Clinical trial NCT04277442
Conditions: Acute Myeloid Leukemia
Sponsor: National Cancer Institute (NCI)
Start date: 2020-03-11; Completion date: 2022-09-06
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial studies the side effects of nivolumab in combination with decitabine and venetoclax and to see how well they work in treating patients with TP53-mutated acute myeloid leukemia. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as decitabine and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This study is being done to find out whether giving nivolumab, decitabine, and venetoclax is better or worse than the usual approach for TP53-mutated acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To obtain preliminary data regarding the safety and tolerability of decitabine and venetoclax in combination with nivolumab when given for frontline therapy in TP53 mutated acute myeloid leukemia (AML) patients.

II. To obtain preliminary data regarding the rate of complete remission (CR), complete remission with incomplete hematological recovery (CRh), and complete remission with incomplete count recovery (CRi) in TP53 mutated AML who are treated with decitabine and venetoclax in combination with nivolumab for frontline therapy.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To obtain preliminary data regarding progression free survival (PFS) for TP53 mutated AML patients receiving combination therapy.

III. To obtain preliminary data regarding the overall survival (OS) for TP53 mutated patients receiving this combination therapy.

IV. To obtain preliminary data regarding minimal residual disease through monitoring TP53 mutational burden prior and throughout treatment.

V. To obtain preliminary data regarding the frequency of graft versus host disease (GVHD) including veno-occlusive disease (VOD) in patients who subsequently receive allogeneic transplantation after this combination therapy.

OUTLINE:

INDUCTION: Patients receive nivolumab intravenously (IV) over 30 minutes on day 15 of cycle 1 and days 1 and 15 of subsequent cycles, decitabine IV over 60 minutes on days 1-10 of induction cycle 1 (and cycles 2 and 3 if needed), and venetoclax orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who achieve a CR or CRi receive nivolumab IV over 30 minutes on days 1 and 15, decitabine IV over 60 minutes on days 1-5, and venetoclax PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Arms: arm 1: INDUCTION: Patients receive nivolumab IV over 30 minutes on day 15 of cycle 1 and days 1 and 15 of subsequent cycles, decitabine IV over 60 minutes on days 1-10 of induction cycle 1 (and cycles 2 and 3 if needed), and venetoclax PO QD on days 1-21. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who achieve a CR or CRi receive nivolumab IV over 30 minutes on days 1 and 15, decitabine IV over 60 minutes on days 1-5, and venetoclax PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Decitabine intervention 2: Nivolumab intervention 3: Venetoclax
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #: 10317  
Version Date: 08.16.2021 
 
i 
 
To:            CTEP Protocol and Information Office 
From:       Alice Mims, M.D. 
Date:  
08/16/2021 
Re: 
Amendment 1 of Protocol #10317:  “A Phase 1 Study of Nivolumab in Combination 
with Decitabine and Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia.”  
 
SUMMARY OF CHANGES – Protocol 
 
I. 
OSU Changes, 08/16/2021 
# 
Section 
Comment(s) 
1. 
Header 
x Updated protocol version date 
2. 
Title Page 
x Updated title to “A Phase 1 Study of Nivolumab in 
Combination with Decitabine and Venetoclax in 
Relapsed/Refractory Acute Myeloid Leukemia”  
x Added Revision # / Version # / Version Date 
3. 
Table of 
Contents 
x Updated Table of Contents 
4. 
Throughout 
x Updated superscripts throughout the protocol due to 
updated references  
x Formatting updates 
5. 
1 
x Updated primary objectives 
x Added new secondary objectives 
6. 
2.1 
x Replaced background section with relapsed/refractory 
AML section 
7. 
2.4 
x Replaced rationale section with new information 
8. 
2.5.1 
x Updated minimal residual disease (MRD) assessment 
9. 
2.5.4 
x Added section for Pharmacokinetic (PK) and 
Pharmacodynamic (PD) studies 
10. 
3.1 
x Updated eligibility criteria 
11. 
3.2 
x Updated exclusion criteria to exclude patients who have 
received any prior BCL-2 inhibitor therapy and patients 
who have received prior hypomethylating therapy for 
treatment of AML  
12. 
3.3 
x Updated inclusion table to include more patients in each 
category 
13. 
5.1 
x Replaced Summary Table for Specimen Collection with 
updated table 
14. 
5.4.1.3 
x Added shipping collection instructions for collection of 


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# 
Section 
Comment(s) 
blood for ventoclax, OATP1B1 biomarker and 
nivolumab pharmacokinetic studies 
15. 
5.5.3 
x Added instructions for shipping of specimens to Ohio 
State PharmacoAnalytical Shared Resource (PhASR) 
16. 
5.6 
x Replaced biomarker plan table with new information 
17. 
5.7 
x Removed integral laboratory study 
18. 
5.8 
x Added the following exploratory/ancillary correlative 
studies: flow cytometry, cytogenetics with kayotyping 
and AML FISH panel, tetramer analysis and cytokine 
production up re-simulation with antigen peptide, 
venetoclas OATP1B1 biomarker and nivolumab PK 
studies 
19. 
6.1 
x Replaced agent administration table with updated table 
20. 
6.3 
x Changed hematological DLT requirements. Failure to 
recover platelet count ≥25,000 (previously 20,000), or 
hemoglobin ≥7 will be considered hematological DLT. 
21. 
6.5.1 
x Updated duration of therapy in cases of CR to consider 
CR/CRi. 
22. 
7.2 
x Added new information for hematologic AE due to 
decitabine or venetoclax 
23. 
7.4 
x Added dosing delays and modifications once at least 
MLFS is achieved 
24. 
7.6 
x Changed the average time to respond to decitabine with 
venetoclax from 1.9 months to 1.3 months 
x Added instructions for patients who achieve a CR or 
Cri within 1.3 months’ time yet also experience a DLT 
25. 
9.3 
x Added new information to analysis of secondary 
endpoints regarding new exploratory/ancillary 
correlative studies 
26. 
10.1.1 
x 
The SPEER grades have been updated. 
 
x 
Added New Risk: 
o Less Likely: CD4 lymphocytes decreased 
o Rare: Enterocolitis; Eye disorders - Other (Vogt-Koyanagi-
Harada); Hepatobiliary disorders - Other (immune-mediated 
hepatitis); Renal and urinary disorders - Other (immune-
mediated nephritis) 
 
x 
Modified Specific Protocol Exceptions to Expedited Reporting 
(SPEER) reporting requirements:  
o Added: CD4 lymphocytes decreased 
 
x 
Provided Further Clarification: 


NCI Protocol #: 10317  
Version Date: 08.16.2021 
 
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# 
Section 
Comment(s) 
x 
Immune system disorders - Other (sarcoid granuloma) is 
now reported as Immune system disorders - Other 
(sarcoidosis). 
27. 
11 
x Removed “Integral TP53 mutation” row from study 
calendar 
x Updated Venetoclax instructions to say “Venetoclax 
will be given on Days 1-28 of induction cycles and 
Days 1-21 of maintenance cycles.” 
x Updated correlative collection calendar 
28. 
12.1 
x Added <5% blasts in bone marrow aspirate as 
requirement for detected morphologic complete 
remission 
29. 
14 
x Updated references list 
30. Appendix C 
x Changed title of Appendix C to “Recommendations for 
initial management of electrolyte abnormalities and 
prevention of tumor lysis ivolumab pharmacokinetic 
studies 
x Added “See Appendix [TLS]” 
31. Appendix F 
x Added Appendix F: Pharmacokinetic Study Sample 
Handling and Shipment 
32. Appendix G 
x Added Appendix G: Medication Diary for Venetoclax 
 
II. 
Recommendations for future post activation amendments: 
# 
Section 
Comments 
1. 
Title Page 
Change the IND number 
PI Response: Done. 
2. 
Schema 
Change nivolumab administration to Days 1 and 15. 
PI Response: Nivolumab is given days 1-5 for cycles 2-3 of induction 
and for all maintenance cycles, but is only given day 15 of cycle 1 of 
induction. This is reflected in the schema. 
3. 
8.3.1 
Reinsert the statement “excursions permitted to 15-30°C (59-86°F).” 
This is found in the decitabine package insert. It was not my intention 
that this statement be removed. 
PI Response: Re-inserted (now section 8.3.1) 
4. 
9.1 
The first sentence after the table should read “Feasibility will be met if 
at least 9 of 13 patients are able to complete 3 cycles of therapy.” 
PI Response: Study design section has changed; this is no longer 


NCI Protocol #: 10317  
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iv 
 
# 
Section 
Comments 
applicable. 
5. 
9.2 
The accrual numbers do not add up correctly in the Planned Enrollment 
Report Table. Please correct the totals with your next amendment 
submission. 
PI Response: This is corrected. 


NCI Protocol #: 10317  
Version Date: 08.16.2021 
 
1 
 
NCI Protocol #: 
10317 
 
Local Protocol #: 
OSU 19305 
 
ClinicalTrials.gov Identifier: NCT04277442 
 
TITLE: A Phase 1 Study of Nivolumab in Combination with Decitabine and Venetoclax in 
Relapsed/Refractory Acute Myeloid Leukemia 
 
Corresponding Organization: LAO-OH007 / Ohio State University Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Alice Mims, MD 
Ohio State University Comprehensive Cancer Center 
B302 Starling Loving Hall 
320 W 10th Avenue 
Columbus, OH 43210, USA 
614-685-6031(phone) 
614-293-7526 (fax) 
Alice.Mims@osumc.edu 
 
Translational PI: 
Dan Jones, MD, PhD 
Ohio State University Comprehensive Cancer Center 
410 W 10th Avenue 
Columbus, OH 43210, USA 
614-293-4875 (phone) 
614-292-7072 
Daniel. Jones@osumc.edu 


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Version Date: 08.16.2021 
 
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Participating Organizations 
 
Statistician: 
Quihong Zhao, PhD 
M200 Starling Loving Hall 
320 W 10th Avenue 
Columbus, OH 43210 
614-366-7523 (telephone) 
Qiuhong.Zhao.osumc.edu 
 
Study Coordinator: 
Kaitlyn Dvorak, PhD 
A075 Starling-Loving Hall 
320 W 10th Avenue 
Columbus, OH 43210 
614-688-9493 (telephone) 
614-584-2763 (fax) 
Kaitlyn.Dvorak@osumc.edu 
 
Responsible Data Manager: 
Matt Baron 
A075 Starling-Loving Hall 
320 W 10th Avenue 
Columbus, OH 43210 
614-293-0752 
614-584-2763 (fax) 
Matthew.Baron@osumc.edu 
 
NCI-Supplied Agent(s): nivolumab (NSC 748726) 
Other Agent(s): decitabine (NSC 127716, supplier - commercial), venetoclax (NSC 766270, 
supplier - commercial) 
 
IND #: 
IND Sponsor: DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: Original/ Version 1/ 7-5-2019 
Revision 1 / Version 1 / 9-15-2019 
Revision 2 / Version 1 / 10-23-2019 
Revision 3 / Version 1 / 12-30-2019 
Revision 4 / Version 1 / 01-30-2020 
 Revision 5 / Version  1 / 08-16-2021
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 


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SCHEMA 
 
 
Induction treatment (28 day cycle up to 3 cycles) will include the following: 
Nivolumab (N) at 240mg on Day 15 for cycle 1 and Days 1 and 15 for cycles 2-3. 
Decitabine 20 mg/m 2 intravenously on Days 1-10 for up to 3 cycles. 
Venetoclax (V) 100mg PO on Day 1, 200mg on Day 2, 400mg on Days 3-28 of cycle (and cycle 2-3 of induction if 
needed). 
If CR, CRi, or CRh is achieved during cycles 1-3, patients will proceed with maintenance at the time response is noted. 
If no response is achieved by cycle 3, patients will come off study. 
Bone marrow biopsy will occur on Day 28 (+/- 2 days) for up to 3 cycles to determine treatment response. 
 
 
Maintenance treatment (28 day cycle) for patients achieving CR or CRi will include the following: 
Nivolumab (N) will be given on Days 1 and 15. 
Decitabine (D) 20 mg/m 2 intravenously on Days 1-5. 
Venetoclax (V) 400mg po daily on Days 1-21. 
Treatment will continue until one of the following occurs: loss of response/disease progression, bone marrow/stem cell 
transplantation, unacceptable toxicities, or patient withdrawal


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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives...................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
TP53 mutated AML .................................................................................................7 
2.2 
CTEP IND Agent .....................................................................................................8 
2.3 
Other Agent(s)..........................................................................................................8 
2.4 
Rationale ..................................................................................................................9 
2.5 
Correlative Studies Background ............................................................................11 
3. 
PATIENT SELECTION ....................................................................................................12 
3.1 
Eligibility Criteria ..................................................................................................12 
3.2 
Exclusion Criteria ..................................................................................................14 
3.3 
Inclusion of Women and Minorities ......................................................................15 
4. 
REGISTRATION PROCEDURES ...................................................................................16 
4.1 
Investigator and Research Associate Registration with CTEP ..............................16 
4.2 
Site Registration .....................................................................................................17 
4.3 
Patient Registration ................................................................................................20 
4.4 
General Guidelines.................................................................................................21 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES.........................................22 
5.1 
Summary Table for Specimen Collection ..............................................................22 
5.2 
Specimen Procurement Kits and Scheduling .........................................................23 
5.3 
Specimen Tracking System Instructions................................................................23 
5.4 
Specimen Collection ..............................................................................................27 
5.5 
Shipping of Specimens from Clinical Site to Other Laboratories..........................27 
5.6 
Biomarker Plan ......................................................................................................28 
5.7 
Integral Laboratory Studies....................................................................................30 
5.8 
Exploratory/Ancillary Correlative Studies.............................................................30 
6. 
TREATMENT PLAN ........................................................................................................31 
6.1 
Agent Administration.............................................................................................31 
6.2 
Order of administration ..........................................................................................32 
6.3 
Definition of Dose-Limiting Toxicity ....................................................................33 
6.4 
General Concomitant Medication and Supportive Care Guidelines ......................34 
6.5 
Duration of Therapy ...............................................................................................36 
6.6 
Duration of Follow-Up...........................................................................................37 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................37 
7.2 
Dose modifications of Decitabine and Venetoclax for non-DLTs ........................37 


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7.3 
Nivolumab ..............................................................................................................38 
7.4 
Special circumstances.............................................................................................45 
8. 
PHARMACEUTICAL INFORMATION ........................................................................46 
8.1 
Investigational Agent .............................................................................................46 
8.2 
Agent Ordering and Agent Accountability ...........................................................47 
8.3 
Commercial Agent .................................................................................................48 
8.3.1 Decitabine ..............................................................................................................48 
9. 
STATISTICAL CONSIDERATIONS..............................................................................49 
9.1 
Study Design/Endpoints ........................................................................................49 
9.2 
Sample Size/Accrual Rate......................................................................................50 
9.3 
Analysis of Secondary Endpoints..........................................................................51 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..........................52 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs)...............52 
10.2 
Adverse Event Characteristics ...............................................................................62 
10.3 
Expedited Adverse Event Reporting .....................................................................62 
10.4 
Routine Adverse Event Reporting .........................................................................66 
10.5 
Pregnancy ...............................................................................................................66 
10.6 
Secondary Malignancy ...........................................................................................66 
10.7 
Second Malignancy ................................................................................................67 
11. 
STUDY CALENDAR.......................................................................................................68 
11.1 
Correlative collection calendar ..............................................................................69 
12. 
MEASUREMENT OF EFFECT .......................................................................................70 
12.1 
Antitumor Effect – Hematologic Tumors ..............................................................70 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ............................................................................................................72 
13.1 
Study Oversight .....................................................................................................72 
13.2 
Data Reporting .......................................................................................................72 
13.3 
Collaborative Agreements Language .....................................................................75 
13.4 
Genomic Data Sharing Plan ...................................................................................76 
13.5 
Incidental/Secondary Findings Disclosure Procedure ...........................................78 
13.6 
Data Quality Portal ................................................................................................78 
14. 
REFERENCES ..................................................................................................................79 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .................................................81 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE ....................................................................................................82 
APPENDIX C 
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]......................................83 


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Abnormality .......................................................................................................................84 
Management Recommendations ........................................................................................84 
APPENDIX D 
PATIENT WALLET CARD .....................................................................89 
APPENDIX E nivolumab AE Management Algorithm: MANAGEMENT 
ALGORITHMS FOR ENDOCRINOPATHY, GASTROINTESTINAL, 
HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND SKIN 
ADVERSE EVENTS .........................................................................................................90 
 
APPENDIX F  
PHARMACOKINETIC STUDY SAMPLE HANDLING AND 
SHIPMENT………………………………………………………………………99 
 
APPENDIX G   
MEDICATION DIARY FOR VENETOCLAX ..................................................102


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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 
To obtain the safety and maximum tolerated dose (MTD) of decitabine and 
venetoclax in combination with nivolumab for relapsed/refractory (R/R) AML 
patients. 
 
1.2 
Secondary Objectives 
 
1.2.1 To determine the composite CR rate (CR+CRi) rate in R/R AML patients who are 
treated with decitabine and venetoclax in combination with nivolumab. 
1.2.2 To determine the overall response rate (CR+CRi+CRh+MLFS) rate in R/R AML 
patients who are treated with decitabine and venetoclax in combination with nivolumab. 
1.2.3 To observe and record anti-tumor activity. Although the clinical benefit of this 
combination of drugs has not yet been established, the intent of offering this treatment is 
to provide a possible therapeutic benefit, and thus the patient will be carefully monitored 
for tumor response and symptom relief in addition to safety and tolerability. 
1.2.4 
To determine progression free survival (PFS) for R/R AML patients receiving 
combination therapy. 
1.2.5 
To determine the overall survival (OS) for R/R AML patients receiving this combination 
therapy. 
1.2.6 
To determine minimal residual disease at best response and follow throughout treatment. 
1.2.7 
To determine the frequency of GVHD including veno-occlusive disease in patients who 
subsequently receive allogenic transplantation after this combination therapy. 
1.2.8 
To perform pharmacokinetic (PK) and pharmacodynamics (PD) of the combination of 
nivolumab with decitabine plus venetoclax. 
 
2. 
BACKGROUND 
 
2.1 
Relapsed/Refractory AML 
 
Acute myeloid leukemia (AML) is an aggressive clonal bone marrow malignancy that has 
very poor long-term survival with traditional therapies. Even with adaptation of cytogenetic 
and molecular risk-stratified therapies, 10-40% of patients do not achieve a complete 
remission (CR) after intensive induction therapy and are deemed to have primary refractory 
disease. For the patients able to achieve CR, greater than 50% subsequently experience disease 
relapse. For patients who relapse, only a small fraction undergo successful salvage treatment 
with ability to attain a second CR. Therefore, this leaves a large unmet clinical need for 
treatment of both relapsed and refractory (R/R) AML. 
Traditionally, R/R AML is treated with intensive chemotherapy re-induction (aka. salvage) 
regimens, typically comprised of a high-dose cytarabine backbone with a variety of 
anthracycline and alkylating counterparts. However, a large number of patients are unable to 
tolerate such intensive chemotherapy, thus, regimens that are better tolerated are needed. 


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2.2 
CTEP IND Agent 
 
2.2.1 
Nivolumab 
 
Nivolumab targets the programmed death–1 (PD-1, cluster of differentiation 279 
[CD279]) cell surface membrane receptor. PD-1 is a negative regulatory receptor 
expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, 
programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-L1 and PD-L2. 
Inhibition of the interaction between PD-1 and its ligands promotes immune responses 
and antigen-specific T-cell responses to both foreign antigens as well as self-antigens. 
 
The indirect drug-drug interaction potential of nivolumab was assessed using systemic 
cytokine modulation data for cytokines known to modulate CYP enzymes. There were 
no meaningful changes in cytokines known to have indirect effects on CYP enzymes 
across all dose levels of nivolumab. This lack of cytokine modulation suggests that 
nivolumab has no or low potential for modulating CYP enzymes, thereby indicating a 
low risk of therapeutic protein-drug interaction. 
 
Adverse events (AEs) associated with Nivolumab exposure may represent an 
immunologic etiology. These AEs may occur shortly after the first dose or several 
months after the last dose of treatment. Nivolumab must be withheld for drug-related 
toxicities and severe or life-threatening AES and prednisone may be given. 
 
The proposed dosing of nivolumab is 240 mg every 2 weeks starting on Day 14 of cycle 
1. This is the package insert dosing scheme used when nivolumab is combined with 
other agents (namely, ipilimumab). We will be combining nivolumab with two other 
agents, therefore this is consistent with current practice. Weight based dosing will allow 
us to mitigate adverse events, especially when combined with other agents. 
 
2.3 
Other Agent(s) 
 
2.3.1 
Decitabine 
 
Decitabine is a cytidine nucleoside analog that inhibits cytosine methylation, thereby 
causing hypomethylation of DNA and re-expression of silenced genes. 
 
Drug interaction studies with decitabine have not been conducted. In vitro studies in 
human liver microsomes suggest that decitabine is unlikely to inhibit or induce 
cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is 
not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of 
decitabine is negligible (<1%), interactions due to displacement of more highly protein 
bound drugs from plasma proteins are not expected. 
 
The proposed dosing of decitabine is 20 mg/m2 daily on days 1-10 of induction cycles 
up to 3 cycles and on days 1-5 of maintenance cycles. This 20 mg/m2 dosing is the 


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package insert dosing for the 5 day regimen. We plan on administering for 10 days 
during cycles 1-3, as opposed to the package insert 5 days, as the shorter 5-day dosing 
scheme appears to be inferior to the longer 10-day dosing scheme in TP53m AML 
patients per recent publications described below. 
 
2.3.2 
Venetoclax 
 
Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor which is an anti-apoptotic protein. 
 
Venetoclax is predominantly metabolized by CYP3A4/5. Venetoclax had no large effect 
on QTc interval (i.e., > 20 ms) and there was no relationship between venetoclax 
exposure and change in QTc interval. Gastric acid reducing agents (e.g., proton pump 
inhibitors, H2-receptor antagonists, antacids) do not affect venetoclax bioavailability. 
Avoid grapefruit products, Seville oranges, and starfruit during treatment. 
 
There is also a risk of developing tumor lysis syndrome (TLS) with venetoclax. For 
prophylaxis, patients should be instructed to drink 6 to 8 glasses water each day, starting 
2 days before the first dose, on the day of the first dose of venetoclax, and each time the 
dose is increased. Consider IV hydration and/or uric acid reducing agents in patients at 
risk for TLS. 
 
The proposed dose for venetoclax is 400 mg daily with ramp-up to this dose during days 
1-3 of cycle 1 and continue on 400mg on days 4-21 of cycle 1 (28 day cycle) with 
subsequent cycle doses of 400mg on days 1-21. Dose ramp up will be 100 mg on day 1 
and 200 mg on day 2 followed by the goal dose of 400 mg on day 3 and onwards. There 
will be dose adjustments for venetoclax based on the FDA label if concurrent use with 
moderate or strong CYP3A inhibitors (See Section 6.3.1 and 6.3.1.1) 
 
2.4 
Rationale 
 
2.4.1 
 AML Treatment with Hypomethylating Agent and Venetoclax: In recent years, the new 
standard of care for newly diagnosed AML patients that cannot tolerate intensive induction 
chemotherapy has transitioned to treatment with a hypomethylating agent (HMA) and 
venetoclax. Phase 3 data with this regimen in the upfront AML setting showed CR+CRi rate 
of 66.4%.4 However, this combination has not been proven to be as effective in the R/R 
AML setting. Gaut et al performed a retrospective study of venetoclax combinations in the 
relapsed AML setting. In the eight patients who had received azacitidine (AZA) with 
venetoclax, 2 patients experienced a response (1 PR and 1 CRi) and in the 5 patients who had 
received decitabine with venetoclax, 2 patients experienced a CRi (no CRs were seen with 
either HMA), which showed a CRi rate of 23.1% (3/13 patients).3 Vigil et al described 
outcomes of patients with R/R AML who received venetoclax in combination with AZA (1 
patient) and decitabine (8 patients) and combined the overall response rate was 44% (4 
patients) and 3 patients achieved CRi (33%), but again no CRs were seen.5 A larger 
retrospective study performed by DiNardo et al investigated 39 R/R AML patients who 
received venetoclax combinations, 9 patients responded (21%) and 8 of these patients 
received an HMA. Of these responders, 2 patients who received AZA achieved CR/CRi (one 
patient each) and 2 patients who received decitabine achieved CR/CRi (one patient each), 


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thus, 2 CRs were seen in this study.6 Therefore, there is room to improve on these results 
with this combination in the R/R AML setting.  
The studies above all investigated giving decitabine for a 5-day course. However, there is 
evidence that a 10-day course of decitabine in combination with venetoclax may be more 
beneficial in certain patient populations, notably R/R AML.1 DiNardo, et al performed a 
prospective phase 2 study in various groups of AML patients and treated patients with an 
initial 10-day course of decitabine with venetoclax followed by 5-day decitabine with 
venetoclax once CR/CRi was achieved. In the R/R AML cohort (n=55), the ORR was 62% 
(34 patients) and the CR/CRi rate was 24%/18% (13/10 patients). This study also exhibited 
an acceptable toxicity profile with expected treatment-emergent adverse events of grade 3/4 
neutropenia (50% of all patients in the study) and febrile neutropenia (29%), but a 30-day 
mortality of only 3.6%. 
2.4.2 
PD-1/PDL-1 expression in AML: Co-expression of Tim-3 and PD-1 identified a CD8+ 
T cell exhaustion phenotype in murine AML models with deficiency in ability to produce 
IFN-gamma, TNF-alpha, and IL-2 in response to PD-1 and Tim-3 ligand expressing 
cells.7  The evaluation of immunotherapy in AML is supported by the observation of 
increased expression of PD-1 in the T cells in the leukemia microenvironment compared 
to healthy individuals. Daver, et al analyzed the PD-1 expression on bone marrow (BM) 
aspirates of 74 AML patients (36 untreated, 38 relapsed) and 8 healthy controls using 
multi-parameter flow cytometry and showed that all T cell subpopulations (CD4 T 
effector cells, CD4 T regulatory cells, and CD8 T cells) had significantly higher PD-1 
expression in untreated and relapsed AML patients when compared to the healthy 
controls.8 These findings further support the development of anti-PD-L1/PD-1 therapy 
for the treatment of AML.  
 
2.4.3    Targeting PD-1/PDL-1 in AML: Both in vitro and in vivo studies in development show 
promising results with PD-1/PDL-1 inhibition in AML. In murine AML models, anti-PD-L1 
monoclonal antibody therapies were not curative, but increased the proliferation and 
function of cytotoxic T cells at tumor sites, reduced AML tumor burden and resulted in 
long-term survival in mice.7 In a recent phase II study by Daver, et al the use of nivolumab 
in combination with AZA was evaluated in 70 patients with relapsed AML.9 Of these 70 
patients, 22% (n = 15) achieved CR/CRi, with median OS of 17.1 months compared to 4.9 
months in non-responders. The safety profile showed grade 3 and grade 2 immune-mediated 
toxicities each at 11% (there were no grade 4 events) including pneumonitis, colitis, 
nephritis, skin rash, and hypophysitis.  All cases of immune related adverse events 
responded rapidly to steroids. There are ongoing trials assessing check point blockade in 
AML in the relapsed/refractory setting in combination with AZA in the post-transplant 
setting for minimal residual disease (MRD) and for patients at high risk of relapse. There is 
also a Phase II trial evaluating nivolumab in combination with standard induction therapy in 
the first-line therapy for AML and high-risk MDS (NCT02464657).10  Nine of these patients 
underwent subsequent allogeneic transplant with 4 patients with GVHD seen and no veno-
occlusive disease reported thus far.  Each of these aforementioned clinical trials are 
performed in all-comers of AML. 
 
2.4.4    Rationale for combination of decitabine, venetoclax and nivolumab for AML:  
The combination of PD-1/PDL-1 inhibitor with hypomethylating agent is supported by 
evidence of upregulation of PD-L1, PD-L2, PD-1 and CTLA4 mRNA expression in 
patients treated with epigenetic therapy as demonstrated by Yang, et al.11 This study also 


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11 
 
showed that treatment of leukemia cells with decitabine resulted in a dose-dependent 
upregulation of these genes. Furthermore,  To investigate this clinically, Daver et al 
performed a phase 2 study combining azacitidine (an HMA) and nivolumab (an anti-PD-
1) in relapsed/refractory AML.12 This combination in 70 patients showed an overall 
response rate (ORR) of 33% with a 22% CR/CR with incomplete count recovery. 
However, the ORR and CR/CRi rates with HMA combined with venetoclax in the 
relapsed/refractory AML setting is about 10 percentage points that the PD-1/HMA 
combination. Therefore, we propose that the triple combination of HMA with 
venetoclax and PD-1 inhibition will lead to increased response rates in the 
relapsed/refractory AML population. 
 
Hence we propose the combination of hypomethylating agent and venetoclax with a PD-
1 inhibitor in the AML population. We are interested in exploring a 10-day course of 
decitabine and venetoclax along with PD-1 inhibitor, nivolumab. The key innovation in 
this research proposal is the use of combination of three novel agents- nivolumab, 
venetoclax and decitabine for relapsed/refractory AML. Combining epigenetic therapy 
with immunotherapy has been shown to have promising synergistic effect with in vivo 
studies and early clinical studies, by upregulating the cytotoxic T cell response and 
reviving the innate immune surveillance. Thus, a positive result from this trial has the 
potential to change the treatment paradigm for AML patients. By understanding the 
interaction between nivolumab, venetoclax and decitabine and its effects in the tumor 
microenvironment, we might obtain useful insights on manipulating the timing of these 
treatments to obtain durable remission even in the post-transplant setting in this patient 
population.   
 
2.5 
Correlative Studies Background 
 
2.5.1 
Minimal residual disease (MRD) assessment 
 
We propose that decitabine, venetoclax and nivolumab in combination will help achieve 
durable response in relapsed/refractory AML. We will be using flow cytometry (aka. 
immunophenotyping), cytogenetics (karyotyping along with an AML FISH panel), and 
next generation sequencing (NGS) to detect minimal residual disease. Minimal (ie. 
measurable) residual disease is defined as persistence of leukemic cells at levels below 
morphologic detection. In AML specifically, it can be used to assess treatment response. 
Furthermore, in AML the presence of MRD has strong and independent prognostic 
significance as patients with MRD have an increased relapse risk and decreased 
survival.13  However, this data on MRD is in relation to patients receiving standard 
intensive chemotherapy regimens and mostly in the upfront treatment setting. Little is 
known about MRD assessment utilization in patients receiving HMA/venetoclax 
combinations, especially in the relapsed/refractory AML setting; the most appropriate 
timepoint(s) to assess MRD and depth of response in relation to survival are poorly 
understood. Therefore, with this study we aim to gather important information on MRD 
assessments in patient’s receiving HMA/venetoclax combinations notably in the 
relapsed/refractory setting. Technologies to measure MRD include 
immunophenotyping, cytogenetics, and mutational analysis. Utilizing NGS to monitor 
mutations with associated targeted therapies (FLT3-ITD, IDH1/2) and mutations with 
prognostic significance (CEBPA, NPM1) has been shown to be feasible in patients with 


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12 
 
AML.14 Therefore, we plan to utilize NGS testing of patients’ bone marrow to determine 
if mutant clones persists following combination therapy with decitabine, venetoclax, 
and nivolumab. 
 
2.5.2 
T cell response assessment 
 
We propose that decitabine, venetoclax and nivolumab in combination will enhance T 
cell mediated cytotoxicity in AML. We will study the T cell response against both tumor 
associated antigen (TAA) and tumor specific antigen (TSA) which are neo-antigens 
formed by peptides that are created by tumor-specific DNA alterations that result in the 
formation of novel protein sequences. The most common and well characterized TAAs 
in AML, including WT-1, Survivin, hTERT and MUC-1. We will also evaluate other 
markers, such as checkpoint molecules and T cell exhaustion markers. T cell recognition 
of neo-antigens has been found to play a major role in checkpoint blockade therapy for 
solid tumors such as melanoma and are proposed to do the same in AML. In early-phase 
trials studying active specific immunotherapy for AML, many leukemia antigens have 
shown clinical effectiveness.15 Furthermore, tumor-reactive T cells can be directed 
against neo-antigens or leukemia-associated antigens. It has also been shown that acute 
leukemias evade the immune system through checkpoint molecules PDL-1 and CTLA- 
4.16 Finally, T cell exhaustion has been demonstrated to not only occur in AML, but to 
be a dominant cause of T cell dysfunction.17,18 
 
2.5.3 
DNA methylation studies 
 
We propose that the DNA methylation and biologically effective dosing of decitabine 
and venetoclax will not be affected by the addition of nivolumab. We will study the 
level of global DNA methylation as well as methylation levels of specific genes 
involved in immune checkpoint, such as PD-L1, PD-L2, PD-1 and CTLA4. DNA 
methylation (and thus inactivation) of tumor suppressor genes has been linked to 
malignant transformation and it has been demonstrated that decitabine decreases global 
DNA methylation.19 In AML patients who received hypomethylating agents, a higher 
level of methylation was associated with a poorer prognosis compared a lower level of 
methylation.20 Furthermore, it has been shown that AML patients with increased PD-L1 
methylation had a significantly prolonged OS and decreased risk of relapse.21 
 
2.5.4 
Pharmacokinetic (PK) and Pharmacodynamic (PD) studies 
 
While the combination of decitabine and venetoclax has been studied and is currently 
being utilized clinically, adding nivolumab to this combination is novel. Venetoclax has 
low bioavailability, high inter-patient PK variability, and is susceptibility to drug-drug 
interactions (DDIs) through inhibition of intestinal CYP3A4, P-glycoprotein (P-gp), 
and BCRP and liver CYP3A4 and OATP1B1. Antifungal agents, which are routinely 
administered concurrently with venetoclax, are moderate-to-strong inhibitors of 
CYP3A4, and the drug transporters P-gp, BCRP, and OATP1B1. The unpredictable PK 
properties of venetoclax and high DDI potetial warrant detailed plasma PK evaluation 
of venetoclax during AML therapy. 
 
Plasma biomarker assays for OATP1B1 activity will also be incorporated to determine 


NCI Protocol #: 10317  
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13 
 
OATP1B1 activity in relation to antifungal and venetoclax treatment (DOI: 
10.1124/dmd.119.089474). As liver uptake by the transporters OATP1B1 can be a rate-
limiting step to CYP3A4-mediated drug metabolism, and azoles and echinocandins are 
potent inhibitors of OATP1B1, we will also measure plasma biomarkers for OATP1B1 
activity before and after administration antifungal/venetoclax. In order to assess the 
degree of OATP1B1 inhibition, analysis of glycochenodeoxycholate sulfate (GCDGA-
S) and chenodeoxycholate-24-glucuronide (CDCA-24G) levels will be performed in 
plasma samples as validated surrogate endogenous substrates of OATP1B1/OATP1B3. 
Previous clinical studies have indicated that the AUC of GCDCA-S can be increased 
>20-fold following treatment with OATP1B1/3 inhibitors, whereas CDCA-24G is only 
detectable after the administration of OATP1B1/3 inhibitors. In addition to these bile 
acids, the co-proporphyrins CP-I and CP-III will be examined as OATP1B1/3 
biomarkers. These compounds are known OATP1B1/3 substrates in vitro, and their 
plasma levels are significantly increased in Oatp1a/1b gene cluster knockout mice, 
compared with wild-type animals (up to 18.4-fold) as well as in humans receiving 
OATP1B1/3 inhibitors. The selectivity of CP-I and CP-III for OATP1B1 and 
OATP1B3 has been confirmed by the demonstration that these compounds are not 
transported by OCT1, OCT2, OAT3, or NTCP. 
 
Antibody drug clearance has been demonstrated as an early biomarker for outcomes 
from immune checkpoint inhibitor therapy in some disease populations [32037060, 
32089494]. In particular, baseline clearance (CL0, the clearance of the first dose of 
antibody drug) and/or changes in clearance over time significantly associate with PFS 
and/or overall survival (OS) for CTLA4-targeted [31709718], PD1-targeted [28573468, 
28182273, 29891725, 30018117, 31710163, 761097Orig1s000], and PDL1-targeted 
agents [30980481, 29243223] (low baseline clearance and decreasing clearance over 
time correlates with better outcomes). Sex is also a significant covariate for nivolumab 
clearance in patients with advanced solid tumors [PMC6767401, PMC5270302]. 
Elevated baseline clearance is also observed in patients with cancer-associated 
cachexia, and decreasing clearance over time trends with weight gain in patients who 
are responding to therapy. It is not currently known if CL0 or change in CL over time 
for nivolumab will serve as a predictive biomarker in this patient population, so we aim 
to evaluate this within the trial. 
 
Integration of venetoclax, decitabine, and nivolumab PK/PD will allow assessment of 
exposure-response relationships. 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 
Patients must have histologically or cytologically confirmed acute myeloid leukemia 
(AML). 
 
3.1.2 
Relapsed or refractory AML without any other reasonable treatment options 
 
3.1.3 
Age ≥18 years. 
 


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14 
 
Because no dosing or adverse event data are currently available on the use of nivolumab 
in combination with venetoclax and decitabine in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials if combination 
therapy deemed to warrant further assessment after this pilot study. 
 
3.1.4 
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.5 
Patients must have adequate organ and marrow function as defined below: 
 
 
total bilirubin 
≤ 1.5 x institutional upper limit of normal (ULN), 
(except for patients with Gilbert’s disease) 
 
AST(SGOT)/ALT(SGPT) 
≤5 × institutional ULN 
 
glomerular filtration rate (GFR) >40 mL/min/1.73 m2 
 
3.1.6 
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
 
3.1.7 
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.8 
Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.9 
Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.1.10 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification. To be eligible 
for this trial, patients should be class 2B or better. A baseline troponin should be within 
normal limits and baseline oxygen saturation should be greater than or equal to 92%. A 
baseline ECG should be normal, or with stable changes if patient has chronic ECG 
changes. 
 
3.1.11 Active infection is permitted if the infection is under control. 
 
3.1.12 WBC must be ≤25,000 at time of Day 1 of study treatment. Cytoreduction with Hydrea and 
leukopheresis is allowed. 
 
3.1.13 Risks from venetoclax and nivolumab to the developing human fetus cannot be ruled 
out.For this reason and because decitabine is knowns to be teratogenic, women of child- 
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation. Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician immediately. 
Contraception use should be continued 6 months after the completion of all study treatments for 


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15 
 
women of child bearing potential. Men treated or enrolled on this protocol must also agree to 
use adequate contraception prior to the study, for the duration of study participation, and 7 
months after completion of decitabine, venetoclax, or nivolumab administration. 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent document. 
Patients with impaired decision-making are allowed to participate as long as the patient 
has a Legally Authorized Representative (LAR) or caregiver. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients who have received any prior BCL-2 inhibitor therapy 
 
3.2.2 
Patients who have received prior hypomethylating therapy for treatment of AML are 
excluded 
 
3.2.3  Patients with known autoimmune disease. Patients with active autoimmune disease or 
history of autoimmune disease that might recur, which may affect vital organ function or 
require immune suppressive treatment including systemic corticosteroids, should be 
excluded. These include but are not limited to patients with a history of immune related 
neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, 
Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, 
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, 
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis 
(TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded 
because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, 
endocrine deficiencies including thyroiditis managed with replacement hormones 
including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and 
other arthropathies, Sjögren’s syndrome and psoriasis controlled with topical medication 
and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid 
antibodies should be evaluated for the presence of target organ involvement and potential 
need for systemic treatment but should otherwise be eligible. 
3.2.4  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger (precipitating event). 
 
3.2.5 
Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration. Inhaled or topical steroids and 
adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the 


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16 
 
absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra- 
articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). 
Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 
mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., 
contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by contact allergen) is permitted. 
 
3.2.6 
Patients with hyperleukocytosis requiring immediate cytoreductive chemotherapy (WBC 
≥100,000 with symptoms of leukostasis) 
 
3.2.7 
Isolated extramedullary leukemia of CNS involvement with leukemia 
 
3.2.8 
Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1) with the exception of alopecia. 
 
3.2.9 
Patients who are receiving any other investigational agents. 
 
3.2.10 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to decitabine, venetoclax, or nivolumab 
 
3.2.11 Patients with uncontrolled intercurrent illness. 
 
3.2.12 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.13 Pregnant women are excluded from this study because fetal risk has been demonstrated 
with decitabine with the potential for teratogenic or abortifacient effects. Because there 
is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with decitabine, breastfeeding should be discontinued if the 
mother is treated with decitabine. These potential risks may also apply to other agents 
used in this study. 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH- 
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 


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17 
 
Planned distribution of subjects 
 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
 
0 
0 
0 
0 
0 
 
Asian 
 
0 
0 
0 
0 
0 
Native Hawaiian or 
Other Pacific Islander 
 
0 
0 
0 
0 
0 
Black or African 
American 
 
4 
4 
0 
0 
8 
 
White 
 
12 
16 
3 
3 
34 
 
More Than One Race 
 
0 
0 
0 
0 
0 
 
Total 
 
16 
20 
3 
3 
42 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925-0001/0002 
 
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to Oncology Patient Enrollment Network (OPEN), Rave, or acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
RCR utilizes five person registration types. 
x IVR: MD, DO, or international equivalent, 
x NPIVR: advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 


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18 
 
x AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(e.g., Roster Update Management System [RUMS], OPEN, Rave,), 
x Associate (A): other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
x Associate Basic (AB): individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
 
 
Documentation Required 
IV 
R 
NPIVR AP 
A 
AB 
FDA Form 1572 
ᤰ
ᤱ 
ᤰ
ᤱ 
Financial Disclosure Form 
ᤰ
ᤱ 
ᤰ
ᤱ 
ᤰ
ᤱ 
NCI Biosketch (education, training, employment, license, and 
certification) 
ᤰ
ᤱ 
ᤰ
ᤱ 
ᤰ
ᤱ 
GCP training 
ᤰ
ᤱ 
ᤰ
ᤱ 
ᤰ
ᤱ 
Agent Shipment Form (if applicable) 
ᤰ
ᤱ 
CV (optional) 
ᤰ
ᤱ 
ᤰ
ᤱ 
ᤰ
ᤱ 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
x Addition to a site roster, 
x Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
x Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
x Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance). 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 


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19 
 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
x Local IRB documentation, 
x IRB-signed CTSU IRB Certification Form, and/or 
x Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
x Holds an Active CTEP status, 
x Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
x If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
x Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
x Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
x An active Federalwide Assurance (FWA) number, 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
x Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 
Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization on the protocol. 
x Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
x Click on Protocols in the upper left of your screen 


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20 
 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-OH007, and 
protocol number 10317, 
x Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.) 
 
4.2.2 
Protocol Specific Requirements For 10317 Site Registration 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject in the 
OPEN credentialing screen, and may need to answer additional questions related to treatment in 
the eligibility checklist. 
 
x Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU. However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Peter Clark and Diana Vulih are the main points of contact at Theradex for the 
training (PClark@theradex.com and DVulih@theradex.com, Theradex phone: 609- 
799-7580). 
 
4.2.3 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website. The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study. To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off. Any individual at the enrolling site on a 
participating roster may initiate the site DTL. Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL. Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements. 


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21 
 
 
4.2.4 
Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website. 
To access the Regulatory Submission Portal, log on to the CTSU members’ website t
Regulatory t Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
4.2.5 
Checking Site Registration Status 
You can verify your site’s registration status on the members’ side of the CTSU website. 
x Log on to the CTSU members’ website 
x Click on Regulatory at the top of your screen 
x Click on Site Registration 
x Enter your 5-character CTEP Institution Code and click on Go 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined above. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
4.3 
Patient Registration 
 
 
4.3.1 
OPEN / IWRS 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access: 
x A valid CTEP-IAM account. 
x To perform enrollments or request slot reservations: Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar. 
Registrars must hold a minimum of an AP registration type. 
x If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
x Have an approved site registration for a protocol prior to patient enrollment. 


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To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
x Patient has met all eligibility criteria within the protocol stated timeframes, and 
x All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
4.3.2 
Special Instructions for Patient Enrollment 
This Study will use the ETCTN Specimen Tracking System (STS). 
 
x All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted. 
x The system is accessed through special Rave user roles: “CRA Specimen Tracking” for 
data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository. 
x Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website under the Rave/DQP tab. 
x Important: Failure to complete required fields in STS may result in a delay in 
sample processing. Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions can be found in Section 5.3. 
 
4.3.3 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 10 days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled. The Study Coordinator should be notified of cancellations as soon as possible. 


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5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Time Point 
Specimen 
Send Specimens To: 
Baseline 
Pre-
venetoclax/azole 
x 4 mL Peripheral Blood (EDTA-containing 
vacutainer) – OATP1B1 plasma 
biomarker 
OSU PharmacoAnalytical 
Shared Resource for ChOP-
KC 
 
x 10 mL of bone marrow aspirate in sodium 
heparin tubes (mandatory) 
x 15 mL blood in ACD tubes (mandatory) 
Ohio State Leukemia Tissue 
Bank 
x Correlatives: Flow cytometry, 
Cytogenetics, Next-generation 
sequencing, Tetramer Analysis, and DNA 
methylation 
Cycle 1 Day 14 (C1D14) 
Pre-venetoclax, 1h, 
2, 4, 7h, 24h 
 
Pre-nivolumab, 4h 
after end of infusion 
x 
4 mL Peripheral Blood (EDTA-containing 
vacutainer) – Venetoclax plasma levels, 
OATP1B1 plasma biomarker assay 
x 
3 mL Peripheral Blood (red top vacutainer) – 
Nivolumab serum levels  
OSU PharmacoAnalytical 
Shared Resource for ChOP-KC
Day 28+/- 1 day of cycles 1, 2, and 3 
 
x 10 mL of bone marrow aspirate in sodium 
heparin tubes (mandatory) 
x 15 mL blood in ACD tubes (mandatory) 
Ohio State Leukemia Tissue 
Bank 
x Correlatives: Flow cytometry, 
Cytogenetics, Next-generation 
sequencing, Tetramer Analysis, and DNA 
methylation 
Day 28 +/- 1 day every 3 cycles starting with cycle 6 (ex. Cycles 6, 9, 12…) 
 
x 10 mL of bone marrow aspirate in sodium 
heparin tubes (mandatory) 
x 15 mL blood in ACD tubes (mandatory) 
Ohio State Leukemia Tissue 
Bank 
x Correlatives: Flow cytometry, 
Cytogenetics, Next-generation 
sequencing, Tetramer Analysis, and DNA 
methylation 
Day 28 +/- 1 day of end of every cycle starting with cycle 4 (excluding cycles 6, 9, 12… as 
above) 
 
x 10 mL blood in ACD tubes (mandatory) 
Ohio State Leukemia Tissue 
Bank 
x Correlatives: DNA methylation 
Induction Cycle 2 Day 1 


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Pre-nivolumab, 
4h after end of 
infusion 
3 mL Peripheral Blood (red top vacutainer) – 
Nivolumab serum levels 
OSU PharmacoAnalytical 
Shared Resource for ChOP-KC 
Maintenance Cycle 1 (Day 1) 
Pre-nivolumab, 
4h after end of 
infusion 
3 mL Peripheral Blood (red top vacutainer) – 
Nivolumab serum levels 
OSU PharmacoAnalytical 
Shared Resource for ChOP-KC 
Maintenance Cycle 3 (Day 14) 
Pre-nivolumab, 30 
min after end of 
infusion 
3 mL Peripheral Blood (red top vacutainer) – 
Nivolumab serum levels 
OSU PharmacoAnalytical 
Shared Resource for ChOP-KC
End of Treatment/Relapse 
 
x 10 mL of bone marrow aspirate in sodium 
heparin tubes (mandatory) 
x 15 mL blood in ACD tubes (mandatory) 
Ohio State Leukemia Tissue 
Bank 
x Correlatives: Flow cytometry, 
Cytogenetics, Next-generation 
sequencing, Tetramer Analysis, and DNA 
methylation 
 
~ 2 weeks after last 
nivolumab infusion 
x 
3 mL Peripheral Blood (red top vacutainer) – 
Nivolumab serum levels 
OSU PharmacoAnalytical Shared 
Resource for ChOP-KC 


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5.2 
Specimen Procurement Kits and Scheduling 
 
5.2.1 
Specimen Procurement Kits 
 
Institutional supplies should be used for shipping specimens. 
 
5.2.2 
Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue: 
x Bone marrow aspirates collected must be sent to the corresponding lab on the same day 
of collection. Bone marrow aspirate can be collected Monday through Friday 
x Fresh blood specimens may be collected and sent Monday through Friday. 
 
5.3 
Specimen Tracking System Instructions 
 
5.3.1 
Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
x Protocol Number 
x Investigator Identification 
o Institution and affiliate name 
o Investigator’s name 
x Eligibility Verification: Patients must meet all the eligibility requirements listed in 
Section 3. 
x Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID. The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this protocol that uses the ETCTN Specimen Tracking System. The 
UPID contains no information or link to the treatment protocol. IWRS will maintain an 
association between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the molecular 
characterization results with the clinical data. 
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave. The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial. For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave. Important: Remove any personally identifying 
information, including, but not limited to, the patient’s name, initials, medical record 
number, and patient contact information from the institutional pathology report prior to 
submission. 


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Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software. 
 
For questions regarding the Specimen Tracking System, please contact the Theradex Help Desk 
at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
5.3.2 
Specimen Labeling 
 
5.3.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 
x Time point 
x Specimen type (e.g., blood, serum) 
x Collection date (to be added by hand) 
 
5.3.2.2 Tissue Specimen Labels \ 
 
Include the following on all tissue specimens or containers (e.g., formalin jar): 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 
x Time point 
x Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, Formalin 
Fixed Tissue, Fresh Tissue in Media, etc.) 
x Tissue type (P for primary, M for metastatic or N for normal) 
x Surgical pathology ID (SPID) number 
x Block number from the corresponding pathology report (archival only) 
x Collection date (to be added by hand) 
 
5.3.2.3 Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 


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The QR code in the above example is for the Specimen ID shown on the second line. 
NOTE: The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
5.3.3 Overview of Process at Treating Site 
 
5.3.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration with eligibility specimen analysis: 
 
1. Site enters first step data into OPEN. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends first step registration data, including the IDs and a TAC of “NOT REG” 
directly to Rave. 
4. The specimen tracking system in Rave is utilized for the specimen that contributes to 
eligibility determination. 
5. Site enters second and any subsequent step data into OPEN including results of specimen 
analysis. 
6. IWRS receives all data from OPEN, then sends it onto Rave with either the treatment 


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TAC or a TAC of “SCRN FAIL”. 
7. In addition to the specimen tracking forms completed to determine eligibility, data entry 
for screen failure patients should include Histology and Disease, all forms in the Baseline 
folder, any lab forms connected to eligibility determination, and Off Treatment/Off 
Study. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.3.3.2 Rave Specimen Tracking Process Steps 
 
Step 1: Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies. Enter the 
initial clinical specimen data: 
x Specimen Tracking Enrollment CRF: Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates unique 
Specimen ID. 
 
Step 2: Print labels using report in EDC and collect specimen. 
x Label specimen containers and write collection date on each label. 
x After collection, store labeled specimens as described in Section 5.4.2. 
x Apply an extra specimen label to each report before scanning. Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports and Pathology Verification form (when applicable). 
Return to Specimen Tracking Enrollment CRF to upload any molecular report (one per 
specimen) and/or specimen specific pathology or related report (one per specimen). 
Uploaded reports should have protected health information (PHI) data, like name, 
mailing address, medical record number or social security number (SSN), redacted. Do 
not redact SPID, block number or relevant dates, and include the UPID and patient study 
ID on each document. 
 
Step 3:  Complete specimen data entry. 
x Specimen Transmittal Form: Enter collection date and time and other required 
specimen details. 
 
Step 4: When ready to ship, enter shipment information. 
x Shipping Status CRF: Enter tracking number, your contact information, recipient, 
number of containers and ship date once for the first specimen in a shipment. 
x Copy Shipping CRF: Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 
Step 5: Print shipping list report and prepare to ship. 
x Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
x Print pathology or other required reports to include in the box. Be sure the printed copy 
includes the specimen label. 


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Step 6: Send email notification. 
x For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7: Ship the specimen(s). 
 
5.4 
Specimen Collection 
 
5.4.1.1 Collection of Bone Marrow Aspirate in Sodium Heparin Tubes for Processing 
 
1. Label EDTA tube(s) according to the instructions in Section 5.4.2. 
2. Collect 8-10 mL of bone marrow aspirate in each EDTA (purple top) tube(s). 
3. Tubes should be inverted gently at least 3 times. 
4. Tubes may be kept at ambient temperature after collection and during shipment 
 
5.4.1.2 Collection of Blood in ADC Tubes for Whole Blood Processing 
 
1. Label ADC tubes according to the instructions in Section 5.4.2. 
2. Collect up to 10 mL blood in each EDTA tube(s) and gently invert tube to mix. 
3. Tubes should be inverted gently at least 3 times. 
4. Tubes may be kept at ambient temperature after collection and during shipment 
 
5.4.1.3 Collection of Blood for Venetoclax, OATP1B1 biomarker and nivolumab pharmacokinetic 
studies 
 
1.   See Appendix F 
 
5.5 
Shipping of Specimens from Clinical Site to Other Laboratories 
 
5.5.1 
Shipping of Specimens to Ohio State CLIA Certified Lab 
5.5.1.1 
Bone marrow aspirate will be collected and sent as normally for molecular 
sequencing to Ohio State University sequencing laboratory 
 
5.5.2 
Shipping of Specimens to Ohio State Leukemia Tissue Bank 
5.5.2.1 
Specimen Shipping Instructions 
Notify the Leukemia Tissue Bank when patient arrives and orders have been pended. 
The LTB staff will pick up the samples when complete. 
 
5.5.2.2 
Shipping Address 
If needed to send to the Leukemia Tissue Bank directly, please see the following 
address: 
300 West Tenth Avenue, Lobby 
Columbus, OH 43210 
 
5.5.2.3 
Contact Information for Assistance 
Chris Manring, Clinical Laboratory Manager 


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30 
 
614 688-9862 or 614-688-4754 or email: Christopher.manring@osumc.edu 
5.5.3    Shipping of Specimens to Ohio State PharmacoAnalytical Shared Resource (PhASR) 
5.5.3.1      See Appendix F 
 


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5.6 
Biomarker Plan 
 
Biomarker Name AND 
Lab PI and Site 
Assay (CLIA: Y/N) 
Use (Integral, 
Integrated, or 
Exploratory) AND 
Purpose 
Tissue/Body Fluid 
Tested and Timing of 
Sample Collection 
M/O 
Use of NCI 
Resources (No 
/ Pending 
Approval / 
Approved) 
Funding Source(s) 
Immunophenotyping 
Gerard Lozanski, MD/The Ohio 
State University, Director of Flow 
Cytometry Laboratory 
Gerard.Lozanski@osumc.edu 
Multiparameter 
flow cytometry 
CLIA: Y 
No Review 
Required 
Exploratory 
Depth of Response 
assessment. 
Bone marrow 
biopsy aspirate 
- Baseline 
- End of cycle 1, 2, 
and 3 
Every 3 months starting 
with cycle 6 
- Relapse/EOT 
M 
ETCTN 
Biorepository: No 
CIMAC: No NCLN 
Genomics 
Laboratory: No 
NO1 
correlative funding 
budget 
Cytogenetics 
Cecelia Miller, PhD/The Ohio 
State University, Director of 
Cytogenetics 
Karyotype and FISH 
analyses 
CLIA: Y 
No Review 
Required 
Exploratory 
Depth of Response 
assessment. 
Bone marrow 
biopsy aspirate 
- Baseline 
- End of cycle 1, 2, 
and 3 
Every 3 months starting 
with cycle 6 
- Relapse/EOT 
M 
ETCTN 
Biorepository: No 
CIMAC: No NCLN 
Genomics 
Laboratory: No 
NO1 
correlative funding 
budget 
Global and gene-specific DNA 
methylation 
Chris Oakes, PhD (PI) /The Ohio 
State University, Experimental 
Hematology Lab 
Christopher.Oakes@osumc.edu 
Quantitative DNA 
methylation with 
MassARRAY 
CLIA: N 
No Review 
Required 
Exploratory 
To assess global DNA 
methylation and 
methylation levels of 
specific genes involved in 
immune checkpoint. 
Peripheral blood 
- Baseline 
- End of each cycle 
(both induction and 
maintenance) 
-Relapse 
M 
ETCTN 
Biorepository: No 
CIMAC: No NCLN 
Genomics 
Laboratory: No 
NO1 
correlative funding 
budget 
 
 
NCLN PD 
Laboratory: No 


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Biomarker Name AND 
Lab PI and Site 
Assay (CLIA: Y/N) 
Use (Integral, 
Integrated, or 
Exploratory) AND 
Purpose 
Tissue/Body Fluid 
Tested and Timing of 
Sample Collection 
M/O 
Use of NCI 
Resources (No 
/ Pending 
Approval / 
Approved) 
Funding Source(s) 
Next generation sequencing 
AML mutational analysis with 
Variant Allele Frequency 
James Blachly, MD (PI)/ The 
Ohio State University, 
Experimental Hematology Lab 
James.Blachly@osumc.edu 
Amplicon Sequencing 
for 96 gene panel 
CLIA: N 
No Review 
Required 
Exploratory 
Depth of Response 
assessment. 
Bone marrow 
biopsy aspirate 
- Baseline 
- End of cycle 1, 2, 
and 3 
- Every 3 months 
starting with cycle 6 
M 
ETCTN 
Biorepository: No 
CIMAC: No NCLN 
Genomics 
Laboratory: No 
NO1 
correlative funding 
budget 
- Relapse/EOT 
 
NCLN PD 
Laboratory: No 
Tetramer analysis and Cytokine 
Production up re-stimulation with 
antigenic peptide 
Meixiao Long, MD, PhD (PI)/ The 
Ohio State University, 
Experimental Hematology Lab 
Meixiao.Long@osumc.edu 
Flow cytometry and 
functional assay 
CLIA: N 
No Review 
Required 
Exploratory 
To identify tumor specific 
T-cell response to AML 
cells. These include T 
cells specific for tumor 
associated antigen (WT1 
and MUC1) as well as T 
cells recognized tumor 
specific “neoantigen”. 
Peripheral blood: 
- Baseline 
- After cycles 1, and 3 
of induction and cycles 
3 and 9 of maintenance 
Bone marrow 
biopsy aspirate: 
M 
ETCTN 
Biorepository: No 
CIMAC: No NCLN 
Genomics 
Laboratory: No 
NO1 
correlative funding 
budget 
- Baseline 
- End of cycles 1, 2, 
and 3 
 
NCLN PD 
Laboratory: No 
- Every 3 months 
starting with cycle 6 
 
- Relapse/EOT 
 
Venetoclax and OATP1B1 biomarker 
studies 
Sharyn Baker, PharmD PhD/ The 
Ohio State University, Division of 
Pharmaceutics and Pharmacology 
Baker.2480@osu.edu 
LC/MS-MS and ELISA 
CLIA: N 
No Review Required 
Exploratory 
To assess the effect of 
antifungal agent on 
venetoclax plasma PK and 
OATP1B1 plasma biomarker 
Peripheral blood 
- Baseline 
Cycle 1 (Day 14/15) 
 
ETCTN 
Biorepository: No 
CIMAC: No NCLN 
Genomics 
Laboratory: No 
U24 ChOP-KC 
Nivolumab PK studies 
Mitch Phelps, PhD/ The Ohio State 
University, Division of Pharmaceutics 
LC/MS-MS and ELISA 
CLIA: N 
Exploratory 
To assess the PK of 
nivolumab in combination with 
Peripheral blood 
 
- Cycle 1 (Day 14) 
-  
 
ETCTN 
Biorepository: No 
U24 ChOP-KC 


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and Pharmacology 
Phelps.XX@osu.edu 
No Review Required 
venetoclax/decitabine 
- Induction Cycle 2 (Day 1) 
-  
- Maintenance Cycle 1 
(Day 1) 
-  
- Maintenance Cycle 3 
(Day 14) 
-  
- End of 
Treatment/Relapse 
 
CIMAC: No NCLN 
Genomics 
Laboratory: No 


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5.7 
Integral Laboratory Studies 
 
None 
 
 
5.8 
Exploratory/Ancillary Correlative Studies 
 
5.8.1 
Flow Cytometry 
5.8.1.1 
Specimen(s) Receipt and Processing at Ohio State University’s Leukemia Tissue 
Bank 
5.8.1.2 
Site(s) Performing Correlative Study 
This exploratory biomarker will be performed locally at the participating institution, then 
the immunephenotyping raw data will be reviewed centrally at The Ohio State University’s 
Flow Cytometry Clinical Lab. 
 
5.8.2 
Cytogenetics with karyotyping and AML FISH panel 
5.8.2.1 
Specimen(s) Receipt and Processing at Ohio State University’s Leukemia Tissue 
Bank 
5.8.2.2 
Site(s) Performing Correlative Study 
This exploratory biomarker will be performed at locally and the chromosome pictures will 
be sent for central review at The Ohio State University’s Cytogenetics Clinical Lab. 
 
5.8.3 
Next generation sequencing AML mutational analysis with Variant Allele Frequency 
5.8.3.1 
Specimen(s) Receipt and Processing at Ohio State University’s Leukemia Tissue 
Bank 
5.8.3.2 
Site(s) Performing Correlative Study 
This exploratory biomarker will be performed at The Ohio State University’s Experimental 
Hematology Lab. 
 
5.8.4 
Tetramer analysis and Cytokine Production up re-stimulation with antigen peptide 
5.8.4.1 
Specimen(s) Receipt and Processing at The Ohio State University’s Leukemia Tissue 
Bank 
5.8.4.2 
Site(s) Performing Correlative Study 
This exploratory biomarker will be performed at The Ohio State University’s Experimental 
Hematology Lab. 
 
5.8.5 
Global and gene-specific DNA methylation 
5.8.5.1 
Specimen(s) Receipt and Processing at The Ohio State University’s Leukemia Tissue 
Bank 
5.8.5.2 
Site(s) Performing Correlative Study 
This exploratory biomarker will be performed at The Ohio State University’s Experimental 
Hematology Lab. 
 
 
5.8.6 
Venetoclax, OATP1B1 biomarker and nivolumab PK studies 
5.8.6.1 
Specimen(s) Receipt and Processing at The Ohio State University’s 
PharmacoAnalytical Shared Resource 


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5.8.6.2 
Site(s) Performing Correlative Study 
This exploratory biomarker will be performed at The Ohio State University for the ChOP-
KC. 
6. 
TREATMENT PLAN 
 
 
6.1 
Agent Administration 
 
Treatment will be administered as either an outpatient or inpatient basis as appropriate. Reported 
adverse events and potential risks are described in Section 10. Appropriate dose modifications 
are described in Section 7. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
 
Dose Scheduling 
Dose level 
Venetoclax* 
Decitabine 
Nivolumab 
Dose level -2 
Cycle 1 Day 1 100mg 
Cycle 1 Day 2 200mg 
Cycle 1 Day 3-14 400mg 
 
Cycle 2 and beyond Day 1-14 
400mg 
Induction 
20 mg/m2 
intravenously on 
Days 1-10 
 
Maintenance 
20 mg/m2 
intravenously on 
Days 1-5 
Flat dose of 240mg  
every 2 weeks 
starting on Day 15 
of Cycle 1 and 
continue Day 1 and 
15 with cycle 2 and 
subsequent cycles 
Dose level -1 
Cycle 1 Day 1 100mg 
Cycle 1 Day 2 200mg 
Cycle 1 Day 3-21 400mg 
 
Cycle 2 and beyond Day 1-21 
400mg 
Dose level 1 
Cycle 1 Day 1 100mg 
Cycle 1 Day 2 200mg 
Cycle 1 Day 3-28 400mg 
 
Cycle 2 and Cycle 3 (if 
needed) Day 1-28 400 mg 
 
Maintenance cycles Day 1-21 
400 mg 
 
 
 
 
 
 
 
 
 
Regimen Description 


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*Please see Section 6.4.1.1 for dose adjustments with concurrent CYP3A inhibitor use 
 
6.2 
Order of administration 
 
When infusions of nivolumab and decitabine are administered on the same day, nivolumab should 
be administered first, followed by decitabine. There should be 30 minutes of time between 
infusions. 
 
6.2.1 
Other Agent(s) 
 
6.2.1.1 
Nivolumab 
No specific premedications are required, but diphenhydramine, hydrocortisone, and 
epinephrine should be available in case of an infusion reaction or anaphylactic 
reaction. There are no known issues with intravenous solutions. 
 
6.2.1.2 
Decitabine 
Premedicate with 8 mg oral ondansetron 30 minutes prior to chemotherapy. There are 
no known issues with intravenous solutions. 
 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
Take precaution for 
infusion/anaphylactic 
reaction 
240mg 
in max 
of 
160ml 
NS 
IV over 30 
minutes 
Days 1 and 
15 (day 15 
only for 
cycle 1) 
28 days 
(4 weeks) 
Decitabine 
Premedicate with 
ondansetron 30 
minutes prior to 
chemotherapy 
20 
mg/m2 
in 
150ml 
NS 
IV over 60 
minutes 
Days 1-10 
for induction 
cycles and 
Days 1-5 for 
maintenance 
cycles 
Venetoclax* 
Take with a meal and 
water. 
Four 
100 mg 
PO in the 
a.m. 
Daily, days 
1-28 (with 
Premedicate with 
tablets 
ramp up for 
allopurinol and 
 
cycle 1 only 
adequate hydration. 
 
– Day 1 
 
 
100mg, Day 
 
 
2, 200mg, 
 
 
and Day 3 
 
 
400mg)  
[note: days 1-
21 for 
maintenance 
cycles] 


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6.2.1.3 
Venetoclax 
Provide anti-hyperuricemic agents (allopurinol 300 mg daily, begin at least 72 hours 
prior to starting treatment with venetoclax) and adequate hydration to all patients 
prior to first dose and continue through ramp-up phase. Patients should be instructed 
to drink 6 to 8 glasses water each day, starting 2 days before the first dose, on the day 
of the first dose of venetoclax, and each time the dose is increased. 
Tablets should be taken orally once daily, at approximately the same time, with a 
meal and water. Do not chew, crush, or break tablets. 
If a dose is missed by less than 8 hours, take the missed dose right away and take the 
next dose as usual. If a dose is missed by more than 8 hours, the patient should wait 
and take the next dose at the usual time. 
Patients should not take an additional dose if they vomit after taking venetoclax. 
They should take the next dose at the usual time the following day. 
Tell the patient to Avoid grapefruit products, Seville oranges, and starfruit during 
treatment. 
6.3 
Definition of Dose-Limiting Toxicity 
 
The dose limiting toxicity period (DLT) will be defined as the time period from the start of 
nivolumab therapy on C1D15 to the end of cycle 3. DLT will be defined as non-hematologic 
toxicity of ≥ grade 3 with the exception of grade 3 nausea and vomiting that resolves to < grade 3 
within 72 hours, and infection (infection-related toxicities such as fever/sepsis, see below). The 
grade 3/4 toxicity, designated to be DLT, should be considered drug-related. Patients with 
transient grade ≥ 3 electrolyte abnormalities that are not clinically significant and are correctable 
within 24 hours will not be considered a DLT. Patients with ≥ grade 3 transient liver function test 
abnormalities (AST, ALT, or alkaline phosphatase) that resolve to < grade 2 within 5 days will 
not be considered DLT only if it is self-limited without steroid treatment. Grade 3 or 4 infection 
will not constitute DLT unless it is felt that the infection resulted from unexpectedly complicated 
myelosuppression (degree or duration). 
 
Hematological DLT will be considered as failure to recover neutrophil count (ANC≥500), or 
platelet count ≥25,000, or hemoglobin ≥7 by Day 42 in patients with <5% blasts in the bone 
marrow, absence of myelodysplastic changes, and/or absence of evidence of disease by flow 
cytometry in the bone marrow. For patients with ≥ 5% blasts, myelodysplastic changes, or 
evidence of disease by flow cytometry/cytogenetics, failure to recover neutrophil, platelet count, 
or hemoglobin may not be considered DLT as this could be the result of persistent disease.  
 
Specifically with nivolumab, any patient who requires high dose steroids (any dose greater than 
the equivalent to 20 mg prednisone daily) will be considered to have experienced a DLT and will 
be taken off nivolumab but allowed to remain on decitabine and venetoclax. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 7. 
 
6.3.1 Evaluable for toxicity 
 
Patients evaluable for safety/toxicity: Any patient receiving study treatment during the DLT eval 
period- start of nivolumab C1D15 to end of cycle 3. Therefore, any patients who do not receive 
nivolumab will not be evaluable for safety and will be replaced. 


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38 
 
 
 
6.3.2 Evaluable for response 
 
Patients evaluable for response: Any patient who receives all of the 3 study drugs. These 
patients will not be replaced. 
 
6.3.3 Progressive disease stopping rule 
 
Stopping rule: if >50% of patients have disease progression prior to finishing cycle 3, the study 
PI and sponsor will consider stopping the study due to ineffective treatment. 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Do not administer live attenuated vaccines prior to, during, or after treatment until B-cell 
recovery occurs. 
 
6.4.1 Concomitant Medications with Venetoclax 
 
Venetoclax is predominantly metabolized by CYP3A4/5. Concomitant use of venetoclax with 
strong inhibitors of CYP3A at initiation and during ramp-up phase is contraindicated. For 
patients who have completed the ramp-up phase and are on a steady daily dose, reduce the dose 
by at least 75% when used concomitantly with strong CYP3A inhibitors. Resume the venetoclax 
dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the 
inhibitor 
Avoid concomitant use of moderate CYP3A inhibitors or P-gp inhibitors. If a moderate CYP3A 
inhibitor or a P-gp inhibitor must be used, reduce the dose by at least 50%. Resume the dose that 
was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after 
discontinuation of the inhibitor. If a narrow therapeutic index P-gp substrate must be used, it 
should be taken at least 6 hours before venetoclax. 
Avoid concomitant use with strong CYP3A inducers or moderate CYP3A inducers. 
Venetoclax may cause a significant increase in Cmax and AUC of warfarin. International 
normalized ratio (INR) should be monitored closely in patients receiving warfarin. 
 
6.4.1.1 Venetoclax Dose Adjustments with Common Antifungals and Other CYP3A Inhibitors 
 
The dose of venetoclax should be adjusted to the following doses if taken with these antifungal 
medications: 
 
Posaconazole: 
Ramp-up Day 1- 20 mg venetoclax 
Ramp-up Day 2- 50 mg venetoclax 
Day 3 and onward- 70 mg venetoclax 
Moderate CYP3A Inhibitors (ex. Fluconazole/Isavuconazole): 
Ramp-up Day 1- 50 mg venetoclax 
Ramp-up Day 2- 100 mg venetoclax 
Day 3 and onward- 200 mg venetoclax 
Strong CYP3A Inhibitors (ex. Voriconazole): 
Ramp-up Day 1- 20 mg venetoclax 


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Ramp-up Day 2- 50 mg venetoclax 
Day 3 and onward- 100 mg venetoclax 
 
Because there is a potential for interaction of nivolumab, decitabine, and venetoclax with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential for drug 
interactions. The study team should check a frequently-updated medical reference for a list of 
drugs to avoid or minimize use of. Appendix D (Patient Drug Interactions Handout and Wallet 
Card) should be provided to patients if available. 
 
6.4.2 Prophylaxis and Management of Tumor Lysis Syndrome 
 
Upon treatment of hematologic malignancies there is a potential for TLS, especially in those 
with elevated pretreatment LDH levels, elevated leukocyte count, renal dysfunction, and 
dehydration. To mitigate the risk for TLS, all patients on this study will be considered high risk 
for TLS and will receive tumor lysis prophylaxis, including hydration (e.g., oral, intravenous) 
and treatment with an agent to reduce the uric acid level (e.g., allopurinol, rasburicase). Patients 
will not be eligible for study if WBC >25,000 as per current recommendations of venetoclax 
with hypomethylating agents per the FDA label. 
 
It is recommended that all subjects receive the following TLS prophylaxis measures: 
• Administration of an oral uric acid reducer (such as allopurinol 300 mg/day) prior to initial 
study therapy administration (ideally at least 72 hours prior when possible) and continued until 
each subject has completed a week at their highest dose level of venetoclax. 
• Chemistry and hematology laboratory tests to be performed the morning of the first dose of 
venetoclax. The investigator's decision to proceed with venetoclax treatment initiation will be 
based on these laboratory values. 
• Rasburicase (given at a flat dose of 6 mg IV x 1, or per institutional standards) must be 
administered per institutional guidelines for subjects with elevated uric acid level at baseline (> 
ULN) as prophylaxis prior to the initial dose of venetoclax. For subjects with a contraindication 
to rasburicase (i.e., glucose-6-phosphate dehydrogenase [G6PD] deficiency), the TLS risk- 
mitigation plan must be reviewed with the Overall PI. 
• Chemistry laboratory tests must be performed STAT at least at the following time points: pre- 
dose (within 4 hours before venetoclax administration), and ever 12 hours during the venetoclax 
ramp-up period. These laboratory values must be reviewed in real time by the investigator. Pre- 
dose laboratory values will be collected and used as baseline to assess potential electrolyte 
abnormalities occurring post venetoclax administration. 
• If any significant laboratory changes are observed within the first 24 hours after initiation of 
dosing, see Appendix C (Recommendations for Initial Management of 
Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome [TLS]), for additional 
laboratory assessments and management guidelines. If aggressive correction of electrolytes 
abnormalities was performed, the subsequent dose of venetoclax can only be given when 
electrolytes have been stable without any further treatment for approximately 24 hours. 
• Hematology laboratory tests will be performed pre-dose (within approximately 4 hours 
before venetoclax administration), and approximately 24 hours post-dose after the first dose of 
venetoclax. 
• During the dose ramp-up period, the subsequent dose should not be administered until the 24 


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40 
 
 
hours post-dose laboratory values are reviewed by the investigator. 
 
* All laboratory assessments may be taken within +/- 2 hour window, and 24 hour 
laboratory assessments within a +/-3 hour window, if necessary. 
6.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
x 
Disease progression/loss of response 
 
x 
Bone marrow/stem cell transplantation 
 
x 
Intercurrent illness that prevents further administration of treatment 
 
x 
Unacceptable adverse event(s) 
 
x 
Patient decides to withdraw from the study 
 
x 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
x 
Clinical progression 
 
x 
Patient non-compliance 
 
x 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
x 
Termination of the study by sponsor 
 
x 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.5.1 Duration of Therapy in cases of CR 
 
If the patient achieves a CR/CRi, even if MRD negative, the patient should continue on therapy 
as long as none of the above instances in 6.5 occurs. However, venetoclax may be interrupted, 
and the subsequent cycle of decitabine may be delayed to allow for absolute neutrophil count 
recovery from day 29 of current cycle until absolute neutrophil count reached at least 500/μL or 


NCI Protocol #: 10317  
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41 
 
 
up to 14 days, then a bone marrow biopsy should be done to assess for continued CR/CRi. If 
patient remains in CR/CRi then dose reductions can occur as follows. For recurrent Grade 4 
neutropenia and thrombocytopenia that lasts >6 weeks from Day 1 of cycle: first dose reduction 
will be to decrease venetoclax to 14 days (days 1-14 of the cycle), the second dose reduction 
will be to decreased to 7 days (days 1-7 of the cycle), the third dose reduction will be to reduce 
decitabine to 4 days (days 1-4 of the cycle), and the fourth/final dose reduction will be to reduce 
decitabine to 3 days (days 1-3 of the cycle). If Grade 4 thrombocytopenia and neutropenia 
recurs after all of these four dose reductions and lasting >56 days, patient will be taken off 
study.   
 
6.6 
Duration of Follow-Up 
 
Patients will be followed for up to 3 years after initiation of therapy or until death, whichever 
occurs first. Patients removed from study for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 Dose Delays/Modifications for DLT 
 
Study treatment (all three drugs) will be held for any patients experiencing a DLT. 
Non-hematologic DLT: Patients may restart therapy when the adverse event recovers to CTCAE 
≤grade 1 or to the patient’s baseline values. If study treatment is restarted and another non- 
hematologic DLT is encountered, the patient must be removed from the study. 
Hematologic DLT: After the 42 day period and confirmed hematologic DLT: If peripheral blasts 
are absent AND the bone marrow blasts are less than 5%, then the patient may restart study 
treatment with decrease of decitabine to 5 days from 10 days of therapy. 
 
If treatment is delayed >6 weeks for an adverse event the patient must be permanently 
discontinued from study therapy. 
 
Patients requiring > two dose delays for the same event should go off protocol therapy. 
Please see specific modifications for Nivolumab (Section 7.3) 
Drugs may be resumed per protocol. If a specific agent (e.g. decitabine or nivolumab or 
venetoclax) is permanently discontinued for toxicity, the other two agents may be continued on 
study. Decitabine and venetoclax doses should not be reduced following toxicity and dose 
interruption, they should continue at the same dose as stated in the protocol. 
 
7.1.1 
Dose Delays/Modifications for other adverse events 
 
All three study drugs will be held for adverse events requiring interruption until the toxicity can 
be evaluated, then resumed unless a drug needs to be permanently discontinued. 
 
7.2 
Dose modifications of Decitabine and Venetoclax for non-DLTs 
 


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Subjects who experience a ≥ grade 3 non-hematologic toxicity with 10 days of decitabine in the 
first cycle will have their dose reduced to 5 days in the second cycle. 
Non-hematologic due to Decitabine or Venetoclax: Any subject who experiences a non- 
hematological AE related to the agent of Grade 3 or 4 that is an escalation from his or her status at 
baseline should have the agent temporarily held until the toxicity Grade returns to less than Grade 
3. The agent should be permanently discontinued if the non-hematological toxicity persists as 
Grade 3 or 4 for more than 21 days, despite the temporary interruption of the agent and patients 
should be taken off treatment with this agent. 
 
Hematologic AE due to decitabine or venetoclax: Decitabine and/or venetoclax doses should not 
be reduced following toxicity and dose interruption. Dose reductions of decitabine and venetoclax 
are allowed in the following manner. For recurrent Grade 4 non that lasts >6 weeks from Day 1 of 
cycle: first dose reduction will be to decrease venetoclax to 14 days (days 1-14 of the cycle), the 
second dose reduction will be to decreased to 7 days (days 1-7 of the cycle), the third dose 
reduction will be to reduce decitabine to 4 days (days 1-4 of the cycle), and the fourth/final dose 
reduction will be to reduce decitabine to 3 days (days 1-3 of the cycle). If Grade 4 
thrombocytopenia and neutropenia recurs after all of these four dose reductions and lasting >56 
days, patient will be taken off study.   
 
7.3      Missed doses of Decitabine and Venetoclax 
 
Decitabine: If decitabine is missed/held, it may be restarted within 48 hours from time of missed 
dose, and the missed days can be made up. If longer than this period, patients will wait for 
further therapy until next cycle of treatment. 
 
Venetoclax: If a dose is missed by less than 8 hours, take the missed dose right away and take the 
next dose as usual. If a dose is missed by more than 8 hours, the patient should wait and take the 
next dose at the usual time. Patients should not take an additional dose if they vomit after taking 
venetoclax. They should take the next dose at the usual time the following day. If a dose is 
vomited within one hour of ingestion, it will be considered a missed dose and recorded as such 
on the patient diary. The dose will not be repeated that same day but the patient will follow 
regular schedule starting the next study dosing day. If vomiting occurs more than 1 hour after 
dosing, it will still be considered a complete dose. 
 
7.4     Dosing delays and modifications once at least MLFS is achieved 
 
Each subsequent cycle of treatment with decitabine+venetoclax should be administered as per the 
FDA decitabine/venetoclax label. Per the label, if grade 4 thrombocytopenia and/or neutropenia 
occurs, hold both decitabine and venetoclax until the neutropenia and thrombocytopenia resolve to a 
grade 2 or less. Please refer to Section 6.5.1 for further details. If a decitabine/venetoclax cycle is 
delayed, nivolumab should also be held and then restarted on Day 1 of the next cycle when 
decitabine/venetoclax is restarted.  
 
 
7.5     Nivolumab 
 
Please refer to the Nivolumab Investigator Brochure or Appendix E to the protocol for toxicity 
management algorithms which include specific treatment guidelines. These algorithms should 


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43 
 
 
be followed unless there are specific clinical circumstances for which the treating physician 
decides an alternative treatment approach is clinically appropriate. Consultation with the study 
PI or drug monitor is recommended. 
 
Adverse events associated with Nivolumab exposure may represent an immunologic etiology. 
These AEs may occur shortly after the first dose or several months after the last dose of 
treatment. Nivolumab must be withheld for drug-related toxicities and severe or life-threatening 
AES. 
 
 Drug will be held for any indication suggestion of cardiac dysfunction of any grade 
pending evaluation 
 Drug will be permanently discontinued for treatment related grade 3 or 4 cardiac 
dysfunction and grade 2 events that do not recover to baseline or that reoccur 
 Treatment as clinically indicated for cardiomyopathy 


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Cardiac *
Management/Next Dose for Nivolumab 
Cardiac Toxicities
Less than
grade 2
Hold dose pending evaluation and observation.** 
Evaluate for signs and symptoms of CHF, 
ischemia, arrhythmia or myositis. Obtain history 
EKG, CK (for concomitant myositis), CK-MB. 
Repeat troponin, CK and EKG 2-3 days. If 
troponin and labs normalize without evidence of 
myocarditis may resume therapy. If labs worsen
or symptoms develop then treat as below.
Grade >2 
with 
suspected 
myocarditis
Hold dose. Admit to hospital. Cardiology consult. 
Rule out MI and other causes of cardiac disease.
Cardiac Monitoring. Cardiac Echo. Consider 
cardiac MRI and cardiac biopsy. Initiate high dose 
methylprednisolone and immune suppression as 
clinically indicated. . If no improvement within 24 
hours consider adding either infliximab, ATG or 
tacrolimus.. May resume therapy if there is a return 
to baseline and myocarditis is excluded or
considered unlikely.
Grade >2 
with 
confirmed 
myocarditis
Off protocol therapy. Admit to CCU (consider 
transfer to nearest Cardiac Transplant Unit). Treat 
as above. Consider high dose methylprednisolone
Add ATG or tacrolimus if no improvement. Off 
protocol treatment.
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and 
troponin
**Patients with evidence of myositis without myocarditis may be 
treated according as “other event”
Note: The optimal treatment regimen for immune mediated 
myocarditis has not been established. Since this toxicity has
caused patient deaths, an aggressive approach is recommended.
≤ Grade 1
Management/Next Dose for Nivolumab
No change in dose.
Grade 2
Hold until ≤ Grade 1 OR baseline (exceptions as noted below).
Grade 3
Hold until ≤ Grade 1 OR baseline and patient no longer on steroid 
treatment if initiated (exceptions as noted below). Permanently 
discontinue for events with a high likelihood of morbidity or 
mortality with recurrent events.
Grade 4
Off protocol therapy.
Recommended management: As clinically indicated


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o
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does 
not respond to topical therapy and does not improve to Grade 1 severity 
within the re-treatment period OR requires systemic treatment should go off 
protocol treatment
o
Any Grade 3 or 4 drug-related laboratory abnormality or electrolyte 
abnormality, that can be managed independently from underlying organ 
pathology with electrolyte replacement, hormone replacement, insulin or that 
does not require treatment does not require discontinuation.
o
Any AE, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the subject 
with continued study drug dosing should go off protocol treatment.
Skin Rash and Oral
Lesions
Management/Next Dose for Nivolumab
≤ Grade 1
No change in dose*.
Grade 2
Hold* until 1≤ Grade resolved. Resume at same dose level.
Grade 3
Hold* until ≤ Grade 1. Resume at same level at investigator discretion
Grade 4
Off protocol therapy.
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, toxic epidermal necrolysis (TEN), and autoimmune bullous disease including oral 
lesions of bullous pemphigus/pemphigoid. Pruritus may occur with or without skin rash and 
should be treated symptomatically if there is no associated liver or GI toxicity. Note skin rash
typically occurs early and may be followed by additional events particularly during steroids 
tapering.
Recommended management: AE management guidelines
Management/Next Dose for Nivolumab
Hold at investigator discretion until ULN or baseline. Resume at same 
dose level.
Grade 2 (3X UNL to 5X UNL): Hold until grade 1 (UNL-3X UNL) or 
baseline. Resume at same dose level at investigator discretion.
Grade 3 (5X UNL to 20X UNL) Hold until grade 1 or baseline. Resume 
at same dose level at investigator discretion with return to grade 1 or 
baseline within 7 days without steroids. If persistent or steroids are
required, off protocol therapy.
Grade 4
Off protocol therapy.


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≤ Grade 1
Management/Next Dose for Nivolumab
Hold until baseline. No change in dose.
Grade 2
Hold until baseline. No change in dose.
Grade 3
Resume at same dose level at investigator discretion if resolved to grade
1 within 7 days without steroids and no evidence of colitis. If persistent 
or steroids are required off protocol therapy.
Grade 4
Off protocol therapy.
See GI AE Algorithm for management of symptomatic colitis.
Patients with Grade 2 symptoms but normal colonoscopy and biopsies may be retreated after 
resolution.
Patients who require systemic steroids should be taken off study treatment.
Please evaluate pituitary function prior to starting steroids if possible without compromising 
acute care. Evaluation for all patients for additional causes includes C. diff, acute and self-
limited infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD.
Recommended management: see GI AE management Algorithm
Pancreatitis
Amylase/Lipase
Management/Next Dose for Nivolumab
≤ Grade 1
Continue at same dose level if asymptomatic at investigator discretion.
Grade 2
Continue at same dose level if asymptomatic at investigator discretion. 
If symptomatic, resume at same dose level when resolved
Grade 3
Continue at same dose level if asymptomatic at investigator discretion. 
Patients should have imaging study when clinically indicated (grade 3 
symptomatic pancreatitis) before resuming treatment. Patients who 
develop diabetes mellitus should be taken off treatment.
Grade 4
Hold until grade 2. Resume at same dose level if asymptomatic. 
Patients who are symptomatic should have imaging study prior to 
resuming treatment and when clinically indicated. Patients who
develop grade 4 symptomatic pancreatitis or diabetes mellitus should be 
taken off treatment.
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as diabetes 
mellitus and diabetic ketoacidosis (DKA). Lipase elevation may occur during the period of 
steroid withdrawal and with other immune-mediated events or associated with colitis, hepatitis, 
and patients who have asymptomatic lipase elevation typically have self-limited course and 
may be retreated.
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation.
Holding drug to evaluate liver function test (LFT) changes and early treatment are 
recommended. LFT changes may occur during steroid tapers from other events and may occur 
together with other GI events including cholecystitis/pancreatitis.
Please note: Grades for liver function follow UNL rather than multiples of baseline.
Recommended management: see Hepatic AE management algorithm


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Pneumonitis 
Management/Next Dose for Nivolumab 
 
≤ Grade 1 
Hold dose pending evaluation and resolution to baseline including 
baseline pO2. Resume no change in dose after pulmonary and/or 
infectious disease (ID) consultation excludes lymphocytic pneumonitis. 
 
Grade 2 
Hold dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation excludes ipilimumab and associated 
lymphocytic pneumonitis as the cause of the pneumonitis. Off study if 
steroids are required. 
 
Grade 3 
Hold dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation excludes ipilimumab and associated 
lymphocytic pneumonitis as the cause of the pneumonitis. Off protocol 
treatment. 
Grade 4 
Off protocol therapy. 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do 
not respond to antibiotics and have no causal organism identified, including influenza. Most 
patients with respiratory failure or hypoxia will be treated with steroids. Bronchoscopy may be 
required and analysis of lavage fluid for lymphocytic predominance may be helpful. Patients 
with new lung nodules should be evaluated for sarcoid like granuloma. Please consider 
recommending seasonal influenza killed vaccine for all patients. 
Recommended management: See Pulmonary AE Management Algorithm 
 
 
Other GI 
NauseaVomiting 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose. 
 
Grade 2 
Hold pending evaluation for gastritis, duodenitis, and other immune 
AEs or other causes. Resume at same dose level after resolution to ≤ 
Grade 1. 
 
Grade 3 
Hold pending evaluation until ≤ Grade 1. Resume at same dose level. 
If symptoms do not resolve within 7 days with symptomatic treatment, 
patients should go off protocol therapy. 
Grade 4 
Off protocol therapy 
Patients with Grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events. 
 
 
 
 
For treatment management of symptomatic pancreatitis, please follow the Hepatic AE 
Management Algorithm. 


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Fatigue
Management/Next Dose for Nivolumab
Grade 2
No change in dose.
Grade 3
Hold until ≤ Grade 2. Resume at same dose level.
Grade 4
Off protocol therapy.
Fatigue is the most common AE associated with immune checkpoint therapy. Grade 2 or 
greater fatigue should be evaluated for associated or underlying organ involvement including 
pituitary, thyroid, and hepatic, or muscle (CPK) inflammation.
Neurologic events
Management/Next Dose for Nivolumab
≤ Grade 1
Hold dose pending evaluation and observation. Resume with no change 
in dose when resolved to baseline.
Grade 2
Hold dose pending evaluation and observation. Hold until ≤ Grade 1. 
Off protocol therapy if treatment with steroids is required. Resume at 
same dose level for peripheral isolated n. VII (Bell’s palsy).
Grade 3
Off protocol therapy.
Grade 4
Off protocol therapy
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other 
than peripheral n. VII), GB syndrome, and myasthenia gravis should be off study.
Recommended management: See Neurologic AE Management Algorithm
Management/Next Dose for Nivolumab
≤ Grade 1
*Hold pending evaluation for evidence of adrenal insufficiency or 
hypophysitis. Asymptomatic thyroid stimulating hormone (TSH) 
elevation may continue treatment while evaluating the need for thyroid 
replacement.
Grade 2
Hold until patients are on a stable replacement hormone regimen. If 
treated with steroids, patients must be stable off steroids for 2 weeks. 
Resume at same dose level.
Grade 3
Hold until patients are on a stable replacement hormone regimen. If
treated with steroids, patients must be stable off steroids for 2 weeks. 
Resume at same dose level.
Grade 4
Off protocol therapy.
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered Grade 3 events. 
Isolated thyroid or testosterone deficiency may be treated as Grade 2 if there are no other 
associated deficiencies and adrenal function is monitored.
Please evaluate pituitary function before beginning steroid therapy or replacement therapy of 
any kind. *Note patients with thyroiditis may be retreated on replacement therapy. Patients


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Renal 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Monitor closely and continue therapy. 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate. Patients may experience 
isolated fever during infusion reactions or up to several days after infusion. Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever. 
 
 
Infusion reaction 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Monitor closely and continue therapy. 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate. Patients may experience 
isolated fever during infusion reactions or up to several days after infusion. Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever. 
 
 
Fever 
Management/Next Dose for Nivolumab 
≤ Grade 1 
Evaluate and continue at same dose level. 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate. Patients may experience 
isolated fever during infusion reactions or up to several days after infusion. Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever. 
See section 6.7 – Treatment of Nivolumab-Related Infusion Reactions. 
 
Any patients who require additional immune suppressive treatment beyond steroids 
should go off study treatment. 
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate 
must be evaluated to rule out pituitary disease prior to initiating thyroid replacement. 
Recommended management: See Endocrine Management Algorithm 


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endocrine testing including cortisol, Cortrosyn® adrenocorticotrophic hormone 
(ACTH), thyroid stimulating hormone (TSH), and thyroxine (T4) must be obtained 
to document baseline. 
 
Please note that in some cases the treatment algorithms recommend steroids if 
symptoms do not resolve in 7 days. However, this recommendation is not meant to 
delay steroid treatment at any time it is clinically indicated. 
 
Any patient started on corticosteroids initially, who is determined to not require 
steroid treatment for an autoimmune AE, may resume therapy after a 2-week 
observation period without further symptoms at the discretion of the PI or investigator. 
 
Any patient requiring high dose steroids (any dose greater than the equivalent to 20 mg 
prednisone) will be considered to have experienced a DLT and will be taken off 
nivolumab. These patients will be allowed to continue receiving decitabine and 
venetoclax on study. 
 
Patients requiring high dose steroid treatment for autoimmune or inflammatory events 
should go off study treatment except for a short course of tapering steroids for infusion 
reaction, skin rash or endocrine events. 
 
Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 
events with resolution and stable replacement treatment. 
 
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted 
with replacement hormones including thyroid hormone and physiologic doses of 
corticosteroids. 
 
Please note that grading and for hypophysitis with symptoms of headache, visual or 
neurologic changes or radiologic evidence of pituitary enlargement and other CNS 
events such as aseptic meningitis or encephalitis should be considered grade 3 events. 
Patients may be dose-delayed for evaluation and restarted depending on results. 
Any patient started on corticosteroids initially who is determined to not require 
steroid treatment for an autoimmune adverse event may resume therapy after a 2- 
week observation period without further symptoms at the discretion of the PI or 
investigator. 
 
If doses of nivolumab are missed/delayed other than reasons for toxicity, they may be 
given +2 days of scheduled dose. 
 
7.6 
Special circumstances 
Given that the average time to respond to decitabine with venetoclax is 1.3 months, it is possible 
that many patients could achieve a CR or CRi within this time yet also experience a DLT. Patients 
who achieve a CR or CRi within the this average 1.3 months’ time to response, yet also 
experience a DLT, will be evaluated and treated at the discretion of the PI and sponsor. These 
patients will not automatically be taken off study, as we do not want to discontinue a study 
treatment that is providing benefit without determining if the specific DLT is significant enough to 


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warrant this. 
 
If a patient experiences a DLT attributed to nivolumab requiring the use of high dose steroids 
(≥20 mg prednisone daily, or the equivalent), they will be allowed to continue on study receiving 
decitabine with venetoclax. 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the commercial agents 
administered in this study can be found in Section 10.1. 
 
8.1 
Investigational Agent 
 
8.1.1 Nivolumab 
 
Description: Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light 
(few) particulates may be present. The drug product is a sterile, nonpyrogenic, single-use, 
isotonic aqueous solution formulated in sodium citrate dihydrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 (Tween® 80), and water for 
injection. Dilute solutions of hydrochloric acid and/or sodium hydroxide may be used for pH 
adjustment (pH 5.5-6.5). 
 
Preparation: Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose. When the dose is based on patient weight (i.e., 
mg/kg), nivolumab injection can be infused undiluted or diluted to protein concentrations as low 
as 0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab 
injection can be infused undiluted or diluted so as not to exceed a total infusion volume of 160 
mL. For patients weighing less than 40 kilograms (kg), the total volume of infusion must not 
exceed 4 mL per kg of patient weight. During drug product preparation and handling, vigorous 
mixing or shaking is to be avoided. Nivolumab infusions are compatible with polyvinyl chloride 
(PVC) or polyolefin containers and infusion sets, and glass bottles. 
 
Storage: Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and protected from 
light and freezing. The unopened vials can be stored at room temperature (up to 25°C, 77°F) and 
room light for up to 48 hours. 
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-8°C and 
quarantine the supplies. Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability: Refer to the package label for expiration. 
The administration of undiluted and diluted solutions of Nivolumab must be completed within 24 
hours of preparation. If not used immediately, the infusion solution may be stored up to 24 hours 
in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 24 hours can be at 


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room temperature (up to 25°C, 77°F) and room light. The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period. 
CAUTION: The single-use dosage form contains no antibacterial preservative or 
bacteriostatic agent. Therefore, it is advised that the product be discarded 8 hours 
after initial entry. 
 
Route of Administration: Intravenous infusion over 30 minutes. Do not administer as an IV 
push or bolus injection. 
 
Method of Administration: Administer through a 0.2 micron to 1.2 micron pore size, low- 
protein binding (polyethersulfone membrane) in-line filter. 
 
Agent Ordering: Nivolumab is supplied by Bristol-Myers Squibb for this study and distributed 
by the Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) 
with a 0.7mL overfill. It is supplied in 10 mL type I flint glass vials, with fluoropolymer film- 
laminated rubber stoppers and aluminum seals 
 
8.2 
Agent Ordering and Agent Accountability 
Availability 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution. The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents. The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status. For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time. Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is necessary to 
return study drug (e.g., sealed vials remaining when a patient permanently discontinues protocol 
treatment, expired vials recalled by the PMB), investigators must return the study drug to the 
PMB using the NCI Return Agent Form available on the NCI home page (http://ctep.cancer.gov) 
or by calling the PMB at 240-276-6575. 
Drug Accountability: The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, disposition, and return of all drugs received from 
the PMB using the NCI Investigational Agent Accountability Record available on the NCI home 
page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. A separate NCI 
Investigational Agent Accountability Record must be maintained for each patient sequence 
number and for each agent on this protocol. 


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Investigator Brochure Availability: The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB OAOP application. Access to 
OAOP requires the establishment of a CTEP IAM account and the maintenance of an “active” 
account status, a “current” password and active person registration status. Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) 
 
8.3 
Commercial Agent 
 
8.3.1 Decitabine 
 
Description: Decitabine (Dacogen) is supplied as a sterile, lyophilized white to almost white 
powder, in a single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of decitabine. 
Preparation: Reconstitution with 10 mL of Sterile Water for Injection results in a concentration 
of 5 mg/mL. Immediately after reconstitution, the solution should be further diluted with infusion 
fluids, such as 0.9% sodium chloride Injection or 5% dextrose injection to a final drug 
concentration of 0.1 - 1 mg/mL. 
Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using 
COLD infusion fluids (2°C - 8°C) and stored at 2°C - 8°C for a maximum of 4 hours. Diluted 
stored solution must be used within 4 hours from the time of preparation. 
Use the diluted, refrigerated solution within 4 hours from the time of preparation or discard. 
Storage: Store vials at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). 
Stability: Refer to the package label for vial expiration. Refer to Preparation (above) for 
infusion stability. 
 
Route of Administration: Intravenous 


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Agent Ordering: The agent is commercially available. 
 
 
8.3.2 Venetoclax 
 
Description: Venetoclax tablets are supplied as oblong, bi-convex pale yellow or beige tablets 
that contain 100 mg venetoclax as the active ingredient. Each tablet also contains the following 
inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl 
fumarate, and calcium phosphate dibasic, iron oxide yellow, polyvinyl alcohol, polyethylene 
glycol, talc, and titanium dioxide. Each tablet is debossed with “V” on one side and a “100” 
corresponding to the tablet strength on the other side. The 100 mg tablets are available in 120 
and 180 count bottles. 
 
How Supplied: 10 mg, 50 mg, 100 mg tablets 
 
Storage: Store at or below 86°F (30°C). 
 
Stability: Refer to the package label for expiration. 
 
Route(s) of Administration: oral with a meal and water at approximately the same time each 
day. Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken prior to 
swallowing. 
 
Agent Ordering: agent is commercially available 
 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This will be a phase 1 study determining the maximum tolerated dose (MTD) with an expansion cohort 
examining the signal for efficacy will be conducted for this study. 
Adult AML patients (>= 18 years) with relapsed or refractory disease are eligible. All patients on study must 
have primary refractory disease following at least one induction regimen or have relapsed disease following 
induction or consolidation or aHSCT. 
 
Nivolumab in a fixed dose will be administered in combination with decitabine and venetoclax. For the 
induction phase of this study, patients will be treated with 10 days of decitabine the first 10 days of the 
cycle. Patients can be treated with up to 3 cycles of 10-day decitabine course before moving on to the 
maintenance phase of the study. For the maintenance phase, patients will be treated with 5 days of 
decitabine the first 5 days of the cycle and this treatment will continue until one of the following occurs: loss 
of response/disease progression, bone marrow/stem cell transplantation, unacceptable toxicities, or patient 
withdrawal.  
 
For all patients on study, if CR, CRi, or CRh is achieved during cycles 1-3, patients will continue on study at 
the time response is noted with the maintenance phase treatment.  If no response is achieved by cycle 3, 


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patients will come off study. Bone marrow biopsy will occur on Day 28 (+/- 2 days) for up to 3 cycles to 
determine treatment response, then Day 28 (+/- 2 days) every third cycle.   
 
Three dose levels (DL 1, -1, -2) illustrated in Section 6.1 are to be examined, and 3+3 design will be used to 
determine the safe and tolerable dose level. DLT will be defined in Section 6.4, and DLT observation period 
will be defined as the time period from the start of nivolumab therapy on C1D15 to the end of cycle 3 (can 
include induction and maintenance cycles based on how many induction cycles are needed). Dose escalation 
process will follow the rules specified below. Patients who do not finish DLT observation period due to 
reasons other than DLT will need to be replaced.  
Number of Subjects 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 subjects at the next dose level. 
1 out of 3 
Enter 3 more subjects at this dose level. 
x If 0 of these 3 subjects experience DLT, 
proceed to the next dose level. 
x If 1 or more of this group suffer DLT, 
then dose escalation is stopped, and this 
dose is declared the maximally 
administered dose. Three (3) additional 
subjects will be entered at the next lowest 
dose level if only 3 subjects were treated 
previously at that dose. 
>2 
Dose escalation will be stopped. This 
dose level will be declared the 
maximally administered dose (highest 
dose administered). Three (3) 
additional subjects will be entered at 
the next lowest dose level if only 3 
subjects were treated previously at that 
dose. 
<1 out of 6 at highest 
dose level below the 
maximally 
administered dose 
This is generally the recommended 
maximally tolerated dose. At least 6 
subjects should be entered at the 
recommended phase 2 dose. 
 
We expect to enroll a minimum of 6 patients (6 patients treated at DL 1 with 1 or less patient experience 
DLT) and a maximum of 18 patients (6 at each of the DL 1, -1 and -2) for dose finding part. Once the MTD 
is determined, patients will be accrued to the expansion cohort to be treated at MTD. Including 6 patients 
treated at MTD from the dose escalation part, we plan to accrual additional 24 R/R AML patients to the 
expansion cohort. A total of 30 patients will be treated at MTD to decide whether the response rate (CR 
rate), P, is less than or equal to 30% (combination drug not of interest) or greater than or equal to 50% 
(combination drug is promising). If the number of responses out of 30 patients is 13 or more, the hypothesis 
that P ≤ 30% is rejected with a target error rate of 0.10 and an actual error rate of 0.084. If the number of 


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responses is 12 or less, the hypothesis that P ≥ 50% is rejected with a target error rate of 0.20 and an actual 
error rate of 0.181. 
To estimate the response rate, defined by CR/Cri, which will be assessed by bone marrow biopsy after cycle 
1, cycle 2, cycle 3, then every 3 cycles after this, and at time of relapse. Since this will study will only have 
a small sample size, it will not be powered to determine an accurate response rate for nivolumab in 
combination with venetoclax and decitabine. We will plan to estimate response rate, as defined by CR/CRi 
in all evaluable patients in this study, regardless of dose level of venetoclax, and will not attempt to evaluate 
response rate for individual dose levels. The response rate along with an exact 95% confidence interval will 
be reported. However, we can consider our study’s response rate in context of recent retrospective studies 
evaluating venetoclax in combination with HMA as well as the historical response rate with high dose 
cytarabine-containing regimens where the CR rate is 30-40%. Therefore, a response rate of 50% would be 
considered promising.  
 
 
Toxicity will be graded and reported according to the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. All patients who receive any amount of the 
study drug (Nivolumab) will be evaluable for toxicity. 
 
Dosing schema and dosing alterations can be found in Section 6.1 and Section 7. 
 
 
9.2 
Sample Size/Accrual Rate 
 
The maximum total of 42 patients will be accrued. With the estimated accrual rate of 2-3 patients per month, 
the maximum accrual time including DLT observation period will be around 18-24 months. 


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PLANNED ENROLLMENT REPORT 
 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
 
0 
0 
0 
0 
0 
 
Asian 
 
0 
0 
0 
0 
0 
Native Hawaiian or 
Other Pacific Islander 
 
0 
0 
0 
0 
0 
Black or African 
American 
 
4 
4 
0 
0 
8 
 
White 
 
12 
16 
3 
3 
34 
 
More Than One Race 
 
0 
0 
0 
0 
0 
 
Total 
 
16 
20 
3 
3 
42 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925-0001/0002 
 
 
9.3 
Analysis of Secondary Endpoints 
 
Every report of our secondary objectives (listed above in Section 1.2) will contain all patients 
included in the study. For the response calculation, the report will contain at least a section with 
all eligible patients. Another section of the report may detail the response rate for evaluable 
patients only. However, a response rate analysis based on a subset of patients will explain which 
patients were excluded and for which reasons. 95% confidence limits will be given. 
 
Data that are collected serially over time will be explored graphically using box plots and/or 
individual time plots as well as analytically with either repeated measures analysis of variance or 
Friedman’s nonparametric test. This trial will form the basis for a follow up proposal to examine 
this combination in a phase 1 study in newly diagnosed AML patients with TP53 mutations. 
 
We will assess MRD by measuring the mutational burden with variant allele frequency, 
cytogenetics, and flow cytometry before and after response is achieved to see if there is a change 
in any of these MRD assessment parameters. We will compare these three MRD tests at the same 
time points to characterize the importance of different MRD tests in different molecular subsets 
of AML. We will also evaluate MRD status at each time point in relation to disease outcome 
using chi square test of independence. This will allow us to determine which MRD assessment(s) 
performed at which timepoint(s) is most meaningful and helpful in determining 
relapsed/refractory AML outcomes. For T-Cell response and DNA methylation studies, analyses 


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of the data will be primarily descriptive in nature given the relatively small sample size. 
 
Plasma venetoclax and serum nivolumab concentration-time profiles will be analyzed by non 
compartmental analysis in Phoenix Winonlin, and subsequently by population mixed effects PK 
modeling using NONMEM. Pharmacokinetic parameters (e.g., Cmax, AUC, CL, V, and t1/2) 
will be estimated.  For venetoclax PK, concurrent antifungal medications will be grouped as 
strong (e.g., posaconazole, voriconaxole) or moderate (e.g., fluconazole, isavuconazole) 
CYP3A4 inhibitors, or OATP1B1 inhibitors (e.g, micagungin) and included as a covariate in the 
venetoclax population PK model.  Associations between: 1) antifungal drug administered and/or 
venetoclax exposure and changes in OATP1B1 plasma biomarkers from baseline to post-
treatment; and 2) drug exposure parameters such as Cmax and AUC with toxicity or response 
will be performed using standard t-tests or Wilcoxon rank sum tests and illustrated using 
boxplots or other graphical displays. Values will be log transformed as appropriate to reflect 
biologic plausibility assessment.  
 
10. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
10.1.1 CAEPR for Nivolumab 
 
     Version 2.4, December 2, 20201 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
Anemia (Gr 3) 
CARDIAC DISORDERS 


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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
 
 
Myocarditis 
 
 
Pericardial tamponade2 
 
 
Pericarditis 
ENDOCRINE DISORDERS 
 
Adrenal insufficiency3 
 
 
Hyperthyroidism3 
 
 
Hypophysitis3 
 
 
Hypothyroidism3 
 
EYE DISORDERS 
 
 
Blurred vision 
 
 
Dry eye 
 
 
Eye disorders - Other (diplopia)3 
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
 
 
Eye disorders - Other (optic neuritis 
retrobulbar)3 
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada) 
 
Uveitis 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
Abdominal pain (Gr 2) 
 
Colitis3 
 
 
 
Colonic perforation3 
 
Diarrhea 
 
Diarrhea (Gr 3) 
 
Dry mouth 
 
Dry mouth (Gr 2) 
 
 
Enterocolitis 
 
 
Gastritis 
 
 
Mucositis oral 
 
Nausea 
 
Nausea (Gr 2) 
 
Pancreatitis4 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
 
 
Fatigue (Gr 3) 
 
Fever 
 
Fever (Gr 2) 
 
Injection site reaction 
 
Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
 
 
Hepatobiliary disorders - Other 
(immune-mediated hepatitis) 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction3 
 
 
Autoimmune disorder3 
 
 
Cytokine release syndrome5 
 
 
Immune system disorders - Other 
(GVHD in the setting of 
allotransplant)3,6 
 
 
Immune system disorders - Other 
(sarcoidosis)3 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Infusion related reaction7 
 


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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased3 
 
Alanine aminotransferase 
increased3 (Gr 3) 
 
Aspartate aminotransferase 
increased3 
 
Aspartate aminotransferase 
increased3 (Gr 3) 
 
Blood bilirubin increased3 
 
Blood bilirubin increased3 (Gr 2) 
 
CD4 lymphocytes decreased 
 
CD4 lymphocyte decreased (Gr 4) 
 
Creatinine increased 
 
 
Lipase increased 
 
 
Lymphocyte count decreased 
 
Lymphocyte count decreased (Gr 
4) 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
Serum amylase increased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
 
Hyperglycemia 
Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition disorders 
- Other (diabetes mellitus with 
ketoacidosis)3 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis) 
 
 
Myositis 
 
 
Rhabdomyolysis 
NERVOUS SYSTEM DISORDERS 
 
 
Encephalopathy3 
 
 
Facial nerve disorder3 
 
 
Guillain-Barre syndrome3 
 
 
Myasthenia gravis3 
 
 
Nervous system disorders - Other 
(demyelination myasthenic 
syndrome) 
 
 
Nervous system disorders - Other 
(encephalitis)3 
 
 
Nervous system disorders - Other 
(meningoencephalitis) 
 
 
Nervous system disorders - Other 
(meningoradiculitis)3 
 
 
Nervous system disorders - Other 
(myasthenic syndrome) 
 
 
Peripheral motor neuropathy 
 
 
Peripheral sensory neuropathy 
 
 
Reversible posterior 
leukoencephalopathy syndrome3 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury3 
 
 
Renal and urinary disorders - Other 
(immune-mediated nephritis) 


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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Pleural effusion3 
 
 
Pneumonitis3 
 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia)3 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Erythema multiforme3 
 
Pruritus3 
 
Pruritus3 (Gr 2) 
 
Rash maculo-papular3 
 
Rash maculo-papular3 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (bullous 
pemphigoid) 
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome)3 
 
 
Skin hypopigmentation3 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3 Nivolumab being a member of class of agents involved in the inhibition of “immune checkpoints”, may result in 
severe and possibly fatal immune-mediated adverse events probably due to T-cell activation and proliferation.  This 
may result in autoimmune disorders that can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune 
nephritis, autoimmune neuropathy, autoimmune thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss 
Syndrome, drug rash with eosinophilia systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve 
paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, 
endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, 
polymyositis, and Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying fever and 
pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in patients 
receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These complications may occur despite 
intervening therapy between receiving Nivolumab and allo-SCT. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or 
difficulty breathing during and immediately after administration of nivolumab. 
 


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Adverse events reported on Nivolumab trials, but for which there is insufficient evidence to suggest that 
there was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular 
arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema  
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal disorders - 
Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune thrombotic 
microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other (protein total 
decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder - Other 
(polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; Dyspnea; 
Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
 
Note: Nivolumab in combination with other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in events never previously associated with 
either agent. 
 
10.1.1.1 
CAEPR for decitabine 
 
Version 2.5, March 28, 20191 
Adverse Events with Possible 
Relationship to Decitabine (5-aza-2'-deoxycytidine) 
(CTCAE 5.0 Term) 
[n= 1832] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Febrile neutropenia 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
Anal mucositis 
 


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Constipation 
 
Diarrhea 
 
Mucositis oral 
 
Nausea 
 
 
Rectal mucositis 
 
Small intestinal mucositis 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
Edema limbs 
 
Fatigue 
 
 
Fever 
 
 
Non-cardiac chest pain 
 
Pain 
 
IMMUNE SYSTEM DISORDERS 
 
Autoimmune disorder 
 
INFECTIONS AND INFESTATIONS 
 
Infection2 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Bruising 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 
Aspartate aminotransferase 
increased 
 
Blood bilirubin increased 
 


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Adverse Events with Possible 
Relationship to Decitabine (5-aza-2'-deoxycytidine) 
(CTCAE 5.0 Term) 
[n= 1832] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Creatinine increased 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
White blood cell decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
Hyperglycemia 
 
Hyperuricemia 
 
Hypoalbuminemia 
 
Hypocalcemia 
 
Hypokalemia 
 
Hypomagnesemia 
 
Hyponatremia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
Back pain 
 
Bone pain 
 
Pain in extremity 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Headache 
 
 
Intracranial hemorrhage 
 
Somnolence 
 
PSYCHIATRIC DISORDERS 
 
Anxiety 
 
Insomnia 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
Dyspnea 
 
Laryngeal mucositis 
 
Pharyngeal mucositis 
 
Pharyngolaryngeal pain 
 
Respiratory hemorrhage3 
 
Tracheal mucositis 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
Pruritus 
 
Purpura 
 
Rash maculo-papular 
 
VASCULAR DISORDERS 
 
Hematoma 
 
Phlebitis 
 
Vascular disorders - Other 
(hemorrhage with decreased 
platelets) 
 


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65 
 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at 
the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the 
investigator, the protocol and the agent should be included in the e-mail. 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, Mediastinal hemorrhage, 
Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS SOC. 
4Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, 
Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra- 
abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS 
SOC. 
5Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal obstruction, J ejunal 
obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal obstruction under the GASTROINTESTINAL DISORDERS 
SOC. 
 
Adverse events reported on decitabine (5-aza-2'-deoxycytidine) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that decitabine (5-aza-2'- 
deoxycytidine) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(coagulopathy); Blood and lymphatic system disorders - Other (lymphadenopathy); Blood and lymphatic 
system disorders - Other (pancytopenia); Blood and lymphatic system disorders - Other (spleen disorder); 
Bone marrow hypocellular; Eosinophilia; Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Atrioventricular block complete; Cardiac arrest; 
Cardiac disorders - Other (cardiac murmur); Cardiac disorders - Other (dilation atrial); Chest pain - 
cardiac; Heart failure; Myocardial infarction; Restrictive cardiomyopathy; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Ear pain; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (eye hemorrhage); Eye disorders - Other (eye 
swelling); Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Ascites; Dyspepsia; 
Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (mouth ulceration); 
Gastrointestinal disorders - Other (oral mucosal blistering); Gastrointestinal hemorrhage4; Gastrointestinal 
obstruction5; Gastrointestinal pain; Hemorrhoids; Ileus; Oral pain; Periodontal disease; Proctitis; Rectal 
pain; Toothache; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Gait disturbance; 
Injection site reaction; Localized edema; Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other 
(cholestasis); Hepatobiliary disorders - Other (hepatomegaly) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture; Infusion related reaction; 
Injury, poisoning and procedural complications - Other (catheter site pain); Injury, poisoning and 
procedural complications - Other (hernia); Injury, poisoning and procedural complications - Other 
(procedural pain); Injury, poisoning and procedural complications - Other (stent occlusion) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase increased; 
Blood bicarbonate decreased; Blood lactate dehydrogenase increased; CPK increased; Cardiac troponin 
I increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; Fibrinogen 
decreased; GGT increased; INR increased; Investigations - Other (blood bicarbonate increased); 
Investigations - Other (blood bilirubin decreased); Investigations - Other (blood chloride decreased); 
Investigations - Other (blood chloride increased); Investigations - Other (blood urea increased); 
Investigations - Other (elevated ammonia); Investigations - Other (platelet count increased); 
Investigations - Other (protein total decreased); Lipase increased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hyperphosphatemia; Hypoglycemia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (malnutrition) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Chest wall pain; Generalized muscle 
weakness; Muscle cramp; Myalgia 


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NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Aphonia; Ataxia; Cognitive disturbance; Dysesthesia; 
Dysgeusia; Ischemia cerebrovascular; Lethargy; Paresthesia; Peripheral sensory neuropathy; Seizure; 
Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Hematuria; Urinary 
fistula; Urinary frequency; Urinary retention; Urinary tract pain; Urinary urgency 
REPRODUCTIVE SYSTEM AND BREAST disorders - Breast pain; Uterine hemorrhage; Vaginal 
hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Atelectasis; Bronchospasm; Hypoxia; Nasal congestion; Pleural effusion; Pneumonitis; 
Postnasal drip; Pulmonary edema; Respiratory failure; Respiratory, thoracic and mediastinal disorders - 
Other (breath sounds abnormal /decreased); Respiratory, thoracic and mediastinal disorders - Other 
(crepitations); Respiratory, thoracic and mediastinal disorders - Other (pulmonary congestion); Sinus 
disorder; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Erythema multiforme; 
Hyperhidrosis; Hyperkeratosis; Skin and subcutaneous tissue disorders - Other (Sweet's syndrome); Skin 
hyperpigmentation; Skin hypopigmentation; Skin ulceration; Stevens-Johnson syndrome; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event; Vascular 
disorders - Other (aortic aneurysm); Vascular disorders - Other (catheter site hemorrhage); Vascular 
disorders - Other (circulatory collapse); Vascular disorders - Other (hemorrhage); Vascular disorders - 
Other (splenic infarct vs hemorrhage/rupture); Vascular disorders - Other (veno-occlusive disease); 
Vasculitis 
 
 
Note: Decitabine (5-aza-2'-deoxycytidine) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
. 
 
10.1.1.2 
CAEPR for venetoclax 
 
Version 2.0, July 25, 20181 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Venetoclax (ABT-199, NSC 766270) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited reporting to 
NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p 
df for further clarification. Frequency is provided based on 1298 patients. Below is the 
CAEPR for Venetoclax (ABT-199). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 


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parentheses next to the AE in the SPEER. If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
Version 2.1, May 8, 20191 
Adverse Events with Possible 
Relationship to Venetoclax (ABT-199) 
(CTCAE 5.0 Term) 
[n= 1298] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
Febrile neutropenia 
GASTROINTESTINAL DISORDERS 
 
Constipation 
Diarrhea 
 
Nausea 
 
 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
 
 
Fever 
INFECTIONS AND INFESTATIONS 
Infection2 
 
INVESTIGATIONS 
 
Lymphocyte count decreased 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
 
Hypocalcemia 
 
Hypokalemia 
 
Hypophosphatemia 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
NERVOUS SYSTEM DISORDERS 
 
Headache 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
VASCULAR DISORDERS 
 
Hypertension 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can 
be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the 


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investigator, the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
 
Adverse events reported on venetoclax (ABT-199) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that 
venetoclax (ABT-199) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Hemolysis; Thrombotic 
thrombocytopenic purpura 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (coronary artery 
disease); Heart failure; Myocardial infarction; Sinus tachycardia; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
GASTROINTESTINAL DISORDERS - Abdominal pain; Belching; Dry mouth; 
Dyspepsia; Dysphagia; Gastrointestinal disorders - Other (Crohn's disease); Small 
intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; 
Edema limbs; Flu like symptoms; General disorders and administration site conditions - 
Other (general physical heath deterioration); General disorders and administration site 
conditions - Other (multiple organ dysfunction syndrome); Injection site reaction; Non- 
cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (hepatic function 
abnormal) 
IMMUNE SYSTEM DISORDERS - Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Infusion related 
reaction; Injury, poisoning and procedural complications - Other (laceration) 
INVESTIGATIONS - Aspartate aminotransferase increased; Blood bilirubin increased; 
Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Dehydration; 
Hyperglycemia; Hyperkalemia; Hyperphosphatemia; Hyperuricemia; Hypoalbuminemia; 
Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to 
thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone 
pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Myelodysplastic syndrome; Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (acute myeloid leukemia); Treatment related secondary 
malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Intracranial hemorrhage; 
Ischemia cerebrovascular; Nervous system disorders - Other (neuropathy peripheral); 
Peripheral sensory neuropathy; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; 


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Dysuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Ovarian rupture 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Aspiration; Dyspnea; Epistaxis; Hypoxia; Nasal congestion; Oropharyngeal pain; Pleural 
effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(asphyxia) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Pruritus; Rash 
acneiform; Rash maculo-papular 
VASCULAR DISORDERS - Hypotension; Thromboembolic event 
 
 
Note: Venetoclax (ABT-199) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or 
the combination may result in events never previously associated with either agent. 
 
 
10.2 
Adverse Event Characteristics 
 
x CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 10.3.4. 
 
x Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 CTEP-AERS 
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP website (https://eapps-ctep.nci.nih.gov/ctepaers). The reporting 
procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event 


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Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be 
downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
These requirements are briefly outlined in the tables below (Section 10.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
 
10.3.2 Rave-CTEP-AERS Integration 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP- 
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting. 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period. The 
Clinical Research Associate (CRA) will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS integration. 
AEs that occur prior to enrollment must begin and end on the baseline Adverse Event 
form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
x The reporting period (course/cycle) is correct, and 
x AEs are recorded and complete (no missing fields) and the form is query-free 
(fields added to the form during study build do not need to be query-free for the 
integration call with CTEP-AERS to be a success). 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements. The CRA completes the report by accessing CTEP- 
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 


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website: 
x Study specific documents: Protocols > Documents > Education and Promotion, 
and 
x Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information > User Guides. 
NCI requirements for SAE reporting are available on the CTEP website: 
x NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid 
elines.pdf. 
 
10.3.3 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals: Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter. CTEP-AERS provides a copy feature for other e-mail recipients. 
 
10.3.4 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1 ) 
Death 
2 ) 
A life-threatening adverse event 
3 ) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4 ) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5 ) 
A congenital anomaly/birth defect. 
6 ) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 


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may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not required 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
10.3.5 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP- 
AERS. However, they still must be reported through the routine reporting mechanism (Section 
10.4): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Infection 
Any 
Any 
Regardless 
Blood and lymphatic system 
disorders 
Anemia 
Bone marrow hypocellular 
Any 
Regardless 
Investigations 
Lymphocyte count decreased 
Neutrophil count decreased 
Platelet count decreased 
Any 
Regardless 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. 


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10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
The following paragraph only applies to trials using Medidata Rave; other trials may delete: 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP. 
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
x Myelodysplastic syndrome (MDS) 
x Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. Given that this 
treatment protocol is for acute myeloid leukemia, it is not anticipated that any secondary 
leukemia or MDS should be reported. 


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10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 


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11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 10 days prior to start of protocol therapy. In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
 
 
 
Pre- 
Study 
Induction 
cycle 1 
Induction 
cycles 2-3 (If 
needed) 
Maintenance 
cycles 
Relapse/Off 
Study 
Decitabine 
 
D 
D 
D 
Nivolumab 
 
N 
N 
N 
Venetoclax 
 
V 
V 
V 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent medsa 
X 
X 
X 
X 
Physical examb 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
Performance statusd 
X 
X 
X 
Serum Chemistrye 
X 
X 
X 
X 
X 
CBC w/difff 
X 
X 
X 
X 
X 
EKG 
X 
Adverse event evaluationg 
X 
X 
X 
X 
X 
Pregnancy testh 
X 
X 
X 
X 
Bone marrowi 
X 
X 
X 
X 
X 
Correlative studiesj 
X 
X 
X 
X 
X 
D: Decitabine will be given on Days 1-10 of Induction cycles and Days 1-5 of maintenance cycles 
N: Nivolumab will be given on Day 15 of cycle 1 and Days 1 and 15 of all subsequent cycles  
V: Venetoclax will be given on Days 1-28 of induction cycles and Days 1-21 of maintenance cycles. Dosing ramp-up on 
days 1-3 or 1-4 (based on concurrent use of CYP3A inhibitors as outlined in Section 6.3.1) 
a: Concurrent medications should be assessed at screening and the beginning of each treatment cycle 
b: Physical exam should be performed at Screening, Days 1 and 15 of every cycle and End of Treatment/Relapse 
c: Vital signs should be performed at Screening, Days 1 and 15 of every cycle and End of Treatment/Relapse. Vitals signs 
include blood pressure, heart rate, temperature, oxygen saturation, and respiratory rate. 
d: Performance status should be evaluated at Screening, Day 1 of each cycle of therapy, and End of Treatment/Relapse  
e: Serum chemistry will include: Na, K, CO2, Cl, BUN, Cr, AST, ALT, AP, TB, TP, albumin, LDH, and uric acid should 
be performed at screening, pre-dose (within 4 hours prior to venetoclax administration), every 12 hours during venetoclax 
ramp-up period (see Appendix C for tumor lysis management guidelines), twice weekly otherwise during induction cycles 
and at the beginning of each maintenance cycle and relapse/EOT 
f: CBC with differential. To be performed at screening, twice weekly during induction cycles, and at the beginning of 
each maintenance cycle and relapse/EOT. 
g: Adverse event evaluation: will occur on Days 1 and 15 of every cycle and End of Treatment/Relapse 
h: Pregnancy test will occur for women of childbearing potential at Screening and the beginning of each cycle of treatment 
i: Bone marrow biopsies will occur at the end of each cycle of induction, then every 3 cycles (starting with cycle 6) and at 
relapse/EOT. 
j: Please see study sample collection table at Section 5.1 and 11.1 for bone marrow and peripheral blood collection time 
details. 


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11.1 Correlative collection calendar 
 
 
Time Point 
Correlative 
Bone Marrow 
collection 
Peripheral 
Blood 
Collection 
Baseline 
Correlatives: Flow cytometry, Cytogenetics, Next-
generation sequencing, Tetramer Analysis, and 
DNA methylation 
X 
X 
Day 28+/- 1 day of cycles 1, 2, and 3 
Correlatives: Flow cytometry, Cytogenetics, Next-
generation sequencing, Tetramer Analysis, and 
DNA methylation 
X 
X 
Day 28 +/- 1 day every 3 cycles starting with cycle 
6 (ex. Cycles 6, 9, 12…) 
Correlatives: Flow cytometry, Cytogenetics, Next-
generation sequencing, Tetramer Analysis, and 
DNA methylation 
X 
X 
Day 28 +/- 1 day of end of every cycle starting with 
cycle 4 (excluding cycles 6, 9, 12… as above) 
Correlatives: DNA methylation 
X 
End of Treatment/Relapse 
Correlatives: Flow cytometry, Cytogenetics, Next-
generation sequencing, Tetramer Analysis, and 
DNA methylation 
X 
X 


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12. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of thus drug combination has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be 
carefully monitored for tumor response and symptom relief in addition to safety and tolerability. 
Patients with measurable disease will be assessed by standard criteria. For the purposes of this 
study, patients should be re-evaluated with bone marrow biopsies as per the study calendar. 
 
12.1 
Antitumor Effect – Hematologic Tumors 
 
Assessment of clinical response will be made according to the International Working Group 
criteria {Cheson 2003}. The major criteria for judging response will include physical 
examination and examination of blood and bone marrow. All laboratory studies that are 
abnormal prior to study will be repeated to document the degree of maximal response. 
 
Morphologic Leukemia-free State (MLFS) 
 
MLFS requires all of the following: 
12.1.1 
< 5% blasts in bone marrow aspirate
12.1.2 
No extramedullary disease
12.1.3 
No blasts with Auer rods         
 
detected Morphologic Complete Remission (CR) CR requires all of the following:< 5% blasts in bone 
marrow aspirate
12.1.4 
blasts in bone marrow aspirate
12.1.5 
Neutrophils ≥ 1,000/μL
12.1.6 
Platelets ≥ 100,000/μL
12.1.7 
No extramedullary disease
12.1.8 
No blasts with Auer rods detected
12.1.9 
Independent of transfusions 
Cytogenetic Complete Remission (CRc) 
CRc requires all of the following:
12.1.10 
< 5% blasts in bone marrow aspirate
12.1.11 
Neutrophils ≥ 1,000/μL
12.1.12 
Platelets ≥ 100,000/μL
12.1.13 
No extramedullary disease
12.1.14 
No blasts with Auer rods detected
12.1.15 
Independent of transfusions
12.1.16 
Reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis


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Morphologic CR with incomplete blood count recovery (CRi) 
 
CRi requires all of the following: 
 
12.1.17 
< 5% blasts in bone marrow aspirate
12.1.18 
Neutrophils < 1,000/μL or Platelets < 100,000/μL
12.1.19 
No extramedullary disease
12.1.20 
No blasts with Auer rods detected
12.1.21 
If blood counts recover within 14 days of a bone marrow evaluation that is 
consistent with CRi, the patient will be considered CR at the time when both neutrophil and 
platelet count recover (neutrophils ≥ 1,000/μL, platelets  ≥ 100,000/μL).
 
Complete remission with hematological improvement (CRh) 
 
CRh meets all Criteria for CR except for residual thrombocytopenia and/or neutropenia defined 
as: 
 
x Bone marrow blasts <5% 
x Absence of circulating blasts on differential from peripheral blood (as determined by 
flow cytometry or blasts with morphologic Auer rods) 
x Absence of extramedullary disease 
x Absolute neutrophil count >500/μL 
x Platelet count >50,000/μL 
 
Partial Remission (PR) 
 
PR requires all of the following: 
 
12.1.22 
≥ 50% decrease in blasts in bone marrow aspirate to a range of 5-25%
12.1.23 
Neutrophils ≥ 1,000/μL
12.1.24 
Platelets ≥ 100,000/μL
12.1.25 
Independent of transfusions
12.1.26 
A value of ≤ 5% blasts may also be considered a PR if Auer rods are detected
 
Treatment Failure (TF) 
 
Treatment failure will be classified as one of the following: 
 
12.1.27 
Resistant disease: Failure to achieve a complete remission (CR, CRc, or CRi) or 
partial remission. Patients who survive ≥ 7 days following completion of initial 
treatment, with evidence of persistent leukemia by blood and/or bone marrow  
examination.
12.1.28 
Death in Aplasia: Patients who survive ≥ 7 days following completion of initial 
treatment, but die while cytopenic, with an aplastic or hypoplastic marrow obtained within 
7 days of death, without evidence of persistent leukemia


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12.1.29 
Death from Indeterminate cause: Patients who die before completion of 
treatment or < 7 days following completion of initial treatment; patients who die ≥ 7 
days following completion of initial treatment with no peripheral blood blasts, but no 
bone marrow examination is available; patients who fail to complete the first cycle of 
therapy
 
Relapse 
 
Relapse is defined as: 
 
12.1.30 
Evidence of morphologic relapse with the reappearance of leukemic blasts in the 
peripheral blood, blasts with Auer rods, ≥ 5% blasts in the bone marrow, or evidence of 
extramedullary disease not attributable to any other cause. In the setting of recent treatment, 
if there are no circulating blasts and the bone marrow contains 5-20% blasts, a bone marrow 
biopsy should be repeated within 1 week to distinguish relapse from bone marrow 
regeneration.
12.1.31 
The reappearance of cytologically proven extramedullary disease also indicates 
relapse. Reappearance of a cytogenetic abnormality is considered a cytogenetic relapse. 
Evidence of bone marrow morphologic involvement or extramedullary disease required.
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study. This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 


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assignments. To access Rave via iMedidata: 
13.2.1 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account, and
13.2.2 
Assigned one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the enrolling site: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required.
o 
To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o 
To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR, and 
o 
To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name. 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
13.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP). Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site 


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audits will be conducted three times annually (one annual site visit and two data audits). For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. 
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received. Queries will be issued by CTMS directly within Rave. The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web- 
based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D) and a description of any dose-limiting toxicities (DLTs). CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and- 
semantics/metadata-and-models). Customized eCRFs will be included when appropriate to meet 
unique study requirements. The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation. CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly 
basis. The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 


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Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
13.3 
Collaborative Agreements Language 
 
 
The agent(s) supplied by CTEP used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. 
Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual 
Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 


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Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non- 
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review. Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13.4 
Genomic Data Sharing Plan 
 
Data Sharing Plan for CTEP study NCI#10317 
 
Acute Myeloid Leukemia is a devastating, difficult-to-treat, and rarely cured malignancy. The 
timely and accurate dissemination of data generated as part of this project is critical to ensure the 
broadest possible access for researchers to advance the field. 
 
What data will be generated: 
We will generate targeted DNA resequencing (<100 genes), tetramer analysis, cytokine 
production, and global and gene-specific DNA methylation data from patient tumor and blood 
samples at different time points. We may generate RNA-sequencing and chromatin profiling in 
the future (e.g. ChIP-seq) in the future. We do not plan to generate whole-genome or whole- 
exome sequencing data. The risk of reidentification is therefore low. 


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What data will be shared: 
We will share joint phenotypic and genotype data associated with the patient samples by 
depositing these data as controlled-access dataset(s) in dbGaP (and Genomic Data Commons 
[GDC] if permitted), which is an NIH-funded repository that has appropriate controls for 
protection of data. Additional data documentation and de-identified data will be deposited for 
sharing along with phenotypic data, which includes demographics (unless a HIPAA protected 
health identifier), clinical data including cytogenetic studies, and pertinent medical history, 
consistent with applicable laws and regulations. We will comply with the NIH Genomic Data 
Sharing Policy (as outlined in NOT-OD-14-124 and updates) and the NCI’s existing policies on 
sharing data on genetics to include secondary analysis of data through the repository. Submitted 
data will conform to relevant data and terminology standards. Data and associated interpretations 
will be made available in scientific presentations at local, national, and international meetings, 
and in published form in an ongoing basis. 
 
Who will have access to the data: 
We agree that data will be deposited and made available through dbGaP (and possibly GDC) 
which is an NIH-funded repository, and that protected data in dbGaP/GDC will be shared with 
investigators working under an institution with a Federal Wide Assurance (FWA) and could be 
used for secondary study purposes such as finding genes that contribute to AML pathobiology. 
We agree that the names and Institutions of persons either given or denied access to the data, and 
the bases for such decisions, will be summarized and shared with CTEP. Meta-analysis data and 
associated phenotypic data, along with the data content, format, and organization, will be made 
available to investigators. All relevant analyses and interpretations will be disseminated as 
posters, presentations, and papers. 
 
Where will the data be available: 
We agree to deposit and maintain the joint genotypic and phenotypic data, and secondary 
analyses at dbGaP which is an NIH-funded repository and has data access policies and 
procedures consistent with NIH data sharing policies. 
 
When will the data be shared: 
We agree to deposit genetic data into dbGaP repository as soon as possible but no later than one 
year of the completion of the clinical study follow-up period or upon acceptance of the data for 
publication, or public disclosure of a submitted patent applications, whichever is earlier. 
 
How will researchers locate and access the data: 
We agree we will identify where the data will be available and how to access the data in any 
publications and presentations that we author or co-author about these data, as well as 
acknowledge the repository and CTEP in any publications and presentations. As we will be using 
dbGaP/GDC, which are NIH-funded repositories, these repositories have policies and procedures 
in place that will provide data access to qualified researchers, fully consistent with NIH data 
sharing policies and applicable laws and regulations. 


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13.5 
Incidental/Secondary Findings Disclosure Procedure 
 
Samples are not being submitted to the Biobanking and Molecular Characterization Initiative, 
and neither whole genome sequencing nor whole exome sequencing is otherwise planned under 
this protocol. 
 
13.6 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 


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14. REFERENCES 
 
1. DiNardo, C. D. et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy 
ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet 
Haematol. 7, e724–e736 (2020). 
 
2. Tenold, M. E. et al. Outcomes of Adults With Relapsed/Refractory Acute Myeloid Leukemia Treated 
With Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center. Front. Oncol. 0, (2021). 
 
3. Gaut, D. et al. Venetoclax combination therapy in relapsed/refractory acute myeloid leukemia: A single 
institution experience. Leuk. Res. 90, 106314 (2020). 
 
4. DiNardo, C. D. et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N. 
Engl. J. Med. 383, 617–629 (2020). 
 
5. Vigil, C. E., Silverman, M. & Carter, T. Hypomethylating Agents and Low-Dose Venetoclax for Relapse 
Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation. Biol. Blood Marrow Transplant. 26, 
S104 (2020). 
 
6. DiNardo, C. D. et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for 
relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am. J. Hematol. 93, 401–
407 (2018). 
 
7. Zhou, Q. et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice 
with disseminated acute myelogenous leukemia. Blood 117, 4501–4510 (2011). 
 
8. Daver, N. et al. Defining the Immune Checkpoint Landscape in Patients (pts) with Acute Myeloid 
Leukemia (AML). Blood 128, 2900–2900 (2016). 
 
9. Daver, N. G. et al. Phase IB/II study of nivolumab with azacytidine (AZA) in patients (pts) with relapsed 
AML. J. Clin. Oncol. 35, 7026–7026 (2017). 
 
10. Ravandi, F. et al. Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid 
leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study. Lancet Haematol. 6, e480–
e488 (2019). 
 
11. Yang, H. et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is 
enhanced by treatment with hypomethylating agents. Leukemia 28, 1280–1288 (2014). 
 
12. Daver, N. et al. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in 
Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. Cancer 
Discov. 9, 370–383 (2019). 
 
13. Ravandi, F. et al. Persistence of minimal residual disease assessed by multiparameter flow cytometry is 
highly prognostic in younger patients with acute myeloid leukemia. Cancer 123, 426–435 (2017). 
 
14. Ravandi, F., Walter, R. B. & Freeman, S. D. Evaluating measurable residual disease in acute myeloid 
leukemia. Blood Adv. 2, 1356–1366 (2018). 
 


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15. Anguille, S., Van Tendeloo, V. F. & Berneman, Z. N. Leukemia-associated antigens and their relevance 
to the immunotherapy of acute myeloid leukemia. Leukemia 26, 2186–2196 (2012). 
 
16. Hobo, W., Hutten, T. J. A., Schaap, N. P. M. & Dolstra, H. Immune checkpoint molecules in acute 
myeloid leukaemia: managing the double-edged sword. Br. J. Haematol. 181, 38–53 (2018). 
 
17. Knaus, H. A. et al. Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with 
response to chemotherapy. JCI Insight 3, 120974 (2018). 
 
18. Kong, Y. et al. T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell 
Exhaustion and Poor Clinical Outcome in AML Patients. Clin. Cancer Res. 22, 3057–3066 (2016). 
 
19. Stewart, D. J. et al. Decitabine effect on tumor global DNA methylation and other parameters in a phase 
I trial in refractory solid tumors and lymphomas. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 15, 
3881–3888 (2009). 
 
20. Zhang, L.-Y. et al. Impact of Global and Gene-Specific DNA Methylation in de Novo or Relapsed 
Acute Myeloid Leukemia Patients Treated with Decitabine. Asian Pac. J. Cancer Prev. APJCP 17, 431–437 
(2016). 
 
21. Goltz, D. et al. PD-L1 (CD274) promoter methylation predicts survival in patients with acute myeloid 
leukemia. Leukemia 31, 738–743 (2017). 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
 
 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
 
 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM 
CREATININE 
 
Formulas to estimate renal function using serum creatinine provided by the NCI’s Investigational 
Drug Steering Committee (IDSC) Pharmacological Task Force in table below. 
 
1. Estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) (Levey et al., 2009). 
 
Formulae: 
 
Race and 
Serum Creatinine (SCr), 
Equation 
Sex 
μmol/L (mg/dL) 
Black 
Female 
≤62 (≤0.7) 
GFR = 166 × (SCr/0.7)−0.329  × (0.993)Age 
>62 (>0.7) 
GFR = 166 × (SCr/0.7)−1.209  × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 163 × (SCr/0.9)−0.411  × (0.993)Age 
>80 (>0.9) 
GFR = 163 × (SCr/0.9)−1.209  × (0.993)Age 
 
White or 
other 
Female 
≤62 (≤0.7) 
GFR = 144 × (SCr/0.7)−0.329  × (0.993)Age 
>62 (>0.7) 
GFR = 144 × (SCr/0.7)−1.209  × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 141 × (SCr/0.9)−0.411  × (0.993)Age 
>80 (>0.9) 
GFR = 141 × (SCr/0.9)−1.209  × (0.993)Age 
 
SCr in mg/dL; Output is in mL/min/1.73 m2 and needs no further conversions. 
2. eGFR using the Modification of Diet in Renal Disease (MDRD) Study (Levey et al., 2006). 
 
175 x SCr–1.154 × age–0.203 × 0.742 (if female) × 1.212 (if black) 
Output is in mL/min/1.73 m2 and needs no further conversions. 
3. Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation (Cockcroft and 
Gault, 1976). 
 
 
Followed by conversion to a value normalized to 1.73 m2 with the patient’s body surface area 
(BSA). 
 
References 
1. Levey, A.S., L.A. Stevens, C.H. Schmid, et al. (2009). A new equation to estimate 
glomerular filtration rate. Ann Inter Med. 150:604-612. 
2. Levey, A.S., J. Coresh, T. Greene, et al. (2006). Using standardized serum creatinine 
values in the modification of diet in renal disease study equation for estimating 
glomerular filtration rate. Ann Intern Med. 145:247-254. 
3. Cockcroft, D.W. and M.H. Gault. (1976). Prediction of creatinine clearance from serum 
creatinine. Nephron. 16:31-41. 


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APPENDIX C 
RECOMMENDATIONS FOR INITIAL MANAGEMENT OF 
ELECTROLYTE ABNORMALITIES AND PREVENTION OF 
TUMOR LYSIS ivolumab pharmacokinetic studies 
See Appendix [TLS] 


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Abnormality 
Management 
Recommendations 
Hyperkalemia (Including Rapidly 
Rising Potassium 
Potassium ≥ 0.5 mmol/L increase 
from prior value (even if 
potassium within normal 
limits) 
x Recheck potassium, 
phosphorous, uric acid, 
calcium and creatinine in 1 
hour STAT. If further ≥ 0.2 
mmol/L increase in 
potassium, but still < upper 
limit of normal (ULN), 
manage as per potassium ≥ 
ULN. Otherwise recheck in 1 
hour. 
x Resume per protocol testing 
if change in potassium is 
<0.2 mmol/L, and potassium 
<ULN, and no other 
evidence of tumor lysis 
x At the discretion of the 
investigator, may recheck 
prior to hospitalization. If 
stable or decreased, and still 
WNL, hospitalization at the 
discretion of the investigator. 
Potassium, phosphorous, uric 
acid, calcium, and creatinine 
must be rechecked within 24 
hours. 


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Potassium > upper limit of normal 
x Perform stat ECG and 
commence telemetry 
x Nephrology notification with 
consideration of initiating 
dialysis 
x Administer Kayexalate 60g 
x Administer furosemide 20mg 
IV x1 
x Administer calcium 
gluconate 100 to 200mg/kg 
IV slowly if there is 
ECG/telemetry evidence of 
life-threatening arrhythmias. 
x Recheck potassium, 
phosphorus, uric acid, 
calcium, and creatinine in 1 
hour STAT 
x If potassium < ULN 1 hour 
later, repeat potassium, 
phosphorous, uric acid, 
calcium and creatinine 1, 2 
and 4 hours, if no other 
evidence of tumor lysis 


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Potassium ≥ 6.0 mmol/L (6.0 
mEq/L) and/or symptomatic 
(e.g., muscle cramps, 
weakness, paresthesias, 
nausea, vomiting, diarrhea) 
x Perform STAT ECG and 
commence telemetry 
x Nephrology assessment with 
consideration of initiating 
dialysis 
x Administer Kayexalate 60g 
x Administer furosemide 20mg 
IV x1 
x Administer insulin 0.1 U/kg 
IV + D25 2 mL/kg IV 
x Administer sodium 
bicarbonate 1 to 2 mEq/kg 
IV push 
x If sodium bicarbonate is 
used, rasburicase should not 
be used as this may 
exacerbate calcium 
phosphate precipitation 
x Administer calcium 
gluconate 100 to 200 mg/kg 
IV slowly if there is 
ECG/telemetry evidence of 
life-threatening arrhythmias. 
Do not administer in same IV 
line as sodium bicarbonate. 
x Recheck potassium, 
phosphorous, uric acid, 
calcium and creatinine every 
hour STAT 
Hyperuricemia 
Uric acid ≥ 8 mg/dL (476 μmol/L) 
x Consider rasburicase (dose 
based on institutional 
standards) 
x If rasburicase is used, sodium 
bicarbonate should not be 
used as this may exacerbate 
calcium phosphate 
precipitation 
x Recheck potassium, 
phosphorous, uric acid, 
calcium, and creatinine in 1 
hour STAT. 


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Uric acid ≥ 10mg/dL (595 μmol/L) 
OR 
Uric acid ≥ 8 mg/dL (476 
μmol/L) with 25% increase and 
creatinine increase ≥ 0.3 mg/dL 
(≥0.027 mmol/L) from predose 
level 
x Administer rasburicase (dose 
based on institutional 
standard) 
x If rasburicase is used, sodium 
bicarbonate should not be 
used as this may exacerbate 
calcium phosphate 
precipitation 
x Notify nephrology 
x Recheck potassium, 
phosphorous, uric acid, 
calcium, and creatinine in 1 
hour STAT. 
x If uric acid < 8.0 mg/dL 1 
hour later, repeat potassium, 
phosphorous, uric acid, 
calcium, and creatinine 2 and 
4 hours, later, if no other 
evidence of tumor lysis 
Hypocalcemia 
Calcium ≤ 7.0 mg/dL (1.75 mmol/L) 
AND subject symptomatic 
(e.g., muscle cramps, 
hypotension, tetany, cardiac 
arrhythmias) 
x Administer calcium 
gluconate 50 to 100 mg/kg 
IV slowly with ECG 
monitoring 
x Telemetry 
x Recheck potassium, 
phosphorous, uric acid, 
calcium, and creatinine in 1 
hour STAT. 
x If calcium normalized 1 hour 
later, repeat potassium, 
phosphorous, uric acid, 
calcium and creatinine 2 and 
4 hours, later if no other 
evidence of tumor lysis 
x Calculate corrected calcium 
and check ionized calcium if 
albumin low 
Hyperphosphatemia 


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Phosphorus ≥ 5.0 mg/dL (1.615 
mmol/L) with ≥ 0.5 mg/dL (0.16 
mmol/L) increase 
x Administer a phosphate 
binder (e.g., aluminum 
hydroxide, calcium 
carbonate, sevelamer 
hydroxide or lanthanum 
carbonate). 
x Nephrology notification 
(dialysis required for 
phosphorus ≥ 10mg/dL) 
x Recheck potassium, 
phosphorous, uric acid, 
calcium, and creatinine in 1 
hour STAT 
x If phosphorous < 5.0 mg/dL 
1 hour later, repeat potassium 
phosphorus, uric acid, 
calcium, and creatinine 2 and 
4 hours, later, if no other 
evidence of tumor lysis 
Creatinine 
Increase ≥ 25% from baseline 
x Start or increase rate of IV 
fluids 
x Recheck potassium, 
phosphorous, uric acid, 
calcium, and creatinine in 1 
to 2 hours STAT 


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CLINICAL TRIAL WALLET CARD
Show this card to all of your 
healthcare providers and 
keep it with you in case you 
go to the emergency room.
Patient Name:
Diagnosis: Acute Myeloid Leukemia
Study Doctor: Alice Mims, MD
Study Doctor Phone #: 843-480-2685 
NCI Trial #: CTEP 10307
Study Drug(S):
Nivolumab/Venetoclax/Decitabine
APPENDIX D
PATIENT WALLET CARD
INSTRUCTIONS FOR PATIENT WALLET CARD TEMPLATE- Give the wallet card to 
the patient at the time of enrollment. The patient will cut out the wallet-sized information card 
and retain it at all times
PATIENT CLINICAL TRIAL WALLET CARD
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov


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APPENDIX E NIVOLUMAB AE MANAGEMENT ALGORITHM: MANAGEMENT ALGORITHMS FOR 
ENDOCRINOPATHY, GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND SKIN 
ADVERSE EVENTS 


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APPENDIX F: Pharmacokinetic Study Sample Handling and Shipment 
 
1.1 Venetoclax and OATP1B1 Biomarker Plasma Pharmacokinetic Samples 
x 
The plasma pharmacokinetic profile of venetoclax and OATP1B1 biomarker will be characterized by collecting blood samples 
(as outlined in the Study Calendar and in the separate PK study worksheet uploaded at the Cancer Trials Support Unit website 
www.ctsu.org). 
x 
Collection of Specimen(s): patients will have 4 mL samples of blood collected in tubes containing K2 ETDA as an 
anticoagulant (purple top) at the time points specified below: 
o Baseline 
o Cycle 1 Day 14 
 
Pre-venetoclax  
 
1 h post venetoclax 
 
2 h post venetoclax 
 
4 h post venetoclax 
 
7 h post venetoclax 
 
24h post venetoclax 
x 
Obtain venous blood by standard phlebotomy technique from a peripheral access point.  NOTE:  Suggest using a minimum 
18G needle to avoid sample hemolysis.  
o Obtain venous blood by standard phlebotomy technique from a peripheral access point. 
x 
Fill-up the tubes as much as possible until blood flow stops. 
x 
GENTLY invert each tube several times (8-10 times) immediately after collection to avoid sample hemolysis. 
x 
Place samples immediately on ice after collection; samples must be processed within 30 minutes. 
 
1.1.1 Handling of Specimens(s)  
  
Processing instructions 
1. Invert sample 8-10 times immediately before processing.   
2. Centrifuge at ~1000-1300 x g (i.e., RCF, not RPM) for 10 minutes in swinging bucket (SW) or 15 minutes in a fixed angel 
(FA) rotor at 4ºC in a refrigerated centrifuge.  Make sure that the centrifuge reaches speed and is maintained throughout 
the entire spin. 
3. Carefully remove tube from centrifuge.  
4. Using a pipette, transfer equal aliquots of plasma into 2-3 labeled 1.2 mL cryovials (e.g., preferred are external thread, 
conical self-standing vials like CorningTM 430658 or ), not exceeding ~1 mL per cryovial.   
5. Label samples as (drug) (matrix) (purpose), including protocol number (#10417), unique patient ID assigned at registration, 
date of collection, draw time, time point, protocol time point, and initials.  
6. Store plasma samples at -70°C or below until shipment. 
 
1.2 Nivolumab Serum Pharmacokinetic Samples  
x 
The plasma pharmacokinetic profile of nivolumab will be characterized by collecting blood samples (as outlined in the Study 
Calendar and in the separate PK study worksheet uploaded at the Cancer Trials Support Unit website www.ctsu.org). 


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x 
Collection of Specimen(s): patients will have 3 mL samples of blood collected in tubes containing heparin as an anticoagulant 
(red top) at the time points specified below: 
o Cycle 1 Day 14 
 
Pre-nivolumab infusion 
 
4h after end of nivolumab infusion 
o Induction Cycle 2 Day 1  
 
Pre-nivolumab infusion 
 
4h after end of nivolumab infusion 
o Maintenance Cycle 1 (Day 1)  
 
Pre-nivolumab infusion 
 
4h after end of nivolumab infusion 
o Maintenance Cycle 3 (Day 14)  
 
Pre-nivolumab infusion 
 
4h after end of nivolumab infusion 
o End of Treatment/Relapse 
 
~ 2 weeks after last nivolumab infusion 
x 
Obtain venous blood by standard phlebotomy technique from a peripheral access point.  NOTE:  Suggest using a minimum 
18G needle to avoid sample hemolysis.  
o Obtain venous blood by standard phlebotomy technique from a peripheral access point. 
x 
Fill-up the tubes as much as possible until blood flow stops. 
x 
GENTLY invert each tube several times (8-10 times) immediately after collection and then allow blood to clot for 30-60 minutes 
at room temperature before centrifugation.  
 
1.2.1 Handling of Specimens(s)  
  
Processing instructions 
1. 30-60 minutes after sample collection (blood has clotted), centrifuge at ~1000-1300 x g (i.e., RCF, not RPM) for 10 
minutes in swinging bucket (SW) or 15 minutes in a fixed angel (FA) rotor at 4ºC in a refrigerated centrifuge.  Make 
sure that the centrifuge reaches speed and is maintained throughout the entire spin. 
2. Carefully remove tube from centrifuge. 
3. Using a pipette, transfer equal aliquots of serum into 2-3 labeled 1.2 mL cryovials (e.g., preferred are external thread, 
conical self-standing vials like CorningTM 430658 or ), not exceeding ~1 mL per cryovial. 
4. Label samples as (drug) (matrix) (purpose), including protocol number (#10417), unique patient ID assigned at 
registration, date of collection, draw time, time point, protocol time point, and initials. 
5. Store serum samples at -70°C or below until shipment. 
 
1.3 Shipping of Specimen(s)  
 
Specimens for venetoclax, OATP1B1 and nivolumab should be stored through the end of Cycle 1 and shipped as a batch 
by participant (more than one participant/shipment is acceptable if the site has >1 participant on-study). After cycle 1,  


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nivolumab samples can be shipped in batch every 3 months, or OSUCCC PhASR may contact the study team to request 
shipment off-schedule.   
Please ship 1 aliquots to the OSUCCC PhASR. Once receipt is confirmed, the back-up aliquot may be shipped.  The 
back-up can be shipped at a later date with subsequent batches.   
 
Preparing the shipment  
*Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH) with dividers. (e.g., VWR Box item number is 
82021-114; divider item number is 82007-154.) 
*Please organize the samples by Patient and Time point in the box.  
*Do not store in plastic bags (they break on dry-ice and labels will detach).  
*A copy of each of the pharmacokinetic sample collection forms (PK study worksheer) for the respective patients or a sample 
list should be included with each shipment. To prevent problems with illegible writing on tubes, consider numbering them (in 
addition to sample label) and numbering samples on the sample sheet.  
*Note the study number, PI, and the drugs used/to be measured.  
*A name, phone number and email address should be included with samples so that receipt can be acknowledged.  
*Please notify the lab by email (phasr@osumc.edu) at least 24 hours prior to shipment.  
 
Shipping  
*All samples should be shipped via overnight express courier in insulated containers with enough dry ice to maintain the 
samples in a frozen state.  
*Overnight shipments should occur on Monday through Wednesday (Tuesday is the preferred day) except when the following 
day is a holiday. 
 
The OSUCCC PhASR 
Attn:  Kasey Hill, Ph.D. (Venetoclax/OATP1B1/Nivolumab Samples) 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, OH 43210 
Phone:  (614) 688-0578 
Fax:  (614) 292-7766 


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APPENDIX G: Medication Diary 
 
Important Instructions for your Venetoclax drug dosing: 
 
Please call your clinic team with any questions related to taking your medication, or if you experience any side 
effects that you are concerned about.   
 
Instructions: When taking Venetoclax as instructed to by your physician, record the date, time, and number of 
pills taken on the appropriate days. 
 
 
Clinic phone: ________________________________ 
 
Study coordinator name: ______________________     Phone number:__________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
 
 
 
Page 1 of 3 
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THE OHIO STATE UNIVERSITY 
AUTHORIZATION TO USE 
PERSONAL HEALTH INFORMATION IN RESEARCH 
 
 
Title of the Study: OSU 19305 (NCI #10317): A Pilot Study of Nivolumab in Combination 
with Decitabine and Venetoclax in TP53-mutated Acute Myeloid Leukemia 
 
Protocol Number: IRB# 2019Y0039 
 
Principal Investigator: Dr. Alice Mims 
  
 
Subject Name__________________________________________________________________ 
 
Before researchers use or share any health information about you as part of this study, The Ohio State 
University is required to obtain your authorization. This helps explain to you how this information will be 
used or shared with others involved in the study.   
 
• 
The Ohio State University and its hospitals, clinics, health-care providers, and researchers are 
required to protect the privacy of your health information.   
• 
You should have received a Notice of Privacy Practices when you received health care services here.  
If not, let us know and a copy will be given to you.  Please carefully review this information. Ask if 
you have any questions or do not understand any parts of this notice. 
• 
If you agree to take part in this study your health information will be used and shared with others 
involved in this study. Also, any new health information about you that comes from tests or other 
parts of this study will be shared with those involved in this study. 
• 
Health information about you that will be used or shared with others involved in this study may 
include your research record and any health care records at The Ohio State University. For example, 
this may include your medical records, x-rays, or laboratory results.  Psychotherapy notes in your 
health records (if any) will not, however, be shared or used. Use of these notes requires a separate, 
signed authorization. 
 
Please read the information carefully before signing this form. Please ask if you have any questions about 
this authorization, the university’s Notice of Privacy Practices or the study before signing this form. 
 
Those Who May Use, Share, and Receive Your Information as Part of This Study 
 
• 
Researchers and staff at The Ohio State University will use, share, and receive your personal health 
information for this research study. Authorized Ohio State staff not involved in the study may be 
aware that you are participating in a research study and have access to your information. If this study 
is related to your medical care, your study-related information may be placed in your permanent 
hospital, clinic, or physician’s office records.  
 
 
 
Initials/Date: _______________ 


 
 
 
Page 2 of 3 
03/16/12 
 
• 
Those who oversee the study will have access to your information, including the following: 
• 
Members and staff of The Ohio State University’s Institutional Review Boards, including the 
Western Institutional Review Board 
• 
The Ohio State University Office of Responsible Research Practices  
• 
University data safety monitoring committees  
• 
The Ohio State University Office of Research.  
 
• 
Your health information may also be shared with federal and state agencies that have oversight of the 
study or to whom access is required under the law. These may include the following:  
• 
Food and Drug Administration 
• 
Office for Human Research Protections 
• 
National Institutes of Health  
• 
Ohio Department of Job and Family Services. 
 
• 
These researchers, companies and/or organization(s) outside of The Ohio State University may also 
use, share and receive your health information in connection with this study: 
• 
The research sponsor and companies owned or connected with the sponsor:  The National 
Cancer Institute, Cancer Trials Support Unit (CTSU), Cancer Therapy Evaluation Program 
(CTEP), and any company supporting the study or the study agent/treatment now or in the 
future.  
 
The information that is shared with those listed above may no longer be protected by federal privacy 
rules. 
 
Authorization Period 
 
This authorization will not expire unless you change your mind and revoke it in writing. There is no set 
date at which your information will be destroyed or no longer used.  This is because the information used 
and created during the study may be analyzed for many years, and it is not possible to know when this 
will be completed.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initials/Date______________ 


 
 
 
Page 3 of 3 
03/16/12 
 
 
Signing the Authorization 
 
• 
You have the right to refuse to sign this authorization.  Your health care outside of the study, payment 
for your health care, and your health care benefits will not be affected if you choose not to sign this 
form.  
• 
You will not be able to take part in this study and will not receive any study treatments if you do not 
sign this form. 
• 
If you sign this authorization, you may change your mind at any time. Researchers may continue to 
use information collected up until the time that you formally changed your mind.  If you change your 
mind, your authorization must be revoked in writing.  To revoke your authorization, please write to: 
Dr. Alice Mims, A343 Starling Loving Hall, 320 W. 10th Ave., Columbus, OH 43210.  Telephone 
(843)-480-2685.   
Or: 
The HIPAA Privacy Manager, the Ohio State University Medical Center, 140 Doan Hall, 410 W. 
Tenth Avenue, Columbus, Ohio 43210, Telephone: (614) 293-4477.  
• 
Signing this authorization also means that you will not be able to see or copy your study-related 
information until the study is completed. This includes any portion of your medical records that 
describes study treatment.  
 
Contacts for Questions 
 
• 
If you have any questions relating to your privacy rights, please contact:  The HIPAA Privacy 
Manager, the Ohio State University Medical Center, 140 Doan Hall, 410 W. Tenth Avenue, 
Columbus, Ohio 43210, Telephone: (614) 293-4477. 
• 
If you have any questions relating to the research, please contact: Dr. Alice Mims, A343 Starling 
Loving Hall, 320 W. 10th Ave., Columbus, OH 43210.  Telephone (843)-480-2685.     
 
Signature 
 
I have read (or someone has read to me) this form and have been able to ask questions. All of my 
questions about this form have been answered to my satisfaction.  By signing below, I permit Dr. Alice 
Mims and the others listed on this form to use and share my personal health information for this study.  I 
will be given a copy of this signed form. 
 
Signature_____________________________________________________________________________  
(Subject or Legally Authorized Representative) 
 
 
Print Name _____________________________________ Date___________ Time __________ AM/PM 
 
_______________________________________________ 
(If legal representative, also print relationship to subject) 


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Research Study Informed Consent Document 
 
 
Study Title for Participants: Testing Nivolumab in combination with Decitabine and 
Venetoclax in Patients with Newly Diagnosed TP53 Gene Mutated  
Acute Myeloid Leukemia  
 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: Protocol 
10317: “A Pilot Study of Nivolumab in Combination with Decitabine and Venetoclax in 
TP53-mutated Acute Myeloid Leukemia (NCT TBD)” 
 
 
Overview and Key Information  
 
What am I being asked to do? 
 
We are asking you to take part in a research study. This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services. We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer.  
We are asking you to take part in this research study because you have Acute Myeloid Leukemia 
(AML) and your cancer has a gene mutation called TP53.  
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
Why is this study being done? 
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for your cancer, which is AML with TP53 gene mutation. The usual approach is 
defined as care most people get for AML. 
 


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One of the study drugs, called Nivolumab, is being looked at to see if it may help treat patients 
with your type of AML.  Nivolumab works by helping your body’s natural defense cells, called 
“T-Cells,” to possibly be able to better attach to cancer cells, which then may be able to help to 
kill the cancer cells.  Nivolumab is not currently approved by the Food and Drug Administration 
(FDA) for use in patients with your type of AML. 
 
What is the usual approach to my Acute Myeloid Leukemia (AML)? 
 
The usual approach for patients who are not in a study is treatment with newly diagnosed AML 
is chemotherapy.  AML patients will receive FDA approved treatment with either: 
• intensive chemotherapy with two chemotherapy drugs (an anthracycline and cytarabine 
given together for 7 days)  or 
• less intensive chemotherapy (azacitidine or decitabine) without or with venetoclax (for 
patients  age 75 and older or for patients younger who are not able to receive the 
intensive chemotherapy treatment).  
 
For patients with TP53 gene mutated AML these treatments may not work well and for patients 
in which it does work they may have a high chance of relapse. For patients who get the usual 
approach for this cancer, about less than 10 out of 100 are free of cancer after 5 years.   
 
What are my choices if I decide not to take part in this study? 
 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
What will happen if I decide to take part in this study? 
 
If you decide to take part in this study, you will take three cancer drugs during your treatment 
named Decitabine, Nivolumab, and Venetoclax.  
 
Cancer drug treatment occurs in cycles. A cycle means that you have a single cancer drug or a 
combination of drugs and then have a rest to allow your body to recover. Then the cycle repeats. 
In this study, there is a 28 day cycle, which means you will start treatment on the first day of the 
cycle, take the three cancer drugs as described below, then have a break at the end of the cycle 
before restarting all of the cancer drugs again with another cycle. At the end of each 28 day 
cycle, your study doctor will determine if you need to have any additional cycles of treatment. 
 
During each cycle you will receive Decitabine on Days 1-10 for the first 3 cycles as needed, and 
then on days 1-5 for each subsequent cycle. 
 
You will receive Nivolumab on Day 15 for the first cycle and on Days 1 and 15 for all of the 
following cycles. 


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You will receive Venetoclax on Days 1-21 of each cycle.   
 
If your leukemia has not responded to treatment after three cycles, you will stop treatment.  If 
you have responded to treatment, the treatment will be given until your health changes and the 
study is no longer in your best interest, you wish to stop the study, or if the study is stopped.  
After you finish the treatment of Decitabine, Nivolumab, and Venetoclax, your doctor will 
continue to follow your AML and watch you for side effects for about 3 years after you initially 
started this treatment combination.  If you experienced any side effects, you will be followed 
until the side effect stop or are stable. 
 
You will be seen by a doctor for follow up on days 1 and 15 of every cycle while you are on this 
study. This will continue as long as you are in the study. If you come off study, follow up will be 
decided by your cancer doctor.  
 
 
 
 
 
 
 
 
 
What are the risks and benefits of taking part in this study? 
 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that the study drugs Decitabine, 
Nivolumab, and Venetoclax may not be as good as the usual approach for your cancer at putting 
your AML in remission. 


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There is also a risk that you could have side effects from the study drugs, Decitabine, 
Nivolumab, and Venetoclax. These side effects may be worse and may be different than you 
would get with the usual approach for your cancer.   
 
Some of the most common side effects that the study doctors know about are: 
• Decitabine: 
o low white blood cell count (cells that help fight infection) 
o low platelets (cells that help your blood clot) 
• Venetoclax: 
o low white blood cell count (cells that help fight infection) 
o Tumor Lysis Syndrome (TLS) which a serious and life threatening condition 
• Nivolumab:  
o A severe immune response which may attack your organs such as your skin, 
lungs, intestines, kidneys, liver and other organs within your body.  These 
immune responses can be severe and possibly fatal 
 
There may be some risks that the study doctors do not yet know about.   
 
Benefits 
 
There is some evidence with AML that adding Nivolumab to Decitabine and Venetoclax to the 
usual approach may stabilize cancer for longer than the usual approach alone, and may  put the 
cancer in remission more frequently than the usual approach alone.  However, we do not know if 
this will happen in people with TP53 gene mutated AML.  It is unlikely that this Nivolumab with 
Dectabine and Venetoclax will help you live longer than the usual approach alone.  This study 
may help the study doctors learn things that may help other people in the future. 
 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  If you stop, you can decide if you want to keep letting the study doctor know how you 
are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
• Your health changes and the study is no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 


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• You do not follow the study rules. 
• For women: You become pregnant while on the study. 
• You complete a bone marrow/stem cell transplantation 
• The study is stopped by the Institutional Review Board (IRB), Food and Drug 
Administration (FDA), or study sponsor, The National Cancer Institute (NCI) the study 
sponsor.  The study sponsor is the organization who oversees the study.   
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? 
 
The purpose of this study is to test the safety of a combination of chemotherapy drugs called 
Nivolumab, Decitabine, and Venetoclax. These drugs are not approved by the FDA to treat 
patients with TP53 gene mutated AML. There will be about 15 people taking part in this study. 
 
The mutation in this study being testing is the TP53 (tumor protein) gene mutation. This protein 
helps stop the growth of tumors.  In order to participate in this study you must have AML with 
the TP53 gene mutation.  To determine if you have this mutation an extra tube of blood will be 
drawn at the time of screening and a bone marrow aspirate will be completed.   
 
What are the study groups? 
 
This study has a screening step.  The purpose of this step is to test your tumor to find out if it has 
a specific mutation.  If it does and you meet all the study requirements, then we can assign you to 
treatment based on these changes.  If we find that your blood or bone marrow aspirate does not 
have the mutation that is needed for this study, then your doctor will discuss other options for 
your care.  This screening test is not approved by the FDA for your AML.   
 
All patients in this study will receive the chemotherapy combination Decitabine, Nivolumab, and 
Venetoclax in 28 day cycles until your health changes and the study is no longer in your best 
interest, you wish to stop the study, or if the study is stopped.   
 
During each cycle you will receive Decitabine (20mg/m2) through a vein in your arm for 
approximately 60 minutes on Days 1-10 for up to the first 3 cycles as needed and then on days 1-
5 for each subsequent cycle. 
 
You will receive Nivolumab (240 mg) through a vein in your arm for approximately 30 minutes 
on Day 15 for the first cycle and on Days 1 and 15 for all subsequent cycles.   
 
You will take Venetoclax by mouth with food and water on Days 1-21 of each cycle. During 
cycle 1 you will take 100mg on Day 1, 200mg on Day 2, and 400 mg on Days 3-21.  After cycle 


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1 you will take 400mgs on Days 1-21. If you are taking certain medications that can interact with 
Venetoclax, this dosing may be adjusted.  
 
You will be able to get additional doses of the Decitabine and Venetoclax if appropriate, as these 
are approved by the FDA for treatment of your disease.  You will not be able to get additional 
doses of the Nivolumab.  This drug is not approved by the FDA for treatment of your disease. 
 
What exams, tests, and procedures are involved in this study? 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study.  
 
Listed below are exams, tests, and procedures that need to be done as part of this study to 
monitor your safety and health, but may not be included in the usual care.  We will use them to 
carefully follow the effects of the study treatment, including preventing and managing side 
effects.  
 
These exams, tests, and procedures to monitor your safety and health include:   
 
• Blood counts (will check your levels to determine risk of infection and if needs for blood 
or platelet transfusions): 
o screening 
o twice weekly during first cycle of induction and during cycles 2-3 of induction if 
these cycles are needed 
o Day 1 of each cycle of maintenance  
o when stopping study treatment  
• Blood testing (to check your electrolytes and your organ function of kidneys and liver 
o 
screening 
o 
every 12 hours during the first 4 days of venetoclax during cycle 1 
o 
twice weekly during first cycle of induction and during cycles 2-3 of induction 
if these cycles are needed 
o 
Day 1 of each cycle of maintenance  
o 
when stopping study treatment  
• A set of questions to determine how well you can complete your daily activities 
o 
 screening  
o 
Day 1 of every cycle  
o 
when stopping study treatment  
• Physical exams  
o 
screening  
o 
Days 1 and 15 of every cycle  
o 
when stopping study treatment  
• Bone Marrow biopsy for AML cells and genetic testing at  


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o 
screening  
o 
End of first cycle of induction and end of cycles 2-3 of induction if these 
cycles are needed 
o 
 every 3 cycles during maintenance cycles a 
o 
when stopping study treatment  
 
This study will use genetic tests that may identify changes in the genes in your tumor DNA.  
Your genes carry information about you and your family, from the color of your eyes to health 
conditions for which you may be at risk, such as certain kinds of cancer.  
 
Finding these changes would not affect your treatment in this study.  However, they could affect 
your health in other ways. If there are changes found that could cause health problems, then your 
study doctor will discuss your options with you. As appropriate, you may be referred for genetic 
counseling.   
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
You will need to have blood and bone marrow samples taken for the study at screening and at the 
end of each cycle of treatment.  These samples will be used for research purposes to look at other 
features of your leukemia cells that may help determine how to better target leukemia cells with 
treatment for future patients with TP53 gene mutations. You and your study doctor will not get 
the results of this testing.  If you agree to take part in the study, you may need to sign a separate 
consent form for the study biopsy at the hospital or clinic where the biopsy is done. 
 
Your study doctor will need to draw some extra liquid during your bone marrow biopsies at 
screening and after cycles 1-3 and every 3 cycles until the end of treatment.  The sample at 
screening will determine if you have a TP53 gene mutation and other samples will be used for 
exploratory biomarkers for research purposes to look at other features of your leukemia cells that 
may help determine how to better target leukemia cells with treatment for future patients with 
TP53 gene mutations. You and your study doctor will get the results of the TP53 gene mutation 
testing but will not get results of other research testing. 
 
Please see the optional research sample section for information regarding the optional research 
studies. 
 
What risks can I expect from taking part in this study? 
 
General Risks 
If you choose to take part in this study, there is a risk that the addition of Nivolumab given with 
Venetoclax and Decitabine may not be as good as the usual approach for your AML at getting it 
into remission.  
 
You also may have the following discomforts: 
 


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• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies.  
 
The Nivolumab, Decitabine, and Venetoclax used in this study could be very harmful to an 
unborn or newborn baby.  There may be some risks that doctors do not yet know about.  It is 
very important that you check with your study doctor about what types of birth control or 
pregnancy prevention to use during the study and for 7 months for men and 6 months for women 
after you have completed the study. 
 
Genetic Testing Risks 
 
The genetic test used in this study will test your tumor for a gene mutation called TP53.  This 
change also may be in your normal tissue and passed down through your family.  For example, 
these genetic changes may be passed down to your children in the same way that eye and hair 
color are passed down.  
 
Since this study is only testing tumor tissue, we will not know if a genetic change in your tumor 
is also in your normal tissue.  If you want to find out if the change is in your normal tissue, then 
you will need to get other tests done outside of this study.  
 
Genetic tests of normal tissue can reveal information about you and also about your relatives.  
Your study doctor will talk with you about what testing your normal tissue may mean for you 
and your family.  He or she also may suggest that you talk with a genetics counselor to learn 
more.  You or your insurance plan would have to pay for any genetic tests and visits to a genetic 
counselor done outside of this study.  
 
Biopsy Risks 
 
Common side effects of a biopsy are a small amount of bleeding at the time of the procedure, 
bruising, and pain at the biopsy site.  Pain can be treated with regular pain medications.  Rarely, 
an infection can occur.  You may sign a separate consent form for the study biopsy that describes 
the risks in more detail.   
 
Side Effect Risks 
 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will test your blood and let you know if changes 
occur that may affect your health. 
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 


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3. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
This study is looking at a combination of the usual drugs used to treat this type of cancer plus a 
study drug.  This different combination of drugs may increase your side effects or may cause 
new side effects.   
 
There is also a risk that you could have other side effects from the study such as side effects from 
the blood draws and bone marrow biopsies.  
 
Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you.  
 
Possible Side Effects for Decitabine  
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving decitabine (5-aza-2'-deoxycytidine), more than 20 and up to 100 may have: 
• 
Anemia, which may require blood transfusion 
• 
Nausea 
• 
Tiredness, fever 
• 
Infection, especially when white blood count is low  
• 
Bruising, bleeding 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving decitabine (5-aza-2'-deoxycytidine), from 4 to 20 may have: 
• 
Pain 
• 
Constipation, diarrhea, vomiting 
• 
Sores in the mouth which may cause difficulty swallowing 
• 
Chills 
• 
Swelling of the body 
• 
Damage to the body by own immune system 
• 
Loss of appetite 
• 
Dizziness, headache 
• 
Worry 


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• 
Difficulty sleeping 
• 
Cough, shortness of breath, sore throat 
• 
Internal bleeding which may cause coughing up blood 
• 
Bleeding from multiple sites including the nose 
• 
Hair loss, itching, rash 
 
RARE, AND SERIOUS 
In 100 people receiving decitabine (5-aza-2'-deoxycytidine), 3 or fewer may have: 
• 
Bleeding in the brain which may cause confusion 
 
 
Possible Side Effects of Nivolumab (Table Version Date:  June 18, 2018) 
 
PLEASE NOTE THE FOLLOWING IN REVIEWING THESE RISKS: 
BMS-936558 (nivolumab) is an agent involved in the inhibition of “immune checkpoints,” and 
may result in severe and possibly fatal immune-mediated side effects probably due to activation 
and growth of immune cells (T-cells).  Immune-mediated side effects have been reported in 
patients receiving BMS-936558 (nivolumab).  In clinical trials, most immune-mediated side 
effects were reversible and managed by stopping BMS-936558 (nivolumab) temporarily, 
administration of corticosteroids, and supportive care. 
 
Special precautions 
Side effects of BMS-936558 (nivolumab, MDX-1106) may happen anytime during 
treatment or even after your treatment has ended.  Some of these problems may happen 
more often when BMS-936558 (nivolumab, MDX-1106) is used in combination with 
ipilimumab.  Call or see your healthcare provider right away if you develop any 
problems listed below or the symptoms get worse. 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving BMS-936558 (nivolumab, MDX-1106), more than 20 and up to 
100 may have: 
• Tiredness 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving BMS-936558 (nivolumab, MDX-1106), from 4 to 20 may have: 
• Anemia, which may require blood transfusion 
• Swelling and redness of the eye  
• Pain 
• Diarrhea or nausea 
• Dry mouth 
• Fever 
• Swelling and redness at the site of the medication injection 
• Bruising or bleeding 


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• Pain or swelling of the joints 
• Loss of appetite 
• Reaction during or following a drug infusion which may cause fever, chills, or rash  
 
BMS-936558 (nivolumab, MDX-1106) may cause your immune system to attack normal 
organs and cause side effects in many parts of the body.  These problems may include but 
are not limited to: 
• Lung problems (pneumonitis and pleural effusion).  Symptoms may include:  new 
or worsening cough, chest pain, or shortness of breath. 
• Intestinal problems (colitis) that can rarely lead to tears or holes in your intestines. 
Signs and symptoms of colitis may include:  diarrhea or increase in bowel 
movements; blood in your stools or dark, tarry, sticky stools; severe belly pain or 
tenderness. 
• Skin problems, including itching; rash, blisters including on the inside the mouth; 
or loss of skin pigment 
• Liver problems (hepatitis) which can cause liver failure.  Signs and symptoms of 
hepatitis may include:  yellowing of your skin or the whites of your eyes, severe 
nausea or vomiting, drowsiness, or pain in the right upper belly 
• Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and 
pancreas).  Signs and symptoms may include:  headaches that will not go away or 
unusual headaches; extreme tiredness, or changes in mood or behavior; decreased 
sex drive; weight loss or weight gain; excessive thirst or urine; or dizziness or 
fainting. 
 
RARE, AND SERIOUS 
In 100 people receiving BMS-936558 (nivolumab, MDX-1106), 3 or fewer may have: 
• Dry eyes 
• Sores in the mouth which may cause difficulty swallowing 
 
BMS-936558 (nivolumab, MDX-1106) may cause your immune system to attack normal 
organs and cause side effects in many parts of the body.  These problems may include but 
are not limited to: 
• Visual disturbances which may cause double vision, blurred vision, or loss of 
vision with a chance of blindness 
• A condition with high blood sugar which leads to tiredness, frequent urination, 
excessive thirst, headache, nausea and vomiting, and can result in coma 
• Kidney problems, including nephritis and kidney failure requiring dialysis.  Signs 
of kidney problems may include decrease in the amount of urine, blood in your 
urine, or ankle swelling. 
• Heart problems, including swelling and heart failure.  Symptoms and signs of heart 
problem may include shortness of breath, or swelling of the ankle and body. 
• Muscle problems, including swelling, which can cause muscle pain and severe 
muscle weakness, sometimes with dark urine 


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• Swelling of the brain (meningitis/encephalitis) which may cause headaches; stiff 
neck; confusion; sleepiness; seizures; injury to the brain; or blindness (also known 
as Reversible Posterior Leukoencephalopathy Syndrome) 
• Nerve problems that can cause paralysis.  Signs and symptoms may include 
numbness; tingling of hands and feet; weakness of the arms, legs, and facial muscle 
movements 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, or swelling of the face or throat 
• Complications associated with stem cell transplant using donor stem cells 
(allogeneic stem cell transplant).  These complications are caused by attack of 
donor cells on the host organs (inducing liver, skin, and gut damage), and can lead 
to death.  If you are considering an allogeneic stem transplant after participating in 
this study, please tell your doctor that you have received nivolumab therapy, since 
the risk and severity of transplant-associated complications may be increased. 
 
Possible Side Effects of Venetoclax (ABT-199): 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving venetoclax (ABT-199), more than 20 and up to 100 may have: 
• Anemia, which may require blood transfusion 
• Diarrhea, nausea 
• Tiredness 
• Infection, especially when white blood cell count is low 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving venetoclax (ABT-199), from 4 to 20 may have: 
• Constipation, vomiting 
• Fever 
• Bruising, bleeding 
• Pain in joints 
• Headache 
• Cough 
• High blood pressure which may cause headaches, dizziness, blurred vision 
 
RARE, AND SERIOUS 
In 100 people receiving venetoclax (ABT-199), 3 or fewer may have: 
• Kidney damage which may require dialysis 
 
 
 
 


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Additional Drug Risks 
 
The study drugs could interact with other drugs.  If you are taking other drugs that suppress your 
immune system, the addition of Nivolumab may make this worse.   
 
Rarely, there are problems getting enough supplies of the Nivolumab.  If that happens, your 
doctor will talk with you about your options. 
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Write down in your medication diary when you take the study drug at home Tell your 
doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
 
For women: Do not get pregnant or breastfeed while taking part in this study.  For men: Do not 
father a baby while taking part in this study.  For all:  Tell your study doctor right away if you 
think that you or your partner have become pregnant during the study or within 7 months for 
men and 6 months for women after your last day of study treatment. 
 
What are the costs of taking part in this study? 
 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for your cancer.  This includes: 
 
• the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
• the costs of getting the IV drugs ready and giving them to you. 
• your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study.  These include:   
 


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• The extra blood samples and bone marrow biopsy samples taken for research. 
• The time points at which each blood sample and bone marrow biopsy will occur are: 
o During screening: blood and bone marrow 
o Day 28 +/- 1 day of cycles 1, 2, and 3: blood and bone marrow 
o Day 28 +/- 1 day every 3 cycles starting with cycle 6 (ex. Cycles 6, 9, 12…): 
blood and bone marrow 
o Day 28 +/- 1 day of end of every cycle starting with cycle 4 (excluding cycles 6,9, 
12…as above): blood only 
o End of Treatment or AML Relapse: blood and bone marrow 
 
You or your insurance provider will not have to pay for the Nivolumab drug itself while you take 
part in this study.  
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
• Have more travel costs. 
• Need to take more time off work. 
• Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment.   
 
What happens if I am injured because I took part in this study? 
 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
The Ohio State University has no funds set aside for the payment of health care expenses for this 
study. 
Who will see my medical information? 
 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  


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Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at or receive copies of some of the information in your 
study records.  Your health information in the research database also may be shared with these 
organizations.  They must keep your information private, unless required by law to give it to 
another group.   
 
Some of these organizations are: 
 
• The study sponsor and any company supporting the study or the study agent/treatment 
now or in the future. This would include any organization helping the company with the 
study. 
• The National Cancer Institute (NCI) Central Institutional Review Board (CIRB), which is 
a group of people who review the research with the goal of protecting the people who 
take part in the study.  
• The Food and Drug Administration (FDA) and the groups it works with to review 
research.   
• The National Cancer Institute (NCI) and the groups it works with to review research. 
• The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research  
• The Ohio State University researchers and staff, who may share or use health information 
about you with others involved in this study.  For example, this may include your medical 
and research records, any imaging tests or scans such as x-rays, and laboratory results.   
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 
may be stored and shared for future use in public databases.  However, your name and other 
personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
• You will not be asked if you agree to take part in the specific future research studies 
using your health information.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
information.  
 


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There are laws that protect your genetic information.  However, there is a risk that someone 
could get access to your genetic information and identify you by name.  In some cases, 
employers could use your genetic information to decide whether to hire or fire you.  The study 
doctors believe the risk of this happening is very small.  However, the risk may increase in the 
future as people find new ways of tracing information.  For more information about the laws that 
protect you, ask your study doctor. 
 
Where can I get more information?   
 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor, Alice Mims, MD at 614-685-6031 or 
Alice.Mims@osumc.edu. 
 
For questions about your rights while in this study, call Ms. Sandra Meadows in The Office of 
Responsible Research Practices at 1-800-678-6251. 
 
Optional studies that you can choose to take part in 
 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading these optional studies hope the results will help other people 
with cancer in the future. The results will not be added to your medical records and you or your 
study doctor will not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to any or all of these studies.  There is no penalty for saying “no.” You and 
your insurance company will not be billed for these optional studies.  If you sign up for, but 
cannot complete any of these studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
Optional sample collections for known laboratory studies and/or storage for possible 
future studies 
 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 


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Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Known future studies 
 
If you choose to take part in this optional study, researchers will collect blood and bone marrow 
for research on leukemia cells with TP53 gene mutations. Your samples will be used for to look 
at other features of your leukemia cells (besides the TP53 gene mutation) that may help 
determine how to better target leukemia cells with treatment for future patients with TP53 gene 
mutations. 
 
Your study doctor will need to draw some extra liquid during your bone marrow biopsies at 
screening and after cycles 1-3 and every 3 cycles until the end of treatment. The sample at 
screening will determine if you have a TP53 gene mutation and other You and your study doctor 
will get the results of the TP53 gene mutation testing but will not get results of other research 
testing. 
 
What is involved in this optional sample collection? 
 
If you agree to take part, here is what will happen next: 
 
1. About ¾ tablespoons of blood will be collected from a vein in your arm (this is from the 
blood draw you are already getting as part of the study). A sample of bone marrow will 
be collected from a biopsy (this is from the biopsies you are already getting as part of the 
study, and is not a separate collection of your bone marrow).  
 
What are the risks in this optional sample collection? 
 
• The most common risks related to drawing blood from your arm are brief pain and maybe 
a bruise.   
• The most commons risks related to bone marrow biopsies are brief pain and maybe a 
bruise.  
• Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
 
 
 


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How will information about me be kept private? 
 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the benefits to taking part in this optional sample collection? 
 
You will not benefit from taking part.  
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments to this optional sample collection? 
 
There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
What if I change my mind about this optional sample collection? 
 
If you decide you no longer want your samples to be used, you can call the study doctor, Alice 
Mims, MD at 843-480-2685, who will let the rest of the study team know.  Then, any sample that 
remains will be destroyed or returned to your study doctor.  This will not apply to any samples or 
related health information that have already been given to or used by researchers. 
 
What if I have questions about this optional sample collection? 
 
If you have questions about the use of your samples for research, contact the study doctor, Alice 
Mims, MD at 843-480-2685. 
 
 
 


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Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for known future studies: 
 
I agree that my samples and related health information may be used for the laboratory (*study or 
studies*) described above. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
 


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My signature agreeing to take part in the study 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.   
 
 
Participant’s signature ______________________________ 
 
 
 
Date of signature ________________ 
 
 
 
 
 
 
 
Time ________________AM/PM 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
___________________________________________________________ 
 
 
Date of signature __________________  
 
 
 
 
 
  
Time ________________AM/PM 
 
 
 
Witness(es) [As applicable to the research] 
 
 
  
Printed name of witness 
 Signature of witness 
 
  
 
AM/PM 
 
 Date and time