Conditions: Leukemia Acute Myeloid Leukemia Myelodysplastic Syndrome
Keywords: Leukemia Acute myeloid leukemia AML Myelodysplastic Syndrome MDS High-risk Nivolumab BMS-936558 Opdivo Idarubicin Idamycin Cytarabine Ara-C Cytosar DepoCyt Cytosine Arabinosine Hydrochloride Solu-Medrol Methylprednisolone Depo-Medrol Medrol Dexamethasone Decadron
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to find the highest tolerable dose of nivolumab that can be give in combination with idarubicin and cytarabine in patients with MDS and AML. The safety and effectiveness of this drug combination will also be studied.

This is an investigational study. Nivolumab is not FDA-approved or commercially available. Idarubicin is FDA-approved and commercially available for the treatment of patients with AML. Cytarabine is FDA approved and commercially available for treatment of patient with AML. The use of these drugs in combination is investigational. The study doctor can explain how the drugs are designed to work.

Up to 75 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 3 groups of 3 - 6 participants will be enrolled in Phase 1 of the study, and up to 70 participants will be enrolled in Phase 2.

If you are enrolled in Phase 1, the dose of nivolumab you receive will depend on when you join this study. There are 3 dose levels being tests in this part of the study: a low dose, a middle dose, and a high dose. The first group of participants will receive the middle dose level of nivolumab. If no intolerable side effects are seen, the next group will receive the highest dose level. However, if there are intolerable side effects, 3 more participants will receive the middle dose. If there are further intolerable side effects seen, the next group will receive the lowest dose of nivolumab.

If you are enrolled in Phase 2, you will receive nivolumab at the highest dose that was tolerated in Phase 1.

All participants will receive the same dose levels of idarubicin and cytarabine.

Study Drug Administration:

You will receive 1- 7 cycles of the drug combination. These cycles will be 28-35 days long.

* On Days 1-3 of each cycle, you will receive idarubicin by vein over about 15-30 minutes.
* On Days 1-4 of each cycle, you will receive cytarabine by vein over about 24 hours. If you are age 60 or older, you will receive the drugs on Days 1-3 only. On these days you will receive drugs to help decrease the risk of side effects.
* On Day 24 (+/- 2 days) of each cycle, you will receive nivolumab by vein over about 1 hour.

After 2 cycles, if the disease appears to get better, you will receive nivolumab by vein about every 2 weeks for up to 1 year.

Study Visits:

At least one (1) time a week during Cycle 1 and then at least once each cycle after that:

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.

You will have a bone marrow aspirate collected for cytogenetics testing between Day 21-28 of each cycle and then, if the doctor thinks it is needed, you will have this performed every 1-2 weeks after that unless a complete response is achieved. After that, you will have bone marrow collected every 3-6 months for 1 year.

After your last dose of study drug, you will have a physical exam.

Length of Study:

You may continue taking nivolumab for up to 1 year. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Arms:
arm 1: Phase I dose of Nivolumab 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle.

Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle.

Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. arm 2: Phase I dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle.

Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle.

Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. arm 3: Phase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle.

Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle.

Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Interventions: intervention 1: Nivolumab intervention 2: Idarubicin intervention 3: Cytarabine intervention 4: Solu-medrol intervention 5: Dexamethasone
Intervention descriptions: intervention 1: Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle.

Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I. intervention 2: Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. intervention 3: Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. intervention 4: Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle. intervention 5: Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Page
Phase I/II Study of Idarubicin, Cytarabine, and Nivolumab in patients with high-risk 
MDS and AML
2014-0907
Core Protocol Information
Short Title 
Nivolumab in AML
Study Chair: 
Farhad Ravandi-Kashani
Additional Contact:
Andrea L. Booker
Shannon L. Bailey
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-7305
Unit:
428
Study Manager:
Shenell A. Alexander
Full Title: 
Phase I/II Study of Idarubicin, Cytarabine, and Nivolumab 
in patients with high-risk MDS and AML
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Activated -- Closed to new patient entry as of 09/25/2019
Version:
15
Document Status:
Saved as "Final"
Submitted by:
Shannon L. Bailey--9/20/2019 1:19:17 PM
OPR Action:
Accepted by:  Melinda E. Gordon -- 9/25/2019 10:29:48 
AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
  


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
1 
 
 
 
Phase I-II study of Idarubicin, Cytarabine, and Nivolumab in 
patients with high-risk MDS and AML 
 
 
Core Protocol Information 
 
 
 
Short Title  
NIVOLUMAB IN AML 
 
Study Chair:  
Farhad Ravandi 
 
 
 
Additional Contact: 
  Lynn Booker 
 
Department: 
Leukemia 
Phone: 
713-792-5630 
 
Unit: 
 
428 
  
Full Title:  
Phase I-II study of Idarubicin, Cytarabine, and Nivolumab in patients with high-risk 
MDS and AML 
 
 
Protocol Type: 
Standard Protocol 
Protocol Phase: 
Phase I/Phase II 
Version Status: 
 
 
 
Version: 
1 
Document Status: 
 
Submitted by: 
 
OPR Action: 
 
 
 
 
 


BMS – Idarubicin, Cytarabine, and Nivolumab 
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2014-0907 
 
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1.0 
Table of Contents 
 
2.0  Background ....................................................................................................................... 3 
2.1 
The Diseases ............................................................................................................... 3 
2.2 
Use of a VEGF, RAF, FLT3 inhibitor as a maintenance agent in MDS/AML ........... 4 
3.0 Objectives ........................................................................................................................... 7 
3.1 
For phase I portion of study ...................................................................................... 7 
3.2 
For phase II portion of study ..................................................................................... 7 
4.0 Patient Eligibility ................................................................................................................ 7 
5.0 Treatment Plan ................................................................................................................. 10 
5.1 
General: ..................................................................................................................... 10 
5.2 
Treatment Schedule: ................................................................................................. 10 
5.3 
Dose modifications during induction therapy: ....................................................... 11 
5.4 
Administration guidelines for induction sorafenib: ............................................... 11 
5.5    
Dose reductions/modifications/delays: ............................................................... 11 
5.6      Myelosuppression ................................................................................................... 11 
5.9   Remission Consolidation/Maintenance .................................................................. 12 
5.10 
 Administration guidelines for consolidation/maintenance sorafenib: ............. 13 
5.11 
 Definition of Dose Limiting Toxicity (DLT) ......................................................... 17 
5.12 
Concomitant medications ..................................................................................... 18 
6.0  Protocol Summary/Schema ........................................................................................... 18 
6.1   Proposed Study ........................................................................................................ 18 
7.0 Pretreatment Evaluation .................................................................................................. 19 
8.0 Evaluation During Study ................................................................................................. 20 
9.0 Criteria for Response and Toxicity ................................................................................. 20 
10.0 Reporting of Adverse Events ........................................................................................ 22 
11.0 Criteria for Removal from the Study ............................................................................. 25 
12.0 Statistical Considerations ............................................................................................. 25 
13.0 Background Drug Information ...................................................................................... 29 
13.1 
 Nivolumab ............................................................................................................. 29 
13.2 
 Idarubicin .............................................................................................................. 32 
13.3 
Cytarabine .............................................................................................................. 34 
14.0 Correlative Studies ........................................................................................................ 36 
15.0 References ...................................................................................................................... 38 
 


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2.0  Background 
 
2.1 
The Diseases 
 
a. 
Myelodysplastic syndrome (MDS) is a marrow disorder characterized by 
paradoxical peripheral cytopenias and a hyperplastic marrow, usually in 
elderly patients (median age 65 years).1  Exposure to carcinogens and a 
high frequency of cytogenetic abnormalities are generally observed.2,3 The 
pathophysiology of the disease appears to be an initial increase in 
apoptosis of the primitive stem cells with compensatory marrow 
proliferation, and later escape of clonal disease with malignant potential 
for transformation to acute leukemia.1,4,5  Overall, 50% of patients 
transform to AML, while the others die of complications of cytopenias 
(infections, bleeding) while in MDS phase.1  MDS is divided into low-risk 
and high-risk.  Low-risk MDS includes refractory anemia (RA) and RA-
sideroblastic (RA-S) by the French-American-British (FAB) classification 
and low or intermediate -1 risk by the International Prognostic Scoring 
System (IPSS).  High-risk MDS (usually marrow blasts > 10%) includes 
RA with excess blasts (RAEB) and RAEB in transformation (RAEB-T) by 
FAB and intermediate –2 or high risk by IPSS.6  Median survival in low-risk 
MDS is 3-4 years, and in high-risk MDS 12 months or less.7,8  
 
There is no current uniformly accepted standard treatment for MDS.  Low-
risk MDS is usually observed and later treated according to complications 
with red cell or platelet transfusions, antibiotics, and growth factors (EPO, 
G-CSF).  Investigational studies include amifostine, thalidomide, TNF- 
inhibitors (e.g. Enbrel), Mylotarg, arsenic trioxide and hypomethylating 
agents.9,10  High-risk MDS is usually treated with investigational therapies 
including AML regimens, topotecan + ara-C, above investigational 
strategies, and allogeneic stem cell transplant.10-12 Recently, 5-azacytidine 
and decitabine have been FDA approved for use in appropriately selected 
patients.  Results have included improved responses (both clinical and 
cytogenetic), better quality of life, but no statistically significant survival 
advantage.  Additionally, lenalidomide has also been FDA approved for 
use in patients with the 5q- syndrome, with an improvement in red blood 
cell transfusion dependence as well as cytogenetic response.  MDS 
affects 12,000 to 20,000 individuals in the USA yearly.  RAS mutations 
occur in 30% to 65% of MDS cases.13,14  
 
b. 
AML: Prognosis in AML in adults has improved modestly.  With modern 
regimens, including anthracyclines plus cytarabine, the CR rates are 60% 
to 70% and the cure rates are 15% to 25%.  Prognosis is related to 1) 
leukemia karyotype, 2) patient age, and 3) performance and organ 
functions.  Patients with t(8;21), inversion 16 or t(15;17) have CR rates of 


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90% and cure rates of 50% to 80%.  Younger patients (age < 50 years) 
with diploid karyotypes have CR rates of 70% to 80% and cure rates of 
20% to 25%.  Older patients and those with adverse karyotypes have CR 
rates of 35% to 50% and cure rates of 10% or less.  Elderly patients with 
AML have a poor prognosis. This is due in part to the poor tolerance to 
therapy, and also the higher frequency of poor prognostic features, such 
as high-risk cytogenetic abnormalities and MDR expression. The 
experience at M.D. Anderson from 1996 to 2000 for patients age 65 years 
or older is a clear example of this poor prognosis. We treated 245 patients 
in this age group during this period. CR was achieved in 118 (48%) while 
induction mortality (i.e., death within 7 weeks from the start of 
chemotherapy) occurred in 54 (22%). 38 patients (18%) were alive in CR 
after 1 year, and 16 (8%) at 2 years.15,16 
 
 
2.2 
Maintenance therapy in MDS and AML 
 
The role of post-remission therapy has been fully established in treating 
adult patients with AML. Several older studies have suggested that there 
is no role for maintenance therapy in AML. An ECOG study randomized 
patients after receiving standard induction therapy into 2 arms; one 
receiving 2 further courses of attenuated induction followed by 
maintenance, versus maintenance therapy only for 2 years. This study 
demonstrated that a more intensive post-remission therapy is necessary 
and questioned the role of maintenance. A randomized CALGB study 
demonstrated that protracted maintenance for 36 months was not superior 
to 8 months of maintenance and led to further questioning of role of 
maintenance. Other studies have also questioned the benefit of 
maintenance therapy.  
On the other hand, several studies have convincingly demonstrated the 
benefit of maintenance therapy in older adults. A study by the German 
AML cooperative group patients achieving CR after receiving a standard 
induction regimen were randomized to receive either a protracted 
maintenance therapy or ‘observation only’. Disease free survival at 3 
years was 30% versus 17% (p=0.003) in favor of the maintenance arm. As 
a result of this study, maintenance therapy has been established as an 
integral part of front-line therapy in AML patients by the German group. 
Other studies, including studies by SWOG and Japanese adult leukemia 
study group (JALSG) have confirmed the benefit of maintenance.  
Therefore, although maintenance therapy is clearly effective its precise 
role has not been well defined. Maintenance therapy is likely to be 
beneficial in older adults with high-risk disease and is less likely to be 
effective in younger adults who are able to tolerate more intensive forms 
of post-remission therapy. An important factor in considering post-
remission therapy in older adults with AML is the availability of an effective 


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and non-toxic regimen. Studies of interleukin- 2 (IL-2) in the maintenance 
setting of AML were largely unsuccessful particularly due to the difficulty in 
delivering the drug due to its significant toxicity.  
 
PD-1 is a negative co-stimulatory receptor on activated T lymphocytes, which 
counters the activation signal provided by TCR ligation.17a PD-1 can also be 
induced in natural killer cells, B cells and monocytes. The two ligands of PD-1 
are PD-L1 and PD-L2. They have distinct cellular expression patterns. 
Expression of PD-L2 is largely restricted to antigen presenting cells while PD-L1 
is broadly expressed in tissues and can be further induced by exposure to 
interferon IFN-γ.17a PD-L1 is the major ligand for PD-1-mediated immune-
suppression. Increased evidence suggests that PD-L1 expression on solid tumor 
cells is capable of dampening antitumor immune responses, and blockade of PD-
L1 inhibits tumor growth and delays progression in murine models.17a Yang and 
colleagues have demonstrated that PD-1 and its two ligands, PD-L1 and PD-L2, 
as well as CTLA4, are aberrantly upregulated in 8–34% of bone marrow CD34+ 
cells from patients with myeloid leukemias.18a Tumor cells may suppress the 
function of tumor infiltration T cells by modulating PD-1. PD-1 has been reported 
to be upregulated on tumor infiltration T cells in melanoma and lung cancer.17 In 
AML and MDS bone marrow biopsies, it has been reported that blasts are 
positive for PD-L1 whereas stroma/non-blast cellular compartment are positive 
for PD-1. Therefore, PD-1 ligands expressed on tumor cells may act through PD-
1-positive stroma within the tumor microenvironment of AML and MDS 
patients.18a 
In another study, Zhang, et al using the murine leukemia cell line, C1498 showed 
that when transferred intravenously into immunocompetent mice, C1498 cells 
grew progressively and apparently evaded immune destruction.(19a) Low levels 
of PD-L1 expression were found on C1498 cells grown in vitro. However, PD-L1 
expression was up-regulated on C1498 cells when grown in vivo. PD-1(-/-) mice 
challenged with C1498 cells generated augmented antitumor T-cell responses, 
showed decreased AML burden in the blood and other organs, and survived 
significantly longer than did wild-type mice. Similar results were obtained with a 
PD-L1 blocking antibody.(19a) These data suggest the importance of the PD-
1/PD-L1 pathway in immune evasion in AML, providing a rationale for clinical 
trials targeting this pathway in leukemia patients. 
 
 We propose to investigate nivolumab in patients with high-risk MDS and AML as 
maintenance following achievement of complete remission after induction with 
idarubicin and cytarabine,  In the phase I portion of the trial, the aim is to define 
the tolerability of the administration of Nivolumab after achieving CR.  In the 
phase II portion of the trial,  the event free survival in newly diagnosed patients 


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with AML and high-risk MDS (> 10% blasts) will be determined and compared to 
historical controls. 
 
2.3 
The Treatment 
 
PD-1 (or CD279),a 55-kd type 1 transmembrane protein, is a member of the 
CD28 family of T-cell costimulatory receptors that include immunoglobulin super 
family members CD28, CTLA-4, inducible co-stimulator (ICOS), and B and T-
lymphocyte attenuator (BTLA). PD-1 is highly expressed on activated T cells and 
B cells. PD-1 expression can also be detected on memory T-cell subsets with 
variable levels of expression. Two ligands specific for PD-1 have been identified: 
PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or 
CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation 
upon binding to PD-1 in both murine and human systems.15,16,17 The interaction 
of PD-1 with its ligands, PD-L1and PD-L2, that are expressed on antigen-
presenting cells (APC) and dendritic cells (DC), transmits negative regulatory 
stimuli to down-modulate the activated T-cell immune response. The absence or 
inhibition of PD-1 in murine models has resulted in the development of various 
autoimmune phenotypes and autoimmune diseases.1 Taken together, these 
results suggests that inhibition of PD-1 binding to its ligands has the potential to 
activate T-cell responses. Since these responses are variable and dependent 
upon various host genetic factors, PD-1 deficiency or inhibition is not 
accompanied by a universal loss of tolerance to self antigens. 
Tumors can express tumor-specific antigens as a result of mutational burden and 
ongoing immune surveillance is believed to control the development of many 
tumors. Tumor progression may depend upon acquisition of mechanisms which 
permit them to evade an effective immune response. One such mechanism of 
evasion may be the expression of ligands which engage inhibitory receptor(s) on 
anti-tumor T-cells of many tumors. PD-L1 expression has been found on a 
number of tumors, and may be a mechanism by which tumors can directly 
engage PD-1 to evade an effective anti-tumor immune response.18,19,20 
Expression of INF-γ by T-cells is known to induce PD-L1 expression in tumors.21 
PD-L1 expression has been associated with poor prognoses in renal,22,23,24 
esophageal,25 gastric,26 ovarian,20 pancreatic,27 and lung cancer.28 PD-1 
engagement on T-cells by PD-L1+ APC or PD-L1+ tumor cells in the tumor 
microenvironment may limit effective immune responses. In contrast to the 
findings above, 
PD-L1 expression may result from CD3+ T-cell infiltration into tumors, which was 
observed to be a positive prognostic factor. Co-localization of lymphoid cell 
infiltrates and PD-L1 staining has been observed in human melanoma lesions.29 
More recent data have implicated the role of PD-1 in human infections, 
particularly in HCV30 and human immunodeficiency virus (HIV).31 In these cases, 
high expression levels of PD-1 have been found in viral-specific CD8+ T-cells 
that also display a non-responsive or exhausted phenotype. The observation that 
PD-1 expression is reduced in antigen loss variants of the target 


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epitope of PD-1 high antigen-specific T-cells is consistent with the chronic 
stimulation hypothesis.8 Non-responsive PD-1 high T-cells have been observed 
in simian immunodeficiency virus (SIV) infection in rhesus macaques. More 
important, treatment of SIV-infected macaques with an anti-PD-1 mAb (3 mg/kg 
x4) resulted in decreased viral loads and increased survival along with expanded 
T-cells with increased T-cell functionality.4 These studies have led to anti-PD-1 
testing in tumor models. 
Studies in multiple tumor models using a chimeric murine anti-mouse PD-1 
antibody showed that PD-1 blockade has anti-tumor activity (Section 4.1.3).32 
Blocking PD-1 in PD-L1+ tumors may reverse the inactivation of tumor-specific 
effector T-cells at the tumor site as well activate anti-tumor responses that are 
limited by PD-L1 expression on “host” DC or APC. The anti-tumor effects of anti-
PD-1 observed in several murine models suggest that both PD-L1+ and PD-L1-
tumors may be targeted using this approach. In addition, in several tumor models 
in which anti-PD-1 has proved ineffective, PD-1 blockade can be combined with 
vaccines or other immunomodulatory antibodies for improved therapeutic 
efficacy.33,34,35 PD-1 blockade by nivolumab is a promising avenue to pursue as 
an anti-tumor therapy for recurrent or treatment-refractory malignancies or as an 
anti-viral therapy for chronic viral infections. 
 
 
3.0 Objectives 
 
3.1 
For phase I portion of study: To determine the tolerability of the combination of 
idarubicin, cytarabine (ara-C), and nivolumab (IAN) in patients with high-risk 
MDS and AML.  
 
3.2 
For phase II portion of study: To determine event-free survival (EFS) where 
the events is defined as death or relapse using the combination of idarubicin, 
cytarabine, and nivolumab in patients with high-risk Myelodysplastic syndrome 
(MDS) and Acute Myeloid Leukemia (AML). 
 
 
  4.0 
Patient Eligibility 
 
 
  
Inclusion Criteria: 
 
4.1 
Diagnosis of 1) AML (WHO classification definition of > 20% blasts), or 2) high 
risk MDS (defined as the presence of 10% blasts). 
 
4.2 
Patients aged 18 to 60 years are eligible.  Patients older than 60 who are 
deemed fit to receive intensive chemotherapy by the treating physician are 
eligible after discussion with the PI. 
4.3 
In the Phase I portion, patients with relapsed or refractory AML/MDS are also 
eligible, as per the treating physician’s discretion. 


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4.4 
For the Phase II portion of the study, patients must be chemo-naïve, i.e. not have 
received any prior chemotherapy (except hydrea or one dose of ara-C ≤ 2g) for 
AML or MDS.  They could have received hypomethylator agents, transfusions, 
hematolopoietic growth factors or vitamins.  Temporary prior measures such as 
apheresis or hydrea or one dose of ara-C ≤ 2g are allowed in order to safely 
control hyperleucocytosis prior to enrollment. 
 
 
4.5 
Serum biochemical values with the following limits unless considered due to 
leukemia: 
- creatinine < 1.5 mg/dl 
- total bilirubin < 1.5 mg/dL, unless increase is due to hemolysis or congenital 
disorder 
- transaminases (SG PT) <2.5x ULN 
 
 
4.6 
Ability to take oral medication. 
 
4.7 
Ability to understand and provide signed informed consent. 
 
4.8 
Baseline test of ejection fraction must be ≥50%. 
 
4.9 
Performance status <3, unless directly related to disease process as determined 
by the Principal Investigator   
 
Exclusion Criteria: 
 
4.10 Subjects with APL. 
 
4.11 Any coexisting medical condition that in the judgment of the treating physician is 
likely to interfere with study procedures or results. 
 
4.12    Nursing women, women of childbearing potential with positive urine pregnancy   
    test, or women of childbearing potential who are not willing to maintain adequate  
    contraception (such as birth control pills, IUD, diaphragm, abstinence, or 
    condoms by their partner) over the entire course of the study. 
 
 
Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. 
WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the 
time required for nivolumab to undergo five half-lives) after the last dose of investigational drug  
 
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab 
 
Women must not be breastfeeding 


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 
Men who are sexually active with WOCBP must use any contraceptive method with a failure 
rate of less than 1% per year Men receiving nivolumab and who are sexually active with 
WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose 
of investigational product Women who are not of childbearing potential (ie, who are 
postmenopausal or surgically sterile as well as azoospermic men do not require contraception 
 
 
4.13    Cardiac disease: Congestive heart failure > class II NYHA.  Patients must not   
have unstable angina (anginal symptoms at rest) or new onset angina (began 
within the last 3 months) or myocardial infarction within the past 6 months. 
  
 
4.14   History of cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within 
past 3 months. 
  
 
4.15   Thrombotic or embolic events such as a cerebrovascular 
 
 
accident including transient ischemic attacks within the past 6 months. 
 
 
 
4.16    Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first   
dose of study drug. 
 
 4.17 Major surgery, open biopsy or significant traumatic injury 
  
within 4 weeks of first study drug. 
 
4.18    Active clinically serious and uncontrolled infection > CTCAE Grade 2  
 
uncontrolled with antibiotics 
 
4.19     Patients should be excluded if they have an active, known or suspected 
autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger 
 
4.20     Patients should be excluded if they are known to be positive test for hepatitis B 
virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) 
indicating acute or chronic infection 
 
4.21    Patients should be excluded if they have known history of testing positive for 
human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome 
(AIDS) 
 
     4.22   History of allergy to study drug components 
 
4.23    Prior immune checkpoint targeting drugs (e.g., anti PD1, anti PDL1, anti-kir, anti 
CD137…etc) 
 


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 5.0 
Treatment Plan 
 
5.1 
General:  All patients should be registered with PDMS. Information pertaining to 
important prognostic factors such as age, performance status and prior therapy 
will be recorded.   
 
5.2 
Treatment Schedule: (Each cycle is approximately 28-35 days) 
 
a. Phase I  
Nivolumab dosed as indicated below starting approximately on day 24 
± 2 days 
Idarubicin 12 mg/m2 IV over 15 to 30 minutes daily x 3 (days 1-3) 
ara-C 1.5 g/m2 IV over 24 hours daily (days 1-4) 
Solumedrol 50 mg or dexamethasone 10 mg IV daily for 3-4 days with 
ara-C (days 1-4) 
All patients may receive a second induction course at the discretion of 
treating physician. 
 
 
The dose of investigational agent, that is, Nivolumab, will be escalated in successive cohorts of 
patients.   Patients will be entered sequentially to each dose level.  If none of the first 3 
patients at a dose level experience first cycle dose-limiting toxicity (DLT), new patients may be 
entered at the next higher dose level. If 1 of 3 patients experience first cycle DLT, up to 3 more 
patients are started at that same dose level. If 1of 6 experience DLT, then new patients may 
be entered at the next higher dose level.  If 2 or more experience first cycle DLT, no further 
patients are started at that dose. The MTD is the highest dose level in which <2 patients of 6 
develop first cycle DLT. The following table lists out the 3 dosage levels that will be used in the 
study, and the starting dose is 1mg/kg IV of Nivolumab. There will be no intra-patient dose 
escalation for Nivolumab.  
The enrollment of participants will be staggered; all the participants in each cohort will be 
observed for approximately 3 weeks from the first dose of Nivolumab before proceeding to the 
next cohort. 
 
 
 
Dose of nivolumab will be as follows: 
 
Dose level 
Nivolumab (mg/kg IV) 
 
No of patients 
-1 
0.3 
3 
0 
1 
3 
1 
3 
3 


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11 
 
 
 
b. 
Phase II (Each cycle is approximately 28-35 days) 
Patients will receive 1 or 2 induction cycles of therapy according to the 
following starting schedule: 
 
Nivolumab starting approximately on day 24 ± 2 days at a dose defined 
by Phase I portion of the study but it is expected that the dose 3 mg/kg 
will be selected based on prior studies. 
Idarubicin 12 mg/m2 IV over 15 to 30 minutes daily x 3 (days 1-3) 
ara-C 1.5 g/m2 IV over 24 hours daily (days 1-4) (days  
1-3 for patients older than 60) 
Solumedrol 50 mg or dexamethasone 10 mg IV daily for 3-4 days with 
ara-C (days 1-4) (days  
1-3 for patients older than 60). 
 
 
Nivolumab will be administered at approximately 2 week intervals for up to 
1 year. 
 
5.3 
Dose modifications during phase II: 
 
 
Patients who experience nivolumab-specific (defined as determined by the 
principal investigator) grade 3-4 extramedullary toxicities during induction cycle 
#1, and who are not in CR after cycle #1, may receive a second induction course 
at a similar or lower dose level with respect to idarubicin and cytarabine. Other 
dose modification schedules felt to be in the best interest of the patient may be 
permitted, after discussion with the principal investigator.  There will be no dose 
modifications of idarubicin or cytarabine for either induction cycle #1, or second 
induction course, secondary to myelosuppression. There will be no dose 
reduction with respect to Nivolumab but dose delays or interruptions are 
permitted after discussion with the PI.  
 
 
5.4 
Administration guidelines for nivolumab:  Nivolumab will be administered by 
IV infusion over approximately 60 minutes ± 10 minutes. The recommended 
infusion duration for the product is 60 minutes and every effort should be made to 
adhere to this time as closely as possible. 
 
5.5      No dose reduction is allowed for Nivolumab.  Dose delays and interruptions 
should follow the guidance in section 6.10.3. 
 
 
 
 
5.6      Myelosuppression 


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12 
 
 
 
Patients with acute leukemia 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 leukemias and myelodysplastic 
syndromes. Thus, no dose adjustments or treatment interruptions for 
myelosuppression will be planned for the first 6 weeks of therapy. After this time, 
treatment interruptions and dose adjustments may be considered according to 
the following guidelines: 
 
 
Patients with neutropenia or thrombocytopenia as a consequence of the disease 
prior to the start of therapy do not require treatment interruptions for 
myelosuppression. Dose reductions of the chemotherapy agents in these 
patients should be considered on an individual case basis and discussed with the 
PI.  
 
 
 
Nivolumab is not associated with myelosuppression – it can be held if necessary 
but no dose reductions are needed after resumption 
 
5.7 
Dose adjustments for only one of the drugs can be made if, in the opinion of 
the treating physician, the toxicity is attributable to one of the drugs. 
 
5.8 
Patients who show no significant anti-tumor effect (i.e. no CR or CRp) after 2 
courses will be taken off the study. 
 
5.9  
Remission Consolidation/Maintenance: Patients achieving a CR or CRp may 
receive consolidation maintenance therapy as follows: 
 
a. Consolidation – Up to 5 additional courses as follows: 
Idarubicin 8 mg/m2 IV over 15 to 30 minutes daily x 2 days (or 
the final induction dose, whichever is lower).(days 1-2)
 Ara-C 0.75 g/m2 IV over 24 hours daily x 3 days (or the final 
induction dose, whichever is lower) (days 1-3) 
 Nivolumab dose as per induction IV every 2 weeks as a 
continuation of the induction treatment. 
 Solumedrol 50-100 mg or dexamethosone 10 mg IV daily x 3 
days with ara-C (days 1-3)
 courses given every 4-6 weeks upon recovery of counts and 
toxicities 
 
b. Maintenance – Nivolumab will be administered every 2 weeks for up to 1 year 
with no breaks except for toxicity. Maintenance will only be administered in 
patients in CR or CRp. 
 
c. Consideration of allogeneic transplant in CR. Patients eligible for allogeneic. 


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13 
 
SCT will be evaluated for the procedure, if felt to be in their best interest. Therapy 
with nivolumab will be discontinued at least approximately one week prior to 
admission for the transplant procedure. 
 
5.9.1 
If judged more beneficial for patient care and disease control, patients 
may have dose reductions to allow for continuation of therapy with 
acceptable myelosuppression. 
 
5.9.2       The dose of chemotherapy treatment (ie idarubicin/cytarbine) in 
subsequent courses will be reduced by 25% for grade 3-4 extramedullary 
toxicities, or for severe life-threatening infections.  
 
5.9.3 
In responding patients, courses will be given at 4 to 6 week intervals 
provided the granulocyte count has recovered to > 1.0x109/L and the 
platelet count to >50x109/L.  In patients with persistent disease, therapy 
could be restarted once counts recover to the pretreatment values. 
 
5.9.4 
Dose adjustments for only one of the drugs can be made if, in the opinion 
of the treating physician, the toxicity is attributable to one of the drugs. 
 
5.10 
 Administration guidelines for consolidation/maintenance nivolumab: 
Nivolumab will be administered IV approximately every 2 weeks starting 
from day 24 ± 2 days of first induction course. If a dose is missed, the next 
dose will not be increased to account for missing a dose. The patient will 
take the next regular dose at the regularly scheduled time. 
 
5.10.1  
Patient Monitoring During Infusion 
Initial dose vital signs should be monitored prior to dosing, approximately every 30 
minutes after initiation of 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 an infusion reaction, the 
patient will be monitored for 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 signs time points. 
 
5.10.2  
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 4.03) guidelines. 
 


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14 
 
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, (at approximately 
40cc/hour but adjusted according to the clinical situation to ensure stabilization of blood 
pressure) 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 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, (at 
approximately 40cc/hour but adjusted according to the clinical situation to ensure 
stabilization of blood pressure) 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 


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15 
 
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 please see the dosing procedure manual. 
 
5.10.3 Nivolumab dose delay for immune-oncology drug-related adverse 
events, clinically significant in the opinion of the investigator 
 
Nivolumab administration should be delayed for the following drug-related AEs: 
 Any Grade >2 non -skin AE, except that  
 Grade 2 fatigue or laboratory abnormalities do not require delay, 
however 
 For a subject with baseline AST, ALT, or total bilirubin within normal 
limits, delay dosing for drug-related Grade >2 values 
 Any Grade 3 skin AE, or Grade 3 laboratory abnormality, with the following 
exceptions: 
    Grade 3 lymphopenia or leukopenia does not require dose delay. 
    If a subject has Grade 1 baseline AST, ALT, or total bilirubin, delay 
dosing for drug-related Grade 3 toxicity 
 Any AE, laboratory abnormality, or intercurrent illness, which in the judgment 
of the investigator, warrants delaying the dose of study medication. 
 Nivolumab dose reductions are not permitted in this study (only dose delays 
when indicated).  
 
            Detailed management algorithms for immune-oncology drug-related adverse 
events (including gastrointestinal, renal, pulmonary, hepatic, endocrine, skin and 
neurological) are provided in Appendix E. These general guidelines constitute 
guidance to the Investigator and may be supplemented by discussions with the 
Medical Monitor representing the Sponsor. If the criterion to resume treatment is 
met, the subject should restart treatment at the next scheduled time-point per 
protocol. 
Criteria to Resume Treatment: 
 
Subjects may resume treatment 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  


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16 
 
 Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin 
 Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Discontinuation Section below) should have treatment 
permanently discontinued 
 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. 
 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation section. 
 
Nivolumab Discontinuation Criteria: 
 
Treatment 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 requires systemic treatment  
 
 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 
 
 Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below: 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
o Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
 AST or ALT > 8 x ULN 
 
 Total bilirubin > 5 x ULN 
 Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 


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o 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 
 
 
o Any dosing interruption lasting > 6 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 > 6 weeks, the Investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted 
 
o Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the Investigator must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted 
 
o Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the subject with continued 
nivolumab dosing 
 
 
 
5.11  
Definition of Dose Limiting Toxicity (DLT) 
Dose-Limiting Toxicity will be graded according to the NCI Common 
Toxicity Criteria version4.03.  See NCI Common Toxicity Criteria for 
definitions of DLT by organ system. 
 
a) 
All > grade 3 drug-related, clinically significant non-hematologic toxicities   
will be considered DLTs. A study drug-related occurrence of an elevation 
in AST/ALT > 3 x ULN and concomitant Bilirubin of > 2 x ULN is a Dose 
Limiting Toxicity and patients meeting this criteria should be permanently 
discontinued from study treatment (nivolumab). 
As the following are common events in patients with leukemia (> 50%), 
they will not be used for the definition of MTD and DLT, nor will they be 
reported as ADRs: low blood pressure due to dehydration requiring fluid 
replacement, abnormalities of LDH (lactate dehydrogenase) and alkaline 
phosphatase, disturbances in electrolytes (magnesium, phosphorus, 


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18 
 
calcium), alopecia, nausea and vomiting (if manageable with supportive 
care measures).  
 
 
 
b) 
Grade 3 hematologic toxicity (criteria for leukemia on the CTC version 3.0) 
lasting for 6 weeks or more after interruption of therapy with a hypocellular 
bone marrow and no marrow blasts.  Anemia will not be considered a 
hematologic DLT. As the following are common events in patients with 
leukemia (> 50%), they will not be used for the definition of MTD and DLT, 
nor will they be reported as ADRs: prolonged myelosuppression (grade 3 - 
4), neutropenic fever without infection (grade 3), non-neutropenic fever 
(grade 3), infections with grade 3 and 4 neutropenia, infections without 
neutropenia (grade 3), readmission associated with NCI grade 3 toxicity 
cytopenias not resulting in death, transfusions of platelets and packed 
RBCs (grade 3). 
 
5.12 
Concomitant medications: In the event of severe anemia, 
thrombocytopenia or neutropenia, patients may receive appropriate 
supportive care (e.g., transfusions, prophylactic antibiotics, antifungals 
and/or antivirals, hematopoietic growth factors). In the event of high white 
blood cell (WBC) counts, patients may receive hydroxyurea (at any dose) 
or 1 dose of cytarabine (up to ≤  2g) prior to start of study treatment in 
order to keep their WBC at an acceptable level while being evaluated for 
the study.  During the trial they may undergo leukopheresis for the same 
purpose.  
 
Concomitant administration of any other therapy specific for MDS or AML, 
including any use of systemic retinoids, is prohibited. Concomitant 
administration of any other anticancer therapy is prohibited. Intrathecal 
chemotherapy is allowed, when indicated. 
 
Subjects may receive anti-infective prophylaxis according to institutional 
practices. Use of recombinant myeloid colony stimulating factors (CSF) is 
allowed, if patients have febrile neutropenia or documented infections. 
 
Concomitant medications will be recorded in the medical records only. 
 
6.0  Protocol Summary/Schema 
 
6.1  
Proposed Study 
We propose to investigate the combination of idarubicin, cytarabine and 
nivolumab in patients with high-risk MDS and AML. In the phase I portion of the 
trial, the aim is to determine the tolerability of the combination.  In the phase II 


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19 
 
portion of the trial, the event free survival in newly diagnosed patients with AML 
and high-risk MDS (> 10% blasts) will be determined. 
 
 
 
 
Schedule of Evaluations/ Study Calendar    
 
(refer to section 7.0 - 8.0 of protocol body) 
 
Parameter 
Prestudy 
Weeklyx4 
During 
first 
course 
Induction 
phase 
every 4-7 
days  
Induction 
phase 
every 1-2 
weeks  
Consolidation 
Maintenance 
phase every 
1-4 wks 
Consolidation 
Maintenance 
phase every 
4-8 wks 
 
 
End of 
Study 
H&P 
x 
x  
  
  
  
  
x 
Weight/BP 
x 
 
 
  
  
  
 
CBC, 
diff+platelet 
x 
x 
x 
  
x 
  
 
Chemistry+Coag: 
  
  
  
  
  
  
 
total bili 
x 
 x 
  
x 
  
x 
 
creatinine 
x 
 x 
  
x 
  
x 
 
SGPT 
x 
 x 
  
x 
  
x 
 
PT/PTT/INR  
x 
  
  
x 
  
x 
 
                      TSH 
x 
 
 
 
 
 
 
pregnancy test*** 
x 
  
  
  
  
  
 
BMA**** 
x 
  
  
  
  
  
 
Echo/Muga 
x 
  
  
  
  
  
 
MRD**** 
x 
  
  
  
  
  
 
Correlative 
studies: see 
section 16 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
*** Blood or Urine pregnancy test on women of childbearing potential  
****Bone Marrow Aspirate Pre-Treatment - within one month with cytogenetics and molecular studies if not done 
before. On-Study: BMA + cytogenetics and molecular studies (if abnormal at start) on day 21-28, then every 1-2 wks 
as required until CR.  Then every 3-6 months. X 1 year.  May be omitted in patients with clear evidence of active 
disease (see section 8.2). 
Minimal residual disease (MRD) studies by flow cytometry to be performed on pre-treatment bone marrow and all 
subsequent bone marrow exams  
 
 
 
 7.0 
Pretreatment Evaluation 


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7.1 
History and physical examination, weight, BP. 
 
7.2 
CBC, platelet count, differential, creatinine, total bilirubin, SGPT, PT, PTT, INR, 
TSH. 
 
Serum or urine pregnancy test for women of childbearing potential. 
 
7.3 
Bone marrow aspirate for morphology (within one month) and cytogenetics and 
molecular studies (if not done before). 
 
7.4 
Blood samples (10cc)/bone marrow, optional, for correlative studies. 
 
7.5 
Echocardiogram or MUGA scan. 
 
 
8.0 Evaluation During Study 
 
8.1 
CBC, platelet, differential (if WBC > 109/L) every 4-7 days during remission 
induction and every 1 to 4 weeks during maintenance therapy. 
 
8.2 
Bone marrow aspirate and cytogenetics and molecular studies (if abnormal at 
start) on day 21-28; then aspirate every 1-2 weeks as required until CR; then 
every 3-6 months in year 1 if deemed necessary by the treating physician. Bone 
marrow aspiration may be omitted in patients where there is clear evidence of 
active disease (e.g., persistent blasts in peripheral blood).   
 
 
8.3 
Creatinine, total bilirubin and SGPT, PT, PTT, and INR every 1-2 weeks during 
induction then every 4-8 weeks on study. 
 
8.4 
Blood samples (10cc)/bone marrow (optional studies, see Section 14) 
 
8.5 
End of Study:  History and physical exam 
End of study evaluation will be performed after the completion of the 
maintenance therapy, or any time before that if the patient withdraws from the 
study or the treatment is discontinued for toxicity or disease relapse/progression. 
 
 
9.0 Criteria for Response and Toxicity 
 
9.1 
Responders are patients who obtain a CR or PR, with or without cytogenetic 
response, or CRp (i.e., CR except for platelet counts <100 x109/L but not 
requiring platelet transfusions). 
 
9.2 
Definitions 


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21 
 
 
a. 
Complete Response (CR): Normalization of marrow (< 5% blasts and of 
peripheral blood counts (neutrophil count > 109/L, platelet count > 100  x 
109/L). 
 
b. 
Partial response (PR): as for CR but with reduction of marrow blasts by 
>50% and to <10%. 
 
c. 
CRp = CR, but platelets <100 x 109/L. 
 
d. 
Progressive disease:  increase of blasts to > 10% after an initial response. 
 
10.0 Reporting of Adverse Events 
These guidelines serve to bring the Department of Leukemia in compliance with the 
institutional policy on Reporting of Serious Adverse Events.  
 
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.  
 
Only unexpected AEs related to leukemia and events resulting in dose modification/delay will 
be recorded in the Case Report Form (CRF).  
 
Expected events during leukemia therapy are: 
 Myelosuppression related events (due to disease or leukemia therapy)  
 Febrile or infection episodes not requiring management in the intensive care unit  
 Epistaxis or bleeding except for catastrophic CNS or pulmonary hemorrhage  
 Anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia  
 Disease related events  
 Symptoms associated with anemia (fatigue, weakness, shortness of breath)  
 Electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, magnesium)  
 Chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, albumin, uric 
acid, alkaline phosphatase, glucose)  
 Coagulation abnormalities  
 Disease specific therapy (induction, maintenance, salvage, or stem cell therapy)  


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22 
 
 Alopecia  
 Bone, joint, or muscle pain  
 Disease progression  
 Abnormal hematologic values  
 General therapy related events  
 Catheter related events  
 Renal failure related to tumor lysis syndrome or antibiotic/ antifungal therapy  
 Rash related to antibiotic use  
 Hospitalization for the management of any of the above expected events  
 Abnormal hematologic values will not be recorded on the case report form. For 
abnormal chemical values, the apogee or nadir (whichever is appropriate) will be 
reported per course on the case report form.  
 
All events that are not listed as expected in section 10.0 will be collected for the purpose of 
grading, and determining attribution to study drug by the PI.  
 
All grade 3 and greater non-hematological events that are felt to be related to protocol 
treatment drugs will be documented on the toxicity log and entered into the case report form. 
The toxicity log and case report form data must reflect relationship to the drug the event is felt 
to be related to. 
 
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 


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23 
 
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 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.  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 the 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. 
 
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. 
 
Adverse events and protocol specific data will be entered into PDMS/CORe and PDMS/CORe 
will be used as the electronic case report form for this protocol. 
 
 
10.1 Adverse Events Requiring Expedited Reporting: 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
24 
 
Briston Meyers-Squibb Adverse Event Reporting: 
Serious adverse events (SAEs) considered associated with therapy 
should be reported to the Principal Investigator within 48 hours of 
observing or learning of the event. All AEs should be reported to the 
research nurse. The principal investigator, in turn, will be responsible for 
reporting the event to the IRB. 
 
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 
 
Serious Adverse Event (SAE): any untoward medical occurrence at any 
dose (including overdose) that: 
 
a. 
Results in death (caused or led to death); or 
b. 
Is life-threatening (placed the subject at immediate risk or death; 
and/or 
c. 
Requires or prolongs inpatient hospitalization (elective 
medical/surgical procedures, scheduled therapies, or routine check-
ups excluded); and/or 
d. 
Is disabling (substantial disruption of the subject’s ability to carry 
out normal life functions); and/or 
e. 
Is a congenital anomaly/birth defect (adverse outcome in a child or 
fetus of a subject exposed to a medicinal product prior to 
conception or during pregnancy; or 
f. 
Does not meet any of the above serious criteria but may jeopardize 
the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
 
Associated Adverse Event: 
 
a.  
If there is a clinically plausible time sequence between the onset of 
the AE and administration of therapy; and/or 
b.  
If there is a biologically plausible mechanism for therapy causing or 
contributing to the AE; and the AE may or may not be attributed to 
concurrent/underlying illnesses, other drugs, or procedures. 
 
10.3 CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 will be utilized for AE reporting.  All 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
25 
 
appropriate treatment areas should have access to a copy of the CTCAE 
version 4.03.  A copy of the CTCAE version 4.03 can be downloaded from 
the CTEP web site (http://ctep.cancer.gov). 
 
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited 
reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and 
italicized in the CAEPR. 
 
 
Attribution of the AE: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
10.4 All safety reports, including SADRs, shall be sent electronically to  
 
 
wh-adverse.events@bayer.com or by fax to (203) 812-6053 to the attention 
 
 
of one of the Bayer Drug Safety Assurance contacts listed below: 
 
 
The Principal Investigator commits to respond promptly to any query from 
 
Bayer regarding SADR reports. 
 
 
 11.0 Criteria for Removal from the Study 
 
11.1 Progressive disease or failure to respond after 2 courses of therapy. 
 
11.2 Unacceptable (Grade 3 or 4) toxicity in the absence of significant antileukemic 
effect. 
 
11.3 Patient request; non-compliance. 
 
12.0 Statistical Considerations 
 
12.1 General Description 
The overall trial objective is to provide a very early assessment of efficacy (phase 
II A) of Nivolumab when used in combination with the standard combination of 
idarubicin and cytarabine.  Initially, a small dose escalation trial will determine the 
dose at which the regimen will be evaluated in the subsequent study of efficacy.  
Once the combination dose is determined, patients meeting phase II eligibility 
criteria will be accrued.   
 
12.2 Phase I study 
 
The 3+3 design will be used to identify the MTD of nivolumab. The following table lists 
out the 3 dosage levels that will be used in the study, and the starting dose is 1mg/kg IV 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
26 
 
of Nivolumab With 3 doses, the maximum total number of patients for phase I part will 
be 12 patients.  
 
The dose of treatment agent, that is, Nivolumab, will be escalated in successive cohorts 
of patients.   Patients will be entered sequentially to each dose level.  If none of the first 
3 patients at a dose level experience first cycle dose-limiting toxicity (DLT), new patients 
may be entered at the next higher dose level. If 1 of 3 patients experience first cycle 
DLT, up to 3 more patients are started at that same dose level. If 1of 6 experience DLT, 
then new patients may be entered at the next higher dose level.  If 2 or more experience 
first cycle DLT, no further patients are started at that dose. The MTD is the highest dose 
level in which <2 patients of 6 develop first cycle DLT.  
 
Table 13.1 Dose levels of nivolumab 
 
Dose level 
Nivolumab (mg/kg IV) 
 
-1 
0.3 
0 
1 
1 
3 
 
 
 
 
Prior to advancing/changing dose levels, a cohort summary will be completed 
and submitted to the IND Office Medical Monitor for review and approval. 
. 
 
12.3 Phase 2 study 
 
The primary outcome of this trial is event-free survival (EFS) which is defined as the 
time from the treatment start till  treatment failure, relapse, or  death whichever comes 
first.. The treatment failure is defined as not achieving CR after two cycles of treatment. 
If the patient achieves remission after the treatment, the relapse occurred in the later 
time would be considered as “event”. We will monitor the EFS as patients accrue and 
are evaluated. The  chemo-naïve patients under MTD in phase I will be included in the 
phase 2 study.  
 
The monitoring  uses the Bayesian method of Thall, et al [2005].  It will be assumed that 
EFS  follows an exponential distribution with median mT under the current 
treatment. The 
 historical median of EFS is denoted by mH given an historical (H) treatment.  For priors,  
we assume the conjugate  inverse gamma (IG) priors mT ~ IG(aT,bT) = IG (3.2,15.6) and  
mH ~ IG(aH,bH) = IG (124.5, 864.5).  Both priors have mean of 7  months while var(mT) = 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
27 
 
 40 and var(mH) = 0.40. That is, the prior on mT is non-informative while the prior on mH  
is  informative.  The trial will be monitored and will be stopped early if, based on the 
 data available at the time, it is unlikely that the median  EFS rate will be at least 7 
 months.  The monitoring is continuous monitoring starting from the 1st patient. 
 
Pr(median EFS under treatment  ≥  median EFS under historical treatment  | data from 
the trial ) < 0.03. 
 
The operating characteristics of this rule for Nmax = 75 patients, computed assuming a  
5 patient/month accrual rate and 24 months of follow up after the last patient is accrued, 
The operating characteristics  are given in the following table.  
 
Table 13.2 Operating characteristics. The operating characteristics for the EFS 
monitoring rule are summarized in the following table.   
 
 
 
 
 
 
 
 
 
The Department of Biostatistics at MD Anderson will provide and maintain a website 
(“Clinical Trial Conduct”:  https://biostatistics.mdanderson.org/ClinicalTrialConduct/) for 
patients enrolled on this study. The Clinical Trial Conduct website resides on a secure 
server, and access is gained through usernames and passwords provided to personnel 
responsible for enrolling patients and updating patient data.  The website is accessed 
through a browser using secure socket layer (SSL) technology. Personnel responsible 
for enrolling patients on trials, which includes the principal investigator(s), research 
nurse(s), and data coordinator(s), will be trained by members of the Department of 
Biostatistics in the use of the trial website; the importance of timely updating of follow-
up times and recording of events will be emphasized in training. 
 
 
We will also monitor the unacceptable nivolumab grade 3 or 4 drug attributable toxicity 
rate by 12 months, and we will stop the trial if we have statistical evidence that this 
unacceptable toxicity rate is more than 10%. The method of Thall, Simon and Estey 
[1995] will be used for toxicity monitoring for this study. The software Multc 
Lean.Version 2.1 was used to run the simulation.  
 We will stop the trial early if 
 
Simulation Results 
Median 
months to death or 
relapse 
Pr(Stop early) 
Mean # pats. (25%, 75% 
percentiles) 
5 
0.8 
51.3 (31,75) 
7 
0.11 
70.5 (75,75) 
9 
0.02 
73.9 (75,75) 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
28 
 
P(unacceptable toxicity by 12 months > 10% | data from the trial) > 0.95. 
 
That is, given the outcomes from the patients who have already been evaluated, if we 
determine that there is more than a 95% chance that the unacceptable toxicity rate is 
more than 10%, we will stop the trial.  This decision rule gives the following stopping 
rule.  We assume a beta(0.2, 1.8) prior distribution for the unacceptable toxicity rate.   
 
The operating characteristics of this decision rule are shown in Table 2.  When the trial 
is completed we will report the posterior probability that the unacceptable toxicity rate by 
12 months is more than 10%, and we will give a 90% credible interval for this rate. 
 
 
 
 
Table 13.3. toxicity stopping boundaries in cohort size of 5.  
Number of patients  
Stop the trial if there are 
this many patients 
achieving toxicity 
5 
3-5 
10 
4-10 
15-20 
5-20 
25 
6-25 
30 
7-30 
35-40 
8-40 
45 
9-45 
50-55 
10-55 
60 
11-60 
65-70 
12-70 
 
 
Table 13.4: Operating characteristics for monitoring of toxicity rate.  
True toxicity 
Rate 
Early 
Stopping 
Probability 
Average 
number of 
patients 
treated 
0.05 
0.01 
75 
0.1 
0.11 
70 
0.15 
0.47 
56 
0.2 
0.83 
38 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
29 
 
0.25 
0.97 
25 
 
 
 
12.4 Analysis plan: 
 
Demographic and disease characteristics of the patients at registration will be 
summarized using descriptive statistics such as mean, standard deviation (SD), median 
and range. Frequency tables will be used to summarize categorical variables.  The EFS 
will be estimated by Kaplan-Merier method, along with the 95% confidence intervals, 
and logrank test will be used to assess the EFS differences under different patient 
subgroups.  The Cox proportional hazards model will be used to analyze the effects of 
treatments and other covariates. 
 
Data from all subjects who receive any study drug will be included in the safety analyses.  
            Subjects who entered the study and did not take any of the study drugs and had this 
confirmed will not be evaluated for safety. The severity of the toxicities will be graded 
according to the NCI CTCAE v4.03 whenever possible. We will follow standard 
reporting guidelines for adverse events. Safety data will be summarized by category, 
severity and frequency. The proportion of patients with AEs will be estimated, along with 
the Bayesian 95% credible interval.  
13.0 Background Drug Information 
 
 
       
 
13.1  Nivolumab 
 
13.1.1 Physical and Chemical Properties 
BMS-936558-01 was selected for dosage form development and is also referred to as 
nivolumab or BMS-936558. Nivolumab is a soluble protein consisting of 4 polypeptide 
chains, which include 2 identical heavy chains and 2 identical light chains.  
 
BMS Number BMS-936558-01 
Other Names Nivolumab, BMS-936558, MDX-1106, ONO-4538, anti-PD-1 
Molecular Weight 143,599 daltons 
Appearance Clear to opalescent, colorless to pale yellow liquid, light (few) particulates 
Solution pH 5.5 to 6.5 
 
13.1.2 Pharmaceutical Properties and Formulation 
BMS-936558-01 Injection 100 mg/Vial (10 mg/mL) 
 
13.1.3 Description of the Dosage Form 


B M S – I d ar u bi ci n, C yt ar a bi n e, a n d Ni v ol u m a b 
A u g u st 1 7, 2 0 1 7 
2 0 1 4- 0 9 0 7  
 
3 0 
 
B M S- 9 3 6 5 5 8- 0 1 I nj e cti o n, 1 0 0 m g/ Vi al ( 1 0 m g/ m L) i s a cl e ar t o o p al e s c e nt, c ol orl e s s t o 
p al e y ell o w li q ui d, li g ht (f e w) p arti c ul a t e s m a y b e pr e s e nt. T he dr u g pr o d u ct i s a st eril e, 
n o n p yr o g e ni c, si n gl e- u s e, i s ot o ni c a q u e o u s s ol uti o n f or m ul at e d at 1 0 m g/ m L i n s o di u m 
citr at e, s o di u m c hl ori d e, m a n ni t ol, di et h yl e n etri a mi n e p e nt a c eti c a ci d ( p e nt eti c a ci d) a n d 
p ol y s or b at e 8 0 ( T w e e n
 8 0), p H 6.0 a n d i n cl u d e s a 7 % o v erfill t o a c c o u nt f or V N S ( vi al, 
n e e dl e, s yri n g e) l o s s. 
It i s s u p pli e d i n 1 0- c c t y p e I fli nt gl a s s vi al s, st o p p er e d wit h b ut yl st o p p er s a n d s e al e d 
wit h al u mi n u m s e al s. 
 
1 3. 1. 4 Dr u g Pr o d u ct Pr e p ar ati o n 
B M S- 9 3 6 5 5 8- 0 1 I nj e cti o n 1 0 0 m g/ Vi al ( 1 0 m g/ m L) 
B M S- 9 3 6 5 5 8- 0 1 i nj e cti o n i s t o b e a d mi ni st er e d a s a n I V i nf u si o n, u si n g a v ol u m etri c 
p u m p wit h a 0. 2/ 0. 2 2 mi cr o n p or e si z e, l o w- pr ot ei n bi n di n g p ol y et h er s ulf o n e m e m br a n e 
i n-li n e filt er at t h e pr ot o c ol- s p e cifi e d d o s e s. It i s n ot t o b e a d mi ni st er e d a s a n I V p u s h or 
b ol u s i nj e cti o n. 
B M S- 9 3 6 5 5 8- 0 1 i nj e cti o n c a n b e i nf u s e d u n dil ut e d ( 1 0 m g/ m L) or dil ut e d wit h 0. 9 % 
S o di u m C hl ori d e I nj e cti o n, U S P  t o pr ot ei n c o n c e ntr ati o n s n o l o wer t h a n 0. 3 5 m g/ m L. 
I n str u cti o n s f or dil uti o n a n d i nf u si o n of B M S- 9 3 6 5 5 8- 0 1 i nj e ctio n m a y b e pr o vi d e d i n t h e 
cli ni c al pr ot o c ol, p h ar m a c y bi n d er, or p h ar m a c y r ef er e n c e s h e et . C ar e m u st b e t a k e n t o 
a s s ur e st erilit y of t h e pr e p ar e d s ol uti o n a s t h e pr o d u ct d o e s n ot c o nt ai n a n y a nti-
mi cr o bi al pr e s er v ati v e or b a ct e ri o st ati c a g e nt. N o i n c o m p ati biliti e s b et w e e n B M S-
9 3 6 5 5 8- 0 1 i nj e cti o n a n d p ol y ol e fi n b a g s h a v e b e e n o b s er v e d. 
 
1 3. 1. 5 R e c o m m e n d e d St or a g e a n d U s e C o n diti o n s 
B M S- 9 3 6 5 5 8- 0 1 I nj e cti o n, 1 0 0 m g/ Vi al ( 1 0 m g/ m L) 
Vi al s of B M S- 9 3 6 5 5 8- 0 1 i nj e cti o n m u st b e st or e d at 2
- 8 C ( 3 6
-4 6 F) a n d pr ot e ct e d ̀
fr o m li g ht a n d fr e e zi n g. 
U n dil ut e d B M S- 9 3 6 5 5 8- 0 1 I nj e cti o n a n d Dil ut e d B M S- 9 3 6 5 5 8- 0 1 I nj e cti o n i n t h e I V B a g 
I V b a g s c o nt ai ni n g u n dil ut e d a n d dil ut e d s ol uti o n s of B M S- 9 3 6 5 5 8- 0 1 i nj e cti o n pr e p ar e d 
f or d o si n g m a y b e st or e d u p t o 2 0 h o ur s i n a r efri g er at or at 2°- 8° C ( 3 6°- 4 6° F) a n d u s e d 
wit hi n 4 h o ur s at r o o m t e m p er at ur e a n d u n d e r r o o m li g ht. T h e m axi m u m 4- h o ur p eri o d 
u n d er r o o m t e m p er at ur e a n d r o o m li g ht c o n diti o n s f or u n dil ut e d a n d dil ut e d s ol uti o n s of 
B M S- 9 3 6 5 5 8- 0 1 i nj e cti o n i n t h e I V b a g s h o ul d b e i n cl u si v e of t he pr o d u ct a d mi ni str ati o n 
p eri o d. 
 
 
 
 P R O D U C T I N F O R M A TI O N 
Dr u g or d eri n g a n d a c c o u nt a bilit y: 
B M S  i s  s u p pl yi n g  st u d y  dr u g,  i nf or m ati o n  i n  t hi s  s e cti o n  m a y  i n cl u d e  h o w  t o  or d er  st u d y  dr u g 
fr o m B M S or fr o m t h e I n v e sti g at or p h ar m a c y. Or t hi s i nf or m ati o n m a y b e i n cl u d e d i n a p h ar m a c y 
m a n u al.  
Pl e a s e s e e A p p e n di x D f or i nf or m ati o n o n pr o vi si o n s f or or d eri n g st u d y dr u g fr o m B M S. 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
31 
 
 
It is possible that sites may have more than one clinical study on the same drug ongoing at the 
same time. It is imperative that only drug product designated for this protocol be used for this 
study 
The investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity) 
 
If concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product, and contact BMS immediately. If commercial 
investigational product is used, it should be stored in accordance with the appropriate local 
labeling 
 
If the study drug(s) are to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal have 
been established according to applicable regulations, guidelines, and institutional procedures 
Product description and dosage form 
 
 
 
 
 
PRODUCT INFORMATION TABLE: Please also see Drug Information Appendix D 
 
 
*Nivolumab may be  labeled as BMS-936558-01 Solution for Injection 
 
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. 
Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab (BMS-
936558-01)* 
Injection drug 
product is a 
sterile, non-
pyrogenic, single-
use, isotonic 
aqueous solution 
formulated at 10 
mg/mL   
100 
mg/Vial 
(10 
mg/mL). 
Carton of 5 or 
10 vials 
10-cc Type 1 
flint glass vials 
stoppered with 
butyl stoppers 
and sealed with 
aluminum 
seals. 
Clear to 
opalescent, 
colorless to pale 
yellow liquid.  May 
contain particles 
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 46 
degrees F) and 
protected from light 
and  freezing  


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
32 
 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator Brochure 
section for “Recommended Storage and Use Conditions”  
 
 
Handling and Dispensing 
The investigator should ensure that the study drug is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as per product information and the Investigator Brochure 
and per local regulations. It is the responsibility of the investigator to ensure that investigational product 
is only dispensed to study subjects. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations. If concerns regarding the quality or 
appearance of the study drug arise, the study drug should not be dispensed and contact BMS 
immediately. 
Please refer to the current version of the Investigator Brochure and/or shipment reference sheets for 
additional information on storage, handling, dispensing, and infusion information for nivolumab. 
 
 
Destruction of study drug 
The drug will be disposed of on-site per MD Anderson Cancer Center Drug Disposal Policy 
13.1.6Dose calculations and administration 
Describe timing of first dose from registration/randomization. For further preparation and administration 
details please refer to the current Investigator Brochure and/or pharmacy reference Appendix. 
 
Nivolumab will be given every two weeks at a target dose of 3mg/kg (as confirmed by the phase I 
portion of the study). Patients may be dosed no less than 12 days from the previous dose of drug.  
The dosing calculations should be based on the actual body weight. If the subject’s weight on the day 
of dosing differs by > 10% from the weight used to calculate the original dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram. There will be no dose modifications 
allowed. 
 
 
 
 
13.2  Idarubicin 
Idarubicin is commercially available. Please see package insert for further information. 
 
13.2.1 Synonyms  
4-Demethoxydaunorubicin; 4-DMDR, Idarubicin Hydrochloride, IDR: IMI30; 
NSC256439, SC 33428 
 
13.2.2 Use  
Treatment of acute leukemias (AML, ANLL, ALL), accelerated phase or blast crisis of 
chronic myelogenous leukemia (CML). 
 
13.2.3 Contraindications  
Hypersensitivity to idarubicin, other anthracyclines, or any component of the 
formulation; bilirubin >5 mg/dl; pregnancy 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
33 
 
 
13.2.4 Warnings/Precautions  
The U.S. Food and Drug Administration (FDA) currently recommends that procedures 
for proper handling and disposal of antineoplastic agents be considered. Can cause 
myocardial toxicity and is more common in patients who have previously received 
anthracyclines or have pre-existing cardiac disease; reduce dose in patients with 
impaired hepatic function. 
 
13.2.5 Adverse Reactions 
>10% 
Cardiovascular: Transient EKG abnormalities (supraventricular 
tachycardia, S-T wave changes, atrial or ventricular extrasystoles); 
generally asymptomatic and self-limiting. Congestive heart failure, 
dose-related. The relative cardiotoxicity of idarubicin compared to 
doxorubicin is unclear. Some investigators report no increase in cardiac 
toxicity at cumulative oral idarubicin doses up to 540 mg/m2; other reports 
suggest a maximum cumulative intravenous dose of 150 mg/m2. 
Central nervous system: Headache 
Dermatologic: Alopecia (25% to 30%), radiation recall, skin rash (11%), 
urticaria 
Gastrointestinal: Nausea, vomiting (30% to 60%); diarrhea (9% to 22%); 
stomatitis (11%); GI hemorrhage (30%) 
Genitourinary: Discoloration of urine (darker yellow) 
Hematologic: Myelosuppression, primarily leukopenia; thrombocytopenia 
and anemia. Effects are generally less severe with oral dosing 
Nadir: 10-15 days 
Recovery: 21-28 days 
Hepatic: Elevations of bilirubin and transaminases (44%) 
1% to 10% 
Central nervous system: Seizures 
Neuromuscular & skeletal: Peripheral neuropathy 
<1%:  Hyperuricemia 
 
13.2.6 Overdosage/Toxicology Symptoms of overdose include severe 
myelosuppression and increased GI toxicity. Treatment is supportive. It is 
unlikely that therapeutic efficacy or toxicity would be altered by 
conventional peritoneal or hemodialysis. 
 
13.2.7  Drug Interactions Patients may experience impaired imune response to 
vaccines; possible infection after administration of live vaccines in patients 
receiving immunosuppressants 
 
13.2.8  Stability Store intact vials of solution under refrigeration at 2°C to 8°C (36°F to 
46°F).  Protect from light.  Solutions diluted in D5W or NS for infusion are stable 
for 4 weeks at room temperature, protected from light.  Syringe and IBPB 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
34 
 
solutions are stable for 72 hours at room temperature and 7 days under 
refrigeration. 
 
13.2.9 Mechanism of Action Similar to doxorubicin and daunorubicin; inhibition 
of DNA and RNA synthesis by intercalation between DNA base pairs 
 
13.2.10 Pharmacodynamics/Kinetics 
Absorption: Oral: Variable (4% to 77%; mean: ~30%) 
Distribution: Vd: 64 L/kg (some reports indicate 2250 L) 
Metabolism: Hepatic to idarubicinol (pharmacologically active) 
Half-life elimination: Oral: 14-35 hours; I.V.: 12-27 hours 
Time to peak, serum: 1-5 hours 
Excretion: 
Oral: Urine (~5% of dose; 0.5% to 0.7% as unchanged drug, 4% as 
idarubicinol); hepatic (8%) 
I.V.: Urine (13% as idarubicinol, 3% as unchanged drug); hepatic (17%) 
 
13.2.11 Extravasation management: Topical cooling may be achieved using ice 
packsor cooling with circulating ice water. Cooling of site for 24 hours as 
tolerated by the patient. Elevate and rest extremity 24-48 hours, then 
resume normal activity as tolerated. Application of cold inhibits vesicant's 
cytotoxicity. Application of heat can be harmful and is contraindicated. If 
pain, erythema, and/or swelling persist beyond 48 hours, refer patient 
immediately to plastic surgeon for consultation and possible debridement. 
 
13.3 Cytarabine 
Cytarabine is commercial available. 
 
 
13.3.1Synonyms  
Arabinosylcytosine; Ara-C; Cytarabine Hydrochloride; 
Cytosine Arabinosine Hydrochloride; NSC-63878 
13.3.2 Use  
Cytarabine is one of the most active agents in leukemia; also active 
against lymphoma, meningeal leukemia, and meningeal lymphoma; has 
little use in the treatment of solid tumors 
 
13.3.3 Contraindications  
Hypersensivity to cytarabine or any component of the formulation; pregnancy 
 
13.3.4 Warnings/Precautions  
The U.S. Food and Drug Administration (FDA) currently recommends that 
procedures for proper handling and disposal of antineoplastic agents be 
considered. Use with caution in pregnant women or women of childbearing age 
and in infants 


BMS – Idarubicin, Cytarabine, and Nivolumab 
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35 
 
 
13.3.5 Adverse Reactions 
>10%: 
Central nervous system: Fever (>80%) 
Dermatologic: Alopecia 
Gastrointestinal: Nausea, vomiting, diarrhea, and mucositis which 
subside quickly after discontinuing the drug; GI effects may be 
more pronounced with divided I.V. bolus doses than with 
continuous infusion 
Hematologic: Myelosuppression; neutropenia and 
thrombocytopenia are severe, anemia may also occur 
Onset: 4-7 days 
Nadir: 14-18 days 
Recovery: 21-28 days 
Hepatic: Hepatic dysfunction, mild jaundice, and acute increases in 
transaminases can be produced 
Ocular: Tearing, ocular pain, foreign body sensation, photophobia, 
and blurred vision may occur with high-dose therapy; ophthalmic 
corticosteroids usually prevent or relieve the condition 
1% to 10%: 
Cardiovascular: Thrombophlebitis, cardiomegaly 
Central nervous system: Dizziness, headache, somnolence, 
confusion, malaise; a severe cerebellar toxicity occurs in about 8% 
of patients receiving a high dose (>36-48 g/m2/cycle); it is 
irreversible or fatal in about 1% 
Dermatologic: Skin freckling, itching, cellulitis at injection site; rash, 
pain, erythema, and skin sloughing of the palmar and plantar 
surfaces may occur with high-dose therapy. Prophylactic topical 
steroids and/or skin moisturizers may be useful. 
Genitourinary: Urinary retention 
Neuromuscular & skeletal: Myalgia, bone pain 
Respiratory: Syndrome of sudden respiratory distress, including 
tachypnea, hypoxemia, interstitial and alveolar infiltrates 
progressing to pulmonary edema, pneumonia 
<1%: 
Increases in amylase and lipase levels; isolated cases of 
pancreatitis have been reported; dysphagia (reported with 
intrathecal use); peripheral neuropathy, neuritis; accessory nerve 
paralysis (reported with intrathecal use); diplopia (reported with 
intrathecal use); cough, hoarseness (reported with intrathecal use); 
aphonia (reported with intrathecal use) 
 
13.3.6 Overdosage/Toxicology  
Symptoms of overdose include myelosuppression, megalobastosis, nausea, 
vomiting, respiratory distress, and pulmonary edema. A syndrome of sudden 


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36 
 
respiratory distress progressing to pulmonary edema and cardiomegaly has been 
reported following high doses. Treatment is symptomatic and supportive. 
 
13.3.7 Drug Interactions 
Decreased effect of gentamicin, flucytosine; decreases digoxin oral tablet 
absorption Increased toxicity: Alkylating agents and radiation; purine analogs; 
methotrexiate 
 
13.3.8 Stability  
Store intact vials of powder at room temperature 15°C to 30°C (59°F to 86°F). 
Reconstitute with SWI, D5W or NS; reconstituted solutions are stable for up to 8 
days at room temperature. Use preservative free cytarabine solution within 24 
hours of reconstitution.  Further dilution in D5W or NS is stable for 8 days at 
room temperature (25°C). 
Standard IV infusion dilution: Dose/250-1000 mL D5W or NS. 
 
13.3.9 Mechanism of Action  
Inhibition of DNA synthesis. Cytosine gains entry into cells by a carrier process, 
and then must be converted to its active compound, aracytidine triphosphate. 
Cytosine is a purine analog and is incorporated into DNA; however, the primary 
action is inhibition of DNA polymerase resulting in decreased DNA synthesis and 
repair. The degree of cytotoxicity correlates linearly with incorporation into DNA; 
therefore, incorporation into DNA is responsible for drug activity and toxicity. 
Cytarabine is specific for the S phase of the cell cycle. 
 
13.3.10 Pharmacodynamics/Kinetics 
Distribution: V6: Total body water; widely and rapidly since it enters the 
cells readily; crosses blood-brain barrier with CSF levels of 40% to 50% of 
plasma level 
Metabolism: Primarily hepatic; aracytidine triphosphaste is the active 
moiety; about 86% to 96% of dose is metabolized to inactive uracil 
arabinoside 
Half-life elimination: Initial: 7-20 minutes; Terminal: 0.5-2.6 hours 
Excretion: Urine (~80% as metabolites) within 24-36 hours 
 
13.3.11 Administration  
Can be administered at a concentration not to exceed 100 mg/mL. 
I.V. doses of >1.5 g/m2 may produce conjuctivitis which can be 
ameliorated with prophylactic use of corticosteroid (0.1% dexamethasone) 
eye drops. Dexamethasone eye drops should be administered at 1-2 
drops every 6 hours during and for 2-7 days after cytarabine is done. 
 
 
 
14.0 Correlative Studies (Optional) 


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37 
 
 
The objective of this portion of the study is to correlate systemic serum markers, 
obtainable by peripheral venous access to patient responses and observed toxicities. 
Voluntary participation in this portion of the protocol is optional for all study participants. 
 
Systemic lymphocyte counts obtained from routine CBC with differential will be 
analyzed and associated with clinical outcomes and toxicities from the lab draws 
obtained throughout this protocol. 
 
Tumor-specific antigens that can elicit cellular and humoral immunity, are expressed on 
leukemia cells and can be identified for development of immunotherapy in these 
patients. Patient serum will be analyzed to assess candidate tumor-associated antigens 
or genes that elicit cellular and humoral immune responses. This analysis will correlate 
antigen-expression and immune responses with patient data such as cytogenetics, 
treatment response, and clinical outcome of patients. 
 
This study will be done in collaboration with Dr. Padmanee Sharma, MD/PhD, and Dr. 
James Allison, PhD and covered by the immunotherapy platform supported by MD 
Anderson Laboratory Protocol PA13-0291. All samples will be collected using 
procedures characterized in this protocol and all patients will be consented for 
procedures done under this protocol separately. Specifically, this study will allow for the 
collection of up to 10 cc of blood, to be drawn at the time of routine blood-draw, to be 
used for biomarker analysis. Serum samples will be collected in red top tubes and PBMC 
cycle of chemotherapy, in 10 cc green top, heparin tubes for biomarker analysis before 
initiation of first cycle of chemotherapy, before every subsequent course of 
chemotherapy (+ 1 week), and approximately every 3 months until completion of 
nivolumab therapy, relapse, or discontinuation of therapy (+ 1 week) whichever comes 
first.  Further samples will be obtained at the end of study visit. 
 
Bone marrow aspirate samples will be obtained at diagnosis and at the time of any 
follow-up bone marrow assessment for molecular analysis of genomic aberrations as a 
part of the AML moonshot program and will be submitted to the laboratories of Dr. Lynda 
Chin and Andrew Futreal under the approved protocol LAB01-473. 


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APPENDIX D 
SAMPLE OF DRUG ORDERING  AND PHARMACY REFERENCE 
MATERIAL 
Nivolumab (BMS-936558) Pharmacy Reference Material 
 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five vials are 
provided in a carton. 
 
Initial Orders  
 
Following submission and approval of the required regulatory documents, a supply of nivolumab 
may be ordered from by completing a Drug Request Form provided by BMS for this specific trial. 
The first request may take place upon screening of the first patient  
 
The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug from BMS 
receipt of the Drug Request Form. Drug is protocol specific, but not patient specific. All drug product 
will be shipped by courier in a temperature-controlled container. It is possible that sites may have 
more than one nivolumab clinical study ongoing at the same time. It is imperative that only drug 
product designated for this protocol number be used for this study. 
 
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents,  In-line 
filters and infusion tubing 
Re-Supply 
 
Drug re-supply request form should be submitted electronically business days before the expected 
delivery date.  Deliveries will be made Tuesday through Friday. 
 
When assessing need for resupply, institutions should keep in mind the number of vials used per 
treatment dose, and that shipments may take 14 business days from receipt of request. Drug is not 
patient-specific. Be sure to check with your pharmacy regarding existing investigational stock to 
assure optimal use of drug on hand. 
Drug Excursions 
 
Drug  excursions should be reported immediately to BMS on the form provided with the study-
specific drug order form 
Please refer to the most recent version of the Investigator Brochure for additional information. 
 
Storage Conditions & Handling: 
 
Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
 
If any temperature excursions are encountered during storage, please report these to BMS for 
assessment via the Temperature Excursion Response Form.    
 
As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet using 
standard precautions for the safe handling of intravenous agents applying aseptic technique.  
 
Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs.  


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46 
 
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. For further information, please either discuss with your 
BMS CSR&O protocol manager or refer to your site IP Destruction policies and procedures  
 
Use Time/Stability: Please refer to section 3.2.3 of the current Investigator Brochure. Due to 
parameters surrounding the use time of Nivolumab, the time of preparation should be noted in the 
Pharmacy Source documents [accountability logs] or in study files as required for investigator 
sponsored research [FDA and GCP] 
 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must be 
completed within 24 hours of preparation. If not used immediately, the infusion solution may be stored 
up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-46°F) and used within 
4for up to 24 hours, and a maximum of 4 hours of the total 24 hours can be at room temperature (20°-
25°C, 68°-77°F) and under room light. The maximum 4-hour period under room temperature and room 
light conditions for undiluted and diluted solutions of BMS-936558-01 injection in the IV bag should be 
inclusive of the includes the product administration period. 
 
 
 
 
 
Preparation and Administration: 
 
1. Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution may have 
a pale-yellow color), or if there is foreign paticulate matter other than a few translucent-to-white, 
amorphous particles. 
Note: Mix by gently inverting several times.  Do not shake. 
2. Aseptically withdraw the required volume of nivolumab solution into a syringe, and dispense into an 
IV. bag.  If multiple vials are needed for a subject, it is important to use a separate sterile syringe and 
needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated 
friction of plunger against syringe barrel wall. Do not enter into each vial more than once.  Do not 
administer study drug as an IV push or bolus injection 
3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose Injection  
solution. It is acceptable to add nivolumab solution from the vials into an appropriate pre-filled bag of 
diluent. 
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 1 mg/mL.  
Note: It is not recommended that so-called “channel” or tube systems are used to transport prepared 
infusions of nivolumab. 
4. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
5. At the end of the infusion period, flush the line with a sufficient quantity of approved diluents. 
 
 
 


BMS – Idarubicin, Cytarabine, and Nivolumab 
August 17, 2017 
2014-0907 
 
47 
 
 
 
Example Dose Calculation [at 3mg/kg] 
Total dose should be calculated as follows  (assuming total dose volume of 210 mL, 70 kg pt, 
dose of 3 mg/kg):  
 
 
Subject body weight in kg x 3 mg (for the 3 mg/kg cohort) = total dose (mg) 
70 kg x 3 mg/kg = 210 mg  
 
Total dose (mg) ÷ 10 mg/mL = Amount of solution to be withdrawn from vials 
210 mg ÷ 10 mg/mL = 21 mL 
 
Example of Total volume of solution to infuse (mL) for a minimum conc solution. – Volume of 10 
mg/mL solution (mL) = Volume of Diluent (mL) to add 
                210 mL – 21 mL = 189 mL 
 
Please note it is perfectly acceptable to dose Nivolumab at a higher drug concentrations, as long as 
the total volume of diluted solution is at or above the minimum  allowable concentration of 1 
mg/mL, below is the calculation based on the above example. Please double check. 
Total dose in mg ÷ Total volume to infuse in mL = Overall drug concentration, mg/mL 
210 mg ÷  210mL = 1 mg/mL