• 
To determine the rate of MRD negative composite responses (includes complete 
remission [CR], complete remission with incomplete count recovery [CRi], and 
morphologic leukemia free state [MLFS]) with azacitidine plus venetoclax 
• 
To determine the median time to achieve a MRD negative composite response 
STUDY DESIGN: 
This is an open label, Phase 2 study for elderly, previously untreated patients with AML 
using azacitidine with venetoclax as “induction” therapy followed by venetoclax 
maintenance in those patients who achieve a MRD negative response to induction. 
After consent and screening, patients will be admitted to the hospital for dose escalation 
of venetoclax. After dose escalation has completed patients may discharge and continue 
management in the outpatient setting if appropriate. 
 
On day 1 of cycle 1, azacitidine 75 mg/m2 SC or IV will be given, and will continue for 7 
days. 
 

 
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Starting on day 1 of cycle 1, venetoclax will be escalated to a target dose of 600 mg. This 
will involve administration of 100 mg on day 1, 200 mg on day 2, 400 mg on day 3 and 
600 mg on day 4. Subsequently, patients will take venetoclax 600 mg daily. 
 
On cycle 1 day 8, a bone marrow biopsy will be performed.  
 
On cycle 1 day 28, a bone marrow biopsy will be performed to determine response status. 
This will include an assessment of MRD, with an ability to quantify and detect disease to 
a level of at least 0.1%.1,2 
 
Patients who do not achieve a MRD negative composite response after the first cycle will 
repeat the cycle, with both azacitidine and 600 mg venetoclax given on day 1. A bone 
marrow biopsy will occur after cycle 2. If there is not a MRD negative composite response, 
patients will receive a third cycle, identical to the second. A bone marrow biopsy will be 
performed after the third cycle.  If there is not a MRD negative composite response after 
the third cycle, patients will continue with azacitidine and venetoclax, now given at 400 mg 
daily, starting on day 1 of each cycle, with bone marrow biopsies after each odd-numbered 
cycle until they achieve a MRD negative composite response, progress or experience 
unacceptable toxicity. If patients achieve a CR/CRi/MLFS that remains MRD positive by 
cycle 9, they will have a bone marrow biopsy after cycle 12 and then every 6 
cyclesthereafter. 
 
Once patients achieve a MRD negative composite response, azacitidine will be 
discontinued and venetoclax decreased to 400 mg daily, defined as “maintenance”. 
Patients will undergo bone marrow biopsies every three cycles for the first year, and every 
six cycles thereafter, with MRD assessments performed with every biopsy. 
STUDY ENDPOINTS 
Primary:  Remission duration 
Secondary: 
• 
Response rate, with responses defined as CR, CRi and MLFS, and the incidence 
of MRD-negative responses, with induction therapy 
• 
Median time to achieve MRD negative composite response  
• 
 
STUDY DURATION: 3-4 years 
TOTAL SAMPLE SIZE: 42 

 
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2 
SCHEDULE OF STUDY ASSESSMENTS1 
Procedures 
Screen2 
Cycle 1 “Induction” 
Induction 
Cycles 2+  
Maintenance 
Cycles 
End of 
Treatment 
Safety 
Follow 
Up3 
Day 1 
Days 2 
to 4 
Days 5 
to 7 
Day 8 
Day 28 
Day 1 
Day 28 
Day 1 
Day 28 
Allowable Window 
28 days 
  
  
  
+/-1 days 
+/-3 days 
+/-7 
days
+/-3 
days
+/-7 
days
+/-3 
days
+/-14 days 
+/-10 days 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
History 
X 
  
  
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
X 
  
  
X 
X 
X 
  
X 
  
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
ECOG PS 
X 
X 
  
  
  
X 
X 
  
X 
  
X 
  
Cytogenetics 
X 
  
  
  
  
X 
  
X5 
  
X6 
X 
  
MRD  
X 
  
  
  
  
X 
  
X6 
  
X6 
X 
  
AE&Con Meds 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
 X6 
12-lead EKG7 
X 
  
  
  
  
  
  
  
  
  
  
  
TLS Labs8 
  
X  
X 
  
  
  
  
  
  
  
  
  
Hematology/Chemistry 
X9 
X 
X 
X 
  
X 
X 
 
X 
 
X 
  
Azacitidine 
  
X 
X 
X 
  
  
 X10 
  
 
 
  
  
Venetoclax 
  
 X 
X 
X 
X 
X 
 X 
 
 X 
 
  
  
BM aspirate and biopsy 
X 
  
  
  
X11 
X 
  
X12 
  
X13 
X15 
  
Calendar & Diary- 
Dispense/Collect 
  
X 
  
  
  
X 
X 
 
X 
 
X 
  
 
1 For detailed description of all elements please see section 5.10 
2 Screening assessments must occur within 28 days of cycle 1 day 1 (unless historical record)  
3 A separate safety visit does not need to be performed for subjects with a final visit ≥30 days after discontinuation of study drug 
4 Includes weight, temperature, blood pressure, pulse, respiratory rate and, if needed, oxygen saturation. All methods of measurement and practices will be per institutional practice 
5 Occurs with each bone marrow biopsy 
6 Only adverse events need to be followed through safety follow up (until 30 days after the patient’s last study treatment), con med collection to end at EOT 
7 A single 12-lead resting EKG will be obtained at screening, and as needed 
8 Within 4 hours prior to the venetoclax dose and again 6 and 12 hours after the dose (+/- 2 hours) 
9 Coagulation testing only occurs at screening 
10 Administer azacitidine on days 1-7 
11 Only Aspirate required; can be performed on D7 after final dose of azacitidine 
12 Will occur after cycle 2 and if needed cycle 3. In the absence of a MRD negative response biopsies will occur at the investigator’s discretion after cycle 3. Biopsies will be mandated after each 
odd # cycle until cycle 9. After this, they may be performed after every 3-6 cycles at the investigator’s discretion. 
13 Will occur every 3 cycles for the 1st year, then every 6 cycles, or at investigator’s discretion 
15 If aspirate & biopsy with cytogenetics and MRD occurred within 14 days of EOT visit, procedure is not required at EOT 

 
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3 
INTRODUCTION 
3.1 
Background and Rationale 
Acute myeloid leukemia (AML) is the most common acute leukemia in 
adults,3 afflicting about 20,000 patients and causing over 10,000 deaths in 
the United States annually.4 The standard of care for newly diagnosed 
patients for over the last 40 years is for them to receive intensive 
chemotherapy with infusional cytarabine and intermittent dosing of an 
anthracyline5. Depending on their risk profiles, some patients who achieve 
a remission can be cured with an allogeneic stem cell transplantation and 
others with more chemotherapy, but the vast majority of patients relapse 
and die from their disease.6 
 
Elderly patients (>60 years) have extremely poor outcomes, with almost no 
patients in this group experiencing long-term meaningful survival.7,8 This is 
due to both biological disease related features that make them more 
resistant to standard chemotherapy approaches, and to increased 
comorbidities that increase treatment-related mortality.9 There are no FDA 
approved agents specific to this population; however, these patients 
constitute the majority of those with AML, as the median age at diagnosis is 
in the seventh to eighth decades of life.9 More effective and more tolerable 
therapies are urgently needed for this population. 
 
Azacitidine (Vidaza™, Celgene) is a pyrimidine nucleoside analog of 
cytidine.  It incorporates into DNA and RNA and binds to DNA 
methyltransferase enzymes, preventing the methylation of cytosine 
residues at CpG dinucleotides and resultant transcription of genes with 
heavily methylated promoter regions.10  In patients with myelodysplastic 
syndrome (MDS) and AML, treatment with azacitidine decreases the 
methylation of tumor suppressor gene promoters, which correlates with 
clinical outcomes.11  Furthermore, in AML patients who attain a clinical 
remission, methylation levels correlate with relapse risk and are inversely 
related to relapse-free survival.12 In older patients with AML who were 
thought to be poor risk candidates for induction chemotherapy, the use of 
single-agent azacitidine had an overall response rate of 60%, a CR rate of 
20%, and in patients who responded, a median survival of over 15 months.13  
Based on this data, although not approved for AML, it has become the de 
facto standard of care treatment for elderly patients with AML. 
 
Venetoclax (ABT-199, Abbvie) is a potent, selective and orally bioavailable 
small molecule inhibitor of BCL-2 that binds with > 1,000-fold higher affinity 
to BCL-2 (Ki < 0.010 nM) than other apoptotic pathway proteins BCL-XL (Ki 
= 48 nm) or MCL-1 (Ki > 444 nM).14  Leukemia stem cells (LSCs) 
overexpress BCL-2,15 and BCL-2 overexpression has been associated with 

 
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worse outcomes in AML16,1716,1716,17.16,17 Pre-clinical studies using cell lines 
and primary specimens showed sensitivity to venetoclax,18 and a single-
agent study in patients with relapsed and refractory disease displayed 
efficacy with an acceptable toxicity profile.19 
 
When used in combination with a hypomethylator (azacitidine or decitabine) 
or with low-dose cytarabine in older patients unfit for standard induction 
chemotherapy who had never before been treated, results were promising. 
The regimen was well tolerated, and remission rates approached 80% with 
durable responses.20  One potential explanation for the improvement in 
efficacy when comparing these two clinical trials is that the venetoclax 
synergizes with the backbone therapy. MCL-1 can result in resistance to 
BCL-2 inhibition, and cytarabine and azacitidine have shown the ability to 
down-regulate MCL-121,22. In support of this concept, pre-clinical studies 
using a less selective BCL-2 inhibitor with azacitidine resulted in synergistic 
cell killing and the prevention of engraftment in an immunocompromised 
mouse model. An alternative explanation for the improvement in outcomes 
in the combination study compared to the single agent study may be due 
more to the setting in which patients were treated. LSCs become 
significantly more abundant and heterogeneous in the relapsed setting;23 
therefore, one might expect a LSC-directed therapy to have better efficacy 
in the up-front treatment setting compared to patients with relapsed 
disease.24 The improved outcomes in the combination study may have less 
to do with the combination and more to do with the fact that venetoclax is 
being given to patients with a relatively homogenous LSC population that 
can be effectively targeted. 
 
As of March 9, 2016, 45 patients 65 or older with newly diagnosed AML who 
were not eligible to receive standard induction therapy were enrolled into 
the escalation stage of the Phase 1b study (M14-358) of venetoclax in 
combination with a hypomethylator. Three dose levels were administered, 
400, 800 and 1200 mg. Venetoclax was administered daily during 
continuous 28-day cycles in combination with decitabine or azacitidine, and 
preliminary safety and efficacy data have been reported.20 The most 
common adverse events (AEs) for all subjects were nausea (53.3%), 
diarrhea (44.4%), febrile neutropenia (40.0%), neutropenia (31.1%), 
thrombocytopenia (28.9%), cough (28.9%), fatigue (28.9%), peripheral 
edema (26.7%), and hypokalemia (26.7%). The majority of patients (91.1%) 
had grade 3 or greater events; the most common was febrile neutropenia 
(40%). Serious adverse events (SAEs) occurred in 60% of patients, 
including febrile neutropenia (24.4%), atrial fibrillation, abdominal pain, non-
cardiac chest pain, pyrexia, pneumonia, sepsis and bone pain (4.4% each, 
each event occurring in a single patient).  
 

 
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This was widely regarded as an acceptable safety profile in this population. 
However, as noted above, hematological toxicity was not insignificant.  
Venetoclax can result in bone marrow suppression; in heavily pre-treated 
patients with chronic lymphocytic leukemia (CLL), the grade 3/4 incidence 
of neutropenia was 40-50%, but lower in patients with non-Hodgkin 
lymphoma who had fewer prior therapies and higher doses of venetoclax.25  
Fewer patients experienced grade 3/4 thrombocytopenia and anemia (12% 
for both)26. With single-agent use of venetoclax in relapsed and refractory 
AML patients, 31% experienced febrile neutropenia. Azacitidine has 
overlapping toxicity when it comes to myelosuppression; in a study of 
elderly AML patients who received azacitidine, 28% had febrile neutropenia, 
26.3% had grade 3/4 neutropenia, 23.7% had grade 3/4 thrombocytopenia 
and 15.7% had grade 3/4 anemia.27 
 
Patients enrolled in the hypomethylator plus venetoclax study were noted 
to have rapid responses, with most remissions occurring within the first two 
cycles of therapy. In addition, there were many deep remissions noted, 
either by molecular analysis or the clearance of a cytogenetic abnormality. 
However, patients receiving this treatment continue therapy indefinitely with 
sequential cycles even after achieving a remission, in the hopes that 
continuous therapy will prolong the remission duration of a regimen not 
thought to be curative. Given the hematological toxicity of continued 
therapy, and the potential for increased complications, costs and negative 
impact on quality of life from treatment-induced bone marrow suppression, 
it would be appealing to adapt the current venetoclax with azacitidine 
regimen to allow for an “induction” phase in which a remission is rapidly 
induced, and quickly follow that up with a “maintenance” phase to prolong 
the remission. 
 
In protocol M14-358, patients receive either 400 or 800 mg of venetoclax 
daily with the standard dose and schedule of azacitidine (75 mg/m2 on d1-
7) of each cycle. There is some suggestion that the 800 mg cohort 
experienced faster remissions than the 400 mg cohort; they also had 
increased hematologic adverse events. Therefore, this protocol will utilize 
an “induction” phase consisting of azacitidine at the same dose and 
schedule, with a higher dose (600mg) of venetoclax. When patients achieve 
a deep response as defined as the absent detection of minimal residual 
disease (MRD), they will enter “maintenance” phase, in which they are 
maintained on only single agent venetoclax at the 400 mg dose, with the 
rationale that a LSC directed therapy as a single agent can continue to 
target low-level disease and prolong remissions24,28, and allow for greater 
tolerability and reduced hematologic toxicity. 
 
 

 
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Hypothesis: Patients who achieve a MRD-negative response with 
“induction” phase of venetoclax with azacitidine can be maintained on 
a reduced dose of venetoclax alone with equivalent response duration 
and less hematologic toxicity compared with indefinite maintenance 
therapy with venetoclax and azacitidine.  
 
3.2 
 
Venetoclax 
3.2.1 Preclinical Pharmacokinetic Profile 
In mouse, rat, monkey, and dogs, the venetoclax pharmacokinetic 
profile was characterized by low plasma clearance (CLp = 0.02 to 
0.27 L/hr•kg) and low volumes of distribution (Vss = 0.3 to 1.1 L/kg). 
Half-lives ranged from 2.2 hours in monkeys to 12.0 hours in dogs. 
Formulation-dependent oral bioavailability was noted in all species. 
Studies in both rat and dog have defined the behavior of the 
amorphous solid dispersion for both toxicology and first-in-human 
evaluation. Plasma concentrations obtained from fed dogs were 30% 
to 50% higher than those obtained from fasted animals. 
Venetoclax and its M27 metabolite are predominantly metabolized 
by cytochrome P450 (CYP) 3A4 (CYP3A4) in vitro; UDP-
glucuronosyltransferases (UGTs) are not involved in the metabolism 
of venetoclax. Venetoclax is also substrate for P-glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP) transporters. No active 
uptake of venetoclax was observed in cells overexpressing organic 
anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Based 
on in vitro results, venetoclax was a P-gp, BCRP, and OATP1B1 
inhibitor. It was not a potent in vitro inhibitor of CYP3A4, CYP1A2, 
CYP2B6, or CYP2D6 (IC50 > 30 μM), and it did not induce CYP3A4 
or CYP1A2 at concentrations up to 10 μM. Venetoclax is also not 
predicted to cause inhibition of CYP2C19, CYP2C8, CYP2C9, and 
UGT1A1 at clinically relevant concentrations. It is not an inhibitor of 
UGT1A4, UGT1A6, UGT1A9 and UGT2B7. 
3.2.2 Preclinical Toxicology 
Toxicology studies completed with venetoclax are general toxicology 
studies with periods of once-daily oral dosing ranging from 2 weeks 
to 6 months in mice, from 2 weeks to 13 weeks in rats, and from 1 
week to 9 months in dogs. In vitro and in vivo genetic toxicology and 
dose range-finding studies in mice and rats to support dose selection 
for possible carcinogenicity assessments, embryo-fetal development 
in mice and rabbits, fertility and early embryonic development in male 
and female mice, dose range-finding in juvenile mice, and 
phototoxicity in mice studies have been performed. Other studies 

 
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were in vitro genetic toxicity testing of the M27 major human 
metabolite and in vitro and in vivo impurity qualification. Reversibility 
of venetoclax-related changes was assessed in the 4-week study in 
mice and in the 2- and 4-week studies in dogs. The primary toxicities 
associated with repeat-dose administration of venetoclax are effects 
on the hematologic system (decreased lymphocytes and red blood 
cell mass in mice, rats and dogs), the male reproductive system 
(testicular germ cell depletion in dogs), and embryo-fetal toxicity in 
mice. Other noteworthy findings are epithelial single cell necrosis in 
multiple tissues and hair coat color change, both in dogs. Maximum 
venetoclax plasma exposures (mean AUC0-24 h, combined male 
and female values) achieved in the 4-week studies were 92 μg•hr/mL 
(at 600 mg/kg/day) in mice and 572 μg•hr/mL (at 150 mg/kg/day) in 
dogs. In the 6-month mouse and 9-month dog chronic toxicity 
studies, AUCs reached 34.1 μg•h/mL (at 300 mg/kg/day) in mice and 
85.6 μg•h/mL (at 20 mg/kg/day) in dogs. In rats, exposures were 
higher in females than in males; at dosages of 150 and 400 
mg/kg/day in the 13-week maximum tolerated dose study, exposures 
ranged up to 83.1 to 127.8 μg•h/mL in females and up to 26.4 to 44.3 
μg•h/mL in males. Venetoclax produced generally dose-related 
decreases in lymphocytes in the peripheral blood (up to –75% in 
mice, –64% in rats, and –81% in dogs) and in lymphoid tissues. 
These findings are consistent with the expected pharmacology of 
venetoclax (a selective Bcl-2 inhibitor)29. Following a 4-week 
recovery period, lymphocyte counts remained minimally decreased 
by 21% to 26% in mice, indicating that reversibility was occurring but 
was not complete. In dogs, the recovery of decreases in peripheral 
blood total lymphocytes and lymphocyte subsets (CD4+ T-cells and 
CD8+ T-cells and [CD21+] mature B cells) was prolonged, requiring 
up to 18 weeks after a single dose or after completion of 2 weeks of 
dosing. B-cells were the most sensitive lymphocyte subtype based 
on the magnitude of decrease (> 90%) and/or the length of time 
required for recovery. Lymphocyte decreases in lymphoid tissues 
were reversible in mice and dogs, but as with peripheral blood 
lymphocytes, required up to 18 weeks in dogs. Decreases in 
lymphocyte counts can be readily monitored in clinical trial subjects.  
In the 4-week mouse and dog studies, dose-related reversible 
decreases in red blood cell (RBC) mass were observed. Effects on 
RBC mass were typified by hemoglobin decreases. At the highest 
dosages administered, decreases in hemoglobin reached 21% in 
mice at 600 mg/kg/day and 23% in dogs at 150 mg/kg/day, and were 
considered to be adverse based on a criterion of 20% decrease. In 
rats, decreases in hemoglobin were more severe than in mice and 
dogs at comparable exposures and reached 30% to 49% at ≥150 

 
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mg/kg/day in female rats. Hematologic parameters are readily 
monitored in clinical trial subjects. 
No effects of venetoclax have been identified on the female 
reproductive tract of mice, rats, and dogs. However, in dogs 
venetoclax 
produced 
adverse, 
non-dose-related 
microscopic 
findings of testicular germ cell loss at all dosages tested (2 to 150 
mg/kg/day). In the 4-week study, testicular spermatogonia were 
decreased at the end of the dosing period, and their loss was 
consistent with the observed depletion of all germ cell types at the 
end of the 4-week recovery period. There were no testicular effects 
in mice or rats; in these animal species, exposures overlapped those 
in dogs. Venetoclax-induced testicular changes may be related to 
venetoclax pharmacology, as one or more members of the Bcl-2 
family of proteins play a role in spermatogenesis.30-32 There are 
currently no data assessing the effect of venetoclax on human 
spermatogenesis, and the actual risk to humans for testicular 
findings similar to those observed in dogs remains unknown. In view 
of the potential treatment benefits of venetoclax, this finding is 
anticipated not to impact the treatment of subjects with advanced 
hematologic malignancies. In the mouse embryo fetal development 
study, increased post-implantation loss and decreased fetal body 
weights occurred at the highest dosage administered (150 
mg/kg/day); the NOAEL was defined at the mid dosage of 50 
mg/kg/day. No fetal toxicity was observed in rabbits, but exposures 
were approximately one-tenth those in mice. Venetoclax was not 
teratogenic in mice or rabbits, and there were no other effects on 
development or fertility.  
Additional effects of venetoclax were white hair coat discoloration in 
dogs at ≥ 6 mg/kg/day and single-cell necrosis in multiple epithelial 
tissues at ≥ 2 mg/kg/day in dogs. Hair coat discoloration (increased 
amount of hair that was white) was observed in the dog after 
approximately 3 months of dosing in the 9-month chronic toxicity 
study. This change was consistent with loss of pigment in the hair 
and correlated histopathologically with decreased pigment in hair 
follicle bulbs. A change to gray coat color was also seen in NZBWF1 
mice treated daily with 33 or 100 mg/kg venetoclax, but not at lower 
dosages. Evidence from Bcl-2 knockout mouse (Bcl-2 -/-) studies 
indicates that hair hypopigmentation occurs due to loss of hair follicle 
melanocytes dependent on Bcl-2 for survival.33 In the dog, 
pigmentation of the skin and in the eye (particularly in the pigmented 
iris and fundus) appeared unaffected; this was confirmed by the 
absence of associated histopathologic findings in skin (other than in 
hair follicles) and in the eye. The risk of hair graying in clinical trial 
subjects treated with venetoclax is unknown.  

 
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Single cell necrosis occurred in the gallbladder, exocrine pancreas, 
epididymides, prostate, and stomach of dogs. These changes were 
minimal except for non-dose dependent minimal to mild single cell 
necrosis in the pylorus of the stomach at ≥ 2 mg/kg/day in the 9-
month study. After 4 weeks of dosing and a 4-week recovery period, 
reversibility was observed in the gallbladder and exocrine pancreas, 
but minimal single cell necrosis was still present in the epididymides 
and prostate (potentially related to the testicular effects) and in the 
stomach. Single-cell necrosis was considered not to be adverse due 
to its minimal to mild magnitude and because no loss of mucosal 
integrity was observed microscopically. Single cell necrosis was not 
found in the mouse or rat; maximum achieved exposures were 
comparable to or greater than the lowest exposures at which this 
finding occurred in dogs. 
There was no evidence of in vitro or in vivo genetic toxicity of 
venetoclax, nor was there evidence of phototoxicity (tested in vivo in 
hairless mice). Venetoclax administration in dogs in the 4-week study 
was associated with dose related, transient post-dose emesis, 
increased salivation, and fecal alterations (unformed or watery feces) 
at dosages of ≥ 5 mg/kg/day. These clinical signs were present 
throughout the dosing phase, but were not dose-limiting and were 
not observed in the recovery phase. In the 9-month dog study, non-
adverse decreases in mean body weight and body weight gain, 
associated with decreases in food consumption, were present at ≥ 2 
mg/kg/day. Dogs at the high dosage of 150 mg/kg/day in the 4-week 
study had clinical signs of swelling of the skin on the ears, head 
(cranial area), and forepaws and/or hindpaws. Most but not all 
animals (8 of 10 dogs) were affected, and in three dogs the swelling 
reaction was observed after the first dose. The clinical signs were 
limited to the 150 mg/kg/dosage, were transient and sporadic in 
occurrence, and were absent during the recovery period. A 
mechanistic basis for the swelling reactions was not established, but 
the clinical signs were mild to moderate in severity and reversible, 
and there were no signs of anaphylaxis. 
M27 is a major human metabolite observed at steady state in chronic 
lymphocytic leukemia (CLL) or non-Hodgkin's lymphoma (NHL) 
patient plasma samples. It is present at significantly lower exposure 
levels (0.04- and 0.06-fold, respectively) in the mouse and dog, and 
therefore is a disproportionate metabolite. M27 was negative in 
Ames and chromosome aberration in vitro assays, has at least 58 
fold less in vitro potency than venetoclax, and demonstrates low off-
target toxicity potential based on in vitro secondary pharmacology 
assays. Taken together, these nonclinical results suggest that M27 
does not represent a significant safety risk, and does not change the 

 
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benefit/risk ratio for clinical trial subjects with advanced hematologic 
malignancies treated with venetoclax. 
Venetoclax was tested in a battery of safety pharmacology assays, 
and produced no effects in the central nervous system 
/neurobehavioral or respiratory studies in mice at oral doses up to 
and including the highest oral dose of 600 mg/kg. No effects on QTc 
were observed up to a maximum plasma concentration of 46 μg/mL 
in dogs. In conscious dogs, venetoclax did not produce any 
cardiovascular effects up to and including the highest oral dose of 
150 mg/kg (Cmax = 16 μg/mL). In the anesthetized dog at higher 
plasma concentrations, venetoclax produced mild reductions in 
myocardial contractility (6% to 13%) and cardiac output (11% to 
19%) at plasma concentrations of ≥ 16 μg/mL and ≥ 32 μg/mL, 
respectively. These concentrations are greater than the plasma 
concentration of venetoclax in humans (average Cmax = 6.09 μg/mL 
at the 1200 mg/day dose). 
On the basis of nonclinical toxicology and safety pharmacology 
evaluations of venetoclax, and on the basis of nonclinical and human 
studies of related anti-apoptotic Bcl-2 family protein inhibitors, 
potential mechanism-based toxicities may include lymphopenia and 
neutropenia, signs of tumor lysis, reduction in red cell mass, 
decreased 
spermatogenesis, 
skin 
swelling, 
and 
hair 
hypopigmentation. Although no effects of venetoclax on female 
reproductive tissues have been observed in general repeat-dose 
toxicology studies, embryo-fetal toxicity studies in animals have 
identified a fetal toxicity risk. Thrombocytopenia has not been a 
significant finding in toxicology studies in mice and dogs. These 
findings are consistent with venetoclax as a Bcl-2 specific (Bcl-XL 
sparing) inhibitor. Consequently, thrombocytopenia is not expected 
to be dose limiting. 
A detailed discussion of the preclinical toxicology, metabolism, and 
pharmacology can be found in the current Investigator's Brochure. 
3.2.3 Clinical Data 
As of 28 November 2015, based on the data available in the AbbVie 
and Genentech/Roche clinical databases, a total of 1509 subjects 
have been exposed to at least 1 dose of venetoclax in the oncology 
development program. Of these, data are available for 1498 
subjects; 102 had AML, 935 subjects had CLL/SLL, 346 subjects had 
NHL, and 115 subjects had multiple myeloma. An additional 66 
subjects were healthy volunteers who participated in the DDI studies. 
Based on the available data, a total of 564 oncology subjects 

 
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received the drug as monotherapy and 933 subjects received the 
drug in combination with other therapies. 
Based on the mechanism of action and nonclinical and clinical data 
available to date, the safety profile of venetoclax is well described. 
The most common adverse drug reactions across all indications are 
nausea, diarrhea, hematological effects, and serious and/or 
opportunistic 
infections. 
Hematologic 
effects 
include 
neutropenia/febrile neutropenia, thrombocytopenia, anemia, and 
lymphopenia. Upper respiratory tract infections are among the most 
common infections. 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 
venetoclax. 
 
Overview of Phase 2 Study M14-212: Venetoclax Monotherapy 
in AML 
In this completed single agent venetoclax trial (Study M14-212) in 
subjects with relapsed/refractory (R/R) AML 32 subjects have been 
dosed. Exposure, safety, and efficacy data are available for this 
study19. The most common adverse events observed in ≥ 10% of the 
subjects in study M14-212 were nausea (59.4%); diarrhea (56.3%); 
hypokalemia, vomiting (40.6% each); fatigue, headache (34.4% 
each); hypomagnesemia (37.5%); febrile neutropenia (31.3%); 
abdominal pain, cough, hypophosphatemia (28.1% each); epistaxis, 
hyperphosphatemia, 
hypocalcemia, 
malignant 
neoplasm 
progression (25.0% each); dyspnea, hypotension, peripheral edema, 
pyrexia, and pneumonia (21.9% each). Serious adverse events were 
reported in 27 subjects (84.4%), the most common being febrile 
neutropenia (28.1%), malignant neoplasm progression (25.0%), and 
pneumonia (15.6%). Three serious adverse events were considered 
to have a reasonable possibility of being related to venetoclax (i.e., 
1 event each of diarrhea, febrile neutropenia, and pseudomonal 
bacteremia). 
As of 11 March 2015, efficacy data for Study M14-212 are available 
for 32 subjects, the majority (30, 94%) of the subjects had R/R AML 
and a few were (2, 6%) deemed unfit for intensive therapy. The ORR 
was 19% (6 of 32 subjects), with complete remission (CR) in 2 (6%) 
and complete remission with incomplete marrow recovery (CRi) in 4 
(13%) subjects. Anti-leukemic activity was observed in and additional 
6 (19%) subjects, with 2 (6%) subjects each showing ≥ 50% 
reduction with 2 cell line recovery with transfusion independence, 1 
cell line recovery, and no hematologic recovery, respectively. 

 
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Treatment failure due to progressive disease or less than a partial 
remission (PR) was observed in 20 (63%) subjects. 
 
Overview of Phase 1b Study (M14-358): Venetoclax in 
Combination with HMA in Treatment Naïve AML 
As of March 9, 2016, a total of 45 subjects ≥ 65 years of age with 
treatment naïve AML ineligible to receive standard induction therapy 
were enrolled into the escalation stage at 3 dose levels of venetoclax 
at 400 mg, 800 mg, and 1200 mg. Venetoclax was administered daily 
during the 28-day cycles in combination with decitabine (20 mg/m2 
intravenously on Days 1 – 5 once every 28 days) or azacitidine (75 
mg/m2 intravenously or subcutaneously on Days 1 – 7 once every 
28 days). Preliminary safety and efficacy data are available from the 
ongoing dose escalation stage of this trial. 
The most common adverse events for all subjects in Study M14-358 
were nausea (53.3%), diarrhea (44.4%), febrile neutropenia (40.0%), 
neutrophil count decreased (31.1%), platelet count decreased, 
cough, and fatigue (28.9% each), edema peripheral and 
hypokalemia (26.7% each). Events grade 3 and above were reported 
for the majority (91.1%) of subjects; the most common event was 
febrile neutropenia (40.0%). Serious adverse events were reported 
for 27 (60.0%) subjects, including febrile neutropenia (11 subjects), 
malignant neoplasm progression (3 subjects) atrial fibrillation, 
abdominal pain, non-cardiac chest pain, pyrexia, pneumonia, sepsis, 
bone pain (2 subjects each). All other events occurred in 1 subject 
each. The combination of venetoclax with decitabine and azacitidine 
demonstrates a tolerable safety profile. 
As of March 9, 2016, the ORR, as assessed by the investigators for 
the subjects enrolled into the 3 dose levels, was 62.2% (28 of 45), 
with CR in 12 (26.7%), CRi in 15 (33.3%), and PR in 1 (2.2%). Four 
subjects (8.9%) were reported to have morphologic leukemia free 
state (less than 5% blasts in bone marrow aspirate sample with at 
least 200 nucleated cells) after completion of Cycle 1. Eight patients 
(17.8%) had resistant disease. However, all of the patients with 
resistant disease had evidence of blast reduction at completion of 
Cycle 1. The patients enrolled into the 1200 mg dose level had a 
shorter follow-up at the time of this analysis. 
The maximum tolerated dose has not been reached in either arm and 
dose escalation stage has completed enrollment. Enrollment into 
safety expansion at 400 mg and 800 mg dose of venetoclax in 
combination with both HMAs is ongoing. 

 
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Additional safety and efficacy data are described in more detail in the 
current version of the Investigator's Brochure. 
3.3 
Azacitidine 
Azacitidine, an analog of the pyrimidine nucleoside cytidine, has 
effects on cell differentiation, gene expression, DNA synthesis and 
metabolism, and causes cytotoxicity. Since the early 1970s, 
azacitidine has been investigated in the US for the treatment of acute 
leukemia, with clinical trials focused primarily on patients with 
refractory disease. These investigations indicated azacitidine has 
activity in the treatment of AML. 
 
The cytotoxic effects of azacitidine may result from multiple 
mechanisms, including inhibition of DNA, RNA and protein synthesis, 
incorporation into RNA and DNA, and activation of DNA damage 
pathways. The ability of azacitidine to cause differentiation is 
attributed to its activity as a hypomethylating agent. Therefore, an 
inhibitor of DNA methylation such as azacitidine would be a rational 
approach to revert epigenetic changes in the malignant clone and re-
establish 
the 
antiproliferative 
signals 
extinguished 
by 
hypermethylation.  
 
3.3.1 Preclinical Pharmacokinetic Profile 
Early PK studies used 14C-radiolabeled azacitidine to evaluate drug 
disposition. Based on total radioactivity in plasma, azacitidine was 
absorbed when given subcutaneously (SC), with maximum 
concentrations found 0.5 to 2 hours after dosing. Azacitidine and/or 
its metabolites were then cleared by the kidneys. The plasma t1/2 (3.4 
to 6.2 hours) and amount of radioactivity recovered in urine (50-98% 
of administered dose) were similar after IV and SC dosing.  
 
Drug-drug interaction studies of azacitidine have not been conducted 
in clinical trials. Two in vitro metabolism studies and three in vitro 
drug interaction studies have been completed. Some evidence of 
hepatic metabolism was observed when azacitidine was incubated 
in human liver fractions. The metabolism of azacitidine was 
compared using [14C]5-azacitidine and hepatic S9 fractions from 
human and mouse origin; the formation of deaminated metabolites 
(formylamidinoribofuranosylbiuret 
and 
ribofuranosylbiure) 
was 
independent of nicotinamide adenine dinucleotide phosphate 
(NADPH), implying that metabolism was catalyzed by cytosolic 
enzymes. Azacitidine was not an inducer of the isozymes 1A2, 2C19, 
or 3A4/5. Azacitidine showed no notable inhibition of P450 

 
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isoenzymes (Cytochrome P450 [CYP450] 1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1 and 3A4) in the concentration range of 0.1 to 100 
μM. Therefore, clinically relevant inhibitory or inductive effects on the 
metabolism of CYP450 substrates are unlikely. Azacitidine is neither 
a substrate nor an inhibitor of P-glycoprotein (P-gp) and therefore 
unlikely to produce any clinically relevant interactions as a P-gp 
substrate or an inhibitor. The effect of inducers or inhibitors on the 
metabolism of azacitidine has not been studied. 
 
3.3.2 Clinical Data 
The safety profile of azacitidine has been well characterized and is 
based on an extensive amount of patient exposure across a wide 
range of doses and indications. Adverse events (AEs) reported most 
frequently 
were 
hematologic 
events 
of 
thrombocytopenia, 
neutropenia, anemia, and leukopenia, and were typically assessed 
as grade 3 or 4 events. Despite the increased percentages of these 
hematologic events, azacitidine did not appear to increase the risk of 
events of infection or bleeding when compared with patients treated 
with best supportive care only. Non-hematological AEs that were 
reported most often were events related to either the administration 
of the drug (injection site reactions, nausea, vomiting) or 
consequences of the antiemetic treatment (constipation). These 
events were generally graded 1 or 2 in intensity. The reporting 
frequencies for the common hematologic and non-hematological 
events were generally highest during cycles 1 and 2, after which time 
the frequencies decreased over subsequent treatment cycles. Within 
the cycle, the hematologic events tended to occur across the first 3 
to 4 weeks of the cycle, whereas the events associated with the 
administration of azacitidine tended to occur in the first week. These 
findings suggested a lack of cumulative toxicity and that adverse 
effects of azacitidine attenuate over time. 
 
A recent randomized phase 3 study of older newly diagnosed 
patients with AML who received azacitidine versus conventional care 
regimens showed a CR+CRi rate of 27.8% and a median OS of 10.4 
months.27 
 
 
3.4 
Differences Statement 
This study will employ MRD testing to adjust the intensity of the 
regimen for each individual patient, in an attempt to minimize 
hematological toxicity. There are ongoing clinical trials of the 
combination of hypomethylators and low dose cytarabine with 

 
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venetoclax for elderly unfit AML patients, as well as a combination 
with cobimetinib or idasunutlin for patients with relapsed or refractory 
AML. In addition, studies with venetoclax are ongoing for other 
indications, including multiple myeloma, MDS and CLL/NHL. 
 
4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
To determine the response duration of “induction” therapy with 
azacitidine plus venetoclax followed by maintenance therapy with 
venetoclax alone for patients who achieve a MRD negative response 
state. 
4.2 
Secondary Objectives 
• To determine the rate of MRD negative composite responses 
(includes CR, Cri/CRp and MLFS) with the “induction phase” of 
azacitidine and venetoclax 
• To determine the median amount of time needed to achieve an 
MRD negative composite response 
• To determine the one-year overall survival (OS) of older, newly 
diagnosed AML patients treated with “induction phase” of 
azacitidine with venetoclax followed by a maintenance phase of 
venetoclax alone 
• To assess the hematologic toxicity of “induction” venetoclax with 
azacitidine followed by maintenance venetoclax alone 
 
5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is an open label, phase 2 single institution pilot study for older, 
untreated AML patients employing an “induction” phase of 
venetoclax with azacitidine followed by maintenance therapy with 
venetoclax alone in patients who experience a MRD negative 
response. 
5.1.1 Study Schema 
After consent and screening, patients will be admitted to the hospital 
for the venetoclax dose escalation during cycle 1. Cycles are defined 
as 28-day periods. After dose escalation has completed patients may 
Commented [BB1]: I think this is general enough that we 
can keep this as is but I’m just highlighting it for review just in 
case. 

 
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discharge and continue management in the outpatient setting if 
appropriate. 
 
On day 1 of cycle 1, azacitidine 75 mg/m2 SC or IV will be given, and 
will continue for 7 days. Antiemetic premedication will be 
administered per institutional protocol. Depending on the cycle or the 
clinical situation, azacitidine may be administered in the inpatient or 
outpatient setting.  The route of administration will be at the discretion 
of the investigators. Administration will be performed in accordance 
with institutional protocol. 
 
Starting on day 1 of cycle 1, venetoclax will be escalated to a target 
dose of 600 mg. This will involve administration of 100 mg on day 1, 
200 mg on day 2, 400 mg on day 3 and 600 mg on day 4 (Figure 1). 
Subsequently, patients will take venetoclax 600 mg daily and may be 
discharged from the hospital if medically appropriate. 
 
On day 8 of cycle 1 (or day 7 after the last dose of azacitidine is 
administered), a bone marrow biopsy will be performed.  
 
On day 28 of cycle 1 (with a 3-day grace period), a bone marrow 
biopsy will be performed to determine response status (see Section 
5.1.2). This will include an assessment of MRD by multi-dimensional 
flow cytometry1,2 or digital droplet PCR, allowing for quantification of 
disease to at least 0.1%. Persistence of cytogenetic abnormalities 
will be defined as MRD positive. Undetectable disease will be defined 
as MRD negative. 
 
Patients who do not achieve a MRD negative composite response 
after the first cycle will repeat another 28-day cycle, this time with 
600 mg venetoclax given days 1-28, with a bone marrow biopsy to 
determine response status at the completion of the cycle, again with 
a 3-day grace period. Patients who do not achieve a MRD negative 
composite response after the second cycle will repeat another 28-
day cycle, identical to cycle 2, with a bone marrow biopsy after the 
third cycle. If a MRD negative response is not achieved after the third 
cycle, patients will continue sequential cycles of azacitidine and 
venetoclax, now dose reduced to 400 mg daily, and given on day 1 
of each cycle. Bone marrow biopsies will occur at the conclusion of 
every odd-numbered cycle until cycle 9. If by cycle 9 a CR/CRi/MLFS 
with persistent MRD occurs, another bone marrow biopsy will occur 
after cycle 12 and then every 6 cycles, or at the discretion of the 
investigator. “Induction phase” will continue until the achievement of 
a MRD negative composite response, progression, or unacceptable 
toxicity. 

 
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Once a patient achieves a MRD negative composite response, 
regardless of when it occurs, they will enter the maintenance phase; 
azacitidine will be discontinued, and the dose of venetoclax will 
decrease from 600 mg daily to 400 mg daily if it has not already been 
reduced. Patients will undergo bone marrow biopsies (to determine 
response status) every 3 cycles for the first year of maintenance 
therapy, and then every 6 cycles thereafter, or at the discretion of the 
investigator. MRD assessments will be performed at each bone 
marrow biopsy. 
 
Figure 5-1 
 
 
5.1.2 Response Assessments 
Response assessments will be made by physical examination and 
evaluation of peripheral blood findings and bone marrow biopsies at 
the required time points (see Section 5.1.1), using the 2017 ELN 
AML response criteria34 and the definition of disease progression 
made according to the IWG35 (see Section 5.11).    
1     2     3     4 

 
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5.1.3 Continuation and Interruptions 
Patients who achieve a response and are tolerating therapy can 
continue to receive sequential treatment cycles indefinitely. Patients 
who experience disease progression or significant treatment-related 
toxicity, as assessed by the investigator or the patient, will 
discontinue therapy.  Patients who proceed to SCT will discontinue.  
 
After cycle 1, subsequent cycle delays are not required for any grade 
of hematologic toxicity; however, cycles may be delayed for any 
grade of hematologic toxicity, and myeloid growth factors may be 
used according to standard practices and at the discretion of the 
investigator, in the absence of evidence of ongoing disease. 
Subjects who require brief interruption of venetoclax for reasons 
other than progression of disease may continue on azacitidine 
therapy alone until they resume venetoclax. When the following cycle 
is resumed, venetoclax and azacitidine will resume on the same day. 
Azacitidine may be delayed at the discretion of the investigator, 
typically for febrile neutropenia, active infection or bleeding 
complications, and be resumed once the condition has improved or 
been stabilized with adequate treatment. Delays of azacitidine do not 
require delays of venetoclax. 
 
Dose decreases can be considered, see Section 5.14. 
5.2 
Study Endpoints 
5.2.1 Primary Endpoint 
• Duration of overall response (CR+CRi+MLFS), as 
measured by the first day a response is documented 
on a bone marrow biopsy to the first day the disease 
progresses, based on bone marrow biopsy, peripheral 
blood findings, clinical examination or radiographic 
study. 
5.2.2 Secondary Endpoints 
• Incidence 
of 
MRD 
negative 
responses 
(CR+CRi+MLFS) 
• Median time to achieve a MRD negative response 
(CR+CRi+MLFS) 
• One-year overall survival, stratified by response type 
and achievement of MRD negative state 
Commented [BB2]: Same comment as on p. 7 above. 

 
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• Incidence of febrile neutropenia, ≥ grade 2 bleeding 
complications and number of transfusions received 
(red blood cells and platelets) 
 
5.3 
Selection of Study Population and Enrollment Procedures 
All subjects will be screened for eligibility.  The investigators will be 
responsible for keeping a record of all subjects who sign an informed 
consent form for entry into the study. After the patient has signed and 
dated the informed consent form, all screening procedures have 
been completed and clinical eligibility has been confirmed, the 
patient can be officially enrolled in the study.  All patients must meet 
the qualifications as outlined below. 
5.3.1 Inclusion Criteria 
A subject will be eligible for study participation if he/she meets the 
following criteria within 28 days prior to the first day of therapy.  
Historical records are permitted per Investigator discretion. 
1. Subject must have confirmation of non-APL AML by WHO 
criteria36 and be ineligible or unwilling to undergo treatment 
with a standard cytarabine and anthracycline induction 
regimen due to co-morbidities or other factors 
2. Subject must have received no prior treatment for AML; 
hydroxyurea is not considered a treatment and is allowed  
3. Subject must be ≥ 60 years of age 
4. Subject must have a projected life expectancy of at least 12 
weeks 
5. Subject must have an Eastern Cooperative Oncology Group 
(ECOG) Performance status of ≤2  
6. Subject must have adequate renal function as demonstrated 
by a calculated creatinine clearance ≥ 30 mL/min; determined 
via urine collection for 24-hour creatinine clearance or by the 
Cockcroft Gault formula 
7. Subject must have adequate liver function as demonstrated by: 
• aspartate aminotransferase (AST) ≤ 3.0 × ULN* 
• alanine aminotransferase (ALT) ≤ 3.0 × ULN* 
• bilirubin ≤ 3.0 × ULN, unless due to Gilbert’s syndrome* 

 
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* Unless considered due to leukemic organ involvement 
8. Non-sterile male subjects must use contraceptive methods 
with partner(s) prior to beginning study drug administration 
and continuing up to 90 days after the last dose of study drug. 
Male subjects must agree to refrain from sperm donation from 
initial study drug administration until 90 days after the last 
dose of study drug. 
9. Female subjects must be either: 
 Postmenopausal; defined as Age > 55 years with no 
menses for 12 or more months without an alternative 
medical cause; 
OR 
 Permanently surgically sterile (bilateral oophorectomy, 
bilateral salpingectomy or hysterectomy) 
10. Subject is informed that consumption of the following fruits is 
prohibited 3 days prior to the initiation of study treatment and 
throughout participation: grapefruit, grapefruit products, 
Seville oranges (including marmalade containing Seville 
oranges) or Star fruit. 
11. Subject must voluntarily sign and date an informed consent, 
approved by an Institutional Review Board (IRB), prior to the 
initiation of any research directed screening or procedures. 
 
5.3.2 Exclusion Criteria 
A subject will not be eligible for study participation if he/she meets 
any of the following criteria: 
1. Subject has received treatment with a hypomethylating agent 
and/or other chemotherapeutic agent either conventional or 
experimental for myelodysplastic syndrome (MDS) or AML 
2. Subject has acute promyelocytic leukemia 
3. Subject has known active CNS involvement from AML 
4. Subject is known to be positive for HIV. HIV testing is not 
required 

 
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5. Subject is known to be positive for hepatitis B or C infection 
with the exception of those with an undetectable viral load. 
Hepatitis B or C testing is not required and subjects with 
serologic evidence of prior vaccination to HBV (i.e., HBs Ag, 
anti-HBs+ and anti-HBc–) may participate 
6. Subject 
has 
received 
anticancer 
therapies 
including 
chemotherapy, radiotherapy or other investigational therapy, 
including targeted small molecule agents within 5 half-lives 
prior to first dose of study drug. ATRA given for clinical 
suspicion of APL will not be exclusionary and no washout will 
be required in this scenario. 
7. Subject has received biologic agents (e.g. monoclonal 
antibodies) for anti-neoplastic intent within 30 days prior to 
first dose of study drug 
8. Subject has received the following within 7 days prior to the 
first dose of the study drug: 
• Steroid therapy for anti-neoplastic intent; 
• Strong and Moderate CYP3A inhibitors (see 
Appendix A for examples) 
• Strong and Moderate CYP3A inducers (see 
Appendix A for examples) 
 
 
 
9. Subject has any history of clinically significant condition(s) 
that in the opinion of the investigator would adversely affect 
his/her participating in this study including, but not limited to: 
• New York Heart Association heart failure > class 2 
• Renal, neurologic, psychiatric, endocrinologic, metabolic, 
immunologic, hepatic, cardiovascular disease, or bleeding 
disorder independent of leukemia 
10. Subject has a malabsorption syndrome or other condition that 
precludes enteral route of administration 
11. Subject exhibits evidence of uncontrolled systemic infection 
requiring therapy (viral, bacterial or fungal) 
12. Subject has a history of other malignancies prior to study 
entry, with the exception of: 

 
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• Adequately treated in situ carcinoma of the breast or cervix 
uteri 
• Basal cell carcinoma of the skin or localized squamous cell 
carcinoma of the skin 
• Prostate cancer with no plans for therapy of any kind 
• Previous malignancy confined and surgically resected (or 
treated with other modalities) with curative intent 
13. Subject has a white blood cell count > 25 × 109/L. Note: 
hydroxyurea is permitted to meet this criteria 
14.  Any subject who is a candidate for intensive induction therapy 
and agrees to receive intensive induction therapy 
 
5.4 
Duration of Study 
After treatment discontinuation, all patients will have a safety follow-
up visit approximately 30 days following patient’s last study 
treatment. 
  
5.5 
Drug Administration 
5.5.1 Venetoclax Administration 
Although it has not been clinically observed thus far, tumor lysis 
syndrome (TLS) may occur upon initiation of dosing with venetoclax 
with azacitidine. 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 to optimize 
the opportunity for achieving a response and enable close subject 
monitoring. For additional safety and efficacy data please refer to the 
current Investigator Brochure. 
 
During cycle 1, venetoclax will be administered orally once daily days 
1 through 28. Each dose of venetoclax will be self-administered with 
approximately 240 mL of water within 30 minutes after the 
completion of a meal, preferably breakfast. The dose should be 
administered at the same time each day. On days the subject is given 
azacitidine, venetoclax must be given first.  
 
If vomiting occurs within 15 minutes of taking venetoclax and all 
expelled tablets are still intact, another dose may be taken and the 

 
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second dose noted in the drug log. Otherwise, no replacement dose 
is to be taken.  
 
Subjects may not consume grapefruit or grapefruit products, Seville 
oranges (including marmalade containing Seville oranges) or Star 
fruit within the 3-day period prior to the first study drug administration 
and until the last day of treatment is completed due to possible 
CYP3A mediated metabolic interaction. 
 
Subjects will be admitted to the hospital where they will be confined 
from cycle 1 day 1 until at least 24 hours after receiving the 600 mg 
target dose. Dose modifications of venetoclax during escalation may 
be implemented for individuals at risk for TLS or any new adverse 
events > Grade 2 (see Section 5.14.3). To mitigate the potential risk 
of TLS37 subjects will receive TLS prophylaxis  which will include 
hospitalization for observation, administration of a uric acid reducing 
agent and adequate oral and intravenous hydration.  
If a subject develops any laboratory changes suggestive of TLS 
within the first 24 hours after either the first dose or during dose 
escalation, venetoclax dose escalation should be withheld or the 
dose should be reduced. Refer to Section 6.10, Management of 
Tumor Lysis Syndrome, for details on TLS prophylaxis. 
 
Venetoclax dose decreases may be considered, see Section 5.14.3, 
and for adverse event management guidelines please refer to 
Section 6. 
 
Patients who take more than the prescribed dose of venetoclax 
should be instructed to seek emergency medical care if needed and 
contact study staff immediately. If a dose of venetoclax is missed or 
forgotten, it should be taken as soon as possible, ensuring it is taken 
within 8 hours of the missed dose with food; otherwise the dose 
should not be taken.  Missed doses should not be made up.  
 
Venetoclax tablets will be packaged in high-density polyethylene 
plastic bottles or blister cards. Each bottle or blister card will be 
labeled per institutional requirements. It must be stored at 15° to 
25°C (59° to 77°F). Venetoclax is for investigational use only and is 
to be used only within the context of this study. It must be maintained 
under adequate security and stored under the conditions specified 
on the label until dispensed for subject use or returned. Abbvie will 
provide venetoclax and it will be kept by the investigational 
pharmacy. 
 

 
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5.5.2 Azacitidine Administration 
Azacitidine 75 mg/m2 should be prepared and administered per the 
package insert and institutional guidelines. IV or subcutaneous 
administration is permitted. 
 
Table 1 Dose escalation of venetoclax with azacitidine 
 
 
5.6 
Assuring Patient Compliance 
The investigator and designated and qualified representatives will 
dispense study drug only to subjects enrolled in the study in 
accordance with the protocol. The study drug must not be used for 
reasons other than that described in the protocol. 
 
Patients will receive all dosages of azacitidine in the inpatient or 
outpatient setting.  
 
After the cycle 1 dose escalation, venetoclax will be self-
administered at home.  Patients will receive a diary to record the 
specific time each dose was taken and to record reasons for any 
missed doses.  Patient compliance will be assessed on day 28 of a 
completed cycle or day 1 of a subsequent treatment cycle.  Patients 
1     2     3     4 

 
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will be required to bring their diary, any remaining capsules, and the 
bottle, even if empty, to clinic during this visit.  Research personnel 
will count and record the number of used and unused drug at each 
visit and reconcile with the patient diary. Compliance will be 
monitored and documented by the study coordinator. Poor 
compliance will result in counseling of the subject by study site 
personnel. Any unused venetoclax will be returned to the pharmacy. 
 
 
5.7 
Drug Accountability 
The investigator and his representatives will verify that study drug 
supplies are received intact and in the proper amounts. This will be 
documented. The investigator or his representatives will administer 
study drug only to subjects enrolled in the study. A current (running) 
and accurate inventory of study drug will be kept by the investigator 
and will include shipping invoices and the date on which study drug 
is dispensed to the subject. Upon completion or termination of the 
study, all original containers (containing partially used or unused 
study drug) will be returned to the sponsor according to their 
instructions. Empty containers will be destroyed at the site. 
 
5.8 
Concomitant Therapy 
5.8.1 Permitted Concomitant Therapy 
Transfusion of blood and blood products, antibiotics, anti-emetics 
and other standard supportive care medications are permitted as 
needed. Hydroxyurea is permitted as needed according to 
institutional guidelines and to decrease the WBC to <25 × 109/L at 
the time of study entry or during the study, as needed. Filgrastrim 
may be used according to institutional guidelines.  Antibiotics will be 
used for patients with known infections or neutropenic fevers. 
 
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 on the appropriate electronic case report form (eCRF). 
 
Strong and moderate CYP3A inducers and inhibitors are excluded 
during the ramp-up stage of venetoclax, and alternative medications 
should be considered. (See Appendix A). If subject requires use of a 

 
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strong/moderate CYP3A inhibitor after reaching the target dose of 
venetoclax, use with caution and reduce the venetoclax dose by 50% 
for moderate inhibitors and at least 75% for strong inhibitors during 
co-administration (see table below).  After discontinuation of CYP3A 
inhibitor, wait for 2 to 3 days before venetoclax dose is increased 
back to the initial maintenance/target dose.   
 
Venetoclax Dose 
Venetoclax Dose Co-
Administered with a 
Moderate CYP3A 
Inhibitor 
Venetoclax Dose Co-
Administered with a 
Strong CYP3A 
Inhibitor 
100 mg (cycle 1 only) 
50 mg 
25 mg 
200 mg (cycle 1 only) 
100 mg 
50 mg 
400 mg 
200 mg 
100 mg 
600 mg 
300 mg 
100 mg 
 
If a subject requires use of strong/moderate CYP3A inducers after 
reaching the target dose of venetoclax, use with caution and contact 
AbbVie for guidance. 
5.8.2 Prohibited Concomitant Therapy 
Anticancer 
therapies 
including 
chemotherapy, 
systemic 
or 
intrathecal, 
immunotherapy, 
radiotherapy, 
biological 
agents 
(monoclonal antibodies) for anti-neoplastic intent, or other 
investigational therapy, including targeted small molecule agents, 
and prednisone >20 mg/day. 
 
A sample list of excluded and cautionary medications can be found 
in Appendix A. It is not possible to produce an exhaustive list of 
medications that fall into these categories, so if in question, please 
refer to the appropriate product label and/or FDA website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Developm
entResources/DrugInteractionsLabeling/ucm080499.htm 
 
Strong and Moderate CYP3A inhibitors  
Exclude during ramp-up stage of venetoclax and consider alternative 
medications. If subject requires use of these medications after 
reaching the target dose of venetoclax, use with caution and reduce 
the venetoclax dose by 50% for moderate inhibitors and at least 75% 
for strong inhibitors during co-administration.  After discontinuation 
of CYP3A inhibitor, wait for 2 to 3 days before venetoclax dose is 
increased back to the initial maintenance/target dose. 
 

 
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Strong and Moderate CYP3A inducers 
Exclude during ramp-up stage of venetoclax and consider alternative 
medications. If subject requires use of these medications after 
reaching the target dose of venetoclax, use with caution and contact 
AbbVie for guidance. 
 
5.9 
Contraception Recommendations 
 
Female subjects must be either postmenopausal defined as: 
o No menses for 12 or more months without an alternative medical 
cause 
OR 
o Permanently surgically sterile (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy) 
 
Male subjects must be surgically sterile (vasectomy with medical 
assessment confirming surgical success) or if the male subject has a female 
partner who is postmenopausal or permanently sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy), no contraception 
is required. 
 
If the male subject is sexually active with female partner(s) of childbearing 
potential, he must agree from enrollment through 90 days after the last dose 
of investigational product to practice contraception with a partner who 
agrees to at least one of the following contraceptive measures: 
o Combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) associated with the 
inhibition of ovulation, initiated at least 1 month prior to enrollment 
o Progestogen-only 
hormonal 
contraception 
(oral, 
injectable, 
implantable) associated with inhibition of ovulation, initiated at least 
1 month prior to enrollment 
o Bilateral tubal occlusion/ligation 
o Intrauterine device (IUD) 
o Intrauterine hormone-releasing system (IUS) 
o True abstinence: Refraining from heterosexual intercourse when this 
is in line with the preferred and usual lifestyle of the subject (periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable) 
 
Additionally, male subject agrees not to donate sperm from randomization 
through 90 days after the last dose of investigational product. 
 

 
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5.10 Study Procedures 
Study procedures listed in section 2 are detailed in this section, with the 
exception of adverse event information (see Section 6). All study data will 
be recorded on eCRFs. 
 
Procedures performed at screening will serve as baseline, unless repeated 
on cycle 1 day 1 prior to dosing, in which case this will serve as baseline. 
Any abnormal laboratory or vital sign between screening and prior to 
administration of therapy will be recorded in the subject’s medical history 
and will also serve as the subject’s baseline.  
 
Subjects who signed the informed consent will obtain a screening/subject 
number. Subjects who signed informed consent, have had at least one 
study procedure conducted, and who are determined to be a screen failure 
will not proceed to the study. The reason for the screen failure will be 
documented in the source document and captured in the eCRF. Screening 
procedures must be performed within 28 days prior to study drug 
administration. Subjects who complete all screening procedures and meet 
the inclusion criteria (see section 5.3.1) and none of the exclusion criteria 
(see Section 5.3.2) will proceed to enrollment. 
 
Informed consent 
Signed informed consent will be obtained from the subject or the subject’s 
legally acceptable representative in order to participate in the study. The 
IRB approved informed consent must be signed and dated by the subject 
or representative prior to undergoing any research directed procedures or 
before any prohibited medications are withheld from the subject in order to 
participate in the study.  Laboratory or procedural results obtained standard 
of care, and prior to consent to research procedures, are considered 
historical records and may be used in some circumstances at the discretion 
of the investigator. 
 
History 
Involves a complete medical history, with documentation of clinically 
significant medical conditions, and AML history including the date of 
diagnosis of AML and any precursor conditions. Also includes review of 
current medications and allergies. 
 
Physical Exam 
Symptom directed, per institutional protocol 
 
 
 
 

 
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Vital Signs 
Includes weight, temperature, blood pressure, pulse, respiratory rate and if 
needed, oxygen saturation. All methods of measurement and practices will 
be per institutional protocol. 
 
ECOG PS38 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
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 
 
Cytogenetics 
By FISH or metaphase cytogenetics, per institutional standards 
 
MRD 
Performed by up to 3 procedures, when relevant. 1) Cytogenetic testing, 
both metaphase cytogenetics and FISH; 2) Multidimensional flow 
cytometric approach based on differences from normal; 3) Digital droplet 
PCR. Flow cytometry will always be performed; if a patient has an 
actionable ddPCR mutation, or cytogenetic abnormality, ddPCR and 
cytogenetic testing will be performed. MRD will be considered positive if any 
of the three above modalities is positive. In all cases, protocol-related 
clinical decision making will only be impacted by MRD testing that is 
performed in a CLIA-certified laboratory. 
 
AE and Con Meds 
On cycle 1 day 1, any serious adverse events observed from the signing of 
informed consent but prior to administration of azacitidine will be reported, 
if considered by the investigator to be causally related to study-required 
procedures. At each visit, including the end of treatment visit, the subject’s 

 
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medical history will be reviewed and any changes from baseline will be 
recorded on the adverse event eCRF. 
 
All medications, prescription and over the counter, including vitamins and/or 
herbal supplements, will be recorded beginning with the screening visit and 
continuing until End of Treatment. Administration of IV fluids does not need 
to be recorded.  
 
12 Lead EKG 
A single 12-lead resting EKG will be obtained at screening or as clinically 
needed. It will be recorded after the subject has been in the supine position 
for at least 5 minutes. Subjects will be instructed to remain stationary for the 
duration of the recording. An investigator will then evaluate it as clinically 
significant or not clinically significant, which will be entered into the CRFs.  
 
TLS Prophylaxis 
See Section 6.10 
 
Clinical Laboratory Tests 
All laboratory tests will be performed at the time points listed in the schedule 
of study assessments, and will be performed at additional time points based 
on institutional guidelines 
 
Hematology 
• Hematocrit 
• Hemoglobin 
• WBC count 
• Differential (if WBC high enough, per institutional standard) 
• Platelet count 
 
TLS Chemistry 
• Calcium 
• Phosphorus 
• Potassium 
• Uric Acid 
• Creatinine 
 
Chemistry 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Total bilirubin 
• Albumin 
• Alkaline phosphatase 
• Sodium 

 
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• Potassium 
• Chloride 
• Carbon dioxide 
• Glucose 
• Blood urea nitrogen (BUN) 
• Creatinine 
• Calcium 
• Magnesium 
• Phosphorus 
• Total Protein 
• Uric acid 
• Lactate dehydrogenase (LDH) 
 
Coagulation 
• Prothrombin time (PT) 
• International normalized ratio (INR) 
• Partial thromboplastin time (PTT) 
• Fibrinogen 
 
Azacitidine 
See Section 5.5.2 
 
Venetoclax 
See Section 5.5.1  
 
Bone marrow aspirate and biopsy  
To be performed at all time points outlined in the schedule of study 
assessments, in addition to at any time upon concern for relapse. Historical 
bone marrow aspirates and biopsy at screening may be acceptable; per 
Investigator discretion.  
 
Attempts to obtain an aspirate and biopsy are required at all listed time 
points except day 8, when an aspirate alone is sufficient. If a patient is not 
aspirable after an attempt is made, additional core biopsy specimens should 
be attempted per institutional protocol. On all time points except for day 8, 
samples should be sent for morphological assessment, flow cytometry, 
cytogenetic analysis and molecular testing, as is clinically appropriate. All 
results will be captured on a CRF. Day 8 aspirates may not involve 
cytogenetic and molecular assessments, as is clinically appropriate.  
 
Dispensing and Collecting Calendar and Diary 
Subject calendars/diaries will be provided at the time of discharge from the 
hospital. Subjects will bring their calendars/diaries back to be reviewed at 
each visit.  

 
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Subjects will record the date and time of each dose of study drug taken, 
including whether any doses of the study drug are missed, and whether or 
not doses were taken within 30 minutes after the completion of a meal 
(preferably breakfast).  
 
The calendars/diaries will be collected at each visit and will be filed by study 
staff in the subject source documents.  
 
Safety Follow Up 
A safety follow up visit should be performed approximately 30 days following 
discontinuation of study drug, and should include a history, physical 
examination and review of systems, and then should be repeated as 
clinically appropriate until any adverse events have resolved. A separate 
safety visit does not need to be performed for subjects with a final visit ≥30 
days after discontinuation of study drug and did not require additional AE 
follow up. Patient refusal or inability to attend safety follow up visits will be 
noted in the source documentation.  
 
 
5.11 Response Assessments 
Assessment of clinical responses will be made according to 2017 ELN AML 
Recommendations.34 Definition of disease progression will be made 
according to IWG criteria.35 The major criteria for judging responses will 
include physical examination and examination of blood and bone marrow. 
In the event that peripheral blood findings improve 14 days after a bone 
marrow biopsy, whether or not in the setting of a delay in treatment, the 
response assessment will be adjusted accordingly. Only subjects who 
complete cycle 1 will be evaluable for response. Patients with un-evaluable 
bone marrows should be reported as indeterminate and a repeat bone 
marrow should be completed within 1 week. Response duration is 
measured from the time all response criteria are first met until relapse is 
documented. 
 
Complete Remission (CR) 
CR requires all of the following: 
• Bone marrow blasts <5% 
• Absence of circulating blasts and blasts with Auer rods. 
• Absence of extramedullary disease 

 
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• Absolute neutrophil count >1.0 x 109/L 
• Platelet count >100 x 109/L 
  
  
Complete Remission with Incomplete Blood Count Recovery (CRi) 
CRi meets all CR criteria except for residual neutropenia or 
thrombocytopenia: 
• Absolute neutrophil count <1.0 x 109/L 
• Platelet count <100 x 109/L   
 
Morphologic Leukemia Free State (MLFS) 
• No hematologic recovery required 
• Marrow should not merely be “aplastic”; at least 200 cells should be 
enumerated or cellularity should be at least 10% 
 
CR/CRi/MLFS with MRD Negativity 
• Any of the above responses with negativity by multi-dimensional flow 
cytometry with a sensitivity to 0.1%  
 
Partial Remission (PR) 
PR meets all hematologic criteria of CR: 
• Absolute neutrophil count >1.0 x 109/L 
• Platelet count >100 x 109/L   
AND 
• Decrease of bone marrow blast percentage to 5% to 25% 
• Decrease of pretreatment bone marrow blast percentage by at least 
50% 
 
Treatment Failure 
Treatment failure will be classified as one of the following: 
• Resistant disease (RD): No CR or CRi or MLFS  or PR in subjects 
who survive at least 7 days after completion of cycle 1, with evidence 
of persistent disease by blood and/or bone marrow biopsy 

 
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• Death in aplasia: Deaths occurring ≥7 days following completion of 
initial treatment while cytopenic, or with an aplastic or hypoplastic 
bone marrow obtained within 7 days of death that shows no evidence 
of persistent leukemia 
• Death from indeterminate cause: Deaths occurring before 
completion of therapy, or <7 days following its completion; or deaths 
occurring ≥7 days following completion of initial therapy with no 
blasts in the blood, but no bone marrow examination available 
 
Relapsed Disease 
Relapse for patients with prior CR/CRi/MLFS/PR, independent of MRD 
status will be defined as: 
• Evidence of morphologic relapse with the appearance or 
reappearance of leukemic blasts in the peripheral blood or ≥ 5% 
blasts in the bone marrow not attributable to any other cause. If 
questionable, a bone marrow biopsy should be repeated within 1 
week to distinguish relapse from bone marrow regeneration 
• The 
appearance 
or 
reappearance 
of 
cytologically 
proven 
extramedullary disease 
 
5.12 Reporting of Results 
At the conclusion of each bone marrow biopsy performed after C1D8, all 
patients will be assessed as one of the following responses: 
• CR 
o With/Without MRD 
• CRi 
o With/Without MRD 
• MLFS 
o With/Without MRD 
• PR 
• RD 
• Death in Aplasia 

 
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5.13 Stopping Rules 
5.13.1 Individual Patient Stopping Rules 
All subjects will be included for analysis of safety data. Subjects have 
the right to withdraw from the study at any time. The investigator will 
discontinue a subject if this is felt to be necessary for any reason 
including:  
• Non-compliance with the study protocol 
• Is it believed to be in the best interests of the subject 
• Disease progression  
• Toxicity related to study drug that requires more than a 4-
week dose interruption of therapy and in the absence of 
clinical benefit 
• Need for other anti-neoplastic agents or radiotherapy for 
the development of a new primary cancer diagnosis 
• Adverse event that precludes further investigational drug 
administration 
• Development of unrelated illness which compromises 
further participation in the study 
• Study endpoints have been achieved 
 
In the event of withdrawal or discontinuation, the reason for 
discontinuation will be recorded and a final visit, including a physical 
examination, vital signs, ECOG PS, bone marrow aspirate and 
biopsy with cytogenetics and MRD, AE assessment with con meds, 
hematology/chemistry 
laboratories 
and 
collection 
of 
the 
calendar/diary, will be performed as soon as possible after 
discontinuation. If the subject had a bone marrow aspirate and 
biopsy with cytogenetics and MRD within 14 days of the end of 
treatment visit, then a repeated procedure is not required. 
 
5.13.2 Study Stopping Rules 
The study will continue until the last patient hasreceiving the last 
dose of study drug and completed the 30-day safety follow-up period. 
If the investigator determines that continued exposure to the study 
drug represents a significant risk to subjects, the study will be 
stopped. In addition, if at any time an ongoing statistical analysis 
reveals the median remission duration to fall below 8 months, the 
study will be stopped (see Section 8.5).  All enrolled subjects will be 
notified of the premature discontinuation and the investigator will 
administer treatments with other regimens as is appropriate. 
 

 
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5.14 Dosing Delays and Modifications 
5.14.1 Missed Doses 
If a dose of venetoclax is missed, it should be taken as soon as 
possible on the same day.  If it is missed for the entire day, it should 
not be made up. Patients will be encouraged to stay on schedule 
even if a dose is missed. Dosing will be tracked in the patients’ 
diaries.   
 
5.14.2 Additional Doses 
Patients who take more than the prescribed dose of venetoclax 
should be instructed to seek emergency medical care if needed and 
contact study staff immediately.  
 
5.14.2.1 Dose Delays 
After Induction cycle 1, the start of each subsequent cycle can 
proceed in the absence of possibly/related > grade 2 toxicity. 
In the presence of possibly/related > grade 2 toxicity, delay of 
the subsequent cycle for up to 14 days is allowed. If the 
possibly/related > grade 2 toxicity resolves to ≤ grade 1 within 
14 days, subsequent cycles may resume.  
 
After cycle 1, subsequent cycle delays are not required for any 
grade of hematologic toxicity; however, cycles may be 
delayed for any grade of hematologic toxicity, and myeloid 
growth factors may be used according to standard practices 
and at the discretion of the investigator, in the absence of 
evidence of ongoing disease.  
 
Subjects who require brief interruption of venetoclax for 
reasons other than progression of disease may continue on 
azacitidine therapy alone until they resume venetoclax.  
 
Azacitidine may be delayed at the discretion of the 
investigator, typically for febrile neutropenia, active infection 
or bleeding complications, and be resumed once the condition 
has improved or been stabilized with adequate treatment. 
This does not require delay of venetoclax. 
 
Dose decreases can be considered, see Section 5.14.3. 
 

 
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Drug interruption for up to 72 hours following transient (<48 
hours) chemical and laboratory TLS are allowed and will not 
require dose reduction. If the TLS has not resolved within 72 
hours, a dose reduction may be considered. 
 
5.14.3 Dose De-Escalation and Re-Escalation 
Dose de-escalation of venetoclax can be considered when 
deemed appropriate by the investigator for toxicity.  
 
During induction and before the completion of cycle 1 or 
documentation of a CR/CRi/MLFS, the venetoclax dose 
should remain 600 mg. After a CR/CRi/MLFS has been 
achieved with ongoing evidence of MRD, every effort should 
be made to maintain the 600 mg dose of venetoclax until an 
MRD negative state is achieved or the completion of cycle 3, 
whichever comes first. However, in the presence of > grade 3 
neutropenia/thrombocytopenia that persists >14 days off 
therapy, the investigator may reduce the dose of venetoclax 
using the following table: 
 
Clinical Scenario 
Venetoclax Dose 
First episode of >grade 3 
neutropenia/thrombocytopenia >14 days 
600 mg daily 
Second episode of >grade 3 
neutropenia/thrombocytopenia >14 days 
400 mg daily 
Third episode of >grade 3 
neutropenia/thrombocytopenia >14 days 
400 mg 21/28 days 
 
If an additional dose reduction is felt to be necessary before 
the patient achieves a MRD negative state, the patient will 
discontinue the study. If dose reduction occurs and there is no 
improvement in the cytopenia, and it is felt to be unrelated to 
venetoclax, venetoclax may be re-escalated. 
 
If venetoclax dose reduction occurred when a patient 
achieved MRD negativity and the patient subsequently loses 
MRD negativity, or if there is concern for this scenario, 
venetoclax may be re-escalated to 600 mg. Likewise, if 
venetoclax dose reduction occurred before MRD negativity 
occurred and it is later felt in the patient’s best interests to re-
escalate to 600 mg venetoclax, this is permitted. 

 
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Azacitidine may be dose adjusted according to the package 
insert. If three induction cycles do not result in an MRD-
negative state, the investigator can opt to discontinue the 
azacitidine and maintain the venetoclax. If it is deemed in the 
subject’s best interests to re-introduce azacitidine after it has 
been discontinued, this may occur during day 1 of any 
subsequent cycle. 
 
During maintenance phase, after MRD negativity has been 
achieved and the azacitidine has been discontinued, dose de-
escalation of venetoclax can be considered using the 
following table: 
 
Clinical Scenario 
Venetoclax 
Dose 
First episode of >grade 3 
neutropenia/thrombocytopenia >14 days 
300 mg daily 
Second episode of >grade 3 
neutropenia/thrombocytopenia >14 days 
200 mg daily 
Third episode of >grade 3 
neutropenia/thrombocytopenia >14 days 
200 mg 21/28 days 
Fourth episode of >grade 3 
neutropenia/thrombocytopenia >14 days 
200 mg 14/28 days 
 
If an additional dose reduction is felt to be necessary, the 
patient will discontinue the study. 
 
The “induction” phase may be modified to escalate to 400 mg 
of venetoclax instead of 600 mg, if the toxicity profile of 600 
mg is deemed prohibitive. In this case, the first cycle of 
“induction” will introduce 100 mg venetoclax on day 1, 200 mg 
on day 2 and 400 mg on day 3, and no more than 400 mg will 
be given with each induction cycle.  
 
 
 

 
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6 
SAFETY PLAN 
6.1 
Adverse Event 
An adverse event (AE) is defined as any untoward medical 
occurrence in a subject on the study. This can include any 
unfavorable or unintended sign, symptom or disease temporally 
associated with the use of the therapy, regardless of causality with 
the therapy. This may include use of the therapy as stipulated in the 
protocol or as labeled or from accidental or intentional overdose. 
Worsening of a pre-existing condition or illness is considered an AE. 
Worsening in severity of a reported AE should be reported as a new 
AE. Laboratory abnormalities and changes in vital signs are AE only 
if they result in study discontinuation, necessitate medical 
intervention, meet protocol specific criteria, and/or are considered by 
the investigator to be clinically significant or AEs. Elective surgeries 
or procedures scheduled to occur during a study are not AEs if the 
surgery/procedure is being performed for a pre-existing condition 
and the surgery/procedure has been pre-planned prior to study entry. 
However, if the pre-existing condition deteriorated unexpectedly 
during the study (e.g. the surgery must be performed earlier than 
planned) then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an AE. 
 
A treatment-emergent AE is defined as any AE reported by a subject 
with onset or worsening from the time that the first dose of study drug 
is administered until end of treatment. 
 
6.2 
Serious Adverse Events 
If an AE meets any of the following criteria it is to be considered a 
serious adverse event (SAE) and must be reported to Abbvie within 
24 hours, see Section 6.8.2. 
 
The PI will then review and submit to the University of Colorado 
regulatory authorities and the FDA, if applicable, in accordance with 
21 CFR 312.32. 
 
All SAEs will be reported using the FDA 3500A Mandatory 
MedWatch report form. SAE form can be found at:  
 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048
334.pdf 
Fatal: 
AE resulted in death 

 
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Life threatening: 
The AEs placed the patient at immediate 
risk of death in the opinion of the 
investigator. This classification does not 
apply to an AE that hypothetically might 
cause death if it were more severe. 
Hospitalization or 
prolongation of 
hospitalization: 
AE that required hospitalization for any 
length of time or prolonged inpatient 
hospitalization. Hospitalizations for 
elective medical or surgical procedures 
or treatments planned before enrollment 
in the treatment plan are not SAEs by 
this criterion. Admissions to an 
outpatient facility, emergency room, 
palliative unit or hospice care facility are 
not considered to be hospitalizations 
and are not SAEs. 
Disabling/incapacitating AE that results in substantial and 
permanent disruption of the patient’s 
ability to carry out normal life functions. 
Does not include experiences of 
relatively minor medical significance 
such as headache, nausea, vomiting, 
diarrhea, influenza and accidental 
trauma (e.g. ankle sprain) 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus 
of a patient exposed to the treatment 
regimen before conception or during 
pregnancy. 
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, 
life-threatening, hospitalization or 
prolongation of hospitalization, 
congenital anomaly or persistent or 
significant disability/incapacity). Any 
elective or spontaneous abortion or 
stillbirth is considered a SAE.  
 

 
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For SAEs that result in death, the date and cause of death will be 
recorded in the case report form.  
 
Deaths due to disease progression will not be recorded as SAEs. 
 
Hospitalization to allow observation and management for the 
purpose of TLS prophylaxis will not be considered SAEs unless there 
is an additional reason for hospitalization or an additional criterion for 
seriousness other than hospitalization (e.g., abnormal post-dose 
TLS laboratories that necessitate therapeutic medical intervention). 
 
Hospitalization of a subject in post-treatment follow up or survival 30 
days or more after discontinuation of the therapy will not be recorded 
as a SAE. 
 
SAEs occurring after informed consent but prior to initiation of 
therapy will be collected only if felt by the investigator to be causally 
related to the study required procedures. 
 
For hospitalizations or surgical or diagnostic procedures, the illness 
leading to the hospitalization or surgical or diagnostic procedure will 
be recorded as the SAE, not the procedure itself. The procedure will 
be captured in the narrative as part of the action taken in response 
to the illness. 
 
6.3 
Adverse Events Commonly Associated with AML 
Certain AEs are anticipated to occur in this study population at some 
frequency independent of drug exposure. For example, cytopenias 
(anemia, neutropenia, thrombocytopenia) are part of the natural 
history of AML. Therefore, persistent cytopenias at the same CTCAE 
grade as at baseline are not to be reported as AEs, unless they meet 
criteria for an SAE, result in permanent discontinuation of a study 
drug, or the investigator has an identifiable cause other than the 
underlying disease.  
 
6.4 
Adverse Event Severity 
The investigator will rate the severity of each adverse event 
according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE version 4.0). If a reported 
AE increases in severity, the initial AE should be given final outcome 
date and a new AE must be reported to reflect the change in severity.  
 

 
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For AEs not captured by the CTCAE, the following should be used: 
 
Grade 1 
The AE is transient and easily tolerated by the subject (mild). 
Grade 2 
The AE causes the subject discomfort and interrupts the 
subject’s usual activities (moderate) 
Grade 3 
The AE causes considerable interference with the subject’s 
usual activities and may be incapacitating (moderate to severe) 
Grade 4 
The AE is life-threatening requiring urgent intervention (severe) 
Grade 5 
The AE resulted in death of the subject (severe) 
 
6.5 
Relationship to Study Drug 
The investigator will use the following definitions to assess the 
relationship of the AE to the use of study drug: 
 
Reasonable Possibility of 
Relationship with 
Azacitidine 
An AE where this is evidence to suggest a 
causal relationship between azacitidine and 
the AE 
No Reasonable Possibility 
of Relationship with 
Azacitidine 
An AE where this is no evidence to suggest a 
causal relationship between azacitidine and 
the AE 
Reasonable Possibility of 
Relationship with 
Venetoclax 
An AE where this is evidence to suggest a 
causal relationship between venetoclax and 
the AE 
No Reasonable Possibility 
of Relationship with 
Venetoclax  
An AE where this is no evidence to suggest a 
causal relationship between venetoclax and 
the AE 
 
For causality assessments, events assessed as having a reasonable 
possibility of being related to the study drug will be considered 
“associated.” Events assessed as having no reasonable possibility 
of being related to study drug will be considered “not associated.” 
When no reasonable possibility of an association between a study 
drug and a SAE exists, the investigator must provide another cause. 
 

 
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6.6 
Deaths 
Death is an outcome of an event. Deaths that occur during the AE 
reporting period that are attributed by the investigator to AML 
progression will be recorded as such. For all deaths, the event or 
condition that caused or contributed to the fatal outcome will be 
recorded as the single medical concept on the AE CRF. If the cause 
of death is unknown and cannot be ascertained, “unexplained death” 
should be recorded. If the cause later becomes available, 
“unexplained death” should be replaced with the established cause 
of death. 
 
6.7 
Recording Adverse Events 
Patient safety will be assessed by reviewing AEs during planned and 
unplanned visits and physical and laboratory examinations from the 
time the patient receives the first dose of study drug until 30 days 
after the patient’s last study treatment. The investigator will assess 
and record AEs in detail including the date of onset, event diagnosis 
(if known) or sign/symptom, severity, time course (end date, ongoing, 
intermittent), relationship of the AE to the study drug, and any action 
taken. For SAEs considered unrelated to study drug, the investigator 
will provide another cause for the event. AEs may be recorded as the 
result of a response to a query, an observation by site personnel, or 
due to a report from a subject. All AEs will be followed to a 
satisfactory conclusion. 
 
6.8 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all Food and Drug 
Administration (FDA) safety reporting requirements. If the FDA 
determines an IND is necessary, it is a requirement of 21 CFR 
312.33 that an annual report be provided to the FDA within 60 days 
of the IND anniversary date.  21 CFR 312.33 provides the data 
elements that are to be submitted in the report.  The annual report 
should be filed in the study's regulatory binder, and a copy provided 
to Abbvie as a supporter of this study. 
 
6.8.1 Adverse Event Reporting  
All AE reports will include the patient’s number, age, sex, weight, 
severity of reaction (mild, moderate, severe), relationship to the study 
(fatal relationship, definitely related, possibly related, unrelated), 

 
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date of administration of test medications and the investigators will 
notify the IRB and DSMC of a SAE according to institutional policy.   
 
6.8.2 Reporting to Abbvie 
Serious adverse events (SAE) are defined in Section 6.2.  
 
In addition to compliance with all FDA reporting requirements 
pursuant to 21 CFR 312, the Principal Investigator shall: 
a) Report to Abbvie all serious adverse events experienced by a 
study subject receiving an AbbVie product within 24 hours of 
learning of the event regardless of the relationship of the event to 
the AbbVie product.  Principal Investigator shall make available 
to AbbVie promptly such records as may be necessary and 
pertinent to investigate any such event, if specifically requested 
by AbbVie; and in addition, report all non-serious adverse events 
of tumor lysis syndrome for studies involving ABT-199. 
b) Copy AbbVie on the submission to the FDA of events meeting the 
definition of IND safety reports at the time of submission to the 
Agency; and, 
c) Notify AbbVie upon any subjects receiving an AbbVie Product 
whose pregnancy has resulted in a negative outcome or 
untoward event during the course of pregnancy or upon delivery. 
AbbVie’s contact for reporting serious adverse drug experiences, 
pregnancy experiences, non-serious adverse events of tumor lysis 
syndrome, and communication of FDA submissions of IND safety 
reports shall be PPDINDPharmacovigilance@abbvie.com 
Product Complaints:  In addition to compliance with all FDA 
requirements pursuant to 21 CFR 211 and 21 CFR 820, Principal 
Investigator will report to AbbVie within 24 hours any suspected 
quality defect in an AbbVie Product or its AbbVie-provided 
packaging, labeling, or medical device component (collectively, 
“Product Complaint”).  Principal Investigator will report Product 
Complaints that involve an AbbVie Product, whether AbbVie has 
supplied the AbbVie Product used in the Study or not.  AbbVie’s 
contact 
for 
reporting 
Product 
Complaints 
shall 
be 
RD_PQC_QS@abbvie.com 

 
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6.8.3 Reporting From Abbvie 
Abbvie will notify the investigators via an IND Safety Report 
of the following information: 
 
• Any AE associated with the use of drug in this study or 
in other studies that is both serious and unexpected 
• Any finding from tests in laboratory animals that 
suggests a significant risk for human subjects including 
reports 
of 
mutagenicity, 
teratogenicity, 
or 
carcinogenicity 
 
The investigators will notify the IRB promptly of these new 
serious and unexpected AEs or significant risks to subjects.  
The investigators must keep copies of all AE information, 
including correspondence with Abbvie and the IRB, on file. 
 
6.9 
Pregnancy 
The likelihood of pregnancy occurring in a subject in this study is very 
small as all subjects will be aged 60 or older. Subjects who become 
pregnant during the study must discontinue study drugs immediately. 
All pre-menopausal subjects will be informed that contraceptive 
measures should be taken throughout the study and for 30 days after 
the last dose of venetoclax. Male subjects will be informed that 
contraceptive measures should be taken by them and by their 
potentially fertile female partners. Information regarding a pregnancy 
occurrence in a study subject and the outcome of the pregnancy will 
be collected. If the subject’s partner should become pregnant during 
the study, this should be reported. Pregnancy in a study subject is 
not an AE. The medical outcome for either mother or infant, meeting 
any serious criteria including an elective or spontaneous abortion is 
considered a SAE and must be reported as such (see Section 6.2). 
 
6.10 Prophylaxis and Management of Tumor Lysis Syndrome 
TLS is a potential risk for all patients with AML, particularly those with 
risk factors such as renal dysfunction and increased WBCs. To 
mitigate this risk, in addition to intra-patient dose escalation over the 
course of several days, patients will receive TLS prophylactic 
measures prior to initial therapy; in some cases, these measures 
may need to be re-implemented in the setting of a treatment 
interruption or dose delay prior to resuming therapy. Despite 
considerations surrounding TLS in CLL patients receiving 

 
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venetoclax, safety data from 94 subjects treated with venetoclax in 3 
AML studies have shown no evidence of TLS. 
 
Below are the minimum requirements for TLS prophylaxis and 
monitoring, which will be performed in addition to institutional 
standards: 
 
• All subjects will be hospitalized on or before cycle 1 day 
1 prior to the administration of the initial dose of study 
treatment, and remain in the hospital for at least 24 
hours after reaching the final escalated dose of 
venetoclax. 
• Administration of uric acid reducing agent, adequate 
oral and intravenous hydration while monitoring the 
fluid status of the subject prior to and during the 
venetoclax dose escalation will be performed per 
institutional standards. 
• TLS chemistry tests (calcium, phosphorus, potassium, 
uric acid and creatinine) will be drawn: A) On the first 
day of venetoclax dosing, within 4 hours prior to the 
dose and again 6 and 12 hours (+/- 2 hours) after the 
first dose, and B) On each day of dose escalation, 
within 4 hours prior to the dose and again 6 and 12 
hours (+/- 2 hours) after the dose. Additional laboratory 
assessment may be performed at the investigator’s 
discretion post-dose during the escalation and up to 48 
hours after reaching the final dose. 
• After dose escalation, TLS will be monitored with serial 
chemistry measurements (see Section 5.10) and more 
intensive measures may be considered for patients felt 
to be at higher risk. 
• Abnormal chemistry tests should be corrected promptly 
• If a subject meets criteria for clinically significant 
laboratory or clinical TLS, no additional venetoclax 
dose should be administered until resolution 
• Prophylactic reductions of potassium, phosphorus 
and/or 
uric 
acid 
above 
normal 
ranges 
are 
recommended prior to beginning study treatment and 
should continue based on the ongoing risk of TLS. 
• In the setting of rasbirucase, follow institutional sample 
handling 
procedures 
to 
ensure 
the 
proper 
measurement of TLS laboratory values 
 

 
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6.11 Decreased Spermatogenesis 
Based on preclinical data, venetoclax has the potential to decrease 
spermatogenesis. Male subjects considering preservation of fertility 
should consider sperm banking before treatment with venetoclax. 
 
 
 
6.12 Management of Infection 
Anti-infective prophylaxis will be implemented per institutional 
guidelines with consideration for possible drug interactions. Please 
see Appendix A for excluded and cautionary medications.  
 
6.13 Management of Other Toxicities 
If other events occur that are related to the study drugs, the 
investigator may interrupt or dose reduce the therapies has 
appropriate. Grade 3 or greater non-hematologic toxicity that is 
related to the study drugs will require interruption and possible 
discontinuation. Therapy may be re-introduced, potentially at a 
reduced dose, if the toxicity returns to baseline if grade 2 at study 
entry or ≤ grade 1. 
 
7 
PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, 
good clinical practice or standard operating procedure requirements. The 
noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. These practices are 
consistent with ICH E6, sections: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3. 
• 5.1 Quality Assurance and Quality Control, section 5.1.1. 
• 5.20 Noncompliance, sections 5.20.1 and 5.20.2. 
Intentional deviations are not allowed unless necessary to eliminate an 
immediate hazard to study subjects. The principal investigator is 
responsible for complying with all protocol requirement and applicable laws 
regarding protocol deviations. If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the study team will keep record of 
deviations and is responsible for reporting to the IRB as required. 
 

 
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8 
STATISTICAL METHODS 
Patients who receive at least one dose of venetoclax or azacitidine will be 
evaluable for safety and efficacy. Patients who do not complete at least one 
cycle of therapy may be replaced. 
 
8.1 
Demographics 
 
Descriptive statistics will be provided for demographic variables. 
 
8.2 
Efficacy Analysis  
Efficacy 
will 
include 
analyses 
of 
ORR 
as 
defined 
as 
PR+CR+CRi+MLFS, MRD positive responses, and MRD negative 
CR+CRi+MLFS (MRD-negative composite responses), median time 
to achieve a MRD negative response, duration of overall response, 
event free survival and overall survival. 
 
8.3 
Safety Analysis 
Safety will be assessed by analysis of AEs, SAEs, all deaths, 
changes in laboratory values and vital sign parameters. Analysis of 
AEs will include only treatment-emergent events (events that had 
onset on or after the first dose of study drug). Analysis of AEs and 
SAEs will not include those that have an onset >30 days after the 
last dose of study drug. Toxicity grades using NCI CTCAE V4.0 and 
relationships to study drugs will be assessed. In addition, incidence 
of febrile neutropenia, ≥ grade 2 bleeding complications (red blood 
cells and platelets) will be assessed. 
 
8.4 
Deaths 
The number of subject deaths will be analyzed by those that occurred 
within 30 days of the last dose of study drug, those that occurred 
more than 30 days after the last dose of study drug, those that 
occurred within the first 30 days of the study, those that occurred 
within the first 60 days of the study, those that were related to study 
drug and those that were unrelated to study drug.  
 
8.5 
Sample Size Determination 
In the M14-358 study combining azacitidine and venetoclax 
(NCT02203773), the median remission duration is 8 months.  For the 

 
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proposed study, we define success as an observed median 
remission duration of 12 months and formally define the research 
hypotheses as follows: H0: The median remission duration is 8 
months and H1: The median remission duration is 12 months.  Under 
the assumptions of uniform accrual over time, no loss to follow-up, 
and exponentially distributed remission times39, we will require 42 
patients to allow for 80% power to detect this difference with a 
significance level of 0.10 given 30 months accrual time and 12 
months of follow-up, and a single sample one-sided log-rank test 
used in the analysis.  To allow for a 20% withdrawal or loss to follow 
up rate, we will enroll 42 patients. A “survival” curve and its 90% 
confidence interval as well as the median remission duration will be 
computed for the data. 
 
 
8.6 
Statistical Analysis Plan 
 
For every relapse that occurs before 8 months in patients accrued to 
the study, the Kaplan-Meier product-limit method will be used to 
estimate the survival function at the time of relapse ti.  For each time 
ti ≤ 8 months that a relapse is observed, the median survival time will 
be estimated using linear interpolation and the estimated survival 
function.  If at any time ti ≤ 8 months the median remission duration 
falls below 8 months, then the study will be stopped.  In some 
instances, too many censored observations (i.e. patients who are still 
in remission) will result in an inability to estimate the median 
remission duration.  However, this will only occur when more than 
half of the enrolled patients have not relapsed and there is therefore 
no statistical evidence to indicate that the observed median 
remission duration is less than ti. This evaluation will be made on a 
continuous basis. 
 
9 
ETHICS 
9.1 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and 
all subject materials will be submitted to the Colorado Multiple 
Institutional Review Board (COMIRB) for review and approval. 
Approval of both the protocol and the consent form must be obtained 
before any subject is enrolled. Any amendment to the protocol will 
require review and approval by COMIRB before the changes are 
implemented to the study. All changes to the consent form will 
COMIRB approved; a determination will be made regarding whether 
previously consented participants need to be re-consented. 

 
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9.2 
Ethical Standards 
Good 
clinical 
practice 
(GCP) 
requires 
that 
the 
protocol, 
amendments, the Investigator’s Brochure, the informed consent and 
all other forms of subject information related to the study and any 
other necessary documents be reviewed by the IRB. The IRB will 
review the ethical, scientific and medical appropriateness of the 
study before it is conducted. IRB approval of the protocol, informed 
consent and subject information will be obtained prior to the 
authorization of drug shipment to the study site. 
 
Amendments to the protocol will require IRB approval prior to 
implementation of any changes made to the study design. The 
investigator will be required to submit, maintain and archive essential 
documents. 
 
During the conduct of the study the investigator will promptly provide 
written reports to the IRB of any changes that affect the conduct of 
the study and/or increase the risk to subjects.  
 
The study will be conducted in accordance with the protocol, 
International Conference on Harmonization (ICH) GCP guidelines, 
applicable regulations and guidelines governing clinical study 
conduct and ethical principles that have their origin in the Declaration 
of Helsinki.  
9.3 
Informed Consent Process 
Prior to the initiation of any screening or study-specific procedures, 
the IRB approved consent form(s) describing in detail the study 
agent, study procedures, and risks will be given to the subject and 
the investigator or her representative will explain the nature of the 
study to the subject and answer all questions regarding the study. 
Each informed consent will be reviewed, signed and dated by the 
subject and the person who administered the informed consent as 
well as the investigator. Written documentation of informed consent 
will be required prior to starting intervention/ administering study 
procedures and a copy of the informed consent will be given to the 
subject with the original placed in the subject’s file. An entry will be 
made in the source documents to confirm that informed consent was 
obtained prior to any study-related procedures and that the subject 
received a signed copy. 
 
Subjects may withdraw consent at any time throughout the course of 
the trial. A copy of the informed consent document will be given to 
the subjects for their records. The rights and welfare of the subjects 

 
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will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to 
participate in this study. 
10 
SOURCE DOCUMENTS AND CASE REPORT FORMS 
Accurate, complete, legible and timely records and data will be kept in the 
source documents of all drug administration, including prescribing and 
dosing.  Source documents are defined as original documents, data and 
records that pertain to the conduct of the study and distribution of the 
protocol therapy. These may include but are not limited to, copies of CRFs, 
hospital records, clinical and office charts, laboratory data/information, 
subject diaries or evaluation checklists, SAE reports, pharmacy dispending 
and other records, recorded data from automated instruments, and/or 
imaging studies. Data collected must be recorded on the appropriate source 
document. 
 
Study documents will be retained for as long as necessary to comply with 
all applicable regulations and institutional requirements.  By signing the 
protocol, the investigators agree to adhere to the document/records 
retention procedures. 
 
The investigator and institution will permit study-related monitoring, audits, 
IRB review and regulatory inspections providing direct access to source 
data documents.  
 
Case report forms (CRFs) must be completed for each subject 
screened/enrolled in the study.  
 
11 
STUDY OVERSIGHT – Quality Assurance and Quality 
Control  
11.1 Data Safety and Study Oversight 
The sponsor investigator will be responsible for monitoring the trial 
per the trial monitoring plan, in addition to overseeing the safety and 
efficacy of the trial including any specimens collected, executing the 
data and safety monitoring (DSM) plan, and complying with all 
reporting requirements to local and federal authorities. This oversight 
will be accomplished through additional oversight from the Data and 
Safety Monitoring Committee (DSMC) at the University of Colorado 
Cancer Center (CU Cancer Center).  The DSMC is responsible for 
ensuring data quality and study participant safety for all clinical 

 
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studies at the CU Cancer Center, which is the coordinating institution 
of this trial.    
 
A summary of the DSMC’s activities is as follows: 
 
• Conduct of internal audits 
• Ongoing review of all serious adverse events (SAEs) and 
unanticipated problems (UAPs) 
• May submit recommendations for corrective actions to the CU 
Cancer Center’s Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs 
are reported to the DSMC, IRB and the sponsor investigator per 
protocol. All SAEs and UAPs are to be reported to the DSMC within 
7 (for fatal or life-threatening events) or 15 (non-life-threatening 
events) calendar days of the sponsor investigator receiving 
notification of the occurrence. 
Each subject’s treatment outcomes will be discussed by the site PI 
and appropriate staff at regularly scheduled meetings.  Data 
regarding 
number 
of 
subjects, 
significant 
toxicities, 
dose 
modifications, and treatment responses will be discussed and 
documented in the meeting’s minutes. 
 
The sponsor investigator will provide a DSM report to the CU Cancer 
Center DSMC on a recurring basis (either every six or twelve months 
based on DSMC vote); this will also be shared with Abbvie at their 
request. The DSM report will include a protocol summary; current 
enrollment numbers; summary of toxicity data to include specific 
SAEs, UAPs and AEs; any dose modifications; all protocol 
deviations; and protocol amendments. The DSM progress report 
submitted to the DSMC will also include, if applicable, the results of 
any 
efficacy 
data 
analysis 
conducted. 
 
Results 
and 
recommendations from the review of this progress report by the 
DSMC will then be provided to the sponsor investigator in a DSMC 
review letter.  The sponsor investigator is then responsible for 
ensuring this letter is submitted to the site’s IRB of record at the time 
of IRB continuing review. 
 
11.2 Clinical Monitoring 
Clinical site monitoring visits will be performed by the CU Cancer 
Center Clinical Monitor on a regular basis, pursuant to the Clinical 
Monitoring Plan (CMP), incorporated herein by reference. The CMP 
describes in detail who will conduct the monitoring, at what frequency 

 
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monitoring will be done, at what level of detail monitoring will be 
performed, and the distribution of the monitoring reports.  
 
Clinical site monitoring will be conducted to ensure that the rights and 
well-being of human participants 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/ 
amendment(s), 
with 
GCP, 
and 
with 
applicable 
regulatory 
requirement(s). During these visits, information recorded on the 
CRFs will be verified against source documents.  Additional 
computer programs that identify selected protocol deviations, out-of-
range data, and other data errors within the electronic data entry may 
also be used to help monitor the study.  As necessary, requests for 
data clarification or correction will be sent to the appropriate site PI. 
 
11.3 Study Auditing 
Independent audits will be conducted by the CU Cancer Center 
DSMC to ensure monitoring practices are performed consistently 
across all participating sites, if applicable, and that monitors are 
following good clinical practices. In addition, audits may be 
conducted at any time by appropriate regulatory authorities and/or 
the IRB. 
 
 
 
 
 
 
 
 
 
 
 
 
12 
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19. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and Biological Correlates of 
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Appendix A:  Excluded and Cautionary Medications and Sample List  
 
Excluded 
Anticancer therapies including chemotherapy, radiotherapy, or other investigational therapy, 
including targeted small molecule agents: Excluded 5 half-lives prior to first dose and throughout 
venetoclax administration 
Biologic agents (e.g., monoclonal antibodies) for anti-neoplastic intent: 
Excluded 30 days prior to first dose and throughout venetoclax administration 
Excluded during ramp-up phase and Cautionary Or Reduced at the Designated Venetoclax Dose:  
Strong and Moderate CYP3A inhibitors  
Exclude during ramp-up phase and consider alternative medications. If subject requires use of these 
medications at the cohort designated dose, use with caution and reduce the venetoclax dose by 50% for 
moderate inhibitors and at least 75% for strong inhibitors during co-administration.  After 
discontinuation of CYP3A inhibitor, wait for 2 to 3 days before venetoclax dose is increased back to the 
initial maintenance/target dose. 
Strong and Moderate CYP3A inducers 
Exclude during ramp-up phase and consider alternative medications. If subject requires use of these 
medications at the cohort designated dose, use with caution and contact AbbVie for guidance. 
Cautionary 
Warfarin  
P-gp substrates 
BCRP substrates 
OATP1B1/1B3 substrates 
P-gp inhibitors 
BCRP inhibitors 
 

 
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Sample List of Excluded and Cautionary Medications 
Excluded during ramp-up phase and Cautionary at the Cohort Designated Dose:  
Strong CYP3A inducers - avasimibe,carbamazepine, enzalutamine, mitotane, phenytoin, 
rifampin, St. John's wort 
Moderate CYP3A inducers - bosentan, efavirenz, etravirine, modafinil, nafcillin 
Strong CYP3A inhibitors - boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, elvitegravir/ritonavir, idelalisib,* indinavir, itraconazole, ketoconazole,  
mibefradil, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, paritaprevir/ritonavir 
combinations, posaconazole, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, 
voriconazole 
Moderate CYP3A inhibitors - amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, 
clotrimazole, crizotinib*, cyclosporine*, darunavir/ritonavir, diltiazem1, erythromycin, 
fluconazole, fosamprenavir, imatinib*, isavuconazole,  tofisopam,  verapamil 
Cautionary 
Warfarin** 
P-gp substrates - Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, 
everolimus*, fexofenadine, lapatinib*, loperamide, maraviroc, nilotinib*, ranolazine, 
saxagliptin, sirolimus*, sitagliptin, talinolol, tolvaptan, topotecan* 
BCRP substrates - Methotrexate*, mitoxantrone*,  irrinotecan*, lapatinib*, rosuvastatin, 
sulfasalazine, topotecan* 
OATP1B1/1B3 substrates - Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, 
rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, telmisartan,  valsartan, 
olmesartan 
P-gp inhibitors - Amiodarone, azithromycin, captopril, carvedilol, dronedarone, felodipine, 
quercetin, quinidine, ronalzine, ticagrelor 
BCRP inhibitors - Geftinib* 
 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/
ucm080499.htm  
 
In addition to the medications listed in this table, subjects receiving venetoclax should not consume 
grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star 
fruits. 
 
* These are anticancer agents; consult contact AbbVie medical monitor before use. 
** Closely monitor the international normalized ratio (INR). 
1 Moderate CYP3A inhibitor per venetoclax FDA USPI.