Conditions: Acute Bilineal Leukemia Acute Biphenotypic Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 150
Healthy volunteers: no

Brief summary:
This will be a phase II, open-label, non-randomized study with a safety lead-in phase. There are 3 Arms in this study each with 2 parts. If you are eligible, you will be assigned to an Arm and a part when you join the study. In each arm, you will receive a different combination of study drugs: Arm 1: nivolumab and azacitidine, Ih Arm 2: nivolumab, azacitidine, and ipilimumab, Arm 3: nivolumab, azacitidine, and venetoclax.

There are 2 parts in each arm: Part A (dose escalation) and Part B (dose expansion).

The goal of Part A of this clinical research study is to find the highest tolerable dose of the study drugs (nivolumab, azacitidine, ipilimumab, and/or venetoclax) that can be given to patients with AML. The goal of Part B of this study is to learn if the dose found in Part A can help to control AML.

Detailed description:
Arm 1 Up to 5 groups of up to 6 participants will be enrolled in Part A of the study, and up to 110 participants will be enrolled in Part B of the study. If you are enrolled in Part A of the study, the dose of nivolumab and azacitidine you receive will depend on when you joined this study. The first group of participants will receive the starting dose levels of nivolumab and azacitidine. If intolerable side effects are seen, the next group may receive a lower dose level of nivolumab and/or azacitidine. This will continue until the highest tolerable combination dose is found.

If you are enrolled in Part B, you will receive nivolumab and azacitidine at the highest dose that was tolerated in Part A.

Arm 2 Up to 4 groups of up to 6 participants will be enrolled in Part A of the study, and up to 84 participants will be enrolled in Part B of the study. If you are enrolled in Part A of the study, the dose of nivolumab, azacitidine, and ipilimumab you receive will depend on when you joined this study. The first group of participants will receive the starting dose levels of nivolumab, azacitidine and ipilimumab. If intolerable side effects are seen, the next group may receive a lower dose level of nivolumab, azacitidine and/or ipilimumab. This will continue until the highest tolerable combination dose is found. If you are enrolled in Part B, you will receive nivolumab, azacitidine, and ipilimumab at the highest dose that was tolerated in Part A.

Arm 3 About 6-18 participants will be enrolled in Part A and up to 60 participants will be enrolled in Part B. If you are enrolled in Part A of the study, the dose of nivolumab, azacitidine, and venetoclax you receive will depend on when you joined this study. The first group of participants will receive the starting dose levels of nivolumab, azacitidine and venetoclax. If intolerable side effects are seen, the next group may receive a lower dose level of nivolumab, azacitidine and/or venetoclax. This will continue until the highest tolerable combination dose is found. If you are enrolled in Part B, you will receive nivolumab, azacitidine, and venetoclax at the highest dose that was tolerated in Part A.

Arms:
arm 1: Patients receive azacitidine IV over 1 hour or SC on days 1-7 or days 1-4 and 7-9. Patients also receive nivolumab IV over 60 minutes on days 1 and 14 (courses 1-4) or on day 1 (course 5 and all subsequent courses). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive azacitidine and nivolumab as Arm I. Patients also receive ipilimumab IV over 90 minutes on day 1 and then every 6 or 12 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive azacitidine IV over 1 hour or SC on days 1-7 or days 1-4 and 7-9. Patients also receive nivolumab IV over 60 minutes on days 1 and 14 (courses 1-4) or on day 1 (course 5 and all subsequent courses). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Patients will receive therapy with nivolumab IV infusion on Day 8 and Day 22 (+/-3 days) of each 5-azacyidine cycle for first 4 cycles or until CR (whichever occurs earlier) followed by a maintenance regimen (one dose of nivolumab on Day 8 of each cycle of 5-azacytdine). Venetoclax will be administered orally daily on Days 1-21 of the first cycle; and Days 1-14 or Days 1-21 for subsequent cycles. arm 5: Patients receive azacitidine and nivolumab as Arm I. Patients also receive ipilimumab IV over 90 minutes on day 1 and then every 6 or 12 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 6: Patients will receive therapy with nivolumab IV infusion on Day 8 and Day 22 (+/-3 days) of each 5-azacyidine cycle for first 4 cycles or until CR (whichever occurs earlier) followed by a maintenance regimen (one dose of nivolumab on Day 8 of each cycle of 5-azacytdine). Venetoclax will be administered orally daily on Days 1-21 of the first cycle; and Days 1-14 or Days 1-21 for subsequent cycles.

Interventions: intervention 1: Azacitidine intervention 2: Ipilimumab intervention 3: Venetoclax intervention 4: Nivolumab
Intervention descriptions: intervention 1: Given SC or IV intervention 2: None intervention 3: Given Orally intervention 4: Given IV

Protocol document:
Prot_SAP_000.pdf: 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2014‐0861 
Protocol Title 
An Open‐label Phase II Study of Nivolumab (BMS‐936558) in Combination 
with 5‐azacytidine (Vidaza), nivolumab in combination with 5‐azacytidine 
and venetoclax, or Nivolumab with Ipilimumab in combination with 5‐
azacytidine for the Treatment of Patients with Refractory/ Relapsed Acute 
Myeloid Leukemia and newly diagnosed older AML (≥65 years) patients 
Protocol Phase 
II 
Protocol Version 
24 
Version Date 
5/26/2021 
Protocol PI 
Naval Daver 
Department 
Leukemia 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
125751 


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An Open-label Phase II Study of Nivolumab (BMS-936558) in 
Combination with 5-azacytidine (Vidaza), nivolumab in 
combination with 5-azacytidine and venetoclax, or Nivolumab 
with Ipilimumab in combination with 5-azacytidine for the 
Treatment of Patients with Refractory/ Relapsed Acute 
Myeloid Leukemia and newly diagnosed older AML (≥65 
years) patients 
 
 
 
 
 
 
Principal Investigator: Naval Daver, M.D.  
Sponsor: University of Texas, MD Anderson Cancer Center 
IND number:125,751 
 
 
 
University of Texas 
 
 
MD Anderson Cancer Center 
Leukemia Department, Unit 428 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
OBJECTIVES 
1.1 
Primary Objectives 
Part a. Lead-in phase: 
1. 
To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of 
nivolumab in combination with 5-azacytidine in patients with refractory/ relapsed acute 
myeloid leukemia (AML). 
2. 
To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of 
nivolumab with ipilimumab in combination with 5-azacytidine in patients with 
refractory/ relapsed acute myeloid leukemia (AML). 
3. 
To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of 
nivolumab in combination with 5-azacytidine and venetoclax in patients with 
refractory/ relapsed AML. 
 
 
Part b. Phase II 
1. 
To determine the overall response rate (ORR) of nivolumab in combination with 5- 
azacytidine in patients with refractory/ relapsed AML. 
2. 
To determine the overall response rate (ORR) of nivolumab in combination with 5- 
azacytidine in older patients (≥65 years) with newly diagnosed AML. 
3. 
To determine the overall response rate (ORR) of nivolumab with ipilimumab in 
combination with 5-azacytidine in patients with refractory/ relapsed AML. 
4. 
To determine the overall response rate (ORR) of nivolumab with ipilimumab in 
combination with 5- azacytidine in older patients (≥65 years) with newly 
diagnosed AML. 
5. 
To determine the overall response rate (ORR) of nivolumab in combination with 5-
azacytidine and venetoclax in patients with refractory/ relapsed AML. 
6. 
To determine the overall response rate (ORR) of nivolumab in combination with 5-
azacytidine and venetoclax in older patients (≥65 years) with newly diagnosed 
AML. 
 
 
1.2 
Secondary Objectives: 
1. 
To determine the number of patients who achieve a > 50% reduction in blasts on therapy 
with either vidaza+nivolumab, vidaza+nivolumab+ipilimumab or 
vidaza+venetoclax+nivolumab.  
2. 
To determine the duration of response, event-free survival (EFS), 4- and 8-week 
mortality, and overall survival (OS) OS of patients with refractory/ relapsed AML treated 
with either vidaza+nivolumab, vidaza+nivolumab+ipilimumab or 
vidaza+venetoclax+nivolumab. 
3. 
To determine the duration of response, event-free survival (EFS), 4- and 8-week 
mortality, and OS in older patients with newly diagnosed AML treated with either 
vidaza+nivolumab, vidaza+nivolumab+ipilimumab or vidaza+venetoclax+nivolumab. 
 


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1.3 
Exploratory Objectives: 
1. 
To study immunological and  molecular  changes  in  the  peripheral  blood  and  bone 
marrow in response to nivolumab and 5-azacytidine therapy or nivolumab with ipilimumab 
and 5-azacutidine therapy or nivolumab with azacytidine and venetoclax therapy, including: 
 
--To investigate possible relationships between response and non-response to the 
combination with pretherapy, on-therapy, and progression gene expression signatures. 
 
--To investigate the characterization of genetic heterogeneity in tumor cell populations, 
by performing targeted single-cell sequencing on longitudinally collected AML tumor 
populations from patients using a novel microfluidic approach that barcodes amplified 
genomic DNA from thousands of individual leukemia cells confined to droplets (single 
cell sequencing). Targeted single-cell sequencing is able to sensitively identify cells 
harboring pathogenic mutations during complete remission and uncover complex clonal 
evolution within AML tumors that are not observable with bulk sequencing. 
 
--To identify individual cell populations (AML blasts, T-cells – both bulk and T-cell 
subsets and coreceptor/ligand expression, macrophages and their coreceptor/ligands) and 
how their signaling state in disease relates to clinical outcomes we will perform CyTOF 
(mass cytometry) using a customized CYTOF panel specifically developed for this study 
on patients’ bone marrow samples and peripheral blood at diagnosis, remission and 
relapse and potentially other time-points on study. 
 
--To store and/or analyze surplus blood or tissue including bone marrow, if available, for 
potential future exploratory research into factors that may influence development of 
AML and/or response to the combination (where response is defined broadly to include 
efficacy, tolerability or safety). 
 
2. 
To determine induction of hypomethylation and DNA damage during therapy with this 
combination and its correlation with response. 
 
2.0 
BACKGROUND 
 
2.1 
Acute myeloid leukemia 
AML is a malignancy of immature granulocytes or monocytes. The malignancy is 
characterized by accumulation of leukemic blastocytes and blockade of normal bone 
marrow production resulting in thrombocytopenia, anemia, and neutropenia. . There are 
approximately 13,000 new cases of AML per year in the United States, with an estimated 
10,000 deaths occurring in the same time period[1]. Almost all newly diagnosed cases, as 
well as deaths, will be in adults[2]. Standard treatment for AML includes systemic 
combination chemotherapy to control bone marrow and systemic disease. Treatment is 
generally divided into an induction phase, to attain remission, and a maintenance phase[2]. 
Approximately 60% to 70% of adults with AML can be expected to attain complete 
remission status following appropriate induction therapy. Remission rates in adult AML are 
inversely related to age, with an expected remission rate of >65% for those younger than 60 
years. Increased morbidity and mortality during induction appear to be directly related to 
age[3-5]. 


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2.2 A Relapsed/ Refractory AML 
 
Approximately, 30-40% of adults with AML fail to achieve CR with 1 or 2 cycles of 
induction chemotherapy, and are deemed primary refractory. The outcome of patients with 
acute myeloid leukemia (AML) who are refractory to induction therapy are dismal, with low 
response rates to salvage chemotherapy and poor long-term survival [6-8]. We have 
previously reported a dismal median OS of 3.8 months for patients with AML who are 
refractory to HiDAC-containing induction therapy (defined as ≥ 1gm/m2 cytarabine per 
dose)[7]. Salvage therapy in such patient populations yielded a response rate of 18% and 
median response duration of 9 months. 
 
These results emphasize the need to explore alternate salvage regimens for patients with 
relapsed/refractory AML. The development of novel and effective anti-AML agents and/or 
combinations is crucial to improving the outcome of AML. 
 
2.2 B Newly Diagnosed AML in Older Patients 
 
AML is primarily a disease of older people with a median age of diagnosis of 68 years. 
There are approximately 13,000 new cases of AML per year in the United States and 55% of 
these occur in individuals who are age 65 years and older. AML in older patients is 
phenotypically different from AML in younger patients. As compared to their younger 
counterparts, older patients with AML more frequently have an antecedent hematological 
disorder or unfavorable cytogenetics, and respond less well to chemotherapy 
 
Elderly patients with AML have a poor prognosis, which is attributed to having disease that 
is inherently more resistant to current standard cytotoxic agents and/or relatively poor 
tolerance of these agents because of comorbidity and reduced tolerance of adverse effects. 
As a result, despite steady progress in the therapy of AML in younger patients, treatment for 
elderly patients with AML has not improved for decades. Among patients 70 years or older 
and those with adverse karyotypes the 4-8 week mortality with intensive chemotherapy is 
30%-50%, and the median survival is 4-7 months. Therefore such patients derive little 
benefit from intensive chemotherapy, and some may in fact be harmed with intensive 
chemotherapy. Such high induction mortality rates and poor tolerance to chemotherapy have 
resulted in a reluctance to treat AML in older patients. A Surveillance Epidemiology and 
End Results database analysis has indicated that 64% of AML patients over age 65 receive 
no therapy for AML, other than supportive care. This untreated group has a dismal median 
survival of 1.7 months. 
 
Hypomethylating agents are the most frequently used agents in the treatment of less fit, 
older patients with AML in the US and Europe. The DACO-016 study compared the 
efficacy and safety of decitabine (20 mg/m2/day for 5 days every 4 weeks) versus treatment 
of choice (TC) (including LDAC 20 mg/m2/day for 10 days every 4 weeks or best 
supportive care) in 485 patients with AML (median age 73 years) ineligible for cytotoxic 
chemotherapy (Kantarjian et al., JCO 2012; Thomas X et al., CLML 2014). The CR rate 
plus CRp was 17.8% with decitabine versus 7.8% with TC (odds ratio, 2.5; P = .001). The 
initial analysis showed a trend toward improved survival with decitabine (7.7 vs. 5.0 


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months; P = 0.108) that became significant (P = 0.037) with further follow-up. Azacitidine 
has shown benefit in elderly patients with AML in two large multicenter trials. In one trial 
patients with AML with 20–30% blasts were evaluated as a subset analysis of the phase III 
 
AZA-001 trial (Fenaux et al., JCO 2010). The patients were randomly assigned to receive 
subcutaneous azacitidine or conventional care regimen CCR (best supportive care [BSC] 
only, low-dose cytarabine (LDAC), or intensive chemotherapy [IC]). The morphologic CR 
rate was 18% (10 of 55 patients) in the azacitidine group and 16% (nine of 58 patients) in 
the CCR group (P = .80). At a median follow-up of 20.1 months, the median OS for 
azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated 
patients (P = 0.005), and 2-year OS rates were 50% and 16%, respectively (P = 0.001). In 
another trial, 488 elderly patient’s with AML with >30% blasts and age ≥65 years were 
randomized to receive either azacitidine (75 mg/m2/day for 7 days every 4 weeks) or a CCR 
(standard induction chemotherapy, LDAC, or supportive care only) (Dombret et al., Blood 
2015). Overall response (CR + CRi) rates were comparable in the azacitidine (27.8%) and 
CCR (25.1%) arms (P = .5384). Median OS was 10.4 months (1-year survival 47%) for 
patients receiving azacitidine compared to 6.5 months (1-year survival 34%) for patients 
receiving CCR (P = 0.0829). A prespecified analysis censoring patients who received AML 
treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 
12.1 months vs 6.9 months (stratified log-rank P = .0190). The dismal prognosis in elderly 
AML patients has resulted in increased efforts and clinical trials to improve the frontline 
therapy in elderly patients (≥ 60 years) with AML. 
 
These results emphasize the need to explore alternate strategies to intensive chemotherapy 
for AML in older patients and/or those unable to tolerate intensive chemotherapy (based on 
predicted high eight-week mortality rates of 30% or more). The development of novel and 
effective anti-AML agents and/or combinations is crucial to improving the outcome of older 
patients (age ≥ 65) with AML. The clinical results with azacytidine and nivolumab in the 
salvage setting are encouraging (see clinical update of ongoing 5-azacytidine and nivolumab 
trial in section 2.3 C on page 4). Therefore, we would like to evaluate the efficacy and 
tolerability of the combination of 5-azacytidine with nivolumab in older patients with AML. 
 
2.3  A Role of PD-1/PD-L1 and CTLA4 interactions in AML 
It is well known that negative regulatory mechanisms within the solid tumor 
microenvironment inhibit antitumor T-cell function. Proteins produced by the tumor cells 
often inhibit the anti-tumor activity of the microenvironment by altering immune cells 
contained within the microenvironment and by recruitment of immune-suppressor cells to 
that microenvironment. One inhibitory mechanism is up-regulation of programmed death- 
ligand 1 (PD-L1) expressed on tumor or stromal cells, which binds to programmed death-1 
(PD-1) on activated T cells[9-12]. PD-1/PD-L1 engagement results in diminished antitumor 
response by producing a state of exhaustion for tumor-infiltrating cytotoxic T-lymphocytes 
(CTLs).  PD-L1 expression is associated with poor prognosis in many cancers, including 
those of the lung, stomach, colon, breast, cervix, ovary, renal cell, and liver, as well as in 
adult T-cell leukemia, glioma, and melanoma[13-15]. Interaction between PD-L1 and PD-1 
plays an important role in controlling immune responses and is involved in peripheral 
tolerance, autoimmunity, allergy, infection, and antitumor immunity[13, 16]. 
 


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The PD-1/PD-L1 pathway plays a major role in immune evasion and cytotoxic T-cell 
exhaustion in hematologic malignancies including AML and MDS[17-19]. Garcia-Manero 
et al identified ≥ 2-fold expression of PD-L1 in 34% of patients with AML or MDS[19]. 
Chen et al found increased expression of PD-L1 at AML progression, which was an 
independent negative prognostic factor for French-American-British type M5 AML[20]. 
 
Similarly, Zhou et al have demonstrated that AML progression in a murine model is 
associated with elevated PD-1 expression on CTLs and increased T-regulatory cells at the 
tumor site[21]. Both these mechanism decrease CTL activity at the tumor site. Elevated PD- 
1 expression independently dampens the anti-leukemic effect of CTLs. T-regulatory cells 
(Tregs) further suppress CTL activity and this suppression depends on PD-1 expression by 
Tregs and PD-L1 expression by antigen-presenting cells. Anti-PD-L1 monoclonal antibody 
treatment increased the proliferation and function of CTLs at tumor sites by reducing the 
interaction between PD1 and PDL1 resulting in decreased Treg-mediated suppression of 
CTLs. The enhanced CTL activity resulted in reduced AML tumor burden, and resulted in 
long-term murine survivors. 
 
CTLA4: The role of CTLA4 in AML is not as well defined in AML. However, recent data 
suggest the CTLA-4 pathway may indeed play a role in AML and MDS, especially postSCT. 
Matthews et al evaluated anti-CTLA4 agent ipilimumab in a phase I/IB study in patients with 
relapsed AML post-allogeneic stem cell transplant (Matthews D et al., NEJM 2016; 375:143-
153). Among 28 patients with post-SCT relapse 13 had relapsed AML (including medullary 
and/or extramedullary relapse). The patients had a median of 3 prior therapies for AML. A 
complete response was obtained in 5/13 patients. The therapy was generally well tolerated, 
with 2/23 cases experience any grade immune AE generally well controlled by early 
recognition and initiation of steroids. In a study at MDACC in patients with MDS who have 
progressed post-hypomethylator therapy we evaluated single-agent nivolumab as well as 
single agent (Garcia-Manero G, Daver N et al., American Society of Hematology, 2016, 
abstract # 344). Nivolumab as a single-agent did not induce a response in 15 patients with 
post-HMA MDS and the nivolumab alone cohort was closed to new patient entry per futility 
stopping rules. In contrast, ipilimumab as a single agent in patients with postHMA MDS 
produced a CR in 2 of 9 patients treated indicating modest activity. The ipilimumab cohort is 
being expanded with plans to proceed to a nivolumab+ipilimumab cohort that is built into the 
MDS protocol and the one expected to have best responses in MDS and possibly AML, 
similar to outcomes noted in solid tumors. 
 
2.3 B Defining PD1, CTLA4 and Immune checkpoint expression in AML (MDACC 
experience) Between March, 2015 and October 2015 we performed 17-color multi-
parameter flow- cytometry (MFC) on 15 untreated AML and 25 relapsed AML to assess 
expression of costim ligands (4-1BBL, B7-1, B7-2, ICOSL, PDL-1, PDL-2, OX40L) on 
leukemic blasts and costim receptors (4-1BB, CTLA-4, ICOS, PD-1, OX40, GITR, LAG-3, 
TIM-3) on Tcell subsets: CD4 T effector cells [Teff]: CD3+CD4+CD127lo/+Foxp3-, CD4 T 
regulatory cells [Treg]: CD3+CD4+CD127-Foxp3+, and CD8 T cells: CD3+CD8+. Four 
healthy human BMs were used as control. Expression is denoted by percentage of specific 
T-cell subset or gated AML blasts positive for the marker indicated. PB mononuclear cells 
(PBMCs) and blasts were evaluated at the same time-point. OX40+ Teffs and OX40+ CD8 


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cells were higher in untreated AML BM as compared to healthy donor BM (median [med]: 
7.2% versus [vs] 0.26%; P=0.0005 and med: 2.03% vs 0.06%; P=0.07, respectively). PD1+ 
Tregs and OX40+ Tregs were also higher in untreated AML BM as compared to healthy 
donor BM (med: 19.7% vs 7.5%; P=0.03 and med: 10.3% vs 0.5%; P=0.02, respectively). 
PD1+ Teffs, OX40+ Teffs, and ICOS+ Teffs were higher in relapsed AML BM as 
compared to healthy donor BM (med: 17.7% vs 6.7%; P= 0.047, med: 12% vs 0.27%, 
P=0.002, and med: 13.3% vs 1.1%; P=0.07, respectively). OX40+ CD8 cells, ICOS+ CD8 
cells, TIM3+ CD8 cells (med: 5.0% vs 0.07%; P=0.04, med: 18.5% vs 2.6%; P=0.09, and 
med: 2.7% vs 0.7%; P=0.01, respectively) and OX40+ Tregs (med: 15.5% vs 0.5%; 
P<0.0001) were also higher in relapsed AML BM as compared to healthy donor BM. 
GITR+ Teffs, PD1+ CD 8 cells, and LAG3+ Tregs were higher in relapsed AML BM as 
compared to new AML BM (med: 10.9% vs 1.7%; P=0.08, med: 36.2% vs 21.3%; P=0.03, 
and med: 46.7% vs 16.9%; P=0.07, respectively). No other noteworthy differences were 
noted for costim receptor expression. CTLA4 expression on CD3+ T-cells as well as Teff, 
Treg, and CD8+ T-cells was evaluated and was found to be expressed on <10% of each 
respective population and was not significantly increased as compared to CTLA4 
expression on corresponding T-cell populations in healthy donors (Daver N, Sharma P et 
al., American Society of Hematology 2016, abstract # 2900). There were no other 
noteworthy differences in ligand expression patterns between relapsed AML and new 
AML. There was significant variability in BM expression of costim receptors and ligands 
between individual pts. The expression of costim receptors and ligands differed 
significantly between BM and PB from the same time-point in the same pt. A larger sample 
size is needed to confirm these data and find additional associations and this is currently 
underway at our institution. 
Thus, it appears clinically targetable checkpoint receptors including PD1 appear to be 
overexpressed in the BM of patients with AML. Relapsed AML had higher expression of 
costim receptors. These data have been submitted (Daver N, Sharma P et al. AACR 2016) 
and further support the evaluation of anti-PD1 based therapies in AML. 
 
2.3 C  5-azacytidne and nivolumab clinical trial update (11/29/2016): 
 
We have thus far treated 70 patients on the vidaza + nivolumab trial for relapsed/refractory 
AML as of Dec 30 2016 (Daver N, Sharma P et al., American Society of Hematology, 2016 
abstract #763). The RP2D of 5-azacytidine and nivolumab was established as 5-azacytidine 
75mg/m2 days 1-7 and nivolumab 3.0 mg/kg on days 1 and 14 of each cycle in the ongoing 
clinical trial. 0/6 patients experienced a DLT at this dose during the safety-run-in phase. All 
subsequent 47 patients have received this RP2D dose of 5-azacytidine and nivolumab.  
51 patients have completed at least 3 cycles and are evaluable for response and toxicity. 51 
pts with a median age of 69 years (range, 45 – 90), secondary AML (55%), poor risk 
cytogenetics (47%), median number of prior regimens 2 (range, 1-7) have been enrolled. All 
51 pts had baseline next generation sequencing and most frequently detected mutations 
included DNMT3A (n=12), TP53 (n=11), TET2 (N=9), ASXL1 (n=7), and RAS (n=7). 35 pts 
are evaluable for response: 6 (18%) achieved complete remission (CR)/ complete remission 
with insufficient recovery of counts (CRi) (3 CR, 3 CRi), 5 (15%) had hematologic 
improvement (HI), 9 (26%) had ≥50% BM blast reduction, 3 pts (9%) had stable disease > 6 
months, and 12 (34%) had progression. 16 pts are early for response assessment (<3 
courses). The median number of courses to CR/CRi/HI was 3 (1 – 9). The CR/CRi/HI 


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(n=11) have been durable with no relapses among pts who achieved CR/CRi/HI [CR 
duration; not reached (NR)]. The 4- and 8-week mortality were 0 and 6%, respectively. The 
median overall survival for the 35 evaluable pts was 9.3 months (range, 1.8 – 14.3) (Fig 1) 
and this compares favorably to historical survival with AZA-based salvage protocols in 
similar pts treated at MDACC.  
Grade 3/4 and Grade 2 immune mediated toxicities were observed in 7 (14%) and 6 (12%) 
pts, respectively. These included 8 episodes of pneumonitis, 2 nephritis, 2 transaminitis, and 
1 skin rash. 1 pt died from grade 4 pneumonitis/epiglottitis. In the remaining 12 cases the 
toxicities responded rapidly to steroids and all 12 pts were successfully rechallenged with 
nivolumab. Time to onset of toxicities ranged from 4 days to 3.5 months. Four pts were 
postSCT and one had a grade 3 flare of GVHD of the skin and gut.  
Multicolor flow-cytometry studies and Mass-cytometry (CyTOF) studies are conducted by 
the Immunotherapy Platform on baseline and on-treatment BM aspirate (end of cycle 1, 2, 
4, 8) and peripheral blood to assess the T-cell repertoire and expression of co-stimulatory 
receptors and ligands on T cell subsets and leukemic blasts respectively. Baseline and end 
of cycle 1 BM was evaluated on 25 of the 35 evaluable patients, including 6 responders 
(CR/CRi/HI) and 19 non-responders. Pts who achieved a CR/CRi/HI had a baseline higher 
live total CD3 (P=0.10), CD8+ T-cells (P=0.02), and lower live CD4+Foxp3+PD1+ T-
regulatory (T-reg) cells (P=0.01) infiltrate in the BM (Figure 2). The ratio of PD1+CD8+ T-
effector cells to PD1+CD4+Foxp3+ T-reg cells was significantly higher in the CR/CRi/HI pts 
vs non-responders (208.4 vs 8.91, P<0.05) in baseline BM. On further evaluation of post 
cycle 1 and post cycle 2 BM aspirates (unpublished – to be presented at ASH 2016) the 
responders demonstrate a progressive increase in the live CD3+ and CD8+ BM infiltrate 
and an increase in CD8+ ICOS+ cells. On the other hand non-responders did not have an 
increase in the live CD3+ or T-cell subsets. However, CTLA4 and Tim3 were up-regulated 
on CD8+, T-eff and to a lesser extent on T-regs post-cycle 2 suggesting up-regulation of 
these exhaustion markers as a potential mechanism of resistance.  
We have treated 5 patients who are older than 60 years and not candidates for induction 
chemotherapy with vidaza in combinaiton with nivolumab as frontline therapy. The patients 
have not completed 3 cycles of therapy and are early for efficacy analysis. The regimen has 
been well tolerated with no patients requiring drug interruptions or discontinuation of 
therapy due to toxicities. Immune mediated toxicities have been noted in 3 patients 
including 2 episodes of Grade 2 pneumonitis and 1 episode of Grade2 nephritis. All 3 cases 
of immune mediated toxicity responded rapidly to steroid therapy and were resolved within 
7 days.  
 
 
2.3 D 5-azacytidne with nivolumab and ipilimumab clinical trial update (08/02/2019): 
 
Cohort 2 of azacitidine with nivolumab and ipilimumab enrolled 6 patients at the dose 
level 0 in Table 5B (i.e. azacitidine 75mg/m2 D1-7 with Nivolumab 3mg/kg Q2weeks 
and Ipilimumab 1mg/kg Q12 weeks). These patients were observed for the DLT period 
(28 days) and no DLTs were encountered among the first 6 patients treated at dose 
level 0. Subsequently, in accordance with Table 5B the dose level +1 was evaluated (i.e. 
azacitidine 75mg/m2 D1-7 with Nivolumab 3mg/kg Q2weeks and Ipilimumab 1mg/kg 
Q6 weeks).  These patients were observed for the DLT period (28 days) and no DLTs 
were encountered among the first 6 patients treated at dose level +1. The RP2D was 


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selected as dose +l (i.e, with ipilimumab Q6 weeks) and study opened to expansion with 
24 additional patients to be enrolled in expansion using the dose level +1.  
 
As of 08/01/2019 (Daver N et al, ASH 2019 Oral abstract #830: attached as Appendix), 
31 R/R AML patients have been treated with Aza+Nivo+Ipi at all dose levels (dose 
level 0 = 6 patients, dose level +1 = 6 patients, and expansion at RP2D= 19 patients).  
Median age 71 years (26-86), secondary AML (49%), ELN unfavorable cytogenetics 
(65%), TP53 mutated (38%), median of salvage 2 (range, 1-4) status. 54% of the 
patients had previously received hypomethylating agent (azacitidine or decitabine)-
based therapies either as single agent or in combination approaches. 4 patients had 
undergone prior allogeneic stem cell transplant (median time from allogeneic stem cell 
transplant of 13 months).  
 
24 patients were evaluable for response and survival, 7 too early (<3 months from start 
of therapy on protocol). CR/CRi was noted in 9 (36%), additionally 2 (8%) had 
hematologic improvement in one or more parameter (HI) maintained >6 months, 4 
(16%) stable disease (SD) (defined as absence of CR, CRi, PR, MLFS; with stable 
disease on treatment for at least 6 months), and 10 (40%) were non-responders (NRs). 
Definitions of CR, CRi, PR, MLFS, stable disease were as per ELN 2017 response 
criteria. The 4-week and 8-week mortality were 0 and 8%, respectively, in this salvage 
population. In all salvage setting the median OS in Aza+Ipi+Nivo (n=24) versus 
Aza+Nivo (n=70) versus contemporary historical HMA-based clinical trial in R/R 
AML at MDACC (n=172), were 10.5, 6.4, and 4.6 months, respectively (p=0.0025) 
(Figure 1). This median OS with Aza+Ipi+Nivo compares favorably even to 
DAC10+venetoclax in R/R AML (med OS: 7.1 months) that will be reported from our 
center in a similar salvage population at ASH 2019 (Maiti A et al, ASH 2019). The 1-
year OS in R/R AML pts with AZA+Nivo+Ipi was encouraging at 45%. The ORR and 
CR/CRi rates were also higher with AZA+Nivo+Ipi compared with AZA+Nivo and 
historical HMA-based controls. Grade 3/4 immune mediated toxicities were observed 
in 6 pts (25%), including rash, pneumonitis, and colitis. One pt required ICU stay but 
no deaths were attributed to immune toxicity. Other grade >2 toxicities were as 
expected for R/R AML population and were mostly infections/febrile neutropenia, and 
electrolyte disturbance. The 4-week mortality was 0, 8-week mortality was 8% and no 
deaths were attributed to immune related adverse events among the 24 evaluable 
patients treated with azacitidine with nivolumab and ipilimumab. 
 
 


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 Figure 1: Median OS in AZA+Nivo+IPi (10.5 months) versus AZA+Nivo (6.4 months) versus 
HMA-based contemporary controls (4.6 months) treated on clinical trials at MDACC between 
2011-2018 
 
Table 1: Response and early mortality rates 
 
Abbreviations: N, number, CR, complete remission, CRi, complete remission with incomplete count recovery, 
PR, partial response, HI, hematologic improvement 
*Hematologic improvement in one or more parameter maintained >6 months on study 
@Stable disease (SD) was defined as the absence of CR, CRi, PR, MLFS, HI without evidence of clinical 
deterioration or proliferative disease, maintained >6 months on study. This particular response was not 
captured for control. 
 
 
Best response 
N (%); Median [Range] 
 
 
Aza+Nivo 
N=70 
Aza+Ipi+Nivo 
=24 
Control 
N=172 
  Overall Response Rate 
23 (33) 
11 (46) 
35 (20) 
       CR 
       CRi/CRp 
       PR 
                  4 (6) 
11 (16) 
                   1 (1) 
1 (4) 
7 (29) 
0 
17 (10) 
15 (9) 
1 (1) 
       HI* (6 months+) 
                 7 (10) 
2 (8) 
2 (1) 
Stable disease (6 months+)@ 
8 (11) 
4 (17) 
NA 
Non responders 
39 (58) 
8 (33) 
131 (76) 
Median cycles to response 
2 [1 – 13] 
2 [1 – 9] 
2 [1 – 6] 
Median follow up, in months 
27.2 [21.7 – 35.1] 
11.8 [ 
51 [0.1 – 64.8] 
4 weeks mortality 
3 (4) 
0 
12 (7) 
8 weeks mortality 
10 (14) 
2 (8) 
34 (20) 


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2.3 E                Venetoclax in AML (Background and unmet need) 
--Venetoclax plus HMA in patients with newly diagnosed AML  
An ongoing phase Ib/II study has reported promising safety and efficacy of 
venetoclax in combination with either azacitidine or decitabine in patients ≥65 
years of age with previously untreated AML and who are ineligible for 
chemotherapy (DiNardo CD et al, Blood. 2019 Jan 3;133(1):7-17). At the most 
recent update (Pollyea D et al ASH 2018 Oral presentation Abstract 285: full 
PowerPoint attached as Appendix), 145 patients were treated with a median age of 
74 years (range, 65-86 years). Cytogenetics were poor risk in 49% of patients. The 
30-day and 60-day mortality rates were 3% and 8%, respectively.  Tumor lysis 
syndrome was not observed. The CR/CRi rate for the entire cohort was 66% with 
a median duration of CR/CRi of 11.0 months. The median overall survival for the 
entire cohort was 17.5 months. These results represent the best survival data for 
older, unfit patients reported to date in newly diagnosed AML. Based on these 
exciting results in this historically difficult-to-treat patient population, in 
November 2018 the US FDA approved venetoclax in combination with either 
LDAC, azacitidine or decitabine for patients with newly diagnosed AML who are 
≥75 years of age or have comorbidities that preclude the use of standard intensive 
chemotherapy.  
 
Emerging clinical and exposure response data have suggested that the 400mg dose 
of venetoclax has the best risk-benefit profile, and a phase III study of venetoclax 
400mg with azacitidine in the frontline setting is ongoing and has recently 
completed enrollment (VIALE A). 
 
--Unmet Need in AML and Need to Continue Improving HMA with 
Venetoclax 
In spite of the encouraging efficacy of HMA with venetoclax in newly diagnosed 
older AML who are not good candidates for cytotoxic induction therapy, the 
median CR/CRi durations are </= 11-12 months and median 3-year OS is <45% 
(DiNardo CD et al, Blood. 2019 Jan 3;133(1):7-17) suggesting that there is room 
for improvement by further improving the durability of CR/CRi’s and thereby 
improving median OS. Similarly, MRD-negative rates with HMA with venetoclax 
are 40-50% and these may be further improved by the addition of an effective and 
tolerable third agent, potentially translating into more durable response and 
improved OS. 
 
The long-term outcomes of patients with poor-risk disease features remain poor. 
Among frontline older poor risk patients treated with HMA with venetoclax 
(defined as patients with TP53 and adverse cytogenetics) evaluated in both the 
MDACC internal data set (Shoukier M et al, Journal of Clinical Oncology 37, 
no. 15_suppl (May 20, 2019) 7034-7034) and in the multicenter phase Ib/II trial of 
HMA with venetoclax (DiNardo CD et al, Blood. 2019 Jan 3;133(1):7-17) the 


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CR/CRi rates were significantly lower at 45-47%, median response durations were 
<6 months, median OS was 6-9 months, and only 14% of the patients achieving 
CR/CRi became MRD-negative. 
 
Venetoclax plus HMA in R/R AML: Several retrospective studies have been 
published evaluating the safety and efficacy of venetoclax plus an HMA in 
patients with R/R AML.  
-A study from MD Anderson evaluated the outcomes of 43 patients with R/R 
myeloid malignancies (n=39, 91% with AML) who received venetoclax in 
combination with other agents (DiNardo CD et al, American journal of 
hematology 2018; 93(3): 401-7). Thirty-one of the evaluated patients (72%) 
received venetoclax with an HMA. Most patients (84%) were treated in salvage 2 
or later (range 2-8) with a median of 3 prior treatment regimens. Objective 
response rate (ORR) was achieved in 9 (21%) patients, including 2 (5%) with CR, 
3 (7%) with CRi, and 4 (9%) with morphologic leukemia‐free state (MLFS). Of 
the 9 responding patients, all responded within 1 cycle of venetoclax combination 
therapy. These nine responding patients included eight (26%) of the patients 
treated with an HMA combination. With a median follow-up of 3 months, the 
estimated 6-month OS rate was 24% and median OS was approximately 5 months.  
-In another study of venetoclax in combination with HMAs in R/R AML from 
City of Hope, 33 patients were treated (Aldoss I et al, Haematologica. 2018 
Sep;103(9):e404-e40). The median number of prior therapies was 2 (range, 1-8). 
Twenty patients (61%) had failed HMA therapy previously and 13 patients (39%) 
had prior allogenic stem cell transplantation. The ORR was 64% (N=21), with 10 
patients (30%) achieving CR, 7 (21%) achieving CRi and 4 (12%) achieving 
MLFS. With a median follow-up of 6.5 months, the 1-year OS rate was 53%.  
 
-The group at Memorial Sloan Kettering Cancer Center has also reported their 
experience with venetoclax in combination with either low-dose cytarabine or an 
HMA in patients with R/R myeloid malignancies (Goldberg A et al, Blood 2017; 
130(Suppl 1): 1353). A total of 24 patients were treated (n=8 with HMA; N=16 
with low-dose cytarabine). Twenty-three patients (96%) had a diagnosis of AML. 
The median number of prior treatments was 3 (range, 1-8); 6 patients (29%) had 
prior stem cell transplantation. Of 21 patients evaluable for efficacy, the ORR was 
29%, including a CR rate of 24% (n=5) and PR rate of 5% (n=1). With a median 
follow-up of 4.1 months, the 3-month OS rate was 72%. 
 
Pre-clinical rationale for combination of venetoclax with immune therapies 
In a series of human in vitro and in vivo syngeneic tumor model studies, venetoclax 
does not appear to antagonize anti-PD-1 therapy with nivolumab (Mathew R et al. 
Blood 2018 132: 3704). Venetoclax was shown to decrease naïve T-cells and B-
cells but not central and effector memory T cells (these being critical to anti-tumor 
immunity) in in vitro studies of human lymphocytes. In a mixed lymphocyte 
reaction assay, venetoclax did not affect IFN-gamma secretion from CD3/CD28 


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stimulated T-cells either by itself or when co-treated with the checkpoint inhibitor 
nivolumab. Similar findings were observed in a cytomegalovirus recall assay, 
suggesting that venetoclax does not impair immune response to infections. In an in 
vivo experiment with the murine syngeneic tumor model MC38, venetoclax did 
not impair the efficacy of anti-PD-1 therapy with nivolumab, and in some solid 
tumor syngeneic models, in fact increased efficacy was noted with the 
combination compared to either venetoclax or nivolumab monotherapy. These 
findings suggest that venetoclax does not impair anti-PD-1 anti-tumor therapy and 
may synergize with immune checkpoint therapy through its favorable modulation 
of the T-cell profile. Lasater et al demonstrated that significant venetoclax-
induced cell death at clinically relevant drug concentrations is limited to the B-cell 
subset and that BCL-2 inhibition is not detrimental to survival or activation of 
NK- or T-cell subsets (Lasater E et al, Blood 2018 132:1118). Both posters 
highlighting the potential for preclinical synergy between venetoclax and immune 
checkpoint inhibitors (specifically PD1 antibodies) are attached as Appendix. 
 
 
2.4 
Nivolumab (BMS-936558, MDX1106): 
 
2.4.1 
Mechanism of Action 
 
Immune activation is tightly regulated by co-stimulatory (e.g. CD28 and ICOS) and 
co-inhibitory (e.g. CTLA-4 and PD-1) receptors expressed on T cells. Agonistic 
antibodies against co-stimulatory T cell receptors and blocking antibodies against co-
inhibitory T cell surface receptors have both been shown to potentiate T cell 
activation for tumor cell killing. 
 
PD-1 is mainly expressed by activated CD4+ and CD8+ T cells, as well as antigen 
presenting cells (APCs). It has two ligands, PD-L1 and PD-L2, with distinct 
expression profiles.[16] PD-L1 is expressed not only on APCs, but also on non- 
hematopoietic cells, including tumor cells. Expression of PD-L2 is largely 
restricted to APCs including macrophages and myeloid dendritic cells, as well as 
mast cells. The role of PD-1 as a negative regulator of T cells was best 
demonstrated by the finding that PD-1 deficient mice developed significant 
autoimmunity with high titers of autoantibodies.[22, 23] Subsequently, blocking 
antibodies against PD-1 were shown to activate immune responses that resulted in 
reduction of tumor metastasis and tumor growth in a number of experimental tumor 
models.[24, 25] Consistent with the immune inhibitory role of PD-1/PD-L1/2 
signaling, forced expression of PD-L1 in murine tumor cell lines allowed increased 
tumor growth in vivo, which was otherwise kept in check by T cells. The inciting 
effect of PD-L1 on tumor growth was reversed by blocking PD-L1 with anti-PD-L1 
 
antibodies.[26] 
 
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype, monoclonal 
antibody that binds PD-1. Blockade of the PD-1 pathway by nivolumab was studied 
using the mixed lymphocyte reaction (MLR). PD-1 blockade resulted in a 
reproducible enhancement of both proliferation and IFN-γ release in the MLR. The 


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effect of nivolumab on antigen-specific recall response was investigated using a 
CMV-restimulation assay with human peripheral blood mononuclear cells 
(PBMCs), and was evaluated by ELISA. These data indicated that nivolumab, 
versus an isotype-matched control antibody, augmented IFN-γ secretion from CMV- 
specific memory T cells in a dose-dependent manner. PD-1 blockade by nivolumab 
is therefore considered a promising immunotherapeutic strategy. 
 
2.4.2 
Summary of Safety Results from Nivolumab Program 
For a complete review of clinical information, please refer to the nivolumab 
Investigator Brochure. 
 
2.4.2.1 
Summary of Safety 
The monitoring of subject safety during and after a clinical study with nivolumab, 
including any special monitoring precautions, tests, or observations, and the 
proper means of recording and reporting adverse safety information [including 
adverse events ( AEs) and abnormal laboratory values] will follow the procedures 
outlined in the specific study protocol. 
 
The overall safety experience with nivolumab is based on experience in 
approximately 1500 subjects as either a monotherapy or in  combination  with 
other therapeutics. In general for monotherapy, the safety profile is similar across 
tumor types. The one exception is pulmonary inflammation AEs which may be 
numerically greater in subjects with non-small cell lung cancer ( NSCLC) 
possibly because in some cases it can be difficult to distinguish between 
nivolumab-related and unrelated causes of pulmonary  symptoms  and 
radiographic changes. The most frequently reported treatment-related AE is 
fatigue, which is almost always low grade. 
 
The safety profile is generally consistent across completed and ongoing clinical 
trials with no maximum tolerated dose (MTD) reached at any dose tested up to 10 
mg/kg. There was no pattern in the incidence, severity, or causality of AEs to 
nivolumab dose level. Most related AEs are thought to be due to the effects of 
inflammatory cells on specific tissues. Most AEs were low-grade (Grade 1 to 
Grade 2) with relatively few related high-grade (Grade 3 to Grade 4) AEs. Most 
high-grade events were manageable with use of corticosteroids or hormone 
replacement therapy (endocrinopathies). 
 
2.4.2.2 
Clinical Safety in Advanced Malignancies (Nivolumab 
Monotherapy) 
 
A total of 306 subjects with treatment-refractory malignancies have been treated 
 
in an ongoing, Phase 1 multidose study (MDX1106-03, CA209003). This is an 
ongoing phase I dose-escalation study of nivolumab monotherapy in patients with 
advanced cancers; 1, 3, or 10 mg/kg nivolumab and 0.1 and 0.3 mg/kg (included as 
part of Amendment 4) administered by IV Q2W; treatment up to 2 years. Results 


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were published by Topalian et al. (NEJM 2012).[27] The baseline disease 
diagnosis by treatment for MDX1106-03 is provided in Table 1. A review of the 
safety data by tumor type (RCC, NSCLC, mCRPC, CRC, and melanoma) did not 
show any clinically meaningful differences in the proportion of subjects with 
AEs noted across tumor type. 
 
Table 1: Baseline Disease Diagnosis by Treatment - MDX1106-03 
 
Abbre
viation
s:   
CRC:  
colore
ctal  
adenoc
arcino
ma;   
mCRP
C:   
metast
atic   
castrat
ion-
resistant 
prostate cancer; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; 
Source: Preliminary data, CA209003. Clinical data cut-off date 18 Mar-2013. 
 
2.4.2.3 
Adverse Events 
There was no pattern in the incidence, severity, or causality of AEs related to 
the dose of nivolumab, between 1 and 10 mg/kg, in MDX1106-03. Of the 306 
treated subjects in MDX1106-03, 303 (99.0%) subjects have at least 1 reported 
AE regardless of causality (Table 2). The most frequently reported AEs were 
fatigue (54.9%), decreased appetite (35.0%), diarrhea (34.3%), nausea (30.1%), 
and cough (29.4%). Treatment-related AEs were reported in 230 (75.2%) of the 
306 subjects. The most frequently reported treatment-related AEs were fatigue 
(28.1%), rash (14.7%), diarrhea (13.4%), and pruritus (10.5%). Most treatment- 
related AEs were low grade. Treatment-related  Grade  3-4  AEs  were 
reported in 52 (17.0%) of subjects. The most frequently reported treatment- 
related high grade AE was fatigue (6.5%). 
 
 
Table 2.: Summary of Adverse Events Reported in ≥15% of All Treated 
Subjects- MDX1106-03 
 
No. of Subjects (%) 
 
Preferred Term 
AEs regardless of causality 
Treatment-related AEs 
 
Any 
 
Grade 3- 
 
Any 
 
Grade 3-4 
   
 
Nivoluma 
b (mg/kg) 
 
 
0.1 mg/kg 
 
 
0.3 mg/kg 
No. of Subjects 
1 mg/kg 
3 mg/kg 
 
 
10 mg/kg 
 
 
TOTA 
L 
  MDX1106-03, 
  Total N  
17 
1 
8  
8 
6  
5 
4  
131 
306 
  NSCLC 
0 
0 
33 
37 
58 
128 
  Melanoma 
17 
18 
35 
17 
20 
107 
  RCC 
0 
0 
18 
0 
16 
34 
  mCRPC 
0 
0 
0 
0 
17 
17 
  CRC 
0 
0 
0 
0 
19 
19 


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Grade 
4 
Grade 
N=306  
 
 
Source: Preliminary data, MDX1106-03. Clinical data cut-off date: 18-Mar-2013 
 
 
2.4.2.4 
Select Adverse Events 
Select AE categories (events with a potential inflammatory mechanism requiring more 
frequent monitoring and/or unique intervention such as immunosuppressant’s and/or 
endocrine replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic 
AEs, skin AEs, and endocrinopathies. In addition, Select AEs include a category for 
infusion reactions. Each category is composed of a discrete set of preferred terms, 
including those of greatest clinical relevance. These Select AEs are considered events 
of interest based on the mechanism of action and were previously referred to as 
immune-related AEs or immune-mediated AEs. 
 
 
 
 
Any AE 
N=306 
 
303 (99) 
N=306 
 
127 (42) 
N=306 
 
230 (75) 
 
 
52 (17) 
Fatigue 
168 (55) 
20 (7) 
86 (28) 
7 (2) 
Decreased appetite 
107 (35) 
3 (1) 
28 (9) 
1(0.3) 
Diarrhea 
105 (34) 
3 (1) 
41 (13) 
3 (1) 
Nausea 
92 (30) 
9 (3) 
27 (9) 
2 (1) 
Cough 
90 (29) 
4 (1) 
11 (4) 
1 (0.3) 
Dyspnea 
80 (26) 
27 (9) 
11 (4) 
0 
Constipation 
78 (26) 
2 (1) 
5 (2) 
0 
Rash 
74 (24) 
0 
45 (15) 
0 
Vomiting 
70 (23) 
7 (2) 
10 (3) 
1 (0.3) 
Back pain 
68 (22) 
7 (2) 
3 (1) 
1 (0.3) 
Arthralgia 
63 (21) 
4 (1) 
15 (5) 
0 
Pyrexia 
61 (20) 
1 (0.3) 
17 (6) 
0 
Headache 
59 (19) 
1 (0.3) 
8 (3) 
0 
Edema peripheral 
59 (19) 
1 (0.3) 
3 (1) 
0 
Dizziness 
56 (18) 
1 (0.3) 
10 (3) 
0 
Pruritus 
56 (18) 
1 (0.3) 
32 (11) 
1 (0.3) 
Weight decreased 
48 (16) 
1 (0.3) 
11 (4) 
0 
Malignant 
neoplasm 
48 (16) 
4 (1) 
1 (0.3) 
1 ( 
progression 
 
 
 
 


Nivolumab and azacytidine 
 
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The  frequencies  of  these  events  are  summarized  in  i n v e s t i g a t o r   b r o c h u r e 
( A p p e n d i x E ) . The 10- m g / kg cohort had numerically greater frequency of high-
grade select AEs including the subcategories of endocrinopathies, GI, pulmonary, 
and infusion reactions. 
 
 
2.4.2.5 
Adverse Events Leading to Discontinuation 
At  least  1  treatment-related  AE  leading  to  discontinuation  was  reported  in  32 
(10.5%) of the 306 treated subjects. Grade 3-4 treatment-related events were reported 
in 14 (4.6%) subjects. The frequency of treatment-related AEs leading to 
discontinuation was not associated with the dose of nivolumab. Pneumonitis was the 
most common treatment-related AE leading to discontinuation (8 subjects, 2.6%); 
pneumonitis reported in 3 (1.0%) subjects was Grade 3-4. Treatment-related AEs 
reported in at least 2 subjects included pneumonitis (8 subjects, 2.6%), colitis (3 
subjects,   1.0%)   and  myalgia,   hepatitis,   hypersensitivity,   and   infusion-related 
r e a c t i o n s (each r e p o r t e d i n 2 subjects, 0.7%). One event of Grade 5 sepsis 
was reported for 1 subject, a 62-year-old male treated with 1 mg/kg nivolumab. 
 
2.4.2.6 
Deaths 
As  of  18-Mar-2013,  195  deaths  have  been  reported  in  MDX1106-03  during  the 
course of the study or within 30 days of last dose of study drug. The majority of the 
deaths were considered secondary to disease progression and malignant disease. 
 
Three subjects in MDX1106-03 died after developing pneumonitis.  A  62-year-old 
male (MDX1106-03-1-699) with NSCLC (adenocarcinoma) in the  1  mg/kg 
treatment group and a 59-year old male (MDX1106-03-1-3582) with CRC in the 10 
mg/kg treatment group both died due to Grade 5 sepsis after having developed Grade 
4 pneumonitis. Sepsis and pneumonitis were considered related to study drug by the 
investigator in both of these cases. In addition, a 40-year- old female (MDX1106-03-5- 
710) with NSCLC (adenocarcinoma) in the 1 mg/kg treatment group died due to 
respiratory failure after having developed Grade 4 pneumonitis and tumor 
progression. In this case, respiratory failure and pneumonitis were considered related 
to study drug by the investigator. 
 
Additional deaths reported as due to “other” in MDX1106-03 included: 
 
 
 MDX1106-03-2-3436 (10 mg/kg): Ischemic cardiomyopathy 
 
 MDX1106-03-4-3484  (10 mg/kg): Death due to abdominal pain c a u s e d b y 
s u p e r i o r mesenteric vein thrombosis 
 MDX1106-03-3-674 (1 mg/kg): Progressive lung cancer 
 
2.4.3 
Summary of Efficacy (Nivolumab monotherapy) 
The clinical activity data presented below are from MDX1106-03 (nivolumab 
monotherapy). 
 
 
Table 3: 
Objective Response Rate and Progression Free Survival 24 Weeks 
Rate in Melanoma Subjects - MDX1106-03 
 


Nivolumab and azacytidine 
 
Page 19 of 99 
 
Dose 
(mg/kg) 
N 
Histolog 
y 
ORR 
No. of Subjects (%) 
PFSR at 24 
weeks (%) 
All NSCLC 
129 
NA 
22 (17) 
34 
1.0 
15 
S 
0 
36 
 
18 
NSQ 
1 (6) 
19 
3.0 
18 
S 
4 (22) 
45 
 
19 
NSQ 
5 (26) 
42 
10.0 
21 
S 
5 (24) 
45 
 
37 
NSQ 
7 (19) 
25 
Abbreviations: ORR: objective 
response rate, PFSR: progression-
free survival rate 
Source: Preliminary data, MDX1106-
03. Clinical cut-off date: 18-Mar-201 
 
 
Table 4: 
Objective 
Response Rate per RECIST 
1.0 and Progression Free 
Survival 24 Weeks Rate by 
Histology in Non-small Cell Lung Cancer Subjects - MDX1106-03 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: NA: not applicable, NSCLC: non-small cell lung cancer; NSQ: non- 
squamous, ORR: objective response rate; PFSR: progression free survival rate, SQ: 
squamous 
Source: Preliminary data, MDX1106-03. Clinical cut-off date 18- Mar-2013. 
 
 
2.4.3.1  Ipilimumab: 
 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal 
immunoglobulin (Ig) G1κ specific for human cytotoxic T lymphocyte antigen 4 
(CTLA-4, CD152), which is expressed on a subset of activated T cells. CTLA-4 is a 
negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and inhibits its 
interaction with ligands on antigen-presenting cells (APCs). The proposed mechanism 
of action for ipilimumab’s effects in subjects with melanoma is indirect, possibly 
through T-cell potentiation and mediation of antitumor immune responses. 
 
Yervoy™ (ipilimumab) has been approved for use in over 40 countries including the 
United States (US, Mar-2011), the European Union (Jul-2011), and Australia (Jul-
2011. Bristol-Myers Squibb (BMS) and Medarex, Inc. (MDX, acquired by BMS in 
Dose (mg/kg) 
N 
ORR 
PFSR at 24 
weeks (%) 
All Melanoma 
107 
33 (31) 
4 
0.1 
17 
6 (35) 
3 
0.3 
18 
5 (28) 
3 
1.0 
35 
11 (31) 
5 
3.0 
17 
7 (41) 
5 
10.0 
20 
4 (20) 
3 


Nivolumab and azacytidine 
 
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Sep-2009) have co-sponsored an extensive clinical development program for 
ipilimumab, encompassing more than 13,800 subjects in several cancer types in 
completed and ongoing studies, as well as a compassionate use program. The focus of 
the clinical program is in melanoma, prostate cancer, and lung cancer, with advanced 
melanoma being the most comprehensively studied indication. Ipilimumab is being 
investigated both as monotherapy and in combination with other modalities such as 
chemotherapy, radiation therapy, and other immunotherapies. Phase 3 programs are 
ongoing in melanoma, prostate cancer, and lung cancer. In melanoma, 2 completed 
Phase 3 studies (MDX010-20 and CA184024) have demonstrated a clinically 
meaningful and statistically significant survival benefit in pretreated advanced 
melanoma and previously untreated advanced melanoma, respectively ®). 
 
The safety profile of ipilimumab is generally consistent across these trials with a) the 
majority AEs being inflammatory in nature consistent with the proposed mechanism 
of action of ipilimumab, b) the same types of such immune-mediated events in the 
gastrointestinal (GI) tract, skin, liver, and endocrine system being reported, and c) 
most of these events being manageable with immune suppressive therapies. In 
melanoma, 2 BMS-sponsored Phase 3 studies are ongoing in subjects with high-risk 
Stage III melanoma (CA184029, with adjuvant immunotherapy) and pretreated and 
treatment-naïve advanced melanoma (CA184169, 3 mg/kg versus 10 mg/kg 
ipilimumab). The completed Phase 3 study CA184043 evaluated ipilimumab in 
subjects with metastatic castration-resistant prostate cancer (mCRPC) who had 
progressed during or following docetaxel. Eligible subjects were randomized to a 
single dose of bone-directed radiotherapy (RT), followed by either ipilimumab 10 
mg/kg or placebo (799 randomized: 399 ipilimumab, 400 placebo). This study did not 
meet its primary endpoint of overall survival (OS). The hazard ratio (HR) of 0.85 
(95% CI: 0.72 to 1.00) for survival favored ipilimumab but did not reach statistical 
significance with a P-value of 0.053. Planned sensitivity analyses favored ipilimumab, 
where the greatest benefit appeared to be in subgroups defined by good prognostic 
features and low burden of disease. Additional evidence of ipilimumab activity 
observed in the study included a reduced risk of disease progression relative to 
placebo (HR = 0.70) and superior clinical outcomes compared to placebo in tumor 


Nivolumab and azacytidine 
 
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regression and declines in prostate specific antigen (PSA). The safety profile in this 
study was consistent with the previously defined adverse event (AE) profile at the 
same dose.  A second Phase 3 study CA184095 evaluating ipilimumab 10 mg/kg 
versus placebo in men with asymptomatic or minimally symptomatic, chemotherapy-
naïve mCRPC with no visceral metastases is ongoing. In addition, a completed large 
Phase 2 study (CA184041) has investigated the addition of ipilimumab to carboplatin 
and paclitaxel using 2 different schedules (concurrent and phased) in subjects with 
nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC, a secondary 
endpoint). The phased, but not the concurrent schedule, demonstrated activity in both 
NSCLC and SCLC, including significant improvement of immune-related 
progression-free survival (irPFS) and a numeric trend for OS improvement (not 
significant). The efficacy and safety of ipilimumab in a phased schedule with 
carboplatin/paclitaxel is also being investigated in an ongoing Phase 3 study in 
subjects with advanced squamous NSCLC (CA184104). The efficacy and safety of 
ipilimumab in a phased schedule with etoposide/platinum in subjects with extensive 
stage disease SCLC is being investigated in an ongoing Phase 3 study (CA184156). 
The unique immune-based mechanism of action is reflected in the clinical patterns of 
anti-cancer activity in some patients. Ipilimumab impacts tumor cells indirectly, and 
measurable clinical effects emerge after the immunological effects. Tumor infiltration 
with lymphocytes and the associated inflammation (documented by biopsy in some 
subjects) is likely the cornerstone of the effect of ipilimumab and can manifest in 
various patterns of clinical activity leading to tumor control. In some cases, 
inflammation may not be noted by radiological examination and objective response is 
observed with the first tumor assessment in a manner seen in patients receiving other 
types of anti-cancer treatments. In other cases, response may be preceded by an 
apparent increase in initial tumor volume and/or the appearance of new lesions, which 
may be mistaken for tumor progression on radiological evaluations. Therefore, in 
patients who are not experiencing rapid clinical deterioration, confirmation of 
progression is recommended, at the investigator’s discretion, to better understand the 
prognosis as well as to avoid unnecessarily initiating potentially toxic alternative 
therapies in subjects who might be benefiting from treatment. Immune-related 
response criteria were developed based on these observations to systematically 


Nivolumab and azacytidine 
 
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categorize novel patterns of clinical activity and are currently being prospectively 
evaluated in clinical studies. In metastatic diseases, stabilization is more common than 
response, and in some instances is associated with a slow, steady decline in tumor 
burden over many months, sometimes improving to partial and/or complete responses. 
Thus, the immune-based mechanism of action of ipilimumab results in durable 
disease control, sometimes with novel patterns of response, which contribute to its 
unique improvement in OS. 
 
The unique immune-based mechanism of action is also reflected in the safety profile. 
The most common treatment-related AEs are inflammatory in nature, consistent with 
the mechanism of action of the drug and generally medically manageable with topical 
and/or systemic immunosuppressants. Such immunological safety events are 
described as irAEs or immune-mediated adverse reactions (imARs). The irAEs are 
described as AEs of unknown etiology, which were consistent with an immune 
phenomenon and were considered causally related to drug exposure by investigators. 
The irAEs primarily involve the GI tract and skin. Immune-related AEs in the liver 
were also observed, particularly in subjects receiving 10 mg/kg. Endocrinopathy and 
neuropathy were important irAEs observed less frequently. The imARs were 
adjudicated in a blinded fashion based on sponsor-physician data review to exclude 
noninflammatory etiologies, such as infection or tumor progression, and to consider 
available evidence of inflammation, such as tumor biopsies or responsiveness to 
steroids, in an effort to determine whether specific AEs or abnormal hepatic 
laboratory values were likely to be immune mediated and associated with ipilimumab 
treatment. The early diagnosis of inflammatory events is important to initiate therapy 
and minimize complications. Inflammatory events are generally manageable using 
symptomatic or immuno-suppressive therapy as recommended through detailed 
diagnosis and management guidelines. The management guidelines for general irAEs 
and ipilimumab-related GI toxicities, hepatitis, endocrinopathy, and neuropathy are 
described in appropriate section. A program-wide independent Data Monitoring 
Committee (DMC) reviews data from the ipilimumab studies, allowing for an ongoing 
safety and benefit/risk assessment in subjects receiving ipilimumab. The DMC charter 
includes explicit stopping rules for some studies, allowing the DMC to recommend 


Nivolumab and azacytidine 
 
Page 23 of 99 
 
discontinuing further treatment across the ipilimumab program, if necessary. 
 
In summary, ipilimumab offers clinically meaningful and statistically significant 
survival benefit to patients with pretreated advanced melanoma (as 3 mg/kg 
monotherapy compared to the melanoma peptide vaccine gp100) and previously 
untreated advanced melanoma (at 10 mg/kg in combination with dacarbazine [DTIC] 
compared to DTIC alone), and evidence of clinical activity in randomized studies in 
other tumor types. These findings, together with evidence of a safety profile that is 
manageable with careful monitoring and appropriate intervention for treatment of 
immune-related toxicities, suggest an acceptable benefit to risk ratio.  
 
For further details please refer to the most recent version of the Ipilimumab 
Investigator Brochure attached as an Appendix.
 
2.5 5-azacytidine (Vidaza): 
 
5-azacytidine, an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and 
metabolism. Since the early 1970s, 5-azacytidine has been investigated primarily 
in the US for the treatment of acute leukemia. Clinical studies have focused 
mainly on patients with disease refractory to conventional chemotherapy. Results 
of these investigations demonstrated activity of 5-azacytidine in the treatment of 
AML. Clinical studies subsequently evaluated the effects of 5-azacytidine in a 
variety of other malignant and hematologic disorders, including solid tumors, 
hemoglobinopathies (eg, thalassemia and sickle cell anemia), and MDS. In 1984, 
the Cancer and Leukemia Group B (CALGB) began a series of clinical studies 
with 5-azacytidine in patients with MDS. These studies, in addition to other 
supportive data, led to the approval of Vidaza® (5-azacytidine) in May 2004 for 
the treatment of MDS. 
 
5-azacytidine inhibits the methylation of newly synthesized DNA by inhibiting 
DNA methyltransferase (DNMT).[28-30] Increased methylation of DNA 
(hypermethylation) may result in the silencing of critical genes responsible for 
cell growth control and differentiation. Hypermethylation of CpG islands 
spanning the promoter regions of tumor suppressor genes is commonly associated 
with cancers.[31] It is now widely recognized that hypermethylation of DNA is 
frequently associated with myelodysplastic syndromes and other cancers,[32-34] 
such as renal,[35] melanoma,[36] breast,[37] colorectal,[38] non-small cell 


Nivolumab and azacytidine 
 
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lung[39] and hematologic malignancies.[40] 5-azacytidine is believed to exert its 
antineoplastic effects through hypomethylation and cytotoxicity on abnormal 
hematopoietic cells in the bone marrow.[41-45] Hypomethylation may restore 
normal function to genes that are critical for differentiation and proliferation.[31, 
46, 47] The cytotoxic effects of 5-azacytidine cause the death of rapidly dividing 
cells, including cancer cells that are no longer responsive to normal  growth 
control mechanisms.[41, 48-50] 
 
The cytotoxicity of 5-azacytidine is proportional to dose and exposure time.[41, 
42] Although the mechanisms of cytotoxicity are complex and multifaceted, there 
is general agreement that incorporation of 5-azacytidine into DNA  and 
ribonucleic acid (RNA), and inhibition of protein synthesis, are critically 
important.[51] Cytotoxicity is greatest in cells that are proliferating (S phase) and 
metabolically active.[41] Cytotoxic effects may also be mediated through 
induction of the DNA damage response pathways.[50] Nonproliferating cells are 
relatively insensitive to 5-azacytidine.[41] 
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus 
monkeys.[52] Most of the studies were performed during the 1970s and early 
1980s according to existing guidelines and standards in place during that period. 
The preclinical studies identified the bone marrow, liver, kidneys, and lymphoid 
tissues (spleen, lymph nodes, and thymus) as the main target organs of toxicity for 
 
 
5- azacytidine.[52] In single-dose studies, the lethal dose of 5-azacytidine 
after intravenous 
(IV) 
administration 
in 
mice, 
rats, 
and 
dogs 
was 
approximately 250 mg/m2. Repeated daily dosing appears to increase the 
toxicity of 5- azacytidine.[52] The genotoxicity of 5-azacytidine is consistent 
with that of other nucleoside analogs that interact with nucleic acids.[52] 
Likewise, similar to other 
agents with cytostatic properties, 5-azacytidine was embryotoxic and reduced the 
reproductive performance in mice and rats.[52] 
 
Limited 5-azacytidine pharmacokinetic data are currently available. Based on 
human plasma concentrations of total radioactivity (which represents parent drug 
plus circulating metabolites), 5-azacytidine is rapidly absorbed when given 
subcutaneously (SC), with maximum plasma concentrations found 0.5 to 2 hours 
after dosing.[52] 5-azacytidine and/or its by-products are then rapidly cleared by 
the kidneys. The half-lives and percent radioactivity recovered in urine are similar 
following IV and SC routes of administration. The effects of renal or hepatic 
impairment, gender, age, or race on the pharmacokinetics of 5-azacytidine have 
not been studied.[52] A single dose (75 mg/m2) SC versus IV crossover study in 6 
MDS subjects[53] revealed an approximate bioavailability of 89% for the SC 
dose (range 52% to 128%) with mean half-lives of 0.69 hour and 0.36 hour after 
SC and IV administration, respectively. These results demonstrated that 5- 
azacytidine is rapidly and nearly completely absorbed after SC administration and 
that  elimination  is  also  rapid.  The  apparent  SC  clearance   (167   L/h   or 
2791 mL/min) and systemic IV clearance (147 L/h) of 5-azacytidine exceeded the 


Nivolumab and azacytidine 
 
Page 25 of 99 
 
glomerular filtration rate (approximately 125 mL/min) and total renal blood flow 
(1200 mL/min) in healthy subjects. This indicates that non-renal elimination (eg, 
metabolism, hydrolysis, and/or degradation) plays a role in the elimination of 
parent 5-azacytidine. In addition, 5-azacytidine 75 mg/m2  was generally well- 
tolerated after single SC injection or IV infusion over 10 minutes.[53] 
 
A number of studies have looked at different parenteral doses and schedules of 5- 
azacytidine, finding maximum tolerated doses of up to 500 mg/m2 when 
administered weekly.[54] 
 
During the two decades between the start of the CALGB studies and the approval 
of 5-azacytidine, a new understanding of MDS has developed, such as the World 
Health Organization (WHO) diagnostic criteria, the International Prognostic 
Scoring System (IPSS), and the International Working Group (IWG) response 
criteria. Silverman et al. reevaluated the combined data (N = 309) from 3 of the 
CALGB studies using the WHO classification system for MDS and AML and the 
IWG response criteria.[55] Using the IWG response criteria in MDS patients, 
response rates were between 40% and 70% in 5-azacytidine treated patients. Ten 
to 17% of patients achieved a complete remission; partial remission was rare; and 
23% to 36% of patients had a hematologic improvement. In patients with AML 
(N = 103), 35% to 48% had hematologic improvement or better responses. The 
median survival time for 27 patients assigned to 5-azacytidine was 19.3 months 
compared with 12.9 months for the 25 patients assigned to observation.[55]
 
A randomized international Phase III trial (Study 5-azacytidine PH GL 2003 CL 
1) 
for higher-risk MDS patients, classified by FAB as RAEB, RAEB-T, or 
CMML with 0-29% marrow blasts, with an IPSS of Intermediate -2 or High by 
central pathology/cytogenetic review was recently reported.[56] Patients were 
randomized to 5-azacytidine (75 mg/m2/day x 7days in 28 day cycles) or 
conventional care regimens (CCR), where CCR was pre-selected by the 
Investigator as best supportive care (transfusions, antibiotics, and G-CSF for 
neutropenic infection), low-dose cytarabine (20 mg/m2/day x 14 days in 28 day 
cycles); or standard chemotherapy (conventional induction/consolidation). 
Patients were stratified by FAB/IPSS and randomized 1:1 to 5-azacytidine or 
CCR. This trial did not allow erythropoietin. Three hundred fifty eight patients 
(70% male) were randomized at 79 centers to 5-azacytidine (N=179) or CCR 
(N=179): best supportive care only (N=105, 59%), low-dose cytarabine (N=49, 
27%), or standard chemotherapy (N=25, 14%). Median age was 69 years (range 
38-88 years). The 5-azacytidine and CCR groups were comparable for baseline 
patient characteristics. At baseline, 95% of patients were higher risk: RAEB 
(58%), RAEB-T/WHO AML (34%), CMML (3%), and other (5%). By IPSS, 
87% were higher risk: Intermediate -2 (40%), High (47%), and 13% 
Indeterminate/other. 5-azacytidine was administered for a median of 9 cycles; 
low-dose cytarabine for 4 cycles. Median follow-up for the survival analysis was 
21.1 months. 5-azacytidine demonstrated statistically superior overall survival 
compared to CCR, with a median overall survival of 24.4 months vs. 15 months 
for CCR (stratified log-rank p=0.0001, hazard ration 0.58). Two-year survival 
approximately doubled in the 5-azacytidine arm compared to CCR: 51% vs. 26% 


Nivolumab and azacytidine 
 
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(p<0.0001). 5-azacytidine was well tolerated with safety data consistent with 
previous reports. 
 
Further details can be found in the 5-azacytidine drug information (Appendix F), 
which contains comprehensive pharmacology, toxicology, pharmacokinetics, 
pharmacodynamics, metabolism, preclinical, and clinical efficacy and safety data 
information.[52] 
 
2.6 Venetoclax Drug Information Summary 
See the Venetoclax Prescribing Label (Appendix) for additional details on 
nonclinical and clinical studies. 
 
Bcl-2 overexpression has been implicated in maintaining the survival of AML 
cells and has been associated with resistance to chemotherapy and inferior overall 
survival (Konopleva M et al, Cancer cell 2006; 10(5): 375-88). Venetoclax 
(VEN) is a potent and selective small-molecule inhibitor of Bcl-2 that has 
demonstrated cell-killing activity against a variety of leukemia cell lines, primary 
patient samples and leukemia stem/progenitor cells (Souers AJ et al, Nat Med 
2013; 19(2): 202-8;  Pan R et al, Cancer discovery 2014; 4(3): 362-75). VEN also 
has been found to synergize with agents known to down-regulate Mcl-1, including 
azacitidine (Tsao T et al, Ann Hematol 2012; 91(12): 1861-70). 
 
Based on the mechanism of action and nonclinical and clinical data available to 
date, the safety profile of venetoclax is well described.  The most common 
adverse drug reactions across all indications are nausea, diarrhea, hematological 
effects, and serious and/or opportunistic infections.  Hematologic effects include 
neutropenia/febrile neutropenia, thrombocytopenia, anemia, and lymphopenia.  
Upper respiratory tract infections are among the most common infections.  TLS is 
an important identified risk and is predominantly seen in the CLL population with 
high tumor burden.  Based on pre-clinical data, decreased spermatogenesis has 
been identified as a potential risk for venetoclax. 
 
Summary of Venetoclax Nonclinical Pharmacology 
Venetoclax is a potent, selective and orally bioavailable small molecule inhibitor 
of Bcl-2 that binds with > 1,000-fold higher affinity for Bcl-2 (dissociation 
constant [Ki] < 0.010 nM) than for Bcl-XL (Ki - 48 nM or Mcl-1 (Ki > 444 nM) 
(Souers AJ et al, Nat Med 2013; 19(2): 202-8). In vitro, venetoclax has 
demonstrated cell killing activity against patient-derived chronic lymphocytic 
leukemia (CLL) cells and a variety of lymphoma and leukemia cell lines (Souers 
AJ et al, Nat Med 2013; 19(2): 202-8). Venetoclax has demonstrated potent 
killing of AML cell lines, primary patient samples, and leukemic stem/progenitor 
cells ex vivo, and has also exhibited anti-tumor efficacy in vivo, inhibiting the 
growth of AML cells systemically engrafted into immunocompromised mice. 
 
Summary of Venetoclax Nonclinical Pharmacokinetics 
The pharmacokinetics of venetoclax was evaluated in mice, rats, monkeys, and 
dogs.  Venetoclax pharmacokinetic (PK) profile was characterized by low plasma 
clearance and low to moderate volumes of distribution.  Half-lives ranged from 


Nivolumab and azacytidine 
 
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2.2 hours in monkeys to 12 hours in dogs.   
 
Venetoclax demonstrated high protein binding to human, rat, dog, and monkey 
plasma proteins ( 99.9%).  Blood to plasma ratios showed that venetoclax does 
not partition preferentially into the red blood cells.  Following oral administration 
of venetoclax to nonclinical species and humans, parent compound and 
metabolites were mainly cleared via biliary excretion and fecal elimination, with 
minimal renal clearance. 
 
Venetoclax is predominantly metabolized by cytochrome P450 (CYP) 3A4 
(CYP3A4) in vitro; UDP-glucuronosyltransferases (UGTs) are not involved in the 
metabolism of venetoclax.  In addition, venetoclax is also a substrate for P-gp and 
BCRP. Active uptake of venetoclax was not observed in cells overexpressing 
OATP1B1, OATP1B3 or OCT1.  In vitro studies indicated that venetoclax is not 
an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 
at clinically relevant concentrations. Venetoclax is a weak inhibitor of CYP2C8, 
CYP2C9, and UGT1A1 in vitro, but it is not predicted to cause clinically relevant 
inhibition due to high plasma protein binding.  Venetoclax is a P-gp and BCRP 
inhibitor and weak OATP1B1 inhibitor in vitro.  In vitro, venetoclax is 
metabolized by CYP3A4 and is a moderate inhibitor of CYP2C8.  Definitive in 
vitro experiments showed that venetoclax is not predicted to be an inducer or 
inhibitor of the metabolism of CYP2C9 substrate compounds.  Venetoclax is not a 
reversible inhibitor of CYP1A2, CYP2B6, CYP2D6, CYP2C19 or CYP3A4 (IC50 
 30 µM) in vitro and does not induce CYP3A4 or CYP1A2 at concentrations up 
to 10 M.  
 
Summary of Nonclinical Toxicology 
Venetoclax has been assessed in repeated-dose general toxicology studies and in 
genetic, developmental/reproductive, and safety pharmacology studies.  The 
primary toxicities associated with venetoclax administration included effects on 
the hematologic system (decreased lymphocytes and erythrocytes) in mice and 
dogs, the male dog reproductive system (testicular germ cell depletion), and 
embryo-fetal toxicity in mice. 
 
Summary of Venetoclax Clinical Data 
Clinical Efficacy Data for Venetoclax: Preliminary efficacy results are available 
for subjects with a variety of hematological neoplasms; the drug is approved for 
the treatment of CLL patients whose cells have a 17p chromosomal deletion. 
Preliminary data indicate that venetoclax shows promising efficacy in AML. 
 In Study M14-212 the CR/CRi rate for subjects treated with venetoclax 
monotherapy was 19% (Konopleva M et al, Cancer discovery 2016; 6(10): 
1106-17). 
 In Study M14-358 the CR/CRi rate for AML subjects (given venetoclax 
plus azacitidine or decitabine) was 66% (DiNardo CD et al, Blood. 2019 
Jan 3;133(1):7-17). 
 In Study M14-387 the CR/CRi rate for AML subjects (given venetoclax 
plus low dose ara-C) was 54% (Wei A et al J Clin Oncol. 2019 May 


Nivolumab and azacytidine 
 
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20;37(15):1277-1284). 
 
Venetoclax Clinical Pharmacology and Pharmacokinetics: Venetoclax clinical 
pharmacology is being evaluated in several Phase I to III clinical trials, and data 
are available from three Phase I studies (M12-175, M13-367, M12-630), four 
Phase Ib studies (M13-365, M12-901, GO29440, GP28331), one Phase II study 
(M14-212) and five dedicated clinical pharmacology studies (Study M13-364, 
M14-497, M13-363, M14-253 and M15-101). 
 
In the Phase 1 Study M14-358, preliminary pharmacokinetic results in 31 
treatment-naïve AML subjects were available for venetoclax doses ranging from 
400 mg to 800 mg when given in combination with decitabine (Arm A) or 
azacitidine (Arm B) and with or without posaconazole (Arm C). For Arm A and 
Arm B, venetoclax steady-state mean Cmax and AUC24 (Cycle 2 Day 5) ranged 
from 1.77 – 3.36 μg/mL and 24.7 – 59.5 μg/mL, respectively. Based on the 
limited preliminary pharmacokinetic data, there was no evidence to suggest a 
marked effect of the co-administration of decitabine and azacitidine on the 
pharmacokinetics of venetoclax. In Arm C of this study, preliminary 
pharmacokinetic results from 6 subjects were available on Cycle 1 Day 20 
(venetoclax 400 mg alone QD until Day 20) and Cycle 1 Day 28 (venetoclax 100 
mg QD with posaconazole given from Day 21 to Day 28). Venetoclax Cmax and 
AUC following co-administration of venetoclax 100 mg with posaconazole were 
2.1- and 2.7-fold higher respectively, compared to venetoclax 400 mg alone. 
 
Preliminary pharmacokinetic results of venetoclax are available from 12 
treatment-naïve subjects with AML in Cohorts 1 (600 mg) and 2 (800 mg) from 
the ongoing Phase 1 combination study of venetoclax and low dose cytarabine 
(Study M14-387). On Cycle 1 Day 10 (with cytarabine), venetoclax mean Cmax 
and AUC24 values ranged from 2.25 – 2.56 μg/mL and 34.7 – 44.6 μg•hr/mL, 
respectively. On Cycle 1 Day 18 (venetoclax alone), mean Cmax and AUC values 
of venetoclax ranged from 2.38 – 2.89 μg/mL and 37.9 – 45.3 μg•hr /mL. Dose-
normalized Cmax and AUC24 of venetoclax on Cycle 1 Day 10 (with cytarabine) 
were comparable to dose normalized Cmax and AUC24 on Cycle 1 Day 18 
(venetoclax alone), suggesting that co-administration of cytarabine did not 
markedly affect venetoclax exposures. 
 
Clinical Safety Data for Venetoclax: As of 05 June 2017, three Phase 1/2 
studies have been conducted in the AML indication as described below. 
 
Overview of Phase 2 Study M14-212: Venetoclax Monotherapy in AML 
This is a completed study with single agent venetoclax in subjects with R/R AML 
and those unfit for intensive therapy.  A total of 32 subjects were dosed.  
Exposure, safety, and efficacy data are available for this study. The most common 
adverse events observed in ≥ 30% of the subjects in Study M14-212 were nausea 
(59.4%); diarrhea (56.3%); hypokalemia, vomiting (40.6% each); fatigue, 
headache (34.4% each); hypomagnesemia (37.5%); febrile neutropenia (31.3%); 
abdominal 
pain, 
cough, 
hypophosphatemia 
(28.1% 
each); 
epistaxis, 
hyperphosphatemia, hypocalcemia, malignant neoplasm progression (25.0% 


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each); dyspnea, hypotension, peripheral edema, pyrexia, and pneumonia (21.9% 
each).  Serious adverse events were reported in 27 subjects (84.4%), the most 
common being febrile neutropenia (28.1%), malignant neoplasm progression 
(25.0%), and pneumonia (15.6%).  Three serious adverse events were considered 
to have a reasonable possibility of being related to venetoclax (i.e., 1 event each 
of diarrhea, febrile neutropenia, and pseudomonal bacteremia).  No cases of TLS 
occurred during venetoclax treatment. 
 
In this phase II multicenter trial single agent VEN produced an overall response in 
5/32 relapsed/refractory AML patients (CR in 1 patient, CRi in 4 patients) 102. Of 
the 5 patients with CR/CRi, 3 had IDH mutations suggesting that patients with 
IDH mutations may be particularly sensitive to VEN. 
 
Two ongoing trials are evaluating VEN combination regimens in treatment naïve 
patients with AML who are ≥65 years of age and who are not eligible for standard 
induction: (a) to evaluate the efficacy and tolerability of the combination of VEN 
with a methyltransferase inhibitor (azacytidine or decitabine) (ClinicalTrials.gov 
Identifier: NCT02203773); (b) to evaluate VEN with low-dose cytarabine 
(ClinicalTrials.gov Identifier: NCT02287233).  
 
Overview of Ongoing Phase 1b Study (M14-358): Venetoclax in Combination 
with HMA in Treatment Naïve AML 
As of 09 March 2016, a total of 45 subjects ≥ 65 years of age with treatment naïve 
AML ineligible to receive standard induction therapy were enrolled into the 
escalation stage at 3 dose levels of venetoclax at 400 mg, 800 mg, and 1200 mg. 
Venetoclax was administered daily during the 28-day cycles in combination with 
decitabine (20 mg/m2 intravenously on Days 1 – 5 once every 28 days) or 
azacitidine (75 mg/m2 intravenously or subcutaneously on Days 1 – 7 once every 
28 days). Preliminary safety and efficacy data are available from the ongoing dose 
escalation stage of this trial. 
 
The most common adverse events for all subjects in Study M14-358 were nausea 
(53.3%), diarrhea (44.4%), febrile neutropenia (40.0%), neutrophil count 
decreased (31.1%), platelet count decreased, cough, and fatigue (28.9% each), 
edema peripheral and hypokalemia (26.7% each). Events grade 3 and above were 
reported for the majority (91.1%) of subjects; the most common event was febrile 
neutropenia (40.0%). Serious adverse events were reported for 27 (60.0%) 
subjects, including febrile neutropenia (11 subjects), malignant neoplasm 
progression (3 subjects) atrial fibrillation, abdominal pain, non-cardiac chest pain, 
pyrexia, pneumonia, sepsis, bone pain (2 subjects each). All other events occurred 
in 1 subject each. The combination of venetoclax with decitabine and azacitidine 
demonstrates a tolerable safety profile.  
 
As of 09 March 2016, the ORR, as assessed by the investigators for the subjects 
enrolled into the 3 dose levels, was 62.2% (28 of 45), with CR in 12 (26.7%), CRi 
in 15 (33.3%), and PR in 1 (2.2%). Four subjects (8.9%) were reported to have 
morphologic leukemia-free state (less than 5% blasts in bone marrow aspirate 
sample with at least 200 nucleated cells) after completion of Cycle 1. Eight 


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patients (17.8%) had resistant disease. However, all of the patients with resistant 
disease had evidence of blast reduction at completion of Cycle 1. The patients 
enrolled into the 1200 mg dose level had a shorter follow-up at the time of this 
analysis.  
 
The maximum tolerated dose has not been reached in either arm and dose 
escalation stage has completed enrollment. Enrollment into safety expansion at 
400 mg and 800 mg dose of venetoclax in combination with both HMAs is 
ongoing. 
 
Study M14-387: Study M14-387 titled, "A Phase 1/2 study of venetoclax in 
combination with low-dose cytarabine in treatment naïve subjects with acute 
myeloid leukemia who are ≥ 65 years of age and who are not eligible for standard 
anthracycline-based induction therapy," is an ongoing, open-label, multicenter 
safety and pharmacokinetics study. The primary objectives of the Phase 1 portion 
are to assess the safety profile, characterize pharmacokinetics, and determine the 
dose schedule, the MTD, and the RPTD of venetoclax in combination with low-
dose cytarabine (LCD) in treatment-naïve AML subjects. The primary objectives 
of the Phase 2 portion of the study are to evaluate preliminary estimates of 
efficacy (including ORR and TTP) and to characterize the toxicities of the 
combination at RPTD. Secondary objectives of the Phase 2 portion include 
evaluating leukemia response (rates of CR, CRi, PR, RD, and HR including 
transfusion support needs) and DOR. An additional exploratory objective includes 
the evaluation of biomarkers that may serve as surrogate or predictors for clinical 
outcomes for future studies. 
Of the 25 subjects in Study M14-387, 24 (96.0%) experienced at least 1 
treatment-emergent adverse event. The most common adverse events for all 
subjects in Study M14-387 were: nausea (54%), febrile neutropenia (41%), 
diarrhea (44%), decreased appetite (33%), and peripheral edema (31%). Adverse 
events leading to study drug discontinuation occurred in 4 (16.0%) subjects, 
including 1 event each of disease progression, acute hepatic failure, Candida 
pneumonia, and subdural hemorrhage. Fatal adverse events occurred in 5 (20.0%) 
subjects: 2 events of malignant neoplasm progression and 1 event each of acute 
hepatic failure, Candida pneumonia, and lung infection.  
 
For further details of venetoclax preclinical studies, clinical studies, toxicities, 
pharmacokinetics, adverse events and references please see the venetoclax 
Prescribing Label (Appendix). 
 
 
 
2.6 Rationale for study: 
Arm 1 and 2: Rationale for azacitidine with nivolumab and azacitidine with 
nivolumab and ipilimumab: 
The PD-1/PD-L1 pathway plays a major role in immune evasion and cytotoxic T- 
cell exhaustion in AML[17, 20, 21]. PD-L1 expression in AML samples is 
increased at the time of disease progression or after exposure to IFN-gamma[20, 
57]. Overexpression of PD-L1 is an independent negative prognostic factor in 


Nivolumab and azacytidine 
 
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AML[20]. Hypomethylating agents may alter immune regulation[58]. Yang et al 
have recently demonstrated that hypomethylating therapy leads to up regulation of 
PD-L1, PD-1, and PD-L2 gene expression[19]. Patients resistant to 
hypomethylating therapy had higher increments in gene expression suggesting 
that PD-1 up regulation may promote resistance to hypomethylating agents. 
Demethylation of the PD-L1 gene by chronic viral infection results in PD-L1 up- 
regulation and CTL exhaustion[59]. Similarly, exposure to decitabine up regulates 
PD-L1, PD-1 and PD-L2 by demethylation of the PD-L1 locus[19]. These data
suggest that blockage of PD-1 by nivolumab may improve response and abrogate 
resistance to hypomethylating agents. The data with the vidaza+nivo 
combination are encouraging as outlined in detail in section 2.3.4 with a higher 
response rate and improved median overall survival as compared to historical 
outcomes with azacytidine or decitabine based prior salvage clinical trials 
performed at MDACC (Daver N, Sharma P et al., ASH 2016, Abst #763), 
however there is much room for improvement in the response rate and OS. 
Immune mediated toxicities occur but are being managed with improved 
awareness and early intervention with steroids and only 2 of 53 patients have 
come off therapy due to immune mediated organ toxicity. Furthermore, all 15 
patients who had an immune mediated grade 2-4 toxicities could continue 
therapy with nivolumab without recurrence of the IO-toxicity except in one 
case. The vidaza+nivo is being evaluated in the frontline older (>65 year) 
patients with AML as well and we have treated 5 patients with no major 
immune mediated G3/4 toxicities observed. The frontline patients are early for 
evaluation of response (none have completed > 3 cycles).  
 
Evaluation of multiple costim receptors from BM aspirates and peripheral blood 
in patients at baseline and every 4-8 weeks on trial by 17-color flow-cytometry 
in collaboration with the Immunotherapy Platform (Dr James Allison) at 
MDACC revealed that the CTLA4 on CD8+, T-eff and to a lesser extent on T-
reg went up in non-responders after 2 cycles of vidaza+nivolumab suggesting 
up-regulation of this inhibitory checkpoint as a potential mechanism of 
resistance. This suggests that simultaneous blockade of the PD1 and CTLA4 
may improve the response rate as has been seen in solid tumors. Based on this 
we propose to evaluate a combination of nivolumab with ipilimumab and vidaza 
in the first and second salvage and as a frontline approach in older AML 
patients >/=65 years not candidates for cytotoxic induction therapy. 
 
Arm 3: Rationale for nivolumab in combination with azacitidine and 
venetoclax: 
Bcl-2 overexpression has been implicated in maintaining the survival of AML 
cells and has been associated with resistance to chemotherapy and inferior 
overall survival as initially shown by our group (Konopleva et al, Cancer cell 
2006; 10(5): 375-88.). Venetoclax (formerly ABT-199) is a potent and selective 
small-molecule inhibitor of Bcl-2 that has demonstrated cell-killing activity 
against a variety of leukemia cell lines, primary patient samples and leukemia 
stem/progenitor cells (Souers A et al Nat Med 2013; 19(2): 202-8;  Pan R et al 


Nivolumab and azacytidine 
 
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Cancer discovery 2014; 4(3): 362-75). Venetoclax also has been found to 
synergize with agents known to down-regulate Mcl-1, including azacitidine 
(Ann Hematol 2012; 91(12): 1861-70). 
 
Studies have evaluated venetoclax in combination with low-intensity therapy in 
older adults with newly diagnosed AML deemed unfit for intensive 
chemotherapy. This is a population of patients in whom standard therapy over 
the last 10-15 years has comprised of either an HMA (e.g. azacitidine or 
decitabine) or low dose cytarabine (LDAC), with published CR/CRi rates of 15-
28% and median OS of 6-10 months with HMA, and CR/CRi rates of 10-15% 
and median OS of 5-7 months with LDAC (Kantarjian H et al JCO 2012; 
Dombret H et al, Blood 2015). An ongoing phase Ib study has reporting 
promising safety and efficacy of venetoclax in combination with either 
azacitidine or decitabine in patients ≥65 years of age with previously untreated 
AML and who are ineligible for chemotherapy (DiNardo CD et al, Blood. 2019 
Jan 3;133(1):7-17). At the most recent update (Pollyea D et al ASH 2018 Oral 
presentation Abstract #285: full PowerPoint attached as Appendix), 145 patients 
were treated with a median age of 74 years (range, 65-86 years). The 30-day 
and 60-day mortality rates were 3% and 8%, respectively.  Tumor lysis 
syndrome was not observed. The CR/CRi rate for the entire cohort was 66% 
with a median duration of CR/CRi of 11.0 months. The median overall survival 
for the entire cohort was 17.5 months. Emerging clinical and exposure response 
data have suggested that the 400mg dose of venetoclax has the best risk-benefit 
profile. Based on these exciting results in this historically difficult-to-treat 
patient population, in November 2018 the US FDA approved venetoclax in 
combination with either low-dose cytarabine, azacitidine or decitabine for 
patients with newly diagnosed AML who are ≥75 years of age or have 
comorbidities that preclude the use of standard intensive chemotherapy.  
 
Confirmatory phase III trials of azacitidine with or without venetoclax (VIALE 
A), and low-dose cytarabine with or without venetoclax (VIALE C) have 
completed enrollment and results are eagerly anticipated.  
 
Despite the encouraging results observed with venetoclax-based regimens in 
frontline older AML not suitable for induction therapy, relapses are still 
common, and it is becoming clear that these regimens are unlikely to be curative 
in the vast majority of these patients. The median CR/CRi durations in this 
population are </= 11 months and 2-3 year OS is approximately 45% suggesting 
there is room for significant improvement by further improving the durability of 
CR/CRi’s and thereby improving median OS. The long-term outcomes of 
patients with poor-risk disease features remain poor even among frontline older 
patients. Among frontline poor-risk elderly unfit patients treated with HMA 
with venetoclax (defined as patients with TP53 and adverse cytogenetics) 
evaluated in both the MDACC internal data set (Shoukier M et al, Journal of 
Clinical Oncology 37, no. 15_suppl (May 20, 2019) 7034-7034) and in the 
multicenter phase Ib/II trial of HMA with venetoclax (DiNardo CD et al, Blood. 


Nivolumab and azacytidine 
 
Page 33 of 99 
 
2019 Jan 3;133(1):7-17) the CR/CRi rates were significantly lower at 45-47%, 
median response durations were <6 months, median OS was only 6-9 months, 
and only 14% of these frontline patients achieving CR/CRi became MRD-
negative. 
 
Similarly, among R/R AML the efficacy of HMA with venetoclax are dismal 
with multiple datasets showing CR/CRp/CRi rates of 20-40% with CR durations 
<6 months and median OS 4-7 months (DiNardo CD et al, American journal of 
hematology 2018; 93(3): 401-7;  Aldoss I et al, Haematologica. 2018 
Sep;103(9):e404-e40;  Goldberg A et al, Blood 2017; 130(Suppl 1): 1353), 
suggesting that there is scope for significant improvement by rational addition 
of therapies that could further improve response rates and DOR in these 
patients.  
 
Preclinical Rationale for this combination:  
In a series of human in vitro and in vivo syngeneic tumor model studies, 
venetoclax does not appear to antagonize anti-PD-1 therapy with nivolumab 
(Mathew R et al. Blood 2018 132: 3704). Venetoclax was shown to decrease 
naïve T-cells and B-cells but not central and effector memory T cells (these 
being critical to anti-tumor immunity) in in vitro studies of human lymphocytes. 
In a mixed lymphocyte reaction assay, venetoclax did not affect IFN-gamma 
secretion from CD3/CD28 stimulated T-cells either by itself or when co-treated 
with the checkpoint inhibitor nivolumab. Similar findings were observed in a 
cytomegalovirus recall assay, suggesting that venetoclax does not impair 
immune response to infections. In an in vivo experiment with the murine 
syngeneic tumor model MC38, venetoclax did not impair the efficacy of anti-
PD-1 therapy with nivolumab, and in some solid tumor syngeneic models, in 
fact increased efficacy was noted with the combination compared to either 
venetoclax or nivolumab monotherapy. These findings suggest that venetoclax 
does not impair anti-PD-1 anti-tumor therapy and may synergize with immune 
checkpoint therapy through its favorable modulation of the T-cell profile. 
Lasater et al demonstrated that significant venetoclax-induced cell death at 
clinically relevant drug concentrations is limited to the B-cell subset and that 
BCL-2 inhibition is not detrimental to survival or activation of NK- or T-cell 
subsets (Lasater E et al, Blood 2018 132:1118). Both posters highlighting the 
potential for preclinical synergy between venetoclax and immune checkpoint 
inhibitors (specifically PD1 antibodies) are attached as Appendix. 
 
We have developed a great deal of expertise with venetoclax and developed and 
published optimized dosing schedules, assessment time-points, safety 
monitoring, and biomarker assays. Additionally, with >150 frontline elderly 
HMA with venetoclax treated patients at MDACC we have developed robust 
internal controls for expected outcomes with HMA with VEN based therapies in 
older AML in each cytogenetic and molecular subset of AML to allow for rapid 
comparison with emerging HMA and VEN triplets in this space to quickly 
decide on "go" or "no go" signals. We have also led the development of T-cell 


Nivolumab and azacytidine 
 
Page 34 of 99 
 
immune checkpoint therapies in AML and believe this combination triplet of 
HMA with venetoclax with PD1 inhibitor could be very important.  
 
Furthermore, myelosuppression is not a major issue with nivolumab. The lack 
of significant neutropenia and thrombocytopenia with nivolumab suggest that 
the combination of AZA+VEN with nivolumab may not result in severe and/or 
prolonged cumulative neutropenia/thrombocytopenia, and thereby be more 
feasible than a number of other ongoing doublet/triplet combinations of other 
AML drugs with venetoclax that often incorporate two myelosuppressive agents 
and encounter problems due to cumulative myelosuppression. This may be an 
added tolerability benefit for this combination. 
 
 
 
3.1 
STUDY DESIGN 
 
 
This will be a phase II, open-label, non-randomized study with a safety 
lead-in phase. 
 
 
Patients will receive 5-azacytidine subcutaneously or intravenously daily for 7 
days of each treatment cycle. For the lead-in portion, the length of the cycle will 
be at least 28 days to evaluate DLT. Subsequently, cycles will be repeated 
approximately every 28 days (+/-7 days), and therapy will be continued until 
clinically significant disease progression or documentation of unacceptable 
toxicity. 
 
 
 
Arm 1 (Vidaza+Nivolumab): Patients will receive therapy with nivolumab IV 
infusion on Day 1 and day 14 (+/-3 days) of each 5-azacyidine cycle for first 4 
cycles or until CR (whichever occurs earlier) followed by a maintenance 
regimen (one dose of nivolumab on day 1 of each cycle of 5-azacytdine). 
Patients who have evidence of budding relapse or seem to have clinical benefit 
may continue or revert back to receiving nivolumab on Day 1 and day 14 (+/-3 
days) of each cycle of 5-azacytidine. Patients may receive nivolumab more or 
less frequently during the maintenance regimen at the discretion of the treating 
physician only after discussion with the PI.  
Arm 1 includes a salvage cohort and a frontline AML >/= 65 years age cohort. 
The salvage cohort of vidaza+nivolumab has completed accrual of 70 patients 
as of 12/15/16 and will not enroll any more patients at this time. The frontline 
cohort of vidaza+nivolumab has enrolled 5 patients as of 12/15/16 and will 
continue to enroll frontline older AML (>65 years) patients. 
 
 
Arm 2: Patients will receive therapy with nivolumab IV infusion on Day 1 
and day 14 (+/-3 days) of each 5-azacyidine cycle for first 4 cycles or until CR 
(whichever occurs earlier) followed by a maintenance regimen (one dose of 
nivolumab on day 1 of each cycle of 5-azacytdine). Patients who have 
evidence of budding relapse or seem to have clinical benefit may continue or 
revert back to receiving nivolumab on Day 1 and day 14 (+/-3 days) of each 
cycle of 5-azacytidine. Patients may receive nivolumab more or less frequently 


Nivolumab and azacytidine 
 
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during the maintenance regimen at the discretion of the treating physician only 
after discussion with the PI. Patients will receive Ipilimumab starting on day 1 
and every 6 (or 12) weeks (+/-3 days) there after. The plan is to give a total of 
4 doses of the ipilimumab at 6 (or 12) week intervals and then stop therapy. 
Patients who have evidence of budding relapse or seem to have clinical benefit 
may continue the ipilimumab every 6 (or 12) weeks.  
Arm 2 includes a salvage cohort and a frontline AML >/= 65 years age cohort. 
The salvage cohort of vidaza+nivolumab+ipilimumab will have 66 slots and 
will the priority protocol in salvage setting as the vidaza+nivolumab has 
already completed enrollment of 70 patients and has no additional slots. The 
frontline cohort of vidaza+nivolumab+ipilimumab and vidaza+nivolumab will 
be open simultaneously and we will enroll alternately to these two frontline 
protocols with close monitoring for futility and toxicity as specified in the 
predefined statistical efficacy and futility stopping rules in Statistics Section 
11.0. This will allow us to closely assess differences in efficacy and toxicity 
among these two protocols in a similar patient population. 
 
 
Arm 3 (Vidaza + Nivolumab + Venetoclax): Patients will receive therapy 
with nivolumab IV infusion on Day 8 and Day 22 (+/-3 days) of each 5-
azacyidine cycle for first 4 cycles or until CR (whichever occurs earlier) 
followed by a maintenance regimen (one dose of nivolumab on Day 8 of each 
cycle of 5-azacytdine). Patients who have evidence of budding relapse or seem 
to have clinical benefit may continue or revert back to receiving nivolumab on 
Day 8 and day 22 (+/-3 days) of each cycle of 5-azacytidine. Patients may 
receive nivolumab more or less frequently during the maintenance regimen at 
the discretion of the treating physician only after discussion with the PI. 
Venetoclax will be administered orally daily on Days 1-21 of the first cycle; 
and Days 1-14 or Days 1-21 for subsequent cycles based on response achieved 
and degree of myelosuppression as described later in the protocol.  
 
Arm 3 includes a part a lead-in phase (n=6-18) followed by part b expansion 
in two cohorts: a salvage cohort (n=30) and a frontline cohort AML >/= 65 
year age cohort (n=30) (see inclusion 4.2.1 for detailed eligibility to these 
cohorts).  
 
During the lead-in phase (part a), see Table 5C below, only R/R AML patients 
will be enrolled. Once the lead in phase (part a) is completed and 
recommended phase 2 dose established the part b will open with both salvage 
and frontline cohorts.  
 
4.1 
PATIENT SELECTION 
 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion and exclusion criteria. Results of all baseline evaluations, 
which assure that all inclusion and exclusion criteria have been satisfied, must be 
reviewed by the Principal Investigator or his/her designee prior to enrollment of that 
patient. In addition, the patient must be thoroughly informed about all aspects of the 


Nivolumab and azacytidine 
 
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study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained from 
the patient prior to initiating treatment or any study-specific procedures. The following 
criteria apply to all patients enrolled onto the study unless otherwise specified. 
 
4.2 
Inclusion Criteria 
 
4.2.1 
A. Arm 1 Salvage cohort: Patients with AML or biphenotypic or 
bilineage leukemia who have failed prior therapy. Patients with AML 
should have failed prior therapy or have relapsed after prior therapy will be 
eligible for Arm 1. 
 
B. Arm 2 and 3 Salvage cohorts: Patients with AML who have failed up 
to two prior therapeutic regimens (i.e. salvage 1 or 2 status) will be 
eligible for Arm 2 relapse cohort. Allogeneic stem cell transplant for 
patients in remission at the time of stem cell transplant will not be 
considered a salvage regimen. Similarly, hydroxyurea if used alone will 
not be considered a salvage regimen.  
During the lead-in phase (part a) of Arm 3, see Table 5C below, only R/R 
AML patients who meet the “Salvage cohorts” criteria will be enrolled. 
 
C. Arm 1, 2 and 3 Frontline cohorts: Not considered candidates for 
intensive remission induction chemotherapy at time of enrollment based 
on EITHER: 
A. ≥75 years of age OR 
 
B. <75 years of age with at least 1 of the following: 
-Poor performance status (ECOG) score of 2-3. 
-Clinically significant heart or lung comorbidities, as reflected by at least 1 
of: 
a. Left ventricular ejection fraction (LVEF) ≤50%. 
b. Lung diffusing capacity for carbon monoxide (DLCO) ≤65% of 
expected. 
c. Forced expiratory volume in 1 second (FEV1) ≤65% of expected. 
d. Chronic stable angina or congestive heart failure controlled with 
medication. 
-Liver transaminases >3 × upper limit of normal (ULN). 
-Other contraindication(s) to anthracycline therapy (must be documented). 
-Other comorbidity the investigator judges incompatible with intensive 
remission induction chemotherapy, which must be documented and 
approved by the PI. 
Patients with newly diagnosed AML with poor risk karyotype or complex 
karyotype and/or TP53 deletions/mutations equal or younger than 60 year 
old will be eligible for the Frontline cohort as well. 
 
4.2.2 Patients with MDS or CMML who received therapy for the MDS or 
CMML and progress to AML are eligible at the time of diagnosis of AML 
regardless any prior therapy for MDS or CMML. The WHO 


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Page 37 of 99 
 
classification will be used for AML. Prior therapy for MDS or CMML 
will not be considered as a prior therapy for AML, hence such patients 
will be considered as frontline AML and eligible for the frontline elderly 
cohort. 
 
4.2.3 Prior therapy with hydroxyurea, chemotherapy, biological or targeted 
therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic 
growth factors is allowed as long as within restrictions outlined in 
inclusion 4.2.1 
 
4.2.4 Age >/=18 years 
 
4.2.5 White blood cell count <20 x 109/L  
 
4.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Status </=2 
 
4.2.7 Adequate organ function: total bilirubin </= 2 times upper limit of normal 
(x ULN) (</= 3 x ULN if considered to be due to leukemic involvement or 
Gilbert’s      syndrome);      aspartate      aminotransferase      or      alanine 
 
 
aminotransferase </= 2.5 x ULN (</= 5.0 x ULN if considered to be due to 
leukemic involvement); serum creatinine </= 2 x ULN or GFR>/=50 
 
4.2.8 Patients must provide written informed consent 
 
4.2.9 In the absence of rapidly progressing disease, the interval from prior 
treatment to time of initiation of protocol therapy will be at least 2 
weeks OR at least 5 half-lives for cytotoxic/noncytotoxic agents. The 
half-life for the therapy in question will be based on published 
pharmacokinetic literature (abstracts, manuscripts, investigator brochure’s, 
or drug-administration manuals) and will be documented in the protocol 
eligibility document. Since the effect of immune checkpoint therapy and 
hypomethylating agents may be delayed, use of one dose of cytarabine 
(up to 2 g/m2) or hydroxyurea  for  patients  with  rapidly  proliferative  
disease  is  allowed before the start of study therapy and during the 
study 
treatment. Concurrent 
therapy 
for 
CNS 
prophylaxis 
or 
continuation of therapy for controlled CNS disease is permitted 
 
4.2.10 Females must be surgically or biologically sterile or postmenopausal 
(amenorrheic for at least 12 months) or if of childbearing potential, must 
have a negative serum or urine pregnancy test within 72 hours before the 
start of the treatment 
 
4.2.11 Women of childbearing potential must agree to use an adequate method of 
contraception during the study and until 3 months after the last treatment. 
Males must be surgically or biologically sterile or agree to use an adequate 
method of contraception during the study until 3 months after the last 


Nivolumab and azacytidine 
 
Page 38 of 99 
 
treatment. 
 
Adequate methods of contraception include: 
 
Total abstinence when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
 
Female sterilization (have had surgical bilateral oophorectomy 
with or without hysterectomy) or tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up 
hormone level assessment 
 
Male sterilization (at least 6 months prior to screening). For female 
patients on the study, the vasectomized male partner should be the sole 
partner for that patient 
 
Combination of any of the two following (a+b or a+c or b+c) 
a. 
Use of oral, injected or implanted hormonal methods of 
contraception  or  other  forms  of  hormonal  contraception  that  have 
 
 
comparable efficacy (failure rate <1%), for example hormone vaginal ring 
or transdermal hormone contraception 
b. 
Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
c. 
Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ 
vaginal suppository 
 
In case of use of oral contraception, women should have been stable 
on the same pill before taking study treatment. 
 
Note: Oral contraceptives are allowed but should be used in conjunction 
with a barrier method of contraception due to unknown effect of drug-drug 
interaction. 
 
Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
 
4.2.11 Patients with GVHD active < grade 2 who are on a stable dose of 
immunosuppressive therapy (tacrolimus, cyclosporine, or other) for > 2 
weeks will be included. Note: Subjects may be using systemic 
corticosteroids or topical or inhaled corticosteroids. 
 


Nivolumab and azacytidine 
 
Page 39 of 99 
 
 
 
4.3  
Exclusion Criteria 
 
4.3.1 
Patients with known allergy or hypersensitivity to nivolumab, 
ipilimumab, 5- azacytidine, venetoclax or any of their 
components. 
 
4.3.2 
Patients with a known history of severe interstitial lung disease or severe 
pneumonitis or active pneumonitis that is uncontrolled in the opinion of the treating 
physician. 
 
4.3.3 
Patients who have previously been treated with nivolumab and/or 
ipilimumab in combination with 5-azacytidine will be excluded. 
 
4.3.4 
Patients with a known history of any of the following autoimmune 
diseases are excluded: (a) patients with a history of inflammatory bowel 
disease (including Crohn’s disease and ulcerative colitis) (b) patients with 
a history of rheumatoid arthritis, systemic progressive sclerosis 
[scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis 
[e.g., Wegener’s Granulomatosis]). 
 
4.3.5 
Patients with organ allografts (such as renal transplant) are excluded
 
4.3.6 
Patients with active GVHD > grade 1 will be excluded. Patients with 
recent increase in the immunosuppressive medication dose within last 2 
weeks to control GVHD will not be included. Patients with grade 1 or 
lower GVHD on </= 10 mg prednisone without any additional 
immunosuppressive therapies (tacrolimus, prograf, etc) will be eligible.  
 
4.3.7 
Patients with symptomatic CNS leukemia or patients with poorly 
controlled CNS leukemia. 
 
4.3.8 
Subjects may be receiving systemic corticosteroids (daily doses ≤10 mg 
of prednisone or equivalent if indicated for adrenal replacement or 
antiemetic therapy), topical, or inhaled corticosteroids at study 
enrollment. Patients receiving prednisone >10mg of prednisone or 
equivalent will not be eligible.  
 
4.3.9 
Active and uncontrolled disease/(active uncontrolled infection, 
uncontrolled hypertension despite adequate medical therapy, active and 
uncontrolled congestive heart failure NYHA class III/IV, clinically 
significant and uncontrolled arrhythmia) as judged by the treating 
physician. 
 
4.3.10 Patients with known Human Immunodeficiency Virus seropositivity will 
be excluded. 
 
4.3.11 Known  to  be  positive  for  hepatitis  B  by  surface  antigen  expression. 


Nivolumab and azacytidine 
 
Page 40 of 99 
 
Known to have active hepatitis C infection (positive by polymerase chain 
reaction or on antiviral therapy for hepatitis C within the last 6 months) 
 
4.3.12 Any other medical, psychological, or social condition that may interfere 
with study participation or compliance, or compromise patient safety in 
the opinion of the investigator 
 
4.3.13 Patients unwilling or unable to comply with the protocol. 
 
4.3.14 Pregnant or breastfeeding 
 
4.3.15 Acute promyelocytic leukemia (APL). 
 
 
 
5 
TREATMENT PLAN 
 
5.1 
General 
 
All patients will be registered through CORe. The objective will be to administer 
nivolumab and 5-azacytidine OR nivolumab and ipilimumab with 5-azacytidine 
OR nivolumab with 5-azacitidine and venetoclax at established published doses 
from solid tumor and leukemia studies.  
 
5.2 
Schedule 
 
The Investigator is responsible for completing the cohort summary template and 
submitting to the IND office Medical Monitor for review and approval prior to 
advancing subjects to the next protocol specified cohort/dose level. A copy of the 
cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”.  This should be submitted after the first six patients. 
 
5.2.1  Patients will be treated according to the following schedule: 
 
 Arm 1: 5-azacytidine will be administered subcutaneously (SQ) or 
intravenously (IV) for 7 days of every cycle with daily schedule of 7 
consecutive days (Days 1-7) or for days 5-2-2 which is 5 consecutive 
weekdays (Days 1-5) with rest on the 2 weekend days (Days 6 and 7) and 
then dosing the first two weekdays of the next week (Days 8 and 9) of 
each 28-day cycle as determined by treating physician. Alternative dosing 
schedules such as 4-2-3 which is 4 consecutive weekdays (Days 1-4) with rest 
on the 2 weekend days (Days 5 and 6) and then dosing the first three 
weekdays of the next week (Days 7, 8, and 9) of each 28-day cycle or other 
schedules allowing the 2 day weekend interruption may be applied as long as 
we make every attempt to give the 7 days of azacytidine as consecutively as 
possible. This must be clearly documented in the medical record as 
determined by treating physician after approval from the PI. Both SQ and IV 
forms of administration are FDA approved and considered interchangeable. 
Patients may start receiving 5-azacytidine by one route and changed to the 


Nivolumab and azacytidine 
 
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other, and also administration schedules from one schedule and changed to 
the other at any time as needed based on patient and/or physician 
preference. 
 
Nivolumab will be administered as an approximately 60 minute IV infusion 
on Day 1 and day 14 (+/-3 days) of each 5-azacyidine cycle for the first 4 
cycles or until CR (whichever occurs earlier) followed by a maintenance 
regimen (one dose of nivolumab on day 1 of each cycle of 5-azacytdine). 
Patients who have evidence of budding relapse or seem to have clinical 
benefit may continue or revert back to receiving nivolumab on Day 1 and day 
14 (+/-3 days) of each cycle of 5-azacytidine. Patients may receive nivolumab 
more or less frequently during the maintenance regimen at the discretion of 
the treating physician only after discussion with the PI. Nivolumab will be 
administered every cycle with no interruptions unless there are adverse events 
as described in Section 5.3. 
 
 Arm 2: Azacytidine and nivolumab will be administered as described for 
Arm 1. Ipilimumab will be administered  as a 90 minute IV infusion on day 1 
and then every 6 weeks (+/- 3 days) or every 12 weeks (+/- 3 days) depending 
on the dose level being evaluated during the lead in phase (Table 5B). The 
Ipilimumab will be planned to be administered for 4 doses but may be 
continued beyond dose #4 if there is reason to believe this will be of clinical 
benefit. The ipilimumab may also be resumed if there is evidence of a 
budding relapse.  
 
 Arm 3: Azacytidine will be administered subcutaneously (SQ) or 
intravenously (IV) for 7 days of every cycle with daily schedule of 7 
consecutive days (Days 1-7) or for days 5-2-2 which is 5 consecutive 
weekdays (Days 1-5) with rest on the 2 weekend days (Days 6 and 7) and 
then dosing the first two weekdays of the next week (Days 8 and 9) of 
each 28-day cycle as determined by treating physician. Alternative dosing 
schedules such as 4-2-3 which is 4 consecutive weekdays (Days 1-4) with rest 
on the 2 weekend days (Days 5 and 6) and then dosing the first three 
weekdays of the next week (Days 7, 8, and 9) of each 28-day cycle or other 
schedules allowing the 2 day weekend interruption may be applied as long as 
we make every attempt to give the 7 days of azacytidine as consecutively as 
possible. This must be clearly documented in the medical record as 
determined by treating physician after approval from the PI. Both SQ and IV 
forms of administration are FDA approved and considered interchangeable. 
Patients may start receiving 5-azacytidine by one route and changed to the 
other, and also administration schedules from one schedule and changed to 
the other at any time as needed based on patient and/or physician 
preference. 
 
Nivolumab will be administered as an approximately 60 minute IV infusion 
on Day 8 and Day 22 (+/-3 days) of each 5-azacyidine cycle for the first 4 
cycles or until CR (whichever occurs earlier) followed by a maintenance 
regimen (one dose of nivolumab on Day 8 of each cycle of 5-azacytdine). 


Nivolumab and azacytidine 
 
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Patients who have evidence of budding relapse or seem to have clinical 
benefit may continue or revert back to receiving nivolumab on Day 8 and 
Day 22 (+/-3 days) of each cycle of 5-azacytidine. Patients may receive 
nivolumab more or less frequently during the maintenance regimen at the 
discretion of the treating physician only after discussion with the PI. 
Nivolumab will be administered every cycle with no interruptions unless 
there are adverse events as described in Section 5.3. 
 
Venetoclax will be administered orally daily on Days 1-21 of the first cycle; 
and Days 1-14 for subsequent cycles depending on the dose level being 
evaluated in the lead in phase (Table 5C).  
 
 5-azacytidine at a dose of 75 mg/m2 on days 1-7 or days 5-2-2 has been 
shown to be safe in combination with multiple agents including 
lenalidomide[60], bortezomib[60], and vorinostat[61, 62].  Alternative dosing 
schedules such as 4-2-3 which is 4 consecutive weekdays (Days 1-4) with rest 
on the 2 weekend days (Days 5 and 6) and then dosing the first three 
weekdays of the next week (Days 7, 8, and 9) of each 28-day cycle or other 
schedules allowing the 2 day weekend interruption may be applied as long as 
we make every attempt to give the 7 days of azacytidine as consecutively as 
possible. The maximum dose for this trial of nivolumab 3.0 mg/kg every 2 
weeks is the same dose and schedule used in global Phase 3 studies. Based on 
these data we have proposed the starting dose level 0 of 5-azacytidine 75 
mg/m2 x 7 days and nivolumab 3.0 mg/kg on days 1 and 14 of each cycle. 
The lead-in phase is to ensure that the combination is well tolerated with no 
unexpected side effects. Nivolumab infusion should begin right after 
administration of 5-azacytidine on Day 1 in Arms 1 and 2, as described above, 
whenever possible or on Day 8 in Arm 3. The dosing calculations should be 
based on the body weight. All doses should be rounded to the nearest 
milligram. There will be no dose reductions (only interruptions when 
indicated) allowed for nivolumab and ipilimumab on this trial. 
 
5.2.1.1 The starting dose will be dose level 0 in Arm 1, Arm 2 and 3. 
 
Table 5A. Arm 1: Dose levels of 5-azacytidine and nivolumab during the lead-
in phase (part a) 
 
 
 
The goal of the lead-in phase is to identify the dose at which <2/6 patients 
Dose level 5-azacytidine 
(mg/m2/d, Days 1- 
7) 
Nivolumab (mg/kg, 
day 1 and 14) 
-4 
25 
0.1 
-3 
50 
0.1 
-2 
50 
0.3 
-1 
75 
1.0 
0 
75 
3.0 (starting dose) 


Nivolumab and azacytidine 
 
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experience DLT. During the lead-in phase the dose’s of 5- azacytidine and 
nivolumab may be reduced if 2 or more patients experience DLT at any given 
dose. After the lead-in phase the dose of nivolumab may not be reduced in the 
phase II portion of the study. For potential nivolumab related AEs only dose 
interruptions will be permitted. Dose reductions or escalations of 5-
azacytidine are permitted in the phase II portion of the study and dose 
reductions or escalations of 5-azacytidine beyond those mentioned in table 5A 
or different to the doses specified should be discussed with the PI and 
documentation of the justification recorded in the chart. 
 
5.2.1.2 The dose and /or schedule of administration is subject to modification 
pending information from ongoing clinical trials of nivolumab as a 
single agent and in combination with other drugs. 
 
5.2.1.3  
Table 5B: Arm 2: Dose levels of 5-azacytidine, nivolumab and ipilimumab 
during the lead-in phase (part a) 
 
 
The goal of the lead-in phase is to identify the dose at which <2/6 
patients experience DLT. During the lead-in phase the dose’s of 
nivolumab and/or ipilimumab may be reduced if 2 or more patients 
experience DLT at any given dose. After the lead-in phase the dose of 
nivolumab and ipilimumab may NOT be reduced in the phase II portion 
of the study. For potential nivolumab and/or ipilimumab related AEs 
only dose interruptions will be permitted. Dose reductions or 
escalations of 5-azacytidine are permitted in the phase II portion of the 
study and dose reductions or escalations of 5-azacytidine beyond those 
mentioned in table 5B or different to the doses specified in Table 5B 
may be allowed after discussion and approval from the PI and 
documentation of the justification recorded in the chart. 
 
The dose and /or schedule of administration is subject to modification 
pending information from ongoing clinical trials of nivolumab or 
ipilimumab as a single agent and in combination with other drugs. 
 
5.2.1.4  
Table 5C: Arm 3: Dose levels of 5-azacytidine, nivolumab and venetoclax 
during the lead-in phase (part a) 
 
Dose level 
5-azacytidine 
(mg/m2/d, Days 1- 
7) 
Nivolumab (mg/kg, 
day 1 and 14) 
Ipilimumab q6 weeks 
-2 
75 
1.0 
0.3 mg/kg q6 weeks 
-1 
75 
1.0 
1.0 mg/kg q6 weeks 
0 (starting dose) 
75 
3.0 (starting dose) 
1.0 mg/kg q12 weeks 
+1 (target dose) 
75 
3.0 (starting dose) 
1.0 mg/kg q6 weeks 


Nivolumab and azacytidine 
 
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The goal of the lead-in phase is to identify the MTD i.e. the dose at 
which <2/6 patients experience DLT. During the lead-in phase the 
dose’s/duration of nivolumab and/or venetoclax may be reduced if 2 or 
more patients experience DLT at any given dose as shown in Table 5C. 
The RP2D will be selected at the end of the lead-in phase and may be 
the MTD dose or a dose level lower than the MTD.  
 
Once the RP2D is decided the expansion (part b) will open in 2 
cohorts: Frontline cohort (n=30) and Salvage Cohort (n=30) with 
eligibility as defined in 4.2.1. See “statistics” section for more details. 
 
After the lead-in (part a) the dose of nivolumab may NOT be reduced 
in the expansion (part b) of the study. For potential nivolumab related 
AEs only dose interruptions will be permitted. Dose reductions or 
escalations of venetoclax and 5-azacytidine are permitted in the 
expansion (part b) of the study and dose reductions or escalations of 5-
azacytidine or venetoclax beyond those mentioned in table 5C or 5.3.2 
should be discussed with the PI and documentation of the justification 
recorded in the chart. Only Salvage patients as defined in Inclusion 
criteria 4.1B will be enrolled during in the lead-in phase. 
 
The dose and /or schedule of administration is subject to modification 
pending information from ongoing clinical trials of nivolumab or 
ipilimumab or venetoclax as a single agent and in combination with 
other drugs. 
 
DLT is defined as clinically significant non-hematologic adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, 
intercurrent illness, or concomitant medications and occurring during the first 
cycle on study that meets any of the following criteria: 
 
 
 CTCAE Grade 3 AST (SGOT) or ALT (SGPT) for >/= 7 days or 
grade 3 hyperbiliribunemia for >/= 7 days 
 
 CTCAE Grade 4 AST (SGOT) or ALT (SGPT) of any duration 
 
 All other clinically significant non-hematological adverse event 
that is Grade 3 or 4 according to the NCI common terminology 
criteria version 4.0 with the following exceptions: 
 
Dose level 
5-azacytidine 
(mg/m2/d, Days 1- 
7) 
Nivolumab (mg/kg, 
day 8 and 22) 
Venetoclax (400mg or 
equivalent) 
-2 
75 
1.0 
D1-14 
-1 
75 
1.0 
D1-21 
0 (starting dose 
and target dose)) 
75 
3.0 (starting dose) 
D1-21 


Nivolumab and azacytidine 
 
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 
Grade 3 or 4 nausea, vomiting and diarrhea will be 
considered DLT only if not controlled by optimal therapy. 
 
 
 
Grade 3 biochemical abnormalities (e.g., lipase or bilirubin 
elevation) will only be considered DLT if accompanied by 
clinical consequences.  Grade 3 or 4 electrolyte 
abnormalities will only be considered DLT if possibly 
related to study drug and not corrected by optimal 
replacement therapy. 
 
• 
Results in discontinuation of therapy 
 
• 
Any treatment-related death;  
 
Hematologic DLT is defined as grade ≥3 neutropenia and/or 
thrombocytopenia with a hypocellular bone marrow (<10% cellularity) 
lasting for 42 days or more from Cycle 1 Day 1 in the absence of 
residual leukemia (i.e., with less than 5% blasts or residual leukemia by 
flow-cytometry or RT-PCR). Anemia will not be considered for the 
definition of DLT.  
 
-Patients that are removed from study before day 28 for any reason 
other than toxicity and have not experienced DLT will be replaced. 
Patients who come off study earlier than 28 days during the DLT 
evaluation period may continue to receive protocol therapy if they are 
having clinical benefit, after discussion with the PI. The rationale for 
continuing therapy must be clearly documented in the patients chart.  
 
-Patients who do not receive venetoclax on day 1 due to logistical 
and/or financial reasons, the DLT period will be extended to 28 days 
from the first dose of venetoclax.  For evaluation of neutropenia-related 
DLT, the DLT period will be 42 days from the first dose of venetoclax. 
 
5.2.1.5 Arm 1: We will first treat 6 patients at dose level 0 in the lead-in phase. 
If DLT occurs in >/=2/6 patients, this dose level would exceed the 
MTD, and 6 patients will be treated at the next lower dose level (i.e. 
dose level -1). The dose de-escalation (Table 5) will continue in cohorts 
of 6 until we reach a dose level at which <2/6 patients experience a 
DLT in the first 28 days. The dose level at which 0-1/6 patients 
experience a DLT in the first 28 days of treatment will be the MTD and 
will be used to treat an additional patients in the phase II portion of the 
study. If >/=2/6 patients experience DLT at dose level -4, the study will 
be revised to consider additional lower dose levels (based on potential 
synergistic toxicity). 
 
If DLT is observed in the first 28 days of treatment in 0 or 1/6 at dose 
level 0, then dose level 0 will be used for the phase II portion of the 
study. 


Nivolumab and azacytidine 
 
Page 46 of 99 
 
 
Patients that are removed from study before day 28 for any reason other 
than toxicity and have not experienced DLT will be replaced. 
 
5.2.1.6 Arm 2: We will first treat 6 patients at dose level 0 in the lead-in phase. 
If DLT occurs in >/=2/6 patients, this dose level would exceed the 
MTD, and 6 patients will be treated at the next lower dose level (i.e. 
dose level -1). If DLT occurs in </=1/6 patients, this dose level would 
not exceed the MTD, and 6 patients will be treated at the next higher 
dose level (i.e. dose level +1).  The dose escalation or de-escalation 
(Table 5b) will continue in cohorts of 6 until we reach a dose level at 
which <2/6 patients experience a DLT in the first 28 days or if </=1/6 
patients experience a DLT at dose level +1. The highest dose level at 
which 0-1/6 patients experience a DLT in the first 28 days of treatment 
will be the MTD and will be used to treat an additional 54 salvage 1 
and 2 patients (Arm 2 Salvage Cohort) and 30 frontline AML >/= 65 
years not candidates for induction therapy (Arm 2 Frontline cohort) in 
the phase II portion of the study. If >/=2/6 patients experience DLT at 
dose level -2, the study will be revised to consider additional lower 
dose levels (based on potential synergistic toxicity). 
 
Patients that are removed from study before day 28 for any reason other 
than toxicity and have not experienced DLT will be replaced. 
 
5.2.1.7 Arm 3: We will first treat 6 patients at dose level 0 in the lead-in phase 
(part a). If DLT occurs in >/=2/6 patients, this dose level would exceed 
the MTD, and 6 patients will be treated at the next lower dose level (i.e. 
dose level -1). The dose de-escalation (Table 5C) will continue in 
cohorts of 6 until we reach a dose level at which <2/6 patients 
experience a DLT in the first 28 days. The dose level at which 0-1/6 
patients experience a DLT in the first 28 days of treatment will be the 
MTD. If >/=2/6 patients experience DLT at dose level -3, the study will 
be revised to consider additional lower dose levels (based on potential 
synergistic toxicity). 
 
If DLT is observed in the first 28 days of treatment in 0 or 1/6 at dose 
level 0, then dose level 0 will be the MTD. The RP2D will be 
selected at the end of the lead-in phase and may be the MTD dose 
or a dose level lower than the MTD. 
 
Patients that are removed from study before day 28 for any reason other 
than toxicity and have not experienced DLT will be replaced. 
 
 
Venetoclax will be administered orally daily on Days 1-21 of the first cycle; 
and Days 1-14 for subsequent cycles.  
 
 
In cycle 1, patients should undergo a bone marrow aspiration and biopsy on 
day 21 (+/- 4 days). Patients who achieve marrow remission (i.e. bone 


Nivolumab and azacytidine 
 
Page 47 of 99 
 
marrow blasts <5% by morphology) or marrow aplasia/hypoplasia (</=10% 
cellularity or insufficient sample) should discontinue venetoclax for the 
remainder of the cycle and be monitored for count recovery.  
 
a)  If the Day 21 bone marrow shows <5% blasts, the venetoclax should be 
held, and cycle 2 should not be initiated till ANC>0.5 and platelets are 
>30K without platelet transfusion support for >5 days.  
 
b)  If the Day 21 bone marrow shows aplasia/hypoplasia (</=10% 
cellularity or insufficient sample), the venetoclax should be held on Day 
21, and a repeat bone marrow should be performed on Day 28 (+/- 4 
days) for response and MRD assessment. If the Day 28 bone marrow 
shows >/=5% blasts proceed with cycle 2 if this is in the best interest of 
the patient (those with C1D28 bone marrow >/=5% are allowed to 
receive 21 days of venetoclax in cycle#2). If the Day 28 bone marrow 
shows <5% blasts, the venetoclax should continue to be held, and cycle 
2 should not be initiated till ANC>0.5 and platelets are >30K without 
platelet transfusion support for >5 days. If the Day 28 bone marrow 
shows persistent aplasia/hypoplasia (</=10% cellularity or insufficient 
sample) continue to hold the venetoclax and repeat a bone marrow in 
approximately 10-14 days. 
 
c) If a bone marrow remission (<5% blasts) or aplasia/hypoplasia is not 
confirmed on the Day 21 bone marrow, patients should continue 
venetoclax until day 28 and have a repeat bone marrow on Day 28 (+/- 
5 days). If the Day 28 bone marrow shows >/=5% blasts proceed with 
cycle 2 if this is in the best interest of the patient (those with C1D28 
bone marrow >/=5% are allowed to receive 21 days of venetoclax in 
cycle #2). If the Day 28 bone marrow shows <5% blasts or 
aplasia/hypoplasia follow steps outlined in “a” and “b” above. 
 
d) Treatment interruptions and dosing schedules other than the ones 
mentioned above can be considered after discussion with the PI and 
proper documentation of the rationale. 
 
e) Of note the nivolumab infusion will continue as scheduled and will not 
be impacted or adjusted based on venetoclax dosing schema or 
venetoclax related delays. 
 
 
Physicians should leukoreduce with hydroxyurea to reduce the peripheral 
white blood count to below 15,000/μL prior to the administration of the first 
dose of venetoclax. If the WBC is >15,000/μL the venetoclax should not be 
initiated till the white count is brought down to below 15,000/μL. 
 
 
As venetoclax is obtained commercially, some patients may have delays in 
beginning venetoclax due to financial or other logistical considerations. 
Even if venetoclax is not yet available, patients may begin azacitidine and 
nivolumab on day 1.  Venetoclax should be started when it is obtained and 
continued as above (i.e. through day 21 bone marrow and subsequent 
dosing of venetoclax will be based on the Day 21 bone marrow results as 
described above in a - c). 
 


Nivolumab and azacytidine 
 
Page 48 of 99 
 
 
Failure to begin venetoclax on day 1 will not be considered a protocol 
deviation or violation. 
 
 
The patient will be admitted to the hospital for at least the first 14 days of 
the 1st cycle of concomitant azacitidine-venetoclax-nivolumab therapy (e.g., 
Days 1 through Day 14) of cycle 1, potentially admission will be longer if we 
encounter TLS, infections or other complications that would be better 
managed inpatient. To mitigate the risk for tumor lysis syndrome, patients 
must be receiving tumor lysis prophylaxis, including hydration (oral, 
intravenous) and treatment with a uric acid reducing agent (allopurinol, 
rasburicase) prior to the start of venetoclax therapy and continued during 
Cycle 1.  
 
TLS chemistry tests (potassium, uric acid, creatinine, calcium and 
phosphorus) will be obtained prior to dosing and 5-8 hours after each new 
venetoclax dose during the venetoclax ramp-up period. TLS chemistry test 
results will be reviewed by the investigator in real time and prior to the 
subject receiving the next higher dose of venetoclax to ensure appropriate 
and timely management. If a subject meets criteria for clinically significant 
laboratory or clinical TLS, no additional venetoclax should be administered 
until resolution of the TLS. Venetoclax interruption for up to 72 hours 
following transient (< 48 hours) chemical changes and laboratory TLS will 
be allowed and will not require a dose reduction. 
 
 
See section 6.4 for details of TLS management.  
 
 
During cycle 1, venetoclax will be dose escalated daily to the goal dose of 
400mg daily.  Patients will receive 100mg on Day 1, 200mg on Day 2 and 
400mg on Day 3 and onwards, or adjusted dose if on concomitant azoles 
(discussed below in section 6.3). Venetoclax dose ramp-up as described in 
section 6.4. 
 
 
If venetoclax is not available at the start of therapy due to different reasons 
(insurance, financial, transportation, others), azacitidine and nivolumab can 
start and venetoclax is added when it becomes available.  
 
 
If azacitidine cycles are delayed, venetoclax therapy may continue on Days 
1-21 of a 4-week cycle after discussion with the PI or Co-PI and 
documentation in the medical record. If azacitidine cycles are delayed, 
nivolumab may continue as scheduled (q2 weeks) after discussion with the 
PI or Co-PI and documentation in the medical record. 
 
 
5.2.2 
One cycle of therapy is defined as 28 days. Patients will receive one 
cycle of therapy every 28 days (+/- 7 days). The ipilimumab will be 
given every 6 weeks (+/-3 days).  
 
5.2.2.1 
In the expansion (part b) portion of the study (once the 
MTD/RP2D dose has been defined) cycles may be started 
early (but not earlier than day 21) for patients with active 
disease if judged in the best interest of the patient. 


Nivolumab and azacytidine 
 
Page 49 of 99 
 
For the lead-in (part a) cohort, DLT defining period is 28 
days. As such, cycle 2 should not be started before 28 days 
for the patients being treated on the lead-in cohort. 
 
5.2.2.2 
Subsequent cycles may be delayed for recovery of toxicity or 
other medical conditions (e.g. infections). Delays in start of 
subsequent cycles greater than 8 weeks will be acceptable only 
for patients who are deriving clinical benefit and after 
discussion with the principal investigator of potential 
risk/benefit ratio. 
 
5.2.2.3 
In instances where one drug has to be discontinued 
transiently because  of safety, the administration of the 
other drug may continue as scheduled. If the drug that is held 
can resume at a later time, no doses will be made up and the 
administration will follow the originally defined schedule 
calendar according to the drug that was continued.   
 
5.2.2.4 
Subsequent 
courses 
of 
5 - a z a c yt i di n e  
a nd  
n i v o l u ma b  O R  5-azacytidine w i t h  nivolumab and 
ipilimumab 
O R  
5-azacytidine 
w i t h  
nivolumab and 
venetoclax may be administered regardless of peripheral 
blood counts during the first 4 cycles and/or in the presence 
of residual leukemia. 
 
If prolonged myelosuppression (more than 8 weeks) WITH 
evidence of a hypocellular marrow (marrow cellularity less 
than 5% without evidence of leukemia) is observed, 5- 
azacytadine and nivolumab OR 5-azacytidine wih nivolumab 
and ipilimumab O R  5-azacytidine w i t h  nivolumab and 
venetoclax will 
be 
discontinued. 
Delays 
in start of 
subsequent cycles greater than 8 weeks will be acceptable 
only for patients who are deriving clinical benefit and after 
discussion with the principal investigator of potential 
risk/benefit  ratio.  If  the  peripheral  counts  do  not  recover 
(ANC <1 x109/L and/or platelets <30 x109/L) but there is 
evidence of residual leukemia in the bone marrow by 
morphology or flow-cytometry, subsequent cycles can be 
administered at the discretion of the treating physician not 
earlier than 21 days after the prior cycle. 
 
5.2.2.5 
For patients who discontinue therapy, the reason for treatment 
discontinuation will be captured. 
 
5.2.2.6 
Patients must receive at least 5 of 7 planned doses of 
azacitidine, 2 of 2 planned doses of nivolumab and 18 of 
21 planned doses of venetoclax during the first 28 days 
on trial (i.e. during cycle 1) to be considered evaluable 


Nivolumab and azacytidine 
 
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during the DLT phase. Patients who receive less than 
these doses of each drug during the first 28 days on trial 
will not be considered evaluable during the DLT phase. 
However, if such patients develop a toxicity that would 
normally be considered a DLT this will still be captured 
as a DLT. Any toxicity that meets the criteria for DLT 
during the first 28 days of trial in a patient who has 
received at least one dose of either azacitiidne, 
venetoclax or nivolumab will constitute a DLT. Patients 
not considered evaluable due to insufficient dosing and 
who do not develop a toxicity that is considered a DLT 
will be replaced. These patients may continue therapy 
on trial after discussion with the PI if they are having 
clinical benefit and the reasons for continuation and 
potential benefit/risk profile for the patient must be 
clearly documented in the medical records. In the 
expansion phase (part b), DLT will not be monitored. We 
will perform continuous safety monitoring every 5 
patients for “drug-related non-hematological Grade 3/4 
AE’s.” 
 
5.2.2.7 
Dose modifications other than the ones mentioned above 
can be considered after discussion with the PI and 
proper documentation of the rationale. 
 
5.2.2.8 
Clinical trial update: The safe dose of 5-azacytidine and 
nivolumab has been established as 5-azacytidine 75mg/m2 
days 1-7 and nivolumab 3.0 mg/kg on days 1 and 14 of each 
cycle in the ongoing clinical trial. 1/6 patients experienced a 
DLT   at   this   dose   during   the   safety-run-in   phase.   All 
subsequent patients (including relapsed/refractory AML and 
newly diagnosed elderly AML) will receive this dose of 5- 
azacytidine and nivolumab. For the 5-azacytidine with 
nivolumab and ipilimumab the MTD established from the run-
in phase will be used to treat both salvage and frontline 
patients. For the 5-azacytidine with nivolumab and venetoclax 
the MTD/RP2D established from the lead-in part a (Table 5C) 
will be used to treat both salvage patients and frontline 
patients in the expansion part B: see “statistics” section for 
more details. 
 
5.3 Venetoclax Administration 
 
-If a dose is missed or vomited, the next dose should not be 
increased to account for missing a dose. The subject should 
take the next regular dose at the regularly scheduled time. 
 
-Day 1 of each cycle will be counted from the start of the 
azacitidine infusion. Treatment may be prolonged beyond the 


Nivolumab and azacytidine 
 
Page 51 of 99 
 
planned 28 days of each cycle if the start of the next course 
of azacitidne is delayed. However, if there are adverse 
events that mandate treatment interruption or it is considered 
in the best interest of the patient for safety reasons to 
interrupt nivolumab and/or venetoclax therapy, nivolumab 
and/or 
venetoclax 
administration 
can 
be 
transiently 
discontinued and re-started as per guidelines in section 6.0.  
 
 
5.3.0 
Dose Adjustments 
 
Toxicity Directly Attributable to Study Drugs 
 
Patients experiencing unacceptable toxicity directly attributable to the study 
drugs should temporarily stop treatment according to the guidelines in the dose 
adjustment schema. 
 
5.3.1 Nivolumab, Ipilimumab, Venetoclax and 5-azacytidine dose 
adjustments for hematological drug- related adverse events (AE): 
 
Dose reduction/interruption/discontinuation decisions should be based on the 
CTCAE version 4.0 (Appendix C) of the toxicity and the guidelines provided 
below. 
 
 Patients with acute leukemia’s usually present with abnormal peripheral 
blood counts at the time therapy is started and myelosuppression is an 
expected event during the course of therapy for acute leukemia’s. Thus, 
no dose adjustments or treatment interruptions for myelosuppression 
 
 
will be planned for the first 4 cycles and/or in the presence of residual 
leukemia. After that, treatment interruptions and dose adjustments may 
be considered according to the following guidelines only when there is 
no evidence of active leukemia (e.g., only if <5% blasts in the bone 
marrow by morphology or flow-cytometry or cytopenias not 
considered to be related to leukemia). 
 
 Patients with a response (no marrow evidence of leukemia) and 
pre-cycle counts of neutrophils >1x109/L and platelets >50 
x109/L who have sustained low counts of neutrophils <0.5 
x109/L or a platelet count <20 x 109/L for more than 2 
consecutive weeks in the current cycle, may have the treatment 
with 5-azacytidine and/or venetoclax interrupted at the 
discretion of the treating physician after discussing with the 
PI until neutrophils recover to ≥1 x109/L and platelets to ≥50 
x109/L. Nivolumab and ipilimumab have not ben associated 
with neutropenia and/or thrombocytopenia in prior studies 
and should generally not be interrupted or discontinued for 
myelosuppression. 


Nivolumab and azacytidine 
 
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 If there are persistent peripheral blood blasts, or the bone 
marrow shows >5% blasts or evidence of leukemia by flow 
cytometry, treatment may be continued regardless of 
neutrophil and platelet count with supportive care as needed. 
Dose-interruptions of 5- azacytidine a n d / o r  v e n e t o c l a x  
in these patients should be considered on an individual case 
and discussed with the PI. 
 
 Patients with a response (no marrow evidence of leukemia) and 
pre-cycle counts of neutrophils <1x109/L and platelets <50 
x109/L may be continued regardless of neutrophil and platelet 
count with supportive care as needed. Dose-interruptions of 
5- azacytidine a n d / o r  v e n e t o c l a x  in these patients 
should be considered on an individual case and discussed 
with the PI. 
 
 Investigators should, whenever possible, determine which 
medication is causing the toxicity and interrupt or dose reduce 
5-azacytidine and/or venetoclax and/or interrupt nivolumab 
and/or ipilimumab or both, as applicable. No dose reductions 
are permitted for nivolumab and ipilimumab once the RP2D 
is established. Nivolumab and ipilimumab have not ben 
associated with neutropenia and/or thrombocytopenia in prior 
studies and should generally not be interrupted or discontinued 
for myelosuppression. 
 
5.3.2 Nivolumab, Ipilimumab, Venetoclax and 5-azacytidine dose adjustments 
for non-hematologic drug- related AEs 
Investigators should, whenever possible, determine which medication is 
causing the toxicity and interrupt or dose reduce 5-azacytidine and/or 
venetoclax or interrupt nivolumab or ipilimumab or both, as applicable. 
No dose reductions (only interruptions) are permitted for nivolumab and 
ipilimumab. 
 
 Dose reductions of azacitidine will be as follows: Baseline dose level: 
75 mg/m^2 x 7 days, dose level -1 of azacitidine: 50 mg/m^2 x 7 days, 
dose level -2: 37.5 mg/m^2 x 7 days, dose level -3: 25 mg/m^2 x 7 days. 
Further reductions or modifications to schedule beyond what is shown 
above or alternative reductions (e.g. 75mg/m2 x 5 days) may be allowed 
if deemed in the patient’s best interest by the treating physician. 
 
Dose reductions of venetoclax will be as follows: Baseline dose level 
of venetoclax: 400mg, dose level -1 of venetoclax: 200mg, dose level -
2: 100mg, dose level -3, 50mg. Alternatively, the duration of venetoclax 
administration can be decreased (e.g. decrease from 21-days per cycle to 
14-day per cycle to 10 days per cycle) rather the dose being reduced. 
 


Nivolumab and azacytidine 
 
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Table 6A  Arm 1: Dose adjustments for non-hematologic drug-related AEs,  
clinically significant in the opinion of the investigator 
 
 
 
                       Table 6B     Arm 2: Dose adjustments for non-hematologic drug-related AEs,  clinically 
significant in the opinion of the investigator 
 
Grade 
Occurrence 
Dose modification 
1 or 2 
Any time 
No dose reduction 
3or 4 
 
(Persistent 
grade 2: 
Consider 
similar dose 
adjustments if 
persistent and 
not 
responding to 
optimal 
management 
in the opinion 
of PI and 
treating 
physician) 
1st and 
2nd time 
Hold nivolumab and 5-azacytidine. 
Resume nivolumab and 5-azacytidine at prior dose if recovery 
to ≤ Grade 1 occurs within 14 days. 
If toxicity persists for 15-28 days, hold therapy and resume 
Nivolumab at prior dose and 5-azacytidine at prior dose if 
recovery to ≤ Grade 1 OR resume nivolumab at prior dose and 
5-azacytidine at ONE dose level below current dose if recovery 
to ≤ Grade 2. 
Dose re-escalation to prior dose of 5-azacytidine is permitted in 
accordance with the dose-escalation guidelines in section 5.3.6. 
3rd and 4th 
time 
Hold nivolumab and 5-azacytidine. 
Follow until toxicity ≤ Grade 2. 
Resume nivolumab at prior dose and 5-azacytidine at ONE 
dose level below current dose. 
Dose re-escalation of 5-azacytidine to prior dose is permitted in 
accordance with the dose-escalation guidelines in section 5.3.6.. 
5th time 
Take patient off the study. 
Grade 
Occurrence 
Dose modification 
1 or 2 
Any time 
No dose reduction 
3or 4 
 
(Persistent 
grade 2: 
Consider 
similar dose 
adjustments if 
persistent and 
not 
responding to 
optimal 
management 
in the opinion 
of PI and 
treating 
physician) 
1st and 
2nd time 
Hold nivolumab, ipilimumab and 5-azacytidine. 
Resume nivolumab and/or ipilimumab and 5-azacytidine at 
prior dose if recovery to ≤ Grade 1 occurs within 14 days. 
If toxicity persists for 15-28 days, hold therapy and resume 
nivolumab and/or ipilimumab at prior dose and 5-azacytidine at 
prior dose if recovery to ≤ Grade 1 OR resume nivolumab 
and/or ipilimumab at prior dose and 5-azacytidine at ONE dose 
level below current dose if recovery to ≤ Grade 2. 
Dose re-escalation to prior dose of 5-azacytidine is permitted in 
accordance with the dose-escalation guidelines in section 5.3.6. 
3rd and 4th 
time 
Hold nivolumab and ipilimumab and 5-azacytidine. 
Follow until toxicity ≤ Grade 2. 
Resume nivolumab and ipilimumab at prior dose and 5-
azacytidine at TWO dose level below current dose. 
Dose re-escalation of 5-azacytidine to prior dose is permitted in 
accordance with the dose-escalation guidelines in section 5.3.6.. 


Ni v ol u m a b  a n d  az acyti di n e  
 
P a g e  5 4  of  9 9  
 
 
 
T a ble 6 C     Ar m 3: D ose a dj ust me nts f or n o n- he m a t ol o gic dr u g-rel ate d A Es, cli nic all y si g nific a nt i n 
t he o pi ni o n of t he i n vesti g at or 
 
 
5. 3. 3  Ni v ol u m a b or I pili m u m a b or b ot h d o se del a y/i nterr u pti o n f or i m m u ne-
o nc ol o g y dr u g-rel at e d A Es, cli nic all y  si g nific a nt i n t he o pi ni o n of t he 
i n vesti g at or 
 
Ni v ol u ma b ( Ar m 1 or 3) or ni v ol u ma b +i pili m u ma b ( Ar m 2) a d mi nistrati o n 
s h o ul d be dela ye d f or t he f oll o wi n g dr u g-relate d A Es, cli nicall y si g nifica nt i n 
t he o pi ni o n of t he i n vesti gat or: 
 A n y Gra d e >/ = 2 n o n -s ki n A E, e x ce pt t hat 
 Gra de 2 fati g ue or la b orat or y a b n or malities d o n ot re q uire dela y, 
h o we ver 
 Patie nts wit h A L T or A S T > 3 a n d u p t o 5 x U L N or t otal bilir u bi n 
gr eater > 1. 5 a n d u p t o 3 x U L N or creati ni ne > 1. 5 a n d u p t o 6 
5t h ti me 
Ta ke patie nt off t he st u d y. 
Gra de
 Occ urre nce
 
D ose
 
m o dificati o n
 
1 or 2 
A n y ti me  
N o d ose re d ucti o n 
3 or 4 
 
( Persiste nt 
gra de 2: 
C o nsi der 
si milar d ose 
a dj ust me nts if 
persiste nt a n d 
n ot 
res p o n di n g t o 
o pti mal 
ma na ge me nt 
i n t he o pi ni o n 
of PI a n d 
treati n g 
p h ysicia n) 
1st a n d 
2 n d ti me 
- H ol d m ost li kel y offe n di n g a ge nt. 
- Res u me ni v ol u ma b a n d/ or ve net ocla x a n d 5-a zac yti di ne at 
pri or d ose if rec o ver y t o ≤ Gra de 1 occ urs wit hi n 1 4 da ys. 
-If t o xicit y persists f or 1 5- 2 8 da ys, h ol d t hera p y a n d res u me 
ni v ol u ma b a n d/ or ve net ocla x at pri or d ose a n d 5-azac yti di ne at 
pri or d ose if rec o ver y t o ≤ Gra d e 1 O R res u me ni v ol u ma b at 
pri or d ose a n d 5-a zac yti di ne a n d ve net ocla x at O N E d ose le vel 
bel o w c urre nt d ose if rec o ver y t o ≤ Gra de 2. 
- D ose re-escalati o n t o pri or d ose of 5-azac yti di ne is per mitte d 
i n acc or da nce wit h t he d ose-escalati o n g ui deli nes i n secti o n 
3 rd  
ti me 
- H ol d m ost li kel y offe n di n g a ge nt. 
- F oll o w u ntil t o xicit y ≤ Gra de 2. 
- Res u me ni v ol u ma b at pri or d ose a n d 5-azac yti di ne a n d 
ve net ocla x at T W O d ose le vel bel o w c urre nt d ose. 
- D ose re-escalati o n of 5-azac yti di ne t o pri or d ose is per mitte d i n 
acc or da nce wit h t he d ose-escalati o n g ui deli nes i n secti o n 5. 3. 6.. 
4t h ti me 
Ta ke patie nt off t he st u d y. 


Nivolumab and azacytidine 
 
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x ULN (or greater than 1.5 times baseline) should have nivolumab 
(Arm 1 or 3) or nivolumab+ipilimumab (Arm 2) treatment withheld. 
 Any Grade 3 skin AE, or Grade 3 laboratory abnormality, with the following 
exceptions: 
 Grade 3 lymphopenia or leukopenia does not require dose delay.
 
 However, patients with ALT or AST >5 x ULN or total bilirubin 
greater > 3 x ULN or creatinine >6 x ULN should be discontinued 
from nivolumab treatment (Arm 1 or 3) or nivolumab and 
ipilimumab treatment (Arm 2). 
 Any AE, laboratory abnormality, or intercurrent illness, which in the 
judgment of the investigator, warrants delaying the dose of study medication. 
 Nivolumab and ipilimumab dose reductions are not permitted in this study 
(only dose delays when indicated). 
 
Subjects may resume treatment with nivolumab (Arm 1 and 3) or nivolumab 
and ipilimumab (Arm 2) with study drug when the drug-related AE(s) resolve 
to Grade ≤1 or baseline value, with the following exceptions: 
 Subjects may resume treatment in the presence of Grade 2 fatigue 
 Subjects who have not experienced a Grade 3 drug-related skin AE may 
resume treatment in the presence of Grade 2 skin toxicity 
 Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed 
 Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment 
 
If the criteria to resume treatment are met, the subject should restart 
treatment at the next scheduled timepoint per protocol. However, if the 
treatment is delayed past the next scheduled timepoint per protocol, the next 
scheduled timepoint will be delayed until dosing resumes. Patients who 
receive combination therapy in whom continuation of 5-azacytidine and/or 
venetoclax is considered to be inadequate, or inappropriate (e.g., because of 
pancytopenia) can discontinue 5-azacytidine and/or venetoclax and continue 
with nivolumab only. 
 
If treatment is delayed > 8 weeks, the subject must be permanently 
discontinued from study therapy, except as specified in discontinuation 
section. Delays in start of subsequent cycles greater than 8 weeks will be 
acceptable only for patients who are deriving clinical benefit and after 
discussion with the principal investigator of potential risk/benefit ratio. 
 
5.3.4 Nivolumab (Arm 1 and 3) or nivolumab+ipilimumab (arm 2) 
Discontinuation Criteria 
Treatment with IO-agent/s should be permanently discontinued for the following: 
 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 lasting > 7 days with systemic treatment. 


Nivolumab and azacytidine 
 
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 Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, diarrhea, colitis, neurologic adverse event, 
hypersensitivity reactions, and infusion reactions: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic adverse event, hypersensitivity reaction, or infusion 
reaction of any duration requires discontinuation 
 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below: 
 
 
 Any drug-related liver function test (LFT) abnormality that 
meets the following criteria require discontinuation: ALT or 
AST >5 x ULN or total bilirubin greater > 3 x ULN 
or creatinine >6 x ULN 
 
 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except for 
the following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not 
associated with symptoms or clinical manifestations of pancreatitis and 
decrease to < Grade 4 within 1 week of onset. 
 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72 hours of their 
onset 
 
 Any dosing interruption lasting > 8 weeks with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage drug- 
related adverse events are allowed. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 8 weeks, the Principal Investigator must 
be consulted. Tumor/Leukemia assessments should continue as per protocol 
even if dosing is interrupted. 
 
o Dosing interruptions > 8 weeks that occur for non-drug-related reasons may 
be allowed if approved by the Principal Investigator. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 8 weeks, the 
Principal Investigator must be consulted. Tumor/Leukemia assessments 
should continue as per protocol even if dosing is interrupted. 
 
o Delays in start of subsequent cycles greater than 8 weeks will be acceptable 
only for patients who are deriving clinical benefit and after discussion with 
the principal investigator of potential risk/benefit ratio. 
 
5.3.5 Detailed management algorithms for immune-oncology drug-related adverse 
events (including gastrointestinal, renal, pulmonary, hepatic, endocrine, skin and 


Nivolumab and azacytidine 
 
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neurological) are provided in Appendix G. These general guidelines constitute 
guidance to the Principal Investigator and may be supplemented by discussions 
with the IND Sponsor in specific cases. 
 
5.3.6 CYP3A4 Inhibitors: Dose modifications 
Venetoclax 
-Venetoclax should be administered at 50% dose 
reduction in the setting of moderate CYP3A inhibitor 
and at 75% dose reduction in the setting of strong 
CYP3A inhibitor for the duration of co-administration. 
The dose will be reduced by 75% if patient is on 
posaconazole.  
 
-In the event the co-administered CYP3A inhibitor is 
discontinued, the assigned venetoclax dose should 
be resumed 2-3 days after discontinuation. 
 
-Every effort should be made to adhere venetoclax 
dose reduction. Variations in schedule of events such 
as late/missed interventions that do not affect the 
rights and safety of the patient will not be considered 
as deviations.   
 
5.3.7 
Tumor Lysis Prophylaxis (TLS) 
-The venetoclax dose titration scheme utilized in the AML 
studies performed to date to mitigate the risk of tumor lysis 
syndrome (TLS) will be employed. All patients will be 
hospitalized for the entirety of the venetoclax dose escalation 
starting at least on day 1 of treatment initiation and until 24 hours 
after the completion of venetoclax dose escalation. During cycle 
1, venetoclax will be dose escalated daily to the goal dose of 
400mg daily.  Patients will receive 100mg on Day 1, 200mg on 
Day 2 and 400mg on Day 3 and onwards, or adjusted dose if on 
concomitant azoles (discussed below in section 6.3).  
 
-To mitigate the risk for TLS, subjects must be receiving tumor 
lysis prophylaxis, including hydration (oral, intravenous) and 
treatment with a uric acid reducing agent (allopurinol, 
rasburicase) prior to start of venetoclax and at least during the 
first cycle of therapy.  
 
-TLS chemistry tests (potassium, uric acid, creatinine, calcium 
and phosphorus) will be obtained prior to dosing and 5-8 hours 
after each day of a new venetoclax dose. TLS chemistry test 
results will be reviewed by the investigator in real time and prior 
to the subject’s next dose to ensure appropriate management. If 
a subject meets criteria for clinically significant laboratory or 
clinical TLS, no additional venetoclax should be administered 
until resolution. 
 


Nivolumab and azacytidine 
 
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-Venetoclax interruption for up to 72 hours following transient (< 
48 hours) chemical changes and laboratory TLS will be allowed 
and will not require a dose reduction. 
 
5.3.8 
Meals and Dietary Requirements: 
-Each dose of venetoclax should be taken with approximately 
240 mL of water within 30 minutes after the completion of a 
meal, preferably breakfast. 
 
-Subjects should not consume grapefruit or grapefruit products, 
Seville oranges, or Star fruit within the 3-day period prior to the 
first venetoclax administration and until the last day of 
venetoclax is completed due to possible CYP3A mediated 
metabolic interaction. 
 
 
5.3.9 
Intra-patient dose re-escalation for patients who have had dose-reductions 
due to hematological or non-hematological toxicity: 
Once the MTD has been established in the lead-in, the nivolumab dose 
(Arm 1 or 3) or nivolumab+ipilimumab dose (Arm 2) will not be reduced 
or escalated during the phase II portion. Intra-patient dose re-escalation of 
5-azacytidine and/or venetoclax will be permitted provided: 
 
 
Patient has completed >/=1 cycle at their current dose level 
 
 
Patient has not experienced any grade 3 or higher non-hematologic 
drug-related toxicity, and 
 
 
Patient has not experienced drug-related hematologic DLT, and 
 
 
At least 6 patients have been treated at the next higher dose level 
and followed for at least 28 days without experiencing DLT. 
 
 
The dose may be escalated by one dose level per cycle (per section 
5.3.2) provided such dose level does not exceed the established 
MTD or dose level 0, whichever is lower. Dose level 0 (Table 
5A, 5B, 5C) is the maximum dose allowed on this study. No dose 
escalation beyond dose level 0 will be permitted. 
 
5.3.10 Modifications of dose schedules other than the above will be allowed within the 
following guidelines: 
 
5.3.7.1 Further dose reductions can be made to keep clinically significant toxicities 
grade < 2. 
 
5.3.7.2 Dose adjustments by more than 1 dose level at a time (e.g., from 5-azacytidine 
75 mg/m2 to 25 mg/m2) can be considered when judged in the best interest of 
the patient (e.g. severe myelosuppression) when toxicity has resolved. The 
reason for this reduction must be discussed and approved by the PI or Co-


Nivolumab and azacytidine 
 
Page 59 of 99 
 
PI and documented in the medical record. 
 
5.3.7.3 A patient who has had a dose reduction because of any of the reasons 
mentioned above may have their dose escalated provided the patient has 
remained free of toxicity requiring dose adjustments as defined above for at 
least 1 month. Escalation will be made by 1 dose-level increment only, and 
not more frequent than every month. 
 
5.3.7.4 Treatment interruptions and dose modifications other than the ones mentioned 
above can be considered after discussion and approval by the PI or Co-PI 
and proper documentation of the rationale.. Dose adjustment/delay of only 
one of the agents is permissible if the toxicity is most likely judged to be 
related to one of the agents by the investigator (e.g., in patients with 
autoimmune thyroiditis or autoimmune hepatitis this would be likely 
secondary to 
nivolumab or nivolumab+ipilimumab, in patients with 
cytopenia’s this would be likely secondary to 5-azacytidine or venetoclax). 
 
5.4   Duration of Therapy 
In  the  absence  of  treatment  delays  due  to  adverse  events,  treatment  may 
continue until one of the following criteria applies: 
 
1. Clinically significant progressive disease, or 
 
2. Intercurrent illness that prevents further administration of treatment, or 
 
3. Patient request, or 
 
4. General or  specific  changes  in  the  patient's  condition  render  the  patient 
unacceptable for further treatment in the judgment of the investigator, or 
 
5. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to 
continue therapy. 
 
5.4.1    It is planned that up to a total of 24 cycles of therapy will be administered 
for patients deriving benefit from this regimen. Continuation of therapy 
for patients completing 24 cycles of therapy may be considered on a case- 
by-case basis after discussion with the principal investigator. 
 
5.4.2. All patients receiving at least one dose of any of the two drugs will be 
considered evaluable for toxicity. 
 
5.5 Supportive Care: 
Supportive care measures including blood products, infection prophylaxis and 
growth factors will be administered according to institutional and Leukemia 
Department guidelines. 
Management Algorithms for Treatment of Nivolumab or Ipilimumab Related 
Adverse Events Immuno-oncology (I-O) agents are associated with AEs 


Nivolumab and azacytidine 
 
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that can differ in 
severity  and   duration   than   AEs   caused   by  other   therapeutic   classes. 
Nivolumab and ipilimumab are considered immuno-oncology agent in this 
protocol. Early recognition and management of AEs associated with immuno-
oncology agents such as nivolumab and/or ipilimumab may mitigate severe 
toxicity. Nivolumab and ipilimumab have a known safety profile however, a 
general principle is that differential diagnoses should be diligently evaluated 
according to standard medical practice. Non- inflammatory etiologies should 
be considered and appropriately treated. Corticosteroids are a primary 
therapy for immuno-oncology drug-related adverse events, and nivolumab 
o r  i p i l i m u m a b  no exception. The oral equivalent of the recommended 
IV doses may be considered for ambulatory patients with low-grade 
toxicities. The lower bioavailability of oral corticosteroids should be taken 
into account when switching to the equivalent dose of oral corticosteroids. 
 
 
Management Algorithms have been developed to assist investigators in 
assessing and managing the following groups of adverse events: 
Endocrinopathy, Gastrointestinal, Hepatic, Neurological Pulmonary, 
Renal and Skin. These algorithms are found in the “Nivolumab Investigator 
Brochure” (Appendix E), Ipilimumab Investigator Brochure (Appendix J) and 
“Management algorithms for immuno-oncology drug-related adverse events” 
(Appendix G) of this protocol. The guidance provided in these algorithms 
should not replace the Investigator’s medical judgment but should 
complement it. 
 
Finally, consultation with a medical or surgical specialist, especially prior to 
an invasive diagnostic or therapeutic procedure, is highly recommended. 
 
 
5.6  Concomitant Medications: 
Consistent with subject safety and comfort, administration of any prescription 
or over-the-counter drug products other than study medication should be 
minimized during the study period. Subjects should be discouraged from use of 
street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol during the clinical study. 
 
If considered necessary for the subject’s wellbeing, drugs for concomitant 
medical conditions or for symptom management may be given at the discretion 
of the investigator. The investigator’s decision to authorize the use of any drug 
other than study drug should take into account subject safety, the medical need, 
the potential for drug interactions, the possibility for masking symptoms of a 
more significant underlying event, and whether use of the drug will 
compromise the outcome or integrity of the study. 
 
Subjects should be instructed about the importance of the need to inform the 
clinic staff of the use of any drugs or remedies (whether prescribed, over-the- 


Nivolumab and azacytidine 
 
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counter, or illicit) before and during the course of the study. 
 
Recommendations with regard to specific types of concomitant therapies, 
supportive care; diet and other interventions are as follows: 
 
Concomitant medications are recommended as prophylaxis for nausea, 
vomiting, and infections, and are allowed for managing myelosuppression as 
shown in Table 8. Myelosuppression is expected in patients with AML due to 
underlying disease, as well as due to chemotherapy (such as 5-azacytidine and 
venetoclax), or both. Most patients have neutropenia, thrombocytopenia, or 
both at study entry. Significant or life-threatening myelosuppression may be 
managed with growth factor support and blood transfusion according to 
institutional standard of care, American Society of Clinical Oncology (ASCO) 
Practice Guidelines, and/or NCCN Practice Guidelines. 
 
 
Infections secondary to myelosuppression are common in patients with AML, 
and may be related to underlying disease, chemotherapy, or both. Therefore, 
the use of prophylactic antibiotics, antifungal agents, and antiviral agents is 
recommended according to institutional standards. 
 
Since the effect of both nivolumab and 5-azacytidine may be delayed, patients 
with high WBC counts may receive hydroxyurea and up to 1 dose of 
cytarabine (up to 2 g/m2) prior to study entry. Hydroxyurea is allowed before 
the start of study therapy and during the study treatment. Hydrea and 
cytarabine use would be recorded in the CRF. Concurrent therapy for CNS 
prophylaxis or continuation of therapy for controlled CNS disease is permitted. 
With the exception of these agents, concomitant systemic chemotherapy or 
concurrent radiation therapy for other (non AML) cancers should be discussed 
with the PI and may be approved by the PI on a case-by-case basis. Subjects 
are not allowed to participate concurrently in any other therapeutic clinical 
study. 
 
Subjects may be receiving systemic corticosteroids (daily doses ≤10 mg of 
prednisone or equivalent if indicated for adrenal replacement or antiemetic 
therapy), topical, or inhaled corticosteroids at study enrollment. They may 
receive systemic, topical, inhaled, or enteric corticosteroids while on study 
without limitation if they develop conditions that require corticosteroid 
therapy; such subjects are not required to discontinue study participation. 
 
All ongoing medications and therapies (including herbal products, nutritional 
supplements, and nontraditional medications) at screening will be considered 
prior medications. Concomitant medication data will not be collected or 
entered into the case report form other than hydrea and cytarabine as 
mentioned above; however, the subject’s medication record will contain a list 
of concomitant medications. If a prohibited medication is inadvertently 
administered/ taken by the patient, the patient may remain on study as long as 
the prohibited medication is discontinued as soon as feasible. If a prohibited 


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medication is considered essential for the patient well being, continuation on 
study with concomitant administration of such medication(s) will need to be 
discussed with and approved by the principal investigator and medical monitor. 
 
Investigational agents that are not used for treatment of the leukemia per se 
(e.g. anti-infective prophylaxis or therapy) will be allowed. Other supportive 
care studies are allowed, even if under an IND. 
 
 
Table 8: Instructions for the use of concomitant medications and therapies 
 
 
 
 
 
Platelet transfusion 
None 
None 
 
 
White blood cell 
transfusion 
At investigators discretion 
according to standard of 
care at MDACC 
None 
 
Myeloid growth factors or 
platelet growth factor 
At investigators discretion 
according to standard of 
care at MDACC 
None 
 
Erythropoietin or 
darbepoetin 
At investigators discretion 
None 
 
Any other medication for 
supportive care 
 
 
MDACC = MD Anderson Cancer Center 
At investigators discretion 
according to standard of 
care at MDACC 
None 
 
 
6.0 
STUDY MEDICATIONS 
 
6.1  Nivolumab (Anti-PD1) 
Nivolumab is a fully human, IgG4 (kappa) isotype, monoclonal antibody that binds PD-1. 
Nivolumab will be supplied in vials of 100 mg (10 mg/mL) and packaged in an open- 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Prophylactic antibiotics, 
antifungal agents, and 
antiviral agents 
Strongly encouraged 
None 
 
Antiemetic agents 
According to standard of 
care at MDACC 
None 
Allowed 
Oral allopurinol or 
rasburicase 
At investigators discretion 
None 
 
Leukapheresis 
According to standard of 
care at MDACC 
Before induction 1 day 1 
only 
 
 
Red blood cell transfusion 
 
None 
 
None 


Nivolumab and azacytidine 
 
Page 63 of 99 
 
label fashion. Ten nivolumab vials (each 10 mL) will be packaged within a carton. The 
vials are not subject specific although there will be specific vial assignments by subject 
distributed by the Pharmacy in order to track drug usage and re-supply. 
 
6.1.1 Dose Calculation of nivolumab 
Total dose should be calculated as in the following example: 
 
Subject’s actual body weight in kg x MTD in mg = total dose in mg 
 
For example, a subject weighing 70 kg who is scheduled receive a dose of 3 mg/kg would 
be administered 210 mg of nivolumab (70 kg x 3 mg/kg = 210 mg). 
 
6.1.2 Preparation and Dispensing of Nivolumab 
The product storage manager should ensure that the study drug is stored in accordance 
with the environmental conditions (temperature, light, and humidity) as determined by 
the Investigator Brochure. If concerns regarding the quality or appearance of the study 
drug arise, do not dispense the study drug and contact the sponsor immediately. 
 
Investigational product documentation must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (e.g. required diluents, administration sets). 
 
 
 
Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be protected 
from light. If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab include 
laboratory coats and gloves. 
 
For details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the Investigator Brochure section for 
“Recommended Storage and Use Conditions”. Care must be taken to assure sterility of 
the prepared solution, as the product does not contain any anti-microbial preservative or 
bacteriostatic agent. No incompatibilities between nivolumab and polyolefin bags have 
been observed. 
 
Nivolumab is to be administered as an approximately 60 minute IV infusion, using a 
volumetric pump with a 0.2/0.22 micron in-line filter at the protocol-specified dose. 
Variations in infusion times due to minor differences in IV bag overfill/underfill and 
institutional procedure on flushing chemotherapy lines will not result in protocol 
deviation. All infusion times are considered approximate. The drug can be diluted with 
0.9% normal saline for delivery but the total drug concentration of the solution cannot be 
below 0.35 mg/ml. It is not to be administered as an IV push or bolus injection. At the 
end of the infusion, flush the line with a sufficient quantity of normal saline. 
 
6.1.3 Administration of nivolumab 
Patients will receive nivolumab as an approximately 60 minute IV infusion on Day 1 and 


Nivolumab and azacytidine 
 
Page 64 of 99 
 
day 14 (+/-3 days) of a treatment cycle every 28 days for 4 cycles or until CR (whichever 
occurs earlier) followed by a maintenance regimen (one dose of nivolumab on day 1 of 
each cycle of 5-azacytidine). Dosing calculations should be based on the body weight 
assessed at the start of each cycle as described above. All doses should be rounded to the 
nearest milligram. The screening body weight may be used for dosing of cycle 1. 
 
6.1.4 Patient Monitoring During Infusion 
During the first infusion patient vital signs should be monitored prior to dosing, 
approximately every 30 minutes after the initiation of the infusion, and up to 
approximately 60 minutes after the completion of the infusion, or longer if indicated, until 
the vital signs normalize or return to baseline. For subsequent infusions, vital signs should 
be collected prior to dosing, and at the completion of the infusion. If the patient 
experiences and infusion reaction, the patient will be monitored up to 60 minutes after the 
completion of the infusion, or longer if indicated, until the vital signs normalize or return 
to baseline. A+/- 30 minute window applies to all vital sign time points. 
 
6.1.5 Treatment of nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritis, arthralgia’s, hypo- or hypertension, bronchospasm, or other symptoms. All 
Grade 3 or 4 infusion reactions should be reported within 24 hours to the BMS Medical 
Monitor and reported as an SAE if criteria are met. Infusion reactions should be graded 
according to NCI CTCAE (version 4.0) guidelines. 
 
 
Treatment recommendations for nivolumab related infusion reactions are provided below 
and may be modified based on MD Anderson treatment standards and guidelines, as 
appropriate: 
 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention 
not indicated): Remain at bedside and monitor subject until recovery from symptoms. 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg at least 30 
minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g. antihistamines, non-steroidal anti- 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours): 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate. Monitor subject closely. If symptoms recur then no 


Nivolumab and azacytidine 
 
Page 65 of 99 
 
further nivolumab will be administered at that visit. Administer diphenhydramine 50 mg 
IV, and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the case report form (CRF). The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should be 
administered at least 30 minutes before additional nivolumab administrations. If 
necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms [Severe reaction, Grade 3: prolonged (i.e. not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae (e.g. renal impairment, pulmonary infiltrates), Grade 4: life- 
threatening; pressor or ventilatory support indicated]: 
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, 
and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Institutional guidelines will be followed for the treatment of 
anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In 
the case of late-occurring hypersensitivity symptoms (e.g. appearance of a localized or 
 
 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(e.g. oral antihistamine or corticosteroids). 
 
For further details regarding dose-calculation of nivolumab, preparation and dispensing 
of nivolumab, administration of nivolumab, patient monitoring during infusion and 
treatment of nivolumab related infusion reactions please see the dosing procedure manual 
(Appendix I). 
 
6.2 
Azacytidine: 
 
5-azacytidine will be commercially obtained. Standard procedures should be used for 
preparation and administration of 5-azacytidine. The following guidelines are suggested: 
 
Vidaza® (5-azacytidine) (is a cytotoxic drug and, as with other potentially toxic 
compounds, caution should be exercised when handling and preparing Vidaza® (5- 
azacytidine) suspensions. 
 
If reconstituted Vidaza® (5-azacytidine) comes into contact with the skin, 
immediately and thoroughly wash with soap and water.  If it comes into contact with 
mucous membranes, flush thoroughly with water. 
 
The Vidaza® (5-azacytidine) vial is single-use and does not contain any 


Nivolumab and azacytidine 
 
Page 66 of 99 
 
preservatives. Unused portions of each vial should be discarded properly.  See Handling 
and Disposal. Do not save any unused portions for later administration. 
 
6.2.1 Preparation for Subcutaneous Administration: Vidaza® (5- 
azacytidine) should be reconstituted aseptically with 4 mL sterile water for 
injection.  The diluent should be injected slowly into the vial.  Vigorously 
shake or roll the vial until a uniform suspension is achieved.  The 
suspension will be cloudy. The resulting suspension will contain 5- 
azacytidine 25 mg/mL. 
 
6.2.1.1 Preparation for Immediate Subcutaneous Administration: 
Doses greater than 4 mL should be divided equally into 2 
syringes. The product may be held at room temperature for up 
to 1 hour, but must be administered within 1 hour after 
reconstitution. 
 
6.2.1.2 Preparation for Delayed Subcutaneous Administration:  The 
reconstituted product may be kept in the vial or drawn into a 
syringe. Doses greater than 4 mL should be divided equally 
into 2 syringes. The product must be refrigerated immediately, 
and may be held under refrigerated conditions (2ºC–8ºC, 36ºF– 
46ºF) for up to 8 hours. After removal from refrigerated 
conditions, the suspension may be allowed to equilibrate to 
room temperature for up to 30 minutes prior to administration. 
 
 
 
6.2.1.3 Subcutaneous Administration: To provide a homogeneous 
suspension, the contents of the syringe must be re-suspended 
by inverting the syringe 2–3 times and vigorously rolling the 
syringe between the palms for approximately 30 seconds 
immediately prior to administration. Vidaza® (5-azacytidine) 
suspension is administered subcutaneously. Doses greater than 
4 mL should be divided equally into 2 syringes and injected 
into 2 separate sites. Rotate sites for each injection (thigh, 
abdomen, or upper arm). New injections should be given at 
least 1 inch from an old site and never into areas where the site 
is tender, bruised, red, or hard. 
 
6.2.1.4 Suspension Stability: 5-azacytidine reconstituted for 
subcutaneous administration may be stored for up to 1 hour at 
25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F 
and 46°F). 
 
6.2.2 Preparation for Intravenous Administration: Reconstitute the 
appropriate number of Vidaza® (5-azacytidine) vials to achieve the 
desired dose. Reconstitute each vial with 10 mL sterile water for injection. 
Vigorously shake or roll the vial until all solids are dissolved.  The 


Nivolumab and azacytidine 
 
Page 67 of 99 
 
resulting solution will contain 5-azacytidine 10mg/mL. The solution 
should be clear. Parenteral drug product should be inspected visually for 
particulate matter and discoloration prior to administration, whenever 
solution and container permit. 
 
Withdraw the required amount of Vidaza® (5-azacytidine) solution to deliver the desired 
dose and inject into a 50-100 mL infusion bag of either 0.9% Sodium Chloride Injection 
or Lactated Ringer’s Injection. 
 
6.2.2.1 Intravenous Solution Incompatibility: Vidaza® (5-azacytidine) 
is incompatible with 5% Dextrose solutions, Hespan, or 
solutions that contain bicarbonate. These solutions have the 
potential to increase the rate of degradation of Vidaza® (5- 
azacytidine) and should therefore be avoided. 
 
6.2.2.2 Intravenous Administration: Vidaza® (5-azacytidine) solution is 
administered intravenously.  Administer the total dose over a 
period of 10-40 minutes. The administration must be 
completed within 1 hour of reconstitution of the VIDAZA vial. 
 
6.2.2.3 Solution Stability: Vidaza® (5-azacytidine) reconstituted for 
intravenous administration may be stored at 25°C (77°F), but 
administration must be completed within 1 hour of 
reconstitution. 
 
 
 
6.2.3 Storage: Store unreconstituted vials at 25º C (77º F); excursions permitted 
to 15º-30º C (59º-86º F) (See USP Controlled Room Temperature). There 
is no need to protect 5-azacytidine from exposure to light. 
 
6.2.4 Handling and Disposal: Procedures for proper handling and disposal of 
anticancer drugs should be applied. 
 
6.3 Ipilimumab: Please see attached Ipilimumab updated IB for Study 
Medication information. 
 
6.3.1 
Variations in infusion times of nivolumab or 5-azacytidine due to minor differences 
in IV bag overfill/underfill and institutional procedure on flushing chemotherapy lines 
will not result in protocol deviation. All infusion times are considered approximate. 
 
6.3.2 
Unused or expired nivolumab and 5-azacytidine will be safely disposed according 
to MD Anderson pharmacy standard guidelines. 
 
6.3.3 
The administration time for each drug may vary by +/- 30 minutes from the 
specified time period for the infusion of each agent, without constituting a deviation to 
the study. 
 


Nivolumab and azacytidine 
 
Page 68 of 99 
 
6.4 Venetoclax: It is commercially available and will be handled as per the packet 
insert and standards in the MDACC standard institutional pharmacy. Please see 
attached venetoclax updated IB for Study Medication information. 
 
International Non-proprietary name venetoclax (formerly ABT-199) 
Manufacturer Abbvie/Genentech 
Dose 100 - 400 mg daily 
Route of Administration oral 
Formulation Capsule formulation (10 mg, 50 mg and 100 mg) 
Venetoclax will be obtained from commercial source. For further details, 
please refer to the prescribing information (Appendix O). 
 
  
7.1 
PATIENT EVALUATION 
Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol requirements that do 
not affect the rights and safety of the patient will not be considered as deviations.  Such 
variations may include laboratory assessments completed outside of schedule, occasional 
missed required research samples such as correlative assays. 
 
7.2 
Pre-Treatment Evaluation 
 
All pretreatment studies should be obtained within 14 days of entry into the trial, unless 
otherwise stated. 
7.2.1 A complete history and physical, documentation of all measurable disease, 
concomitant medications and performance status. 
 
7.2.2 CBC, platelet count, differential (differential can be omitted if WBC is 
≤0.5 x109/L). 
 
7.2.3 Creatinine, total bilirubin, ALT or AST. 
 
7.2.4 Pregnancy test (urine or plasma) in females of childbearing potential 
should be performed within 72 hours before initiation of study. 
 
7.2.5 Bone marrow aspirate during the last 28 days preceding study initiation. 
Cytogenetics will be obtained prior to therapy (results from prior analysis 
can be used for this purpose). 
 
7.2.6 Pretreatment correlative studies (see below) 
 
7.2.7 Respiratory PCR panel by Nasal Wash/Nasopharyngeal Swab 
(rationale: to rule out underlying viral infection that may be exacerbated 
by Nivolumab) 
 
7.2.8 Chest Xray/CT of the Chest (rationale: to rule out underlying 
pneumonitis that may be exacerbated by Nivolumab 


Nivolumab and azacytidine 
 
Page 69 of 99 
 
 
7.2.9 Routine Urine analysis (UA) 
 
7.2.10 TSH, free T3, free T4 
 
7.2.11 EKG at baseline 
 
7.3 
Evaluation During Treatment 
 
7.3.1 Physical exam at the start of each cycle (± 4 days) and documentation of 
all concomitant medications. 
 
7.3.2 CBC, platelet count, differential once weekly (4 days) for the first 3 
cycles, then every 2-4 weeks (differential can be omitted if WBC is ≤0.5 
x109/L) 
 
7.3.3 Creatinine, total bilirubin, ALT, or AST once weekly (4 days) for the 
first 3 cycles, then every 2-4 weeks. 
 
7.3.4 TSH, free T3, free T4, total cortisol once monthly (4 days) for the 
first 3 cycles, then every 3 cycles (4 days). 
 
7.3.5 EKG once monthly on Day 1 (+/-4 days) of each cycle 
 
7.3.6 Bone marrow aspiration on day 28 (+/- 7 days) for Arms 1 and 2, or on Day 
21 (+/-4 days) on Arm 3, then repeat bone marrow every 1-3 cycles. 
Bone marrow tests can be ordered more frequently if mandated by 
development of peripheral blood counts. No repeat bone marrow is 
necessary if nonresponse or progressive disease can be unequivocally 
diagnosed from peripheral blood tests or, in patients with a WBC < 0.3 if 
the bone marrow test is considered noncontributory by the investigator at 
any time point. 
 
7.3.7 Concomitant medication data will not be collected or entered into the case 
report form except for concomitant hydroxyurea and cytarabine; however, 
the subject’s medication record will contain a list of concomitant 
medications. 
 
7.3.8 Correlative Studies relating to immunologic response (Optional Consent 
for PA13-0291) 
 
Tumor tissue, blood samples and bone marrow aspirate will be collected 
on a separate IRB approved laboratory protocol for immune monitoring as 
previously published [63-66], under the supervision of the 
Immunotherapy Platform (IMT lab Protocol PA13-0291). Patients will be 
consented separately on the IRB approved consent for protocol PA13-
0291. Patients may participate in protocol 2014-0861 irrespective of 


Nivolumab and azacytidine 
 
Page 70 of 99 
 
whether they choose to participate on protocol PA13-0291. In tumor 
tissues, immunohistochemical studies will be performed to evaluate tumor 
and immunological cell markers such as CD4 and CD8 T cells. In 
peripheral blood, we will also evaluate tumor and immune cell 
populations including but not limited to CD4 and CD8 T cells in pre and 
post therapy samples. 
 
 
Peripheral blood up to 45 mL (within 24 hours) will be collected under an 
IRB-approved laboratory protocol (IMT lab protocol PA13-0291) for 
testing of biomarkers at the following time points 
-Baseline (prior to 5-azacytidine dose), on day 14 (prior to nivolumab), 
and between days 21 to 28 on cycle 1 (done at MD Anderson). 
In Arm 3: baseline (prior to azacitidine dosing), on Day 2 and 8 (prior 
to nivolumab dosing), Day 14, and Day 22 (prior to nivolumab dosing) 
-In each subsequent cycle blood samples will be obtained on day 1 (prior 
to 5-azacytidine dose) and day 14 (prior to nivolumab dose) when 
possible. 
In Arm 3 in each subsequent cycle blood samples will be obtained on 
Day 1 (prior to azacitidine dose), on Day 2 and 8 (prior to nivolumab 
dosing), Day 14, and Day 22 (prior to nivolumab dosing) 
 
-Samples will be collected at progression whenever possible. 
 
Bone Marrow: 
-Bone marrow samples for PA13-0291 will be collected under an IRB-
approved laboratory protocol for testing of biomarkers at baseline, at day 
28 (+/-7 days) or in Arm 3 at Day 21 (+/-4 days), then every 1-3 cycles, 
and at progression. All correlative samples are optional. 
 
 
All these samples can be obtained +/- 3 days. Missed samples for 
correlative studies will not constitute protocol deviations. 
 
7.3.9 Study specific correlative studies relating to biomarkers and patient 
response mechanisms will be collected under the clinical trial, up to 
40mLs of peripheral blood and up to 10mls of bone marrow aspiration.  
Samples will be banked for later use or sent fresh to Notable labs (blood 
samples only).   
 
Bone marrow aspiration samples may be collected whenever the patient 
has a bone marrow procedure scheduled for study evaluations as described 
in sections 7.2 and 7.3.   
 
Peripheral blood samples may be collected up to 20mls on the following 
schedule:  
Baseline (prior to 5-azacytidine dose), on Day 7, on day 14 (prior to 
nivolumab), and between days 21 to 28 on cycle 1 (done at MD 


Nivolumab and azacytidine 
 
Page 71 of 99 
 
Anderson). 
In Arm 3: baseline (prior to azacitidine dosing), on Day 2 and 8 (prior 
to nivolumab dosing), Day 14, and Day 22 (prior to nivolumab dosing) 
-In each subsequent cycle blood samples will be obtained on day 1 (prior 
to 5-azacytidine dose) and day 14 (prior to nivolumab dose) when 
possible. 
In Arm 3 in each subsequent cycle blood samples will be obtained on Day 
1 (prior to azacitidine dose), on Day 2 and 8 (prior to nivolumab dosing), 
Day 14, and Day 22 (prior to nivolumab dosing) 
 
All these samples can be obtained +/- 3 days. Missed samples for 
correlative studies will not constitute protocol deviations. 
 
 
 
7.3.10 For patients that remain on study with no significant toxicity for more than 
6 months, subsequent evaluations during study may be modified after 
discussion with the principal investigator.  These include a decrease in 
frequency of bone marrow aspirations to every 6-12 months (or as 
clinically indicated), correlative studies to every 6-12 months (or 
suspension of sample collection for correlative studies), other laboratory 
tests to once every cycle. 
 
7.3.11 ALL treatments with nivolumab and/or ipilimumab must be administered 
at the MDACC outpatient clinic. The first cycle of azacytidine must be fully 
administered at the MDACC outpatient clinic. Starting cycle #2, patients will 
have the option of receiving 5-azacytidine injections or infusions at the 
MDACC outpatient clinic or local ambulatory treatment center. We do not 
intend for the subjects to receive the nivolumab or the ipilimumab at an 
outside physician’s office at any time on the study.  During the first cycle 
all the laboratory evaluations will be done at MDACC. Subsequently, the 
patient may have the laboratory work done at a local clinic and the results 
reported to the research nurse for the study. The laboratory work done at 
the local clinic will be forwarded to the patient’s attending physician at 
MDACC or PI of the study, who will sign off on the labs to verify that the 
results have been reviewed. Patient should have end of cycle visit here at 
MDACC and/or prior to starting next cycle (+/- 4 days). 
 
 
Outside Physician Participation During Treatment 
 
1. MDACC Physician communication with the outside physician is 
required prior to the patient returning to the local physician. 
This will be documented in the patient record. 
 
 
2. A letter to the local physician outlining the patient's participation in a 
clinical trial will request local physician agreement to supervise the 


Nivolumab and azacytidine 
 
Page 72 of 99 
 
patient's care (Appendix H). 
 
3. Protocol required evaluations outside MDACC will be documented by 
telephone, fax or e-mail. Fax and/or e-mail will be dated and signed by the 
MDACC physician, indicating that they have reviewed it. Changes in drug 
dose and/or schedule must be discussed with and approved by the 
MDACC physician investigator, or their representative prior to initiation, 
and will be documented in the patient record. 
 
4. A copy of the informed consent, protocol abstract, treatment schema 
and evaluation during treatment will be provided to the local physician. 
 
5. Documentation to be provided by the local physician will include 
progress notes, reports of protocol required laboratory and diagnostic 
studies and documentation of any hospitalizations. 
 
6. The home physician will be requested to report to the MDACC 
physician investigator all life threatening events within 24 hours of 
documented occurrence. 
 
7. All follow-up visits will be performed at MDACC. 
 
8. Changes in drug dose and/or schedule must be discussed with and 
approved by the MDACC physician investigator, or their representative 
prior to initiation, and will be documented in the patient record. 
 
 
 
 
 
 
 
 
 
Study 
Period/ 
Cycle 
 
Sc
r
e
Treatment 
 
End of 
Study 
(EOS)h 
 
Cycle 1 
 
Cycle 2 
 
Cycle 3 
Subseq
u ent 
Cycles 
Cycle 
Day 
 
 
1 
 
8 
1 
5 
 
22 
 
1 
 
8 
 
15 
 
22 
 
1 
 
8 
 
1
5
2 
2 
 
1 
 
Study 
Day 
-14 
to 
 
1 
 
8 
1 
5 
 
22 
 
29 
 
36 
 
43 
 
50 
 
57 
6 
4 
 
7
1
7 
8  
Complete 
history 
X
X 
 
 
 
X  
 
 
X  
 
 
X 
 
Physical 
examinati ona 
 
X
 
X 
 
 
 
 
X  
 
 
 
X  
 
 
 
X 
 
X 
Performa 
nce status 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Documen 
t all 
measurab 
le disease (if 
present) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomit 
ant 
medicatio 
nsa 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


Nivolumab and azacytidine 
 
Page 73 of 99 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aA 
complete physical examination and documentation of concomitant medications will be done on day 1 of 
each cycle (+/- 4 days). 
bCBC with differential, creatinine, total bilirubin, ALT or AST will be done at least once weekly (+/- 4 
days) for the first 3 cycles, then every 2-4 weeks on subsequent cycles. 
cTSH, free T3, free T4,  total cortisol will be done at least once monthly (+/- 4 days) after the start of 
therapy for the first 3 cycles, then every 3 cycles (+/- 4 days) on subsequent cycles. 
dPregnancy test either urine or plasma should be done in women of childbearing potential 72 hours 
before initiation of protocol therapy.
 
eBone marrow aspiration must be done within 28-days of initiation of therapy. Cytogenetics may be used 
from prior bone marrow analysis if these were not reported on the screening bone marrow. 
fCorrelative studies will be collected on peripheral blood at baseline (prior to 5-azacytidine dose), on Day 
7 on day 14 (prior to nivolumab), and between days 21 to 28 on cycle 1. Subsequently, peripheral blood 
will be obtained on day 1 and day 14 of each cycles, and at progression if possible. All these tests can be 
CBC 
with 
differenti alb 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Creatinin 
e, total 
bilirubin, 
ALT, or 
ASTb 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
TSH, free T3, 
free T4, total 
cortisolc 
c 
 
X 
 
 
 
X  
 
 
X  
 
 
X 
 
EKG 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Respiratory 
PCR panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnanc y 
testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone 
marrow 
aspirate/b 
iopsye 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Respirato 
ry PCR 
panel and 
Chest 
XRay 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative  
 
Cycle 1 
 
Cycle 2 
 
Cycle 3 
Subsequ 
ent 
cycles 
 
EOS 
 
 Correlatives 
on bloodf 
 
 
 
Day 
1 
 
D 
a 
y 
1 
4 
 
 
Da 
y 
1 
 
 
Da 
y 
14 
 
 
Da 
y 
1 
 
 
 
Day 14 
 
 
 
Day 1 
and 14 
 
Correlatives on 
bone 
marrowg 
 
 
Day 
1 
 
 
 
Da 
y 
28 
 
 
 
 
 
 
 
 
 
 
Every 1-3 
cycles 
 


Nivolumab and azacytidine 
 
Page 74 of 99 
 
+/- 3 days 
 gCorrelative studies will be collected on bone marrow at day 28 (+/-7 days), then every 1-3 cycles, and at 
progression. 
hEOS visitis include a physical examination, CBC with differential and platelets and a limited chemistry 
profile (total bilirubin, serum creatinine, SGPT or SGOT). A bone marrow aspiration may be done if 
non- response or progressive disease cannot be unequivocally diagnosed from peripheral blood. 
 
Data regarding adverse events will be collected during the study. Please see Appendix D 
regarding data capturing of adverse events and adverse events source documentation. 
Protocol specific data will be entered into PDMS/CORe. PDMS/CORe will be used as  
the electronic case report form for this protocol. Only unexpected AEs will be recorded in 
the Case Report Form (CRF). The Principal Investigator will sign and date the AE log per 
each patient at the completion of each course. Following signature, the AE log will be 
used as source documentation for the adverse events for attribution. 
 
Treatment may be discontinued for a variety of reasons, including patient withdrawal, 
investigator decision, and reasons specified by the protocol. Reasons for discontinuation 
of treatments are described below. 
 
 
 
8.1 CRITERIA FOR RESPONSE: 
 
Response Criteria for AML 
 
Response criteria will be modified from the International Working Group for 
AML [67]. Responders are patients who obtain a CR, CRi, or PR, with or without 
cytogenetic response, hematologic improvements, and morphologic leukemia-free 
state. Briefly, criteria are as follows: 
 
8.1.1 
Complete remission (CR): 
 
 
Peripheral blood counts: 
No circulating blasts 
Neutrophil count >/=1.0 x109/L 
Platelet count >/=100 x109/L 
 
 
Bone marrow aspirate and biopsy: 
≤5% blasts 
No Auer rods 
No extramedullary leukemia 
 
8.1.2 
Complete Remission with Incomplete Platelet Recovery (CRp): 
 
 
 
For patients to be classified as being in CRp, they must achieve CR 
except for incomplete platelet recovery (<100 × 109/L). 
 


Nivolumab and azacytidine 
 
Page 75 of 99 
 
8.1.3 
Complete remission with incomplete blood count recovery (CRi): 
 
 
Peripheral blood counts: 
No circulating blasts 
Neutrophil count <1.0 x109/L, or 
Platelet count <100 x109/L 
 
 
Bone marrow aspirate and biopsy: 
</= 5% blasts 
No Auer rods 
No extramedullary leukemia 
 
8.1.4 
Partial remission: 
 
All CR criteria if abnormal before treatment except: 
 
>/=50 % reduction in bone marrow blast but still >5% 
 
8.1.5 
Morphologic leukemia-free state: 
 
Bone marrow: </=5% myeloblasts 
 
8.1.6 
Hematologic  Improvement  (HI):   Hematologic  response  must  be 
described by the number of positively affected cell lines. 
 
 
 
Erythroid response (E) (pretreatment Hgb <11 g/dL) 
Hgb increase by >/=1.5 g/dL 
 
 
Platelet response (P) (pretreatment platelets <100 x109/L) 
Absolute increase of >/=30 x 109/L for patients starting with > 20 x 
109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
 
 
 
Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
 
Blast response (B) 
>/=50% reduction in peripheral blood or bone marrow blasts but 
still >5% 
 
9 
DISCONTINUATION OF TREATMENT: 
 
9.1 Discontinuation Criteria for Individual Patients 
 
9.1.1 Patient Withdrawal 
 
 
Patients may voluntarily withdraw consent to participate in the clinical study at any 
time and without giving any reason. Their withdrawal will not jeopardize their 
relationship with their healthcare providers or affect their future care. Patients may 
also choose to withdraw from study treatment, but agree to remain in the study for 


Nivolumab and azacytidine 
 
Page 76 of 99 
 
follow-up procedures. 
 
9.1.2 Investigator Discontinuation of Patient 
The investigator may exercise medical judgment to discontinue study treatment if 
clinically significant changes in clinical status or laboratory values are noted. 
 
9.1.3 Criteria for Protocol-Defined Required Discontinuation of Treatment 
The protocol requires discontinuation of study treatment for the following reasons: 
1. Patient requests discontinuation. 
2. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to 
continue therapy. 
3. Clinically significant progressive disease. 
4. Investigator discretion. 
 
9.1.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Patients who discontinue treatment for any reason should complete end-of-treatment 
procedures when possible. End of treatment procedures will include a physical 
examination, CBC with differential and platelets and a limited chemistry profile (total 
bilirubin, serum creatinine, SGPT or SGOT). A bone marrow aspiration may be 
recommended only if non-response or progressive disease cannot be unequivocally 
diagnosed from peripheral blood. Although treatment will be discontinued at that time, all 
patients who do not withdraw consent for follow-up, die, or become lost to follow-up, 
will remain on study for follow-up evaluations. Subject will be followed for toxicity for  
at least 30 days after the last protocol treatment. The 30-day follow-up visit (+ or – 3 
days) will be scheduled as a clinic visits for clinical evaluation and physical 
examinations. If the patient cannot make it to the MDACC clinic for this visit, the 
required follow up treatment procedures may be done with a local physician and the 
records forwarded to MDACC. The research nurse will contact the patient by telephone 
and get a verbal assessment of the patient’s condition. The phone conversation will then 
be documented in the patient’s charts. 
 
9.2 Study Stopping Rules 
The principal investigator and MDACC IND office have the right to terminate this 
clinical study at any time. The principal investigator and MDACC IND office, as 
appropriate, will be involved in any decisions regarding terminating the study, 
temporarily suspending enrollment, or stopping ongoing treatment with study treatment. 
Reasons for terminating the clinical study or a study site’s participation include, but are 
not limited to, the following: 
 
The incidence or severity of an adverse reaction related to treatment in this study 
or other studies indicates a potential health hazard to patients 
 
Data recording is significantly inaccurate or incomplete 
 
Study site personnel are noncompliant with study procedures
 
 
Pattern of noncompliance is observed 
 
9.3 Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required processes 
or procedures that affect patient safety or benefit potential, or confound assessments of 


Nivolumab and azacytidine 
 
Page 77 of 99 
 
safety or clinical activity. A protocol deviation is a departure from the protocol that does 
not meet the above criteria. Protocol violations or deviations may be grouped into the 
following classes: 
 
Enrollment criteria 
 
Study activities (missed evaluations or visits) except for those allowed per 
protocol 
 
Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay; or discontinuation criteria 
 
Investigational product handling, including storage and accountability 
 
Informed consent and ethical issues 
 
 
 
10 ADVERSE EVENT REPORTING 
 
10.1 
Adverse event is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have a 
causal relationship with this treatment. 
 
Adverse drug reaction is a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for the modification of physiologic function. 
 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) 
the event would not have happened at all, 2) the event would have occurred later 
than it actually did, or 3) the event would have been less severe. 
 
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial. 
 
10.2 
Adverse Events (AEs) will be evaluated according to the latest CTC version 4 
(Appendix C) and documented in medical record.  Only unexpected AEs will 
be recorded in the Case Report Form (CRF).  Expected events during 
leukemia therapy are: 
 
10.2.6 Myelosuppression related events (due to disease or leukemia therapy) 
 
10.2.6.1 
febrile or infection episodes not requiring management in 
the intensive care unit 
 
 
 
10.2.6.2 
epistaxis or bleeding except for catastrophic CNS or 
pulmonary hemorrhage 
 
10.2.6.3 
anemia, neutropenia, lymphopenia, thrombocytopenia, 


Nivolumab and azacytidine 
 
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leukopenia 
 
10.2.7 Disease related events 
 
10.2.7.1 
symptoms associated with anemia 
 
10.2.7.1.1 fatigue 
 
10.2.7.1.2 weakness 
 
10.2.7.1.3 shortness of breath 
 
10.2.7.2 
electrolyte abnormalities (sodium, potassium, bicarbonate, 
CO2, magnesium) 
 
10.2.7.3 
chemistry abnormalities (LDH, phosphorus, calcium, BUN, 
protein, albumin, uric acid, alkaline phosphatase, glucose) 
 
10.2.7.4 
coagulation abnormalities 
 
10.2.7.5 
disease specific therapy (induction, maintenance, salvage, 
or stem cell therapy) 
 
10.2.7.6 
alopecia 
 
10.2.7.7 
bone,  joint, or muscle pain 
 
10.2.7.8 
liver function test abnormalities associated with infection 
or disease progression 
 
10.2.7.9 
disease progression 
 
10.2.7.10 
abnormal hematologic values 
 
10.2.8 General therapy related events 
 
10.2.8.1 
catheter related events 
 
10.2.8.2 
renal failure related to tumor lysis syndrome or antibiotic/ 
antifungal therapy 
 
 
10.2.8.3 
rash related to antibiotic use 
 
10.2.9 Hospitalization for the management of any of the above expected  events 
 
10.3 Abnormal hematologic values will not be captured in the CRFs or the Leukemia 
AE log. Only the highest grade per course of grade 3 or 4 chemistry lab 


Nivolumab and azacytidine 
 
Page 79 of 99 
 
abnormalities will be captured on the AE log as well. All Serious Adverse Events 
will be captured on the Leukemia AE log as well as entered in the CRFs, 
regardless of expectedness. 
 
10.4 Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might have 
caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate 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. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
 Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Sponsor, IND Office. 
 
 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or 
 
 
unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
 
 All life-threatening or fatal events, that are unexpected, and related to 


Nivolumab and azacytidine 
 
Page 80 of 99 
 
the study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in 
the IND Office. 
 
 
 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB. 
 
 Serious adverse events will be captured from the time of the first protocol- 
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Additionally, any serious adverse events 
that occur between Day 31-100 will be captured as immune mediated 
toxicities from checkpoint inhibitors may have delayed manifestations. 
Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the event. 
 
 Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy 
 
10.5 
Serious Adverse event Reporting to Bristol-Myers Squibb Inc. 
All Serious Adverse Events must be reported to BMS Worldwide 
Safety 
 All SAEs, whether related or unrelated to nivolumab and all pregnancies 
must be reported to BMS (by the investigator or designee) within 
24 hours. 
 All SAEs should be reported via confirmed facsimile (fax) transmission, 
or scanned and reported via electronic mail to: 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
 
11.1 
STATISTICAL CONSIDERATIONS 
 
This will be a phase II, three parallel arm, open-label, non-randomized study with a safety 
lead-in phase.  
 
 
11.2 
Sample Size 


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Page 81 of 99 
 
 
Arm 1:  
Part a. Lead-in phase  
The primary objective of the lead-in phase is to determine the safety of nivolumab in 
combination with 5-azacytidine in patients with refractory/ relapsed AML. Up to 30 patients 
will be accrued into the lead-in part of the study. 
 
Part b. Expansion phase  
A. Up to 70 patients (including 6 patients treated at the MTD from the lead-in part) with 
relapsed/refractory AML will be recruited for the Arm 1 Salvage cohort . 
  B. Up to 40 newly diagnosed older AML patients (age ≥ 65) will be recruited for the Arm  
1 Frontline older cohort . 
 
Arm 2:  
Part a. Lead-in phase 
The primary objective of the lead-in phase is to determine the safety of nivolumab with 
ipilimumab in combination with 5-azacytidine in patients with refractory/ relapsed AML. Up to 
24 patients will be accrued into the lead-in part of the study. 
 
Part b. Expansion phase 
A. 
Up to 54 patients (including 6 patients treated at the MTD from the lead-in part) with 
relapsed/refractory AML will be recruited for the Arm 2 Salvage cohort. 
B. 
Up to 30 newly diagnosed older AML patients (age ≥ 65) will be recruited for the Arm 
2 Frontline older cohort. 
The efficacy of the combination will be measured by the overall response rate (ORR), 
defined as CR (complete remission) + CRp (complete remission with incomplete platelet 
recovery) + CRi (complete remission with incomplete count recovery) + PR (partial 
response) + marrow clearance of blasts + hematologic improvement (HI) in platelets, 
hemoglobin, or ANC within 3 months of treatment initiation among adult patients with 
refractory/ relapsed AML AND newly diagnosed older patients with AML. ORR and 
toxicity will be monitored simultaneously using the Bayesian approach of Thall, Simon, 
Estey (1995, 1996) and the extension by Thall and Sung (1998). 
 
Arm 3:  
Part a. Lead-in phase 
The primary objective of the lead-in phase is to determine the safety of nivolumab with 5-
azacytidine and venetoclax in patients with refractory/ relapsed AML. A total of 18 patients (3 
dose levels with a maximum of 6 patients at each dose level) will be accrued into the lead-in 
part of the study. 
 
Part b. Expansion phase 
A. 
A total of 30 patients (excluding 6 patients treated at the MTD from the lead-in part) 
with relapsed/refractory AML will be recruited for the Arm 3Salvage cohort. 
B. 
A total of 30 newly diagnosed older AML patients (age ≥ 65) will be recruited for the 
Arm 3 Frontline older cohort. 
 
Once safety of the MTD has been established, any patients still on study at a dose lower 
than MTD can be dose escalated up to MTD. Patients treated in the lead-in phase at MTD 


Nivolumab and azacytidine 
 
Page 82 of 99 
 
will be included in the Phase II portion of the study. 
 
The efficacy of the combination will be measured by the overall response rate (ORR), 
defined as CR (complete remission) + CRp (complete remission with incomplete platelet 
recovery) + CRi (complete remission with incomplete count recovery) + MLFS within 6 
months of treatment initiation among adult patients with refractory/ relapsed AML AND 
newly diagnosed older patients with AML. ORR and toxicity will be monitored 
simultaneously using the Bayesian approach of Thall, Simon, Estey (1995, 1996) and the 
extension by Thall and Sung (1998). 
 
 
11.3 
Statistical Design 
 
Part a. Lead-in phase 
The MTD is defined as the highest dose level with < 2 out of 6 patients experience a DLT 
during the first 28 days of treatment. DLT is defined in section 5.2.2. The dosing schema for 
the combination treatment during the lead in phase is shown in Tables 5 and 5B in section 
5.2.1. 
 
Part b. Expansion phase 
 
A. Arm 1 Relapsed/Refractory AML cohort (Aza+Nivo) (N=70: completed accrual 
and closed to accrual)
 
Historical data on similar patients show a ORR of 10-15%. The target ORR with the 
experimental treatment is 30%. This regimen of the combination treatment will be 
considered worthy of further investigation if it elicits an increase in ORR to 30% with 
acceptable toxicity.  A >30% drug-related grade 3/4 toxicity rate is considered unacceptable. 
Thus, interim monitoring rules, assuming the prior distributions below, were constructed 
that meet the following two conditions, 
 
1) Stop if Prob{ p(ORR,E )<p(ORR,H) + 0.15 | data} > 0.99, or 
 
2) Stop if Prob{ p(TOX,E)>0.30| data}>0.95, 
 
Where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the combination 
treatment, and p(ORR, H) is the true ORR rate of the standard treatment. The first rule 
provides for stopping the study if the data suggest that it is unlikely (i.e., probability < 1%) 
that ORR rate of the combination treatment is greater than the ORR rate of standard 
treatment by 15.0%. The second condition will stop the study early if excessive therapy- 
related grade 3/4 toxicity (>30%) is highly probable (i.e., probability >95.0%) for the 
combination treatment.  Monitoring for toxicity and futility will not begin until 6 patients 
have been evaluated, and cohort size for future evaluations is 3. 
 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring 
conditions above is found in Table 9. For example, accrual will cease if 5 or more 
patients experience toxicities among the first 6 patients. 
 
 
Table 9. Stop accrual if the number of drug-related grade 3/4 toxicities is greater than or equal to indicated (i.e., # 
patients with toxicities) among the number of patients evaluated 


Nivolumab and azacytidine 
 
Page 83 of 99 
 
 
 
Monitoring the ORR rate, based on the above assumptions and monitoring conditions is 
found in Table 10. For example, accrual will cease if no patient experience an overall 
response within 3 months of initiation of therapy in the first 9 patients treated. 
 
 
 
 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping 
boundaries and the OC table (Table 11). In order to utilize the software for the design, a 
15% constant rate and beta(0.3, 1.7) priors were assumed for the standard treatment 
response distribution and experimental treatment response prior distribution, respectively. In 
addition, a 30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for the 
standard treatment toxicity constant rate and experimental treatment toxicity prior 
distribution, respectively. 
 
 
The probability of stopping the study early if the true ORR of the combination treatment 
was 30% and the true toxicity rate was 30% was 24.7%.  Probabilities of stopping early for 
high true toxicity rates (i.e., 50%) were 97.5% when the true ORR was 30% and 99.6% 
when true ORR rate was 15%. 
 
 
# patients evaluated 
3 
6 
9 
12 
15 
18 
21 
# patients with toxicities 
3 
5-6 
6-9 
7-12 
8-15 
9-18 
11-21 
# patients evaluated 
24 
27 
30 
33 
36 
39 
42 
# patients with toxicities 
12-24 
13-27 
14-30 
15-33 
16-36 
17-39 
18-42 
# patients evaluated 
45 
48 
61 
54 
57 
60 
63 
# patients with toxicities 
19-45 
20-48 
22-51 
23-54 
24-57 
25-60 
26-63 
# patients evaluated 
66 
70 
 
 
 
 
 
 
# patients with toxicities 
 
27-66 
Always stop with 
this many patients 
 
 
 
 
 
Table 10. Stop accrual if the number with overall response is less than or equal to indicated (i.e., # patients with 
overall response) among the number of patients evaluated 
# patients evaluated 
3-6 
9-12 
15-18 
21-24 
27-30 
33 
36-39 
# patients with 
overall response 
Never stop with 
this many patients 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
# patients evaluated 
42 
45-48 
51 
54-57 
60 
63-66 
70 
# patients with 
overall response 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
Always stop with 
this many patients 
Table 11.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.15 
0.8503 
 
0.20 
0.5344 
 
0.25 
0.2466 
 
0.30 
0.0967 
 
0.35 
0.0377 


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Page 84 of 99 
 
 
 
 
 
B. Arm 1 Newly diagnosed older AML (≥65 years) cohort (Aza+Nivo) (N=40: closed to 
accrual as of 11/1/2019, Total Accrual to date was 15 patients) 
 
Historical data on similar patients show an ORR of 18-25% [the historical response rate in 
older newly diagnosed AML (≥65 years) with single agent hypomethylator therapy (5- 
azacytidine or decitabine) in three large randomized phase II trials was 17.5 % with 
decitabine alone in patients with AML (Kantarjian et al., JCO 2012), 18% with azacytidine 
alone in patients with AML and blasts 20-30% (Fenaux et al., JCO 2010), and 27.8% with 
azacytidine alone in patients with AML and blasts >30% (Dombret et al., Blood 2015)]. The 
target ORR with the experimental treatment is 40%. This regimen of the combination 
treatment will be considered worthy of further investigation if it elicits an increase in ORR 
to 40% with acceptable toxicity. A >30% drug-related grade 3/4 toxicity rate is considered 
unacceptable.  Thus, interim monitoring rules, assuming the prior distributions below, were 
constructed that meet the following two conditions, 
 
 
0.40 
0.0157 
0.20 
0.15 
0.8527 
 
0.20 
0.5419 
 
0.25 
0.2587 
 
0.30 
0.1112 
 
0.35 
0.0532 
 
0.40 
0.0315 
0.30 
0.15 
0.8752 
 
0.20 
0.6118 
 
0.25 
0.3718 
 
0.30 
0.2469 
 
0.35 
0.1977 
 
0.40 
0.1793 
0.40 
0.15 
0.9500 
 
0.20 
0.8446 
 
0.25 
0.7485 
 
0.30 
0.6985 
 
0.35 
0.6788 
 
0.40 
0.6714 
0.50 
0.15 
0.9959 
 
0.20 
0.9872 
Table 11.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
 
0.25 
0.9792 
 
0.30 
0.9751 
 
0.35 
0.9735 
 
0.40 
0.9729 


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Page 85 of 99 
 
3) Stop if Prob{ p(ORR,E )<p(ORR,H) + 0.15 | data} > 0.99, or 
 
4) Stop if Prob{ p(TOX,E)>0.30| data}>0.95, 
 
where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the combination 
treatment, and p(ORR, H) is the true ORR rate of the standard treatment. The first rule 
provides for stopping the study if the data suggest that it is unlikely (i.e., probability < 1%) 
that ORR rate of the combination treatment is greater than the ORR rate of standard 
treatment by 15.0%. The second condition will stop the study early if excessive therapy- 
related grade 3/4 toxicity (>30%) is highly probable (i.e., probability >95.0%) for the 
combination treatment.  Monitoring for toxicity and futility will not begin until 6 patients 
have been evaluated, and cohort size for future evaluations is 4. 
 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring 
conditions above is found in Table 12. For example, accrual will cease if 5 or more 
patients experience toxicities among the first 8 patients. 
 
 
 
Monitoring the ORR rate, based on the above assumptions and monitoring conditions is 
found in Table 13. For example, accrual will cease if no patient experience an overall 
response within 3 months of initiation of therapy in the first 8 patients treated. 
 
 
 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping 
boundaries and the OC table (Table 14). In order to utilize the software for the design, a 
25% constant rate, and beta(0.5,1.5) priors were assumed for the standard treatment 
response distribution and experimental treatment response prior distribution, respectively. In 
addition, a 30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for the 
standard treatment toxicity constant rate and experimental treatment toxicity prior 
distribution, respectively. 
 
 
The probability of stopping the study early if the true ORR of the combination treatment 
was 30% and the true toxicity rate was 30% was 17.6%.  Probabilities of stopping early for 
high true toxicity rates (i.e., 50%) were 86.5% when the true ORR was 40% and 93.1% 
when true ORR rate was 25%. 
 
 
Table 12. Stop accrual if the number of drug-related grade 3/4 toxicities is greater than or equal to indicated (i.e., # 
patients with toxicities) among the number of patients evaluated 
# patients evaluated 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
 
# patients with 
toxicities 
 
4 
 
5-8 
 
7-12 
 
9-16 
 
10-20 
 
12-24 
 
13-28 
 
15-32 
 
16-36 
Always stop 
with this many 
patients 
Table 13. Stop accrual if the number with overall response is less than or equal to indicated (i.e., # patients with 
overall response) among the number of patients evaluated 
# patients evaluated 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
 
# patients with overall 
response 
Never stop 
with this many 
patients 
 
0 
 
0-1 
 
0-2 
 
0-3 
 
0-4 
 
0-5 
 
0-6 
 
0-8 
Always stop 
with this many 
patients 


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Page 86 of 99 
 
 
 
 
 
C. Arm 2 First and Second Salvage AML cohort (AZA + Nivo + Ipi)  
 
 Historical data on similar patients show an ORR of 12-15%. The target ORR with the 
experimental treatment is 30%. This regimen of the combination treatment will be 
considered worthy of further investigation if it elicits an increase in ORR to 30% with 
acceptable toxicity.  A >30% drug-related grade 3/4 toxicity rate is considered unacceptable. 
Thus, interim monitoring rules, assuming the prior distributions below, were constructed 
that meet the following two conditions, 
 
5) Stop if Prob{ p(ORR,E )<p(ORR,H) + 0.15 | data} > 0.99, or 
 
6) Stop if Prob{ p(TOX,E)>0.30| data}>0.95, 
 
Table 14.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.25 
0.5185 
 
0.35 
0.1345 
 
0.40 
0.0558 
 
0.45 
0.0217 
 
0.50 
0.0083 
0.20 
0.25 
0.5254 
 
0.35 
0.2975 
 
0.40 
0.0694 
 
0.45 
0.0358 
 
0.50 
0.0226 
0.30 
0.25 
0.5797 
 
0.35 
0.2446 
 
0.40 
0.1759 
 
0.45 
0.1461 
 
0.50 
0.1344 
0.40 
0.25 
0.7494 
 
0.35 
0.5496 
 
0.40 
0.5087 
 
0.45 
0.4909 
Table 14.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
 
0.50 
0.4840 
0.50 
0.25 
0.9309 
 
0.35 
0.8759 
 
0.40 
0.8646 
 
0.45 
0.8597 
 
0.50 
0.8578 


Nivolumab and azacytidine 
 
Page 87 of 99 
 
Where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the combination 
treatment, and p(ORR, H) is the true ORR rate of the standard treatment. The first rule 
provides for stopping the study if the data suggest that it is unlikely (i.e., probability < 1%) 
that ORR rate of the combination treatment is greater than the ORR rate of standard 
treatment by 15.0%. The second condition will stop the study early if excessive therapy- 
related grade 3/4 toxicity (>30%) is highly probable (i.e., probability >95.0%) for the 
combination treatment.  Monitoring for toxicity and futility will not begin until 6 patients 
have been evaluated, and cohort size for future evaluations is 6. 
 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring 
conditions above is found in Table 15. For example, accrual will cease if 5 or 
more patients experience toxicities among the first 6 patients. 
 
 
Table 15. Stop accrual if the number of drug-related grade 3/4 toxicities is 
# patients 
# patients with toxicities 
6 
5-6 
12 
7-12 
18 
9-18 
24 
12-24 
30 
14-30 
36 
16-36 
42 
18-42 
48 
20-48 
54 
Always stop with this many patients 
 
Monitoring the ORR rate, based on the above assumptions and monitoring conditions is 
found in Table 16. For example, accrual will cease if no patient experience an overall 
response within 3 months of initiation of therapy in the first 12 patients treated. 
 
Table 16. Stop accrual if the number with overall response is less than or 
# patients 
# patients with overall response 
6 
Never stop with this many patients 
12 
0 
18 
0-1 
24 
0-2 
30 
0-3 
36 
0-5 
42 
0-6 
48 
0-7 
54 
Always stop with this many patients 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping 
boundaries and the OC table (Table 17). In order to utilize the software for the design, a 
15% constant rate and beta(0.3, 1.7) priors were assumed for the standard treatment 
response distribution and experimental treatment response prior distribution, respectively. In 
addition, a 30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for the 


Nivolumab and azacytidine 
 
Page 88 of 99 
 
standard treatment toxicity constant rate and experimental treatment toxicity prior 
distribution, respectively. 
 
 
The probability of stopping the study early if the true ORR of the combination treatment 
was 30% and the true toxicity rate was 30% was 16.9%.  Probabilities of stopping early for 
high true toxicity rates (i.e., 50%) were 93.5% when the true ORR was 30% and 97.8% 
when true ORR rate was 15%. 
 
Table 17.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.15 
0.6760 
 
0.20 
0.3539 
 
0.25 
0.1404 
 
0.30 
0.0459 
 
0.35 
0.0136 
 
0.40 
0.0040 
0.20 
0.15 
0.6787 
 
0.20 
0.3594 
 
0.25 
0.1477 
 
0.30 
0.0540 
 
0.35 
0.0220 
 
0.40 
0.0124 
0.30 
0.15 
0.7179 
 
0.20 
0.4375 
 
0.25 
0.2516 
 
0.30 
0.1694 
 
0.35 
0.1412 
 
0.40 
0.1328 
0.40 
0.15 
0.8603 
 
0.20 
0.7214 
 
0.25 
0.6293 
 
0.30 
0.5886 
 
0.35 
0.5747 
 
0.40 
0.5705 
0.50 
0.15 
0.9779 
 
0.20 
0.9559 
 
0.25 
0.9414 
 
0.30 
0.9349 
 
0.35 
0.9327 
 
0.40 
0.9321 
 
 
D. Arm 2 Newly diagnosed older AML (≥65 years) cohort (Aza+Nivo+Ipi) (N=30) 
 
Historical data on similar patients show an ORR of 18-25% [the historical response rate in 
older newly diagnosed AML (≥65 years) with single agent hypomethylator therapy (5- 


Nivolumab and azacytidine 
 
Page 89 of 99 
 
azacytidine or decitabine) in three large randomized phase II trials was 17.5 % with 
decitabine alone in patients with AML (Kantarjian et al., JCO 2012), 18% with azacytidine 
alone in patients with AML and blasts 20-30% (Fenaux et al., JCO 2010), and 27.8% with 
azacytidine alone in patients with AML and blasts >30% (Dombret et al., Blood 2015)]. The 
target ORR with the experimental treatment is 40%. This regimen of the Aza+Nivo+Ipi 
combination treatment will be considered worthy of further investigation if it elicits an 
increase in ORR to 40% with acceptable toxicity. A >30% drug-related grade 3/4 toxicity 
rate is considered unacceptable.  Thus, interim monitoring rules, assuming the prior 
distributions below, were constructed that meet the following two conditions, 
 
7) Stop if Prob{ p(ORR,E )<p(ORR,H) + 0.15 | data} > 0.99, or 
 
8) Stop if Prob{ p(TOX,E)>0.30| data}>0.95, 
 
where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the combination 
treatment, and p(ORR, H) is the true ORR rate of the standard treatment. The first rule 
provides for stopping the study if the data suggest that it is unlikely (i.e., probability < 1%) 
that ORR rate of the combination treatment is greater than the ORR rate of standard 
treatment by 15.0%. The second condition will stop the study early if excessive therapy- 
related grade 3/4 toxicity (>30%) is highly probable (i.e., probability >95.0%) for the 
combination treatment.  Monitoring for toxicity and futility will not begin until 6 patients 
have been evaluated, and cohort size for future evaluations is 3. 
 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring 
conditions above is found in Table 18. For example, accrual will cease if 5 or more 
patients experience toxicities among the first 6 patients. 
 
 
Table 18. Stop accrual if the number of drug-related grade 3/4 toxicities is greater than or equal to indicated (i.e., # patients 
with toxicities) among the number of patients evaluated 
# patients evaluated 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
# patients with 
toxicities 
Never stop 
 with this  
many patients 
5-6 
6-9 
7-12 
8-15 
9-18 
11-21 
12-24 
13-27 
Always stop  
with this  
many patients 
 
 
Monitoring the ORR rate, based on the above assumptions and monitoring conditions is 
found in Table 19. For example, accrual will cease if no patient experience an overall 
response within 3 months of initiation of therapy in the first 8 patients treated. 
 
 
Table 19. Stop accrual if the number with overall response is less than or equal to indicated (i.e., # patients with overall 
)
h
b
f
i
l
d
# patients 
l
d
3 
6-9 
12 
15-18 
21 
24 
27 
30 
# patients with 
overall response 
Never stop 
with this 
many patients 
0 
1 
2 
3 
4 
5 
Always stop 
with this 
many patients 
 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping 
boundaries and the OC table (Table 19). In order to utilize the software for the design, a 
25% constant rate, and beta(0.5,1.5) priors were assumed for the standard treatment 
response distribution and experimental treatment response prior distribution, respectively. In 
addition, a 30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for the 
standard treatment toxicity constant rate and experimental treatment toxicity prior 


Nivolumab and azacytidine 
 
Page 90 of 99 
 
distribution, respectively. 
 
 
The probability of stopping the study early if the true ORR of the combination treatment 
was 30% and the true toxicity rate was 30% was 17.6%.  Probabilities of stopping early for 
high true toxicity rates (i.e., 50%) were 86.5% when the true ORR was 40% and 93.1% 
when true ORR rate was 25%. 
 
 
 
 
E. Arm 3 First and Second Salvage AML cohort (AZA + VEN + Nivo) (N=30) 
 
Table 19.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.25 
0.4344 
 
0.30 
0.2594 
 
0.35 
0.1429 
 
0.40 
0.0751 
 
0.45 
0.0384 
 
0.50 
0.0194 
0.20 
0.25 
0.4399 
 
0.30 
0.2665 
 
0.35 
0.1512 
 
0.40 
0.0840 
 
0.45 
0.0477 
 
0.50 
0.0289 
0.30 
0.25 
0.4903 
 
0.30 
0.3326 
 
0.35 
0.2277 
 
0.40 
0.1665 
 
0.45 
0.1335 
 
0.50 
0.1163 
0.40 
0.25 
0.6483 
 
0.30 
0.5395 
 
0.35 
0.4671 
 
0.40 
0.4249 
 
0.45 
0.4021 
 
0.50 
0.3902 
0.50 
0.25 
0.8554 
 
0.30 
0.8107 
 
0.35 
0.7809 
 
0.40 
0.7636 
 
0.45 
0.7542 
 
0.50 
0.7493 


Nivolumab and azacytidine 
 
Page 91 of 99 
 
Historical data for salvage patients with azacitidine and venetoclax show an overall response rate 
(ORR) of 25-50% (DiNardo CD et al, American journal of hematology 2018; 93(3): 401-7;  Aldoss I et 
al, Haematologica. 2018 Sep;103(9):e404-e40;  Goldberg A et al, Blood 2017; 130(Suppl 1): 1353). 
It is expected for the current trial that the three-drug combination will improve the ORR by 35% while 
the toxicity rate is maintained at or below 30%. A sample size of 30 patients ensures that, if the trial 
is not terminated early, a posterior 90% credible interval for ORR will have width of 0.28 at most, 
under the assumption of a 60% of ORR rate. The prior probabilities of ORR and toxicity for the 
experimental regimen are modeled by beta distributions (Beta (0.5, 1.5) and Beta (0.6, 1.4), 
respectively). Denoting the historical proportion of overall response rate and toxicity rate by 
{p(ORR,H) = 25% , p(TOX,H) = 30%}, the following decision criteria will be applied:  
1) Stop if Prob{p(ORR,H) + δOR > p(ORR,E) | data} > 0.975, where δOR = 0.35 
2) Stop if Prob{p(TOX,H) + δTOX < p(TOX,E)| data} > 0.95, where δTOX = 0 
 
Patients will be monitored in cohorts of 5 according to the following stopping boundaries for overall 
response and DLT.


Nivolumab and azacytidine 
 
Page 92 of 99 
 
 
 
# Patients Evaluated 
Stop if this cohort  
≤ this # ORR 
Stop if ≥ this 
 # toxicities 
5 
0-1 
4-5 
10 
0-3 
6-10 
15 
0-5 
8-15 
20 
 0-8 
 10-20 
25 
0-10 
12-25 
30 
Always stop with this many patients 
Always stop with this 
many patients 
 
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials). 
True Toxicity Rate 
True ORR Rate 
PROB(Stop Early) 
0.10 
0.25 
 0.9838 
0.45 
 0.5615 
0.60 
 0.1459 
0.75 
 0.0185 
0.90 
 0.0011 
0.20 
0.25 
 0.9840 
0.45 
 0.5676 
0.60 
 0.1579 
0.75 
 0.0322 
0.90 
 0.0150 
0.30 
0.25 
 0.9856 
0.45 
 0.6094 
0.60 
 0.2393 
0.75 
 0.1258 
0.90 
 0.1102 
0.40 
0.25 
 0.9900 
0.45 
 0.7297 
0.60 
 0.4736 
0.75 
 0.3951 
0.90 
 0.3843 
0.50 
0.25 
 0.9958 
0.45 
 0.8852 
0.60 
 0.7764 
0.75 
 0.7431 
0.90 
 0.7385 
 
 
F. Arm 3 Frontline Elderly AML cohort (AZA + VEN + Nivo) (N=30) 
 
Historical data for frontline patients treated with venetoclax and hypomethylating agents (DiNardo 
CD et al, Blood. 2019 Jan 3;133(1):7-17);  Pollyea D et al ASH 2018 Oral presentation Abstract 285.: 
full PowerPoint attached as Appendix) show ORR of 66%. It is expected for the current trial that the 


Nivolumab and azacytidine 
 
Page 93 of 99 
 
three-drug combination will improve the ORR by 15-20% while the toxicity rate is maintained at or 
below 30%. A sample size of 30 patients ensures that, if the trial is not terminated early, a posterior 
90% credible interval for ORR will have width of 0.28 at most, under the assumption of a 80% of 
ORR. The prior probabilities of ORR and toxicity for the experimental regimen are modeled by beta 
distributions (Beta (1.2, 0.8) and Beta (0.6, 1.4), respectively. Denoting the historical proportion of 
overall response rate and toxicity rate by {p(ORR,H) = 0.60 , p(TOX,H) = 0.30}, the following 
decision criteria will be applied:  
1) Stop if Prob{p(ORR,H) + δOR > p(ORR,E) | data} > 0.95, where δOR = 0.2 
2) Stop if Prob{p(TOX,H) + δTOX < p(TOX,E)| data} > 0.90, where δTOX = 0 
 
Patients will be monitored in cohorts of 5 according to the following stopping boundaries for overall 
response and toxicity. 
# Patients Evaluated Stop this cohort if ≤ this # ORR 
Stop if ≥ this # toxicities 
5 
0-2 
4-5 
10 
0-5 
6-10 
15 
0-9 
8-15 
20 
 0-12 
10-20 
25 
0-16 
12-25 
30 
Always stop with this many patients 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials). 
True Toxicity Rate 
True ORR Rate 
PROB(Stop Early) 
0.10 
0.60 
 0.7956 
0.70 
 0.4433 
0.80 
 0.1221 
0.85 
 0.0441 
0.90 
 0.0114 
0.20 
0.60 
 0.7985 
0.70 
 0.4511 
0.80 
 0.1344 
0.85 
 0.0575 
0.90 
 0.0252 
0.30 
0.60 
 0.8180 
0.70 
 0.5041 
0.80 
 0.2180 
0.85 
 0.1485 
0.90 
 0.1194 
0.40 
0.60 
 0.8740 
0.70 
 0.6569 
0.80 
 0.4589 
0.85 
 0.4109 
0.90 
 0.3907 
0.50 
0.60 
 0.9465 
0.70 
 0.8543 
0.80 
 0.7702 


Nivolumab and azacytidine 
 
Page 94 of 99 
 
True Toxicity Rate 
True ORR Rate 
PROB(Stop Early) 
0.85 
 0.7498 
0.90 
 0.7412 
 
The Investigator is responsible for completing an efficacy/safety summary report, and submitting it to 
the IND Office Medical Affairs and Safety Group, for review and approval.  This should be submitted 
as follows: 
 
Lead-in Phase: 
Every 6 evaluable patients complete cycle 1 of study therapy before advancing/changing dose 
levels. 
 
Expansion Phase: 
After the first 5 evaluable patients per cohort, complete 3 months of study treatment, and every 5 
evaluable patients per cohort, thereafter. 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
Statistical Analysis Plan 
 
All patients who received any dose of the study agent will be included in the analysis for 
efficacy and safety.  Demographic/clinical characteristics (including duration of response) 
and safety data of the patients will be summarized using descriptive statistics such as mean, 
standard deviation, median and range. For the primary efficacy analysis, we will estimate 
the ORR for the combination treatment, along with the 95% confidence interval. Patients 
who drop out of the study before completing all the cycles will be treated as “failures” for 
the primary analysis. Overall response rate (ORR) during the study period will also be 
presented with the 95% confidence interval. The association between ORR and patient’s 
clinical characteristics will be examined by Wilcoxon’s rank sum test or Fisher’s exact test, 
as appropriate. Toxicity type, severity and attribution will be summarized for each patient 
using frequency tables. 
 
The distribution of time-to-event endpoints (DFS and OS) including overall survival and 
progression free survival will be estimated using the method of Kaplan and Meier. 
Comparisons of time-to-event endpoints by important subgroups will be made using the log- 
rank tests. Paired t-tests will be used to determine the immunological and molecular changes 
in the peripheral blood and bone marrow from baseline to the time of response, and to the 
time of disease progression. Correlation analysis (such as logistic regression analysis) will 
be conducted to determine the relationship between induction of hypomethylation / DNA 
damage and clinical response. 
 
 
 
Statistical analysis of biomarker data: Descriptive statistics including plots, mean, median 
and standard deviations will be used to summarize data. For continuous outcomes, t-test and 
ANOVA will be used to compare outcome measures across patient characteristics. 
Dunnett’s and Tukey’s test that properly adjust for multiplicity in multiple tests will be 
implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples 
from each patient . The chi-square test or Fisher’s exact test will be used to test the 
association between two categorical variables such as disease state and performance status. 


Nivolumab and azacytidine 
 
Page 95 of 99 
 
Both univariate and multivariate logistic regressions will be performed to model prognostic 
factors. 
 
12.0 PROTOCOL ADMINISTRATION 
This study will be monitored for compliance by the IND Office. 
 
 
 
Protocol amendments 
 
Changes to the protocol will be made only when protocol amendments have been 
signed by the principal investigator and approved by the sponsor and the IRB of 
the study center. 
 
Archival of data 
 
All patient data (including source data) generated in connection with this study 
will be kept in the archives of the MDACC for at least 15 years after the study has 
been completed. All data will be available for inspection by company 
representatives   of  the  Medical  Department  and  by  regulatory  authorities. 
 
 
13.0 
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14.0 APPENDICES 
Appendix A: Prioritization List 
Appendix B: Protocol Checklist 
Appendix C: CTCAE version 4.0 
Appendix D: Leukemia specific AE recording and reporting guidelines 
Appendix E: Generic-Nivolumab Drug Information 
Appendix F: Generic-Vidaza Drug Information 
Appendix G: Management algorithms for immuno-oncology drug-related adverse events 
Appendix H: Outside Physician Form 
Appendix I: DOSING PROCEDURE MANUAL for Lirilumab and Nivolumab Version 
2.0 
Appendix J: Ipilimumab IB  
Appendix K: Nivolumab and Ipilimumab product information