Conditions: Acute Biphenotypic Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects lirilumab and azacitidine and to see how well they work in treating patients with acute myeloid leukemia that has not responded to treatment or has returned after a period of improvement. Monoclonal antibodies, such as lirilumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving lirilumab with azacitidine may be an effective treatment for relapsed or refractory acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of lirilumab in combination with 5-azacytidine (azacitidine) in patients with refractory/relapsed acute myeloid leukemia (AML). (Part A, Lead-In Phase) II. To determine the overall response rate (ORR) of lirilumab in combination with 5-azacytidine in patients with refractory/relapsed AML. (Part B, Phase II)

SECONDARY OBJECTIVES:

I. To determine the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with refractory/relapsed AML treated with this combination.

II. To determine the safety of lirilumab in combination with 5-azacytidine in patients with refractory/relapsed AML.

OUTLINE:

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and up to 90 days.

Arms:
arm 1: Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

5-Azacitidine 75mg/m\^2 Lirilumab 1.0 mg/kg arm 2: Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

5-Azacitidine 75mg/m\^2 Lirilumab 3.0 mg/kg arm 3: Patients receive azacitidine SC or IV over 1 hour as determined by the treating physician on days 1-7 and lirilumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

5-Azacitidine 75mg/m\^2 Lirilumab 3.0 mg/kg

Interventions: intervention 1: Azacitidine intervention 2: Lirilumab
Intervention descriptions: intervention 1: Given SC or IV intervention 2: Given IV

Protocol document:
Prot_SAP_000.pdf: 
2014-0862
April 3, 2018
Page 
Protocol Page
An Open-label Phase II Study of Lirilumab (BMS-986015) in Combination with 
5-azacytidine (vidaza) for the Treatment of Patients with Refractory/Relapsed Acute 
Myeloid Leukemia
2014-0862
Core Protocol Information
Short Title 
An Open-label Phase II Study of Lirilumab (BMS-986015) in Combination with 5-azacytidine 
(vidaza) for the Treatment of Patients with Refractory/ Relapsed Acute Myeloid Leukemia
Study Chair: 
Naval Daver
Additional Contact:
Dana E. Brown
Nawar Hussin
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-794-4392
Unit:
428
Study Manager:
Nawar Hussin
Full Title: 
An Open-label Phase II Study of Lirilumab (BMS-986015) in Combination with 5-azacytidine 
(vidaza) for the Treatment of Patients with Refractory/Relapsed  Acute Myeloid Leukemia
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 07/13/2018
Version:
13
Submitted by:
Dana E. Brown--4/3/2018 11:14:00 AM
OPR Action:
Accepted by:  Yolanda Shorte -- 4/9/2018 1:31:27 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2014-0862
April 3, 2018
Page 
Protocol Body
 


 
 
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An Open-label Phase II Study of Lirilumab (BMS-986015) in 
Combination with 5-azacytidine (vidaza) for the Treatment of 
Patients with Refractory/ Relapsed Acute Myeloid Leukemia 
 
 
 
Principal Investigator: Naval Daver, M.D. 
Co-Chair: Jorge Cortes, M.D. 
  
 
Sponsor: University of Texas, MD Anderson Cancer Center 
 
 
IND number: 125,496 
 
 
University of Texas  
 
MD Anderson Cancer Center  
 
Leukemia Department, Unit 428  
 
 
 
 


 
 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
Part a. Lead-in phase: 
1.      To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of 
lirilumab in combination with 5-azacytidine in patients with refractory/ relapsed (AML).  
Part b. Phase II: 
       1.      To determine the overall response rate (ORR) of lirilumab in combination with 5-
azacytidine in patients with refractory/ relapsed AML.  
 
1.2 
Secondary Objectives:  
1.To determine the duration of response, disease-free survival (DFS), and overall survival 
(OS) of patients with refractory/ relapsed AML treated with this combination. 
2.To determine the safety of lirilumab in combination with 5-azacytidine in patients with 
refractory/ relapsed AML. 
 
1.3       Exploratory Objectives: 
1. 
To study immunological and molecular changes in the peripheral blood and bone 
marrow in response to lirilumab and 5-azacytidine therapy.  
2. 
To determine induction of hypomethylation and DNA damage during therapy with this 
combination and its correlation with response. 
 
2.0      BACKGROUND 
 
2.1 
Acute myeloid leukemia 
AML is a malignancy of immature granulocytes or monocytes. The malignancy is 
characterized by accumulation of leukemic blastocytes and blockade of normal bone marrow 
production resulting in thrombocytopenia, anemia, and neutropenia. . There are 
approximately 13,000 new cases of AML per year in the United States, with an estimated 
10,000 deaths occurring in the same time period[1]. Almost all newly diagnosed cases, as 
well as deaths, will be in adults[2]. Standard treatment for AML includes systemic 
combination chemotherapy to control bone marrow and systemic disease. Treatment is 
generally divided into an induction phase, to attain remission, and a maintenance phase[2]. 
Approximately 60% to 70% of adults with AML can be expected to attain complete 
remission status following appropriate induction therapy. Remission rates in adult AML are 
inversely related to age, with an expected remission rate of >65% for those younger than 60 
years. Increased morbidity and mortality during induction appear to be directly related to 
age[3-5]. 
 
2.2       Relapsed/ Refractory AML  
            Approximately, 30-40% of adults with AML fail to achieve CR with 1 or 2 cycles of 
induction chemotherapy, and are deemed primary refractory. The outcome of patients with 
acute myeloid leukemia (AML) who are refractory to induction therapy are dismal, with low 
response rates to salvage chemotherapy and poor long-term survival [6-8]. We have 


 
 
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previously reported a dismal median OS of 3.8 months for patients with AML who are 
refractory to HiDAC-containing induction therapy (defined as ≥ 1gm/m2 cytarabine per 
dose)[7]. Salvage therapy in such patient populations yielded a response rate of 18% and 
median response duration of 9 months.  
 
           These results emphasize the need to explore alternate salvage regimens for patients with 
relapsed/refractory AML. The development of novel and effective anti-AML agents and/or 
combinations is crucial to improving the outcome of AML.  
 
2.3       Role of PD-1/PD-L1 interactions and NK-cells in AML 
            PD-1 and CTLA-4 are well known negative regulators of CTL survival and effector function 
in both solid tumors and leukemia [9]. It has been clearly demonstrated that blocking 
ligation of PD-1 and CTLA-4 prevents deletion of CTLs [10, 11]. A third component of the 
negative regulatory pathway is the inhibitory-cell killer immunoglobulin-like receptors 
(KIR) [12]. Inhibitory-cell KIR receptors negatively regulate natural killer (NK) cell-
mediated killing of HLA class I-expressing tumors. NK cells play a crucial role in anti-
tumor responses by killing transformed cells. The activation of NK-cells is regulated by a 
variety of activating and inhibitory receptors that are expressed by the transformed target 
cells [13]. Activating receptors include NKp30, NKp44, NKp46, NKG2D, and DNAM-1 
[14]. For effective activation of NK-cells tumor cells must express stress or activation 
ligands for activating receptors. Negative regulators of NK activating receptors include KIR, 
CD94/NKG2A, and leukocyte Ig-like receptor-1, which recognize MHC-class 1 molecules 
[15]. Effective NK-cell activity occurs when the target cells express stress ligands with 
reduced expression of MHC class 1 ligands. Persistent expression of MHC class 1 ligands 
may result in tumors evading NK-cell mediated immunosurveillance [16]. Lack of KIR-
HLA class I interactions has been associated with potent NK-mediated antitumor efficacy 
and increased survival in AML patients upon haploidentical stem cell transplantation from 
KIR-mismatched donors [17]. Romagne et al developed a monoclonal antibody that cross-
reacts with KIRDL1, -2 and -3 receptors thereby blocking inhibitory signaling via these 
receptors. This resulted in augmented NK-cell mediated lysis of tumor cells but did not 
induce killing of normal peripheral blood mononuclear cells, suggesting a preferential NK-
cell activity against AML cells [12]. Intriguingly inoculation of NK-cells alone did not 
protect against autologous implanted AML in immunodeficient mice, however 
preadministration with KIR monoclonal antibody induced anti-AML activity with long-term 
survival. Lirilumab (IPH2102/BMS-986015) is a fully human monoclonal antibody blocking 
interaction between Killer-cell immunoglobulin-like receptors (KIR) on NK cells with their 
ligands.  
 
2.4 
Lirilumab (IPH2102/BMS-986015): 
Lirilumab (BMS-986015, IPH2102) is a fully human IgG4 monoclonal antibody (mAb) that 
is specific for a subset of human KIRs. Lirilumab is a mAb that blocks the KIR/HLA 
interaction, and lowers the threshold for activation of NK cells without directly activating 
NK cells. Once activated, NK cells release preformed cytotoxic granules into the target cell 
leading to direct killing of cancer cells. The concurrent release of cytokines and chemokines 
also results in a micro-environmental milieu that recruits other immune cells. 
 
Lirilumab is the second anti-KIR antibody. IPH2101 is the first anti-KIR antibody. IPH2101 


 
 
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and lirilumab have identical target specificities. The differences are that IPH2101 is a native 
IgG4 antibody produced from a hybridoma cell line, whereas lirilumab has a single amino 
acid mutation to stabilize the hinge region of the molecule and is produced by Chinese 
hamster ovary (CHO) cells. No additional clinical trials will be conducted with IPH2101. 
Lirilumab is being developed for treatment of patients with hematologic and solid tumor 
malignancies. Lirilumab is currently being tested in 4 clinical trials and will be used in all 
subsequent trials. 
 
Evidence in support of NK cell involvement in the anti-tumor response comes from the 
hematopoietic stem cell transplant setting. Given the diversity of both KIR and HLA, it is 
not surprising that KIR on donor NK cells may not recognize host HLA, referred to as KIR 
mismatch. The finding that patients with acute myeloid leukemia (AML) transplanted with 
KIR-mismatched donor NK cells had lower relapse rates (3% versus 47%, p <0.01) and 
reduced risk of relapse (relative risk: 0.48, 95% confidence interval (CI) [0.29, 0.78]) 
compared to patients transplanted with KIR-matched donor NK cells gave scientific support 
for the role of NK cells in the anti-tumor response[17]. 
 
Lirilumab binds specifically and with high affinity to a subset of KIR, namely KIR2DL-1, 2, 
and 3 and KIR2DS-1 and 2, thus preventing interaction between KIR and HLA-C. Surface 
plasmon resonance analysis demonstrated that the mean (standard deviation [SD]) 
monovalent affinity of lirilumab for recombinant soluble KIR2DL1 was 2.04 x 10-8 (0.31 x 
10-8) M and for KIR2DL3 was 3.01 x 10-10(0.41x10-10) M. 
 
The scientific rationale for the clinical development of lirilumab was based on the following 
findings: 
1) Blockade of inhibitory KIR resulted in killing of AML blasts by KIR-mismatched NK 
cells 
but not by KIR-matched NK cells in vitro. 
2) NOD/SCID mice infused with AML cells and NK cells died of disease within†60 
days. In contrast, all mice treated with KIR blockade survived at Day 75 (p < 0.01)[12]. 
 
Lirilumab also is being developed in combination with the T-cell checkpoint inhibitors, 
ipilimumab and nivolumab. Nonclinical studies combining anti-Ly49 (5E6 F(ab’)2), the 
murine functional homolog of lirilumab, with the mAbs specific for the murine versions of 
either cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) 
demonstrated enhanced anti-tumor efficacy. 
 
Lirilumab does not bind to NK cells from non-human primate or other species traditionally 
used for safety testing. Safety testing was performed in mice because Ly49C/I, the murine 
inhibitory receptors, are functionally homologous to human KIR. Mice treated with 
lirilumab at 10 mg/kg once weekly for 4 weeks, or the surrogate anti-Ly49 (5E6 F(ab’)2) at 
up to 10 mg/kg twice weekly for 13 weeks, showed no signs of toxicity. 
 
Lirilumab is being developed for immunotherapy in patients with various hematologic 
malignancies and solid tumors. A total of 243 subjects have received lirilumab in 3 Phase 1 
studies (1 concluded and 2 ongoing) and 1 ongoing phase 2 study.  
 


 
 
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The first (IPH2102-101) is a monotherapy, dose escalation, Phase 1 trial to determine the 
maximum tolerated dose (MTD). As of the data cut-off date (July 29, 2014) a total of 37 
patients have receive lirilumab on this trial. Of the 20 subjects treated with lirilumab 
monotherapy during the dose escalation period of IPH2102-101, 3 subjects were treated with 
lirilumab 0.015 mg/kg, 3 subjects with 0.3 mg/kg, 4 subjects with 1 mg/kg, 4 subjects with 3 
mg/kg, 3 subjects with 6 mg/kg, and 3 subjects with 10 mg/kg every 4 weeks. There were no 
DLTs, and the MTD was not reached. Of the 17 subjects treated with lirilumab monotherapy 
during the cohort expansion period of the study, 9 subjects were treated with lirilumab at 
0.015 mg/kg and 8 subjects at 3 mg/kg every 4 weeks. A total of 245 AEs were reported by 
36 of 37 (97%) exposed subjects. Overall, most of these AEs were mild (CTCAE Grade 1) 
or moderate (CTCAE Grade 2). 
 
The second (IPH2102-201) is a double-blind, placebo-controlled, Phase 2 trial of lirilumab 
in patients with AML who are in complete remission but ineligible for allogeneic transplant. 
One-third of subjects in this study will be receiving placebo. The doses of lirilumab 
evaluated in this maintenance AML trial were 0.1 mg/kg every 12 weeks and 1.0 mg/kg 
every 4 weeks. A total of 100 patients have been treated with lirilumab on this trial as of the 
data cut-off date (July 29, 2014). One hundred one (67%) subjects have treatment ongoing 
and 50 (33%) subjects discontinued prematurely. In these 50 subjects, the main (or only) 
reason for study discontinuation was relapse of disease (43 subjects), AEs of pancytopenia 
(1 subject) and acute febrile neutrophilic dermatosis (1 subject), withdrawal of consent (2 
subjects), investigator decision (2 subjects), and suspicion of disease progression (2 
subjects). An independent Data and Safety Monitoring Board completed safety analysis of 
86 randomized subjects enrolled in this trial. On 11-Mar-2014, the members of this 
committee recommended continuation of the study without any modification. Adverse 
events were reported by 121 of 150 (81%) subjects exposed to either lirilumab or placebo. 
Most of these AEs were mild (Grade 1) or moderate (Grade 2). Thirty-three (22%) subjects 
reported Grade 3 or Grade 4 AEs (irrespective of causality) including thrombocytopenia in 5 
(3%), arthralgia in 1 (<1%), neutropenia in 7 (5%), fatigue in 1 (<1%), weight increase in 2 
(1%), and urinary tract infection in 1 (1%) patients. One subject reported Grade 5 pulmonary 
embolism, and 1 subject reported Grade 5 general physical health deterioration 
(corresponding to disease progression). Both of the Grade 5 events were considered by the 
investigator to be unrelated to study drug. Sixty-six of 150 (44%) subjects had AEs 
considered to be related to the study drug (either lirilumab or placebo). Most related AEs 
were mild or moderate in severity. Nine (6%) subjects had related Grade 3 AEs (neutropenia 
in 3 subjects and acute febrile neutrophilic dermatosis, sciatica, myalgia, thrombocytopenia, 
increased amylase, and bronchospasm in 1 subject each). One subject (0.7%) had a related 
Grade 4 AE of neutropenia that occurred on Cycle 1/Day 8. Adverse events evaluated as 
related to study drug and reported in >/= 3% of subjects were asthenia in 15 
(10%) subjects, pruritus in 13 (9%) subjects, chills in 7 (5%) subjects, pyrexia in 6 (4%) 
subjects, and neutropenia in 5 (3%) of subjects. Five (3%) subjects reported AEs that led to 
study discontinuation: 4 subjects reported single events that were unrelated to study drug 
(lirilumab or placebo), and 1 subject reported Grade 3 acute febrile neutrophilic dermatosis 
that was considered related to study drug. Seventeen (11%) subjects reported SAEs during 
the study. The only Grade 3 or Grade 4 SAE’a (irrespective of causality) seen in more than 1 
subject was urinary tract infection in 2 (1%). Only 4 of 20 SAEs were considered to be 
related to study drug by the investigator, including one case each of Grade 4 neutropenia, 


 
 
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Grade 3 myalgia, Grade 3 sciatica, and Grade 3 acute febrile neutrophilic dermatosis.  
 
The third (CA223001) and fourth (CA223002) are Phase 1 trials of lirilumab in combination 
with either the anti-PD1 antibody nivolumab or the anti-CTLA-4 antibody ipilimumab, 
respectively, to determine if coordinate modulation of the innate and adaptive immune 
systems results in greater clinical benefit. A total of 88 subjects have received combination 
therapy of nivolumab and lirilumab in clinical trial CA223001 as of the data cut-off date 
(July 29, 2014) including 4 with lirilumab 0.1 mg/kg + nivolumab 3 mg/kg (completed), 13 
with lirilumab 0.3 mg/kg + nivolumab 3 mg/kg (ongoing), 9 with lirilumab 1 mg/kg + 
nivolumab 3 mg/kg, and 62 with lirilumab 3 mg/kg + nivolumab 3 mg/kg. The objective of 
the study is to evaluate the safety of lirilumab in combination with nivolumab in subjects 
with advanced refractory solid tumors. Lirilumab  3mg/kg every 4 weeks in combination 
with nivolumab was well tolerated and was the dose administered to the majority of patients 
on this trial (lirilumab investigator brochure, Appendix E).  
 
As of the data cut-off date (29-Jul-2014), preliminary data include 18 subjects who have 
been treated with the combination of lirilumab and ipilimumab in clinical trial CA223002. 3 
with lirilumab 0.1 mg/kg + ipilimumab 3 mg/kg (completed), 8 with lirilumab 0.3 mg/kg + 
ipilimumab 3 mg/kg, 6 with lirilumab 1 mg/kg + ipilimumab 3 mg/kg, and 1 with lirilumab 
3 mg/kg + ipilimumab 3 mg/kg (ongoing). Two dose levels of ipilimumab (3 mg/kg and 10 
mg/kg) and 4 dose levels of lirilumab (0.1, 0.3, 1, and 3 mg/kg) are being evaluated in 
CA223002, with 3 subjects per dose level if there is no DLT. The 5 dose cohorts are as 
follows (lirilumab dose + ipilimumab dose): Cohort 1: 0.1 mg/kg + 3 mg/kg; Cohort 2: 0.3 
mg/kg + 3 mg/kg; Cohort 3: 1 mg/kg + 3 mg/kg; Cohort 4: 3 mg/kg + 3 mg/kg; Cohort 5: 3 
mg/kg + 10 mg/kg. Subjects receive lirilumab in combination with ipilimumab every 3 
weeks for a total of 4 doses (induction) and then every 12 weeks for an additional 4 doses 
starting at Week 24 (maintenance). 
 
Summary of Safety: Mainly safety data are available, efficacy data available only for the 
IPH2102-101 and no responses observed as of the data cutoff date. As the first clinical trials 
with lirilumab are ongoing or recently concluded, data on safety presented herein are 
preliminary and subject to change. Up until 29-Jul-2014, AEs were reported by 36 of 37 
(97%) subjects treated with lirilumab monotherapy (doses ranging from 0.015 mg/kg to 10 
mg/kg); 121 of 150 (81%) subjects treated with blinded therapy (lirilumab or placebo [2:1]); 
63 of 88 (72%) subjects treated with lirilumab 0.1, 0.3, 1, or 3 mg/kg in combination with 
nivolumab 3 mg/kg; and 17 of 18 (94%) subjects treated with lirilumab 0.1 mg/kg or 0.3 
mg/kg in combination with ipilimumab 3 mg/kg. The majority of AEs were mild or 
moderate (Grades 1 or 2). To date, 12 SAEs were considered to be related to study 
treatment. Additional detailed safety data is available in the Lirilumab investigator brochure 
(Appendix E). 
 
Figure 2-1: Lirilumab Augments NK-mediated Killing of Tumor Cells by 
Blocking the Negative Signaling that Normally Results 


 
 
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Blockade of inhibitory KIR by lirilumab is thus a promising mechanism to promote killing of 
tumor cells by the innate immune system.  IPH2101 is the first fully-human anti-KIR monoclonal 
antibody, and lirilumab is the second generation. Both products bind to the same KIR subtypes with 
similar affinities. Functionally and biologically, the 2 antibodies are similar with the following 
exceptions: 1) IPH2101 is a non-recombinant protein that is produced by a murine hybridoma cell 
line; whereas, lirilumab is a recombinant product produced in CHO cells. 2) Lirilumab has a single 
amino acid substitution of a serine to a proline in the IgG4 heavy chain, resulting in greater stability 
of the compound by reducing the formation of half antibodies. IPH2101 studies were done prior to 
lirilumab studies and safety, efficacy, PKs, and immunologic correlates of IPH2101 in a phase 1 
trial in elderly AML in first remission have been published (Vey N, et al., Blood, 2012 Nov 
22;120(22):4317-23).  Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 following a 
3 + 3 design. The doses that elicited full occupancy were: 1 week = 0.075 mg/kg, 2 weeks = 1 
mg/kg, and for at least 4 weeks = 3 mg/kg. There was a clear correlation between mAb exposure 
and KIR occupancy. The maximum tolerated dose was not reached, although full KIR saturation (> 
90%) was sustained for 4 weeks only at the 3 mg/kg. Lirilumab dose of 3 mg/kg every 4 weeks is 
also the highest dose to be tested in BMS study of lirilumab in combination with elotuzumab for 
multiple myeloma: A Phase I Open Label Dose Escalation and Randomized Cohort Expansion 
Study of the Safety and Tolerability of Elotuzumab (BMS-901608) Administered in Combination 
With Either Lirilumab (BMS-986015) or Urelumab (BMS-663513) in Subjects With Multiple 
Myeloma” (study identifier: NCT02252263). Based on this data and the tolerability of lirilumab in 
combination with other agent (namely nivolumab) in the CA223001 trial we would like to evaluate 
escalating doses of lirilumab to a maximum potential dose of 3.0 mg/kg every 4 weeks in this study.  
  
For details of lirilumab preclinical studies, clinical studies, toxicities, pharmacokinetics, and adverse 
events please see the most recent version of the Lirilumab Investigator Brochure (Appendix E). 
 
2.5 5-azacytidine (Vidaza):  
 
5-azacytidine, an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and 
metabolism. Since the early 1970s, 5-azacytidine has been investigated primarily in 


 
 
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the US for the treatment of acute leukemia. Clinical studies have focused mainly on 
patients with disease refractory to conventional chemotherapy. Results of these 
investigations demonstrated activity of 5-azacytidine in the treatment of AML. 
Clinical studies subsequently evaluated the effects of 5-azacytidine in a variety of 
other 
malignant 
and 
hematologic 
disorders, 
including 
solid 
tumors, 
hemoglobinopathies (eg, thalassemia and sickle cell anemia), and MDS. In 1984, the 
Cancer and Leukemia Group B (CALGB) began a series of clinical studies with 5-
azacytidine in patients with MDS. These studies, in addition to other supportive data, 
led to the approval of Vidaza® (5-azacytidine) in May 2004 for the treatment of 
MDS.  
 
5-azacytidine inhibits the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase 
(DNMT).[18-20] 
Increased 
methylation 
of 
DNA 
(hypermethylation) may result in the silencing of critical genes responsible for cell 
growth control and differentiation. Hypermethylation of CpG islands spanning the 
promoter regions of tumor suppressor genes is commonly associated with 
cancers.[21] It is now widely recognized that hypermethylation of DNA is frequently 
associated with myelodysplastic syndromes and other cancers,[22-24] such as 
renal,[25] melanoma,[26] breast,[27] colorectal,[28] non-small cell lung[29] and 
hematologic malignancies.[30] 5-azacytidine is believed to exert its antineoplastic 
effects through hypomethylation and cytotoxicity on abnormal hematopoietic cells in 
the bone marrow.[31-35] Hypomethylation may restore normal function to genes that 
are critical for differentiation and proliferation.[21, 36, 37] The cytotoxic effects of 
5-azacytidine cause the death of rapidly dividing cells, including cancer cells that are 
no longer responsive to normal growth control mechanisms.[31, 38-40]  
 
The cytotoxicity of 5-azacytidine is proportional to dose and exposure time.[31, 32] 
Although the mechanisms of cytotoxicity are complex and multifaceted, there is 
general agreement that incorporation of 5-azacytidine into DNA and ribonucleic acid 
(RNA), and inhibition of protein synthesis, are critically important.[41] Cytotoxicity 
is greatest in cells that are proliferating (S phase) and metabolically active.[31] 
Cytotoxic effects may also be mediated through induction of the DNA damage 
response pathways.[40] Non-proliferating cells are relatively insensitive to 5-
azacytidine.[31]  
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus 
monkeys.[42] Most of the studies were performed during the 1970s and early 1980s 
according to existing guidelines and standards in place during that period. The 
preclinical studies identified the bone marrow, liver, kidneys, and lymphoid tissues 
(spleen, lymph nodes, and thymus) as the main target organs of toxicity for 5-
azacytidine.[42] In single-dose studies, the lethal dose of 5-azacytidine after 
intravenous (IV) administration in mice, rats, and dogs was approximately 250 
mg/m2. Repeated daily dosing appears to increase the toxicity of 5-azacytidine.[42] 
The genotoxicity of 5-azacytidine is consistent with that of other nucleoside analogs 
that interact with nucleic acids.[42] Likewise, similar to other agents with cytostatic 
properties, 5-azacytidine was embryotoxic and reduced the reproductive performance 
in mice and rats.[42] 


 
 
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Limited 5-azacytidine pharmacokinetic data are currently available. Based on human 
plasma concentrations of total radioactivity (which represents parent drug plus 
circulating 
metabolites), 
5-azacytidine 
is 
rapidly 
absorbed 
when 
given 
subcutaneously (SC), with maximum plasma concentrations found 0.5 to 2 hours 
after dosing.[42] 5-azacytidine and/or its by-products are then rapidly cleared by the 
kidneys. The half-lives and percent radioactivity recovered in urine are similar 
following IV and SC routes of administration. The effects of renal or hepatic 
impairment, gender, age, or race on the pharmacokinetics of 5-azacytidine have not 
been studied.[42] A single dose (75 mg/m2) SC versus IV crossover study in 6 MDS 
subjects[43] revealed an approximate bioavailability of 89% for the SC dose (range 
52% to 128%) with mean half-lives of 0.69 hour and 0.36 hour after SC and IV 
administration, respectively. These results demonstrated that 5-azacytidine is rapidly 
and nearly completely absorbed after SC administration and that elimination is also 
rapid. The apparent SC clearance (167 L/h or 2791 mL/min) and systemic IV 
clearance (147 L/h) of 5-azacytidine exceeded the glomerular filtration rate 
(approximately 125 mL/min) and total renal blood flow (1200 mL/min) in healthy 
subjects. This indicates that non-renal elimination (eg, metabolism, hydrolysis, 
and/or degradation) plays a role in the elimination of parent 5-azacytidine. In 
addition, 5-azacytidine 75 mg/m2 was generally well-tolerated after single SC 
injection or IV infusion over 10 minutes.[43]  
 
A number of studies have looked at different parenteral doses and schedules of 5-
azacytidine, finding maximum tolerated doses of up to 500 mg/m2 when 
administered weekly.[44] 
 
During the two decades between the start of the CALGB studies and the approval of 
5-azacytidine, a new understanding of MDS has developed, such as the World 
Health Organization (WHO) diagnostic criteria, the International Prognostic Scoring 
System (IPSS), and the International Working Group (IWG) response criteria. 
Silverman et al. reevaluated the combined data (N = 309) from 3 of the CALGB 
studies using the WHO classification system for MDS and AML and the IWG 
response criteria.[45] Using the IWG response criteria in MDS patients, response 
rates were between 40% and 70% in 5-azacytidine treated patients. Ten to 17% of 
patients achieved a complete remission; partial remission was rare; and 23% to 36% 
of patients had a hematologic improvement. In patients with AML (N = 103), 35% to 
48% had hematologic improvement or better responses. The median survival time 
for 27 patients assigned to 5-azacytidine was 19.3 months compared with 12.9 
months for the 25 patients assigned to observation.[45] 
 
A randomized international Phase III trial (Study 5-azacytidine PH GL 2003 CL 
001) for higher-risk MDS patients, classified by FAB as RAEB, RAEB-T, or CMML 
with 0-29% marrow blasts, with an IPSS of Intermediate -2 or High by central 
pathology/cytogenetic review was recently reported.[46] Patients were randomized 
to 5-azacytidine (75 mg/m2/day x 7days in 28 day cycles) or conventional care 
regimens (CCR), where CCR was pre-selected by the Investigator as best supportive 
care (transfusions, antibiotics, and G-CSF for neutropenic infection), low-dose 


 
 
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cytarabine (20 mg/m2/day x 14 days in 28 day cycles); or standard chemotherapy 
(conventional induction/consolidation). Patients were stratified by FAB/IPSS and 
randomized 1:1 to 5-azacytidine or CCR. This trial did not allow erythropoietin. 
Three hundred fifty eight patients (70% male) were randomized at 79 centers to 5-
azacytidine (N=179) or CCR (N=179): best supportive care only (N=105, 59%), 
low-dose cytarabine (N=49, 27%), or standard chemotherapy (N=25, 14%). Median 
age was 69 years (range 38-88 years). The 5-azacytidine and CCR groups were 
comparable for baseline patient characteristics. At baseline, 95% of patients were 
higher risk: RAEB (58%), RAEB-T/WHO AML (34%), CMML (3%), and other 
(5%). By IPSS, 87% were higher risk: Intermediate -2 (40%), High (47%), and 13% 
Indeterminate/other. 5-azacytidine was administered for a median of 9 cycles; low-
dose cytarabine for 4 cycles. Median follow-up for the survival analysis was 21.1 
months. 5-azacytidine demonstrated statistically superior overall survival compared 
to CCR, with a median overall survival of 24.4 months vs. 15 months for CCR 
(stratified log-rank p=0.0001, hazard ration 0.58). Two-year survival approximately 
doubled in the 5-azacytidine arm compared to CCR: 51% vs. 26% (p<0.0001). 5-
azacytidine was well tolerated with safety data consistent with previous reports.  
 
Further details can be found in the 5-azacytidine Drug Information (Appendix F), 
which contains comprehensive pharmacology, toxicology, pharmacokinetics, 
pharmacodynamics, metabolism, preclinical, and clinical efficacy and safety data 
information.[42]  
 
2.6 Rationale for study:  
            NK cells play a crucial role in anti-tumor responses by killing transformed cells. 
Inhibitory-cell KIR receptors negatively regulate natural killer (NK) cell-mediated 
killing of HLA class I-expressing tumors. Negative regulators of NK activating 
receptors include KIR, CD94/NKG2A, and leukocyte Ig-like receptor-1, which 
recognize MHC-class 1 molecules [15]. Lack of KIR-HLA class I interactions has 
been associated with potent NK-mediated antitumor efficacy and increased survival 
in AML patients upon haploidentical stem cell transplantation from KIR-mismatched 
donors [17]. Romagne et al developed a monoclonal antibody that cross-reacts with 
KIRDL1, -2 and -3 receptors thereby blocking inhibitory signaling via these 
receptors. This resulted in augmented NK-cell mediated lysis of tumor cells but did 
not induce killing of normal peripheral blood mononuclear cells, suggesting a 
preferential NK-cell activity against AML cells [12]. Intriguingly inoculation of NK-
cells alone did not protect against autologous implanted AML in immunodeficient 
mice, however prea-dministration with KIR monoclonal antibody induced anti-AML 
activity with long-term survival. Lirilumab (IPH2102/BMS-986015) is a fully human 
monoclonal antibody blocking interaction between Killer-cell immunoglobulin-like 
receptors (KIR) on NK cells with their ligands. Hypomethylating agents may alter 
immune regulation [47]. Yang et al have recently demonstrated that hypomethylating 
therapy leads to up regulation of PD-L1, PD-1, and PD-L2 gene expression [48]. 
Patients resistant to hypomethylating therapy had higher increments in gene 
expression suggesting that PD-1 up-regulation may promote resistance to 
hypomethylating agents. Hypomethylating agents also possess anti-leukemia activity 
when given on their own. Blockade of the KIR-receptors by lirilumab may improve 


 
 
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response rates and abrogate immune-mediated resistance to hypomethylating agents 
in AML via reactivation of NK-cell mediated leukemic cell lysis.  
 
            In this initial trial, we propose to investigate whether the lirilumab in combination 
with 5-azacytidine improve the response rates in patients with refractory/ relapsed 
AML. In this proposal we propose to introduce lirilumab blockade early, when there 
are still leukemia cells that can prime the immune competent cells for eventual 
eradication. If the combination proves to be well tolerated and results in improved 
response rates, we would expand the use of this approach in the frontline setting for 
AML. 
 
3.0 
STUDY DESIGN 
 
x 
This will be a phase II, single-arm, open-label, non-randomized study with a safety 
lead-in phase. 
 
x 
Patients will receive 5-azacytidine subcutaneously or intravenously daily for the first 
7 days of each treatment cycle. For the lead-in portion, the length of the cycle will be 
at least 28 days to evaluate DLT. Subsequently cycles will be repeated 
approximately every 28 days (+/-7 days), and therapy will be continued until 
clinically significant disease progression or documentation of unacceptable toxicity. 
 
x 
Patients will receive therapy with lirilumab IV infusion on Day 8 (+/-2 days) of each 
5-azacyidine cycle. 
 
x 
The historical experience in relapsed/refractory AML patient population is that 
response with single agent hypomethylator therapy (5-azacytidine or decitabine), 
when available, is 10-15%. In many instances (eg, patients with relapsed/refractory 
AML beyond first salvage) no standard therapy is available. Thus, an overall 
response rate of 30% will be considered significant. 
 
4.0 
PATIENT SELECTION 
 
Patients must have baseline evaluations performed prior to the first dose of study drug and 
must meet all inclusion and exclusion criteria. Results of all baseline evaluations, which 
assure that all inclusion and exclusion criteria have been satisfied, must be reviewed by the 
Principal Investigator or his/her designee prior to enrollment of that patient. In addition, the 
patient must be thoroughly informed about all aspects of the study, including the study visit 
schedule and required evaluations and all regulatory requirements for informed consent. The 
written informed consent must be obtained from the patient prior to initiating treatment or 
any study-specific procedures. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
 
4.1 
Inclusion Criteria 
 
 4.1.1  Patients with AML or biphenotypic or bilineage leukemia who have failed at 
least one prior therapy. Patients with AML should have failed prior therapy 


 
 
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or have relapsed after prior therapy.  
 
4.1.2  Patients should not be eligible or able to receive approved therapy of 
confirmed clinical benefit in this patient population 
 
4.1.3   Patients with MDS or CMML who received therapy for the MDS or CMML 
and progress to AML are eligible at the time of diagnosis of AML regardless 
any prior therapy for AML. The WHO classification will be used for AML. 
 
4.1.4 Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy 
(e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth 
factors is allowed. 
 
4.1.5 Age t18 years. 
 
4.1.6 Eastern Cooperative Oncology Group (ECOG) Performance Status d2.  
 
4.1.7 Adequate organ function: total bilirubin ≤ 2 times upper limit of normal (x 
ULN) (≤ 3 x ULN if considered to be due to leukemic involvement or 
Gilbert’s syndrome); aspartate aminotransferase or alanine aminotransferase 
≤ 2.5 x ULN (≤ 5.0 x ULN if considered to be due to leukemic involvement); 
serum creatinine ≤ 2 x ULN or GFR >/=50 
 
4.1.8 Patients must provide written informed consent 
 
4.1.9 In the absence of rapidly progressing disease, the interval from prior 
treatment to time of initiation of 5-azacytidine and lirilumab will be at least 2 
weeks OR at least 5 half-lives for cytotoxic/noncytotoxic agents. Use of one 
dose of cytarabine (up to 2 g/m2) is allowed prior to the start of study therapy 
or hydroxyurea for patients with rapidly proliferative disease is allowed 
before the start of study therapy and while the patient is on active study 
treatment, as needed, for clinical benefit and after discussion with the PI. 
Concurrent therapy for CNS prophylaxis or continuation of therapy for 
controlled CNS disease is permitted 
 
4.1.10 Females must be surgically or biologically sterile or postmenopausal 
(amenorrheic for at least 12 months) or if of childbearing potential, must have 
a negative serum or urine pregnancy test within 72 hours before the start of 
the treatment  
 
4.1.11 Women of childbearing potential must agree to use an adequate method of 
contraception during the study and until 3 months after the last treatment. 
Males must be surgically or biologically sterile or agree to use an adequate 
method of contraception during the study until 3 months after the last 
treatment. 
 
Adequate methods of contraception include: 


 
 
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x 
Total abstinence when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
x 
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment 
x 
Male sterilization (at least 6 months prior to screening). For female 
patients on the study, the vasectomized male partner should be the sole 
partner for that patient 
x 
Combination of any of the two following (a+b or a+c or b+c) 
a. 
Use of oral, injected or implanted hormonal methods of contraception 
or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception 
b. 
Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
c. 
Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ 
vaginal suppository 
       In case of use of oral contraception, women should have been stable on 
the same pill before taking study treatment. 
Note: Oral contraceptives are allowed but should be used in conjunction with 
a barrier method of contraception due to unknown effect of drug-drug 
interaction. 
        Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not 
of child bearing potential. 
 
 
4.2 
Exclusion Criteria 
 
4.2.1       Patients with known allergy or hypersensitivity to lirilumab, 5-azacytidine, 
or any of their components. Patients who have previously been treated with 
lirilumab in combination with 5-azacytidine will be excluded. 
 
4.2.4 
Patients with a known history of severe interstitial lung disease or severe 
pneumonitis or active pneumonitis that is uncontrolled in the opinion of the 


 
 
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treating physician. 
 
4.2.5 
Patients with a known history of any of the following autoimmune diseases 
are excluded: (a) patients with a history of inflammatory bowel disease 
(including Crohn’s disease and ulcerative colitis) (b) patients with a history 
of rheumatoid arthritis, systemic progressive sclerosis [scleroderma], 
Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener’s 
Granulomatosis]).  
 
4.2.6 
Patients with organ allografts (such as renal transplant) are excluded 
 
4.2.7 
Patients with allogeneic stem cell transplantation within the last 6 months or 
patients with active GVHD will be excluded  
 
4.2.8 
Ongoing 
immunosuppressive 
therapy, 
including 
cyclosporine 
and 
tacrolimus. Patients who are on high dose steroid. Note: Subjects may be 
using systemic corticosteroids (daily doses ≤10 mg of prednisone or 
equivalent) or topical or inhaled corticosteroids.  
 
4.2.9 
Patients with symptomatic CNS leukemia or patients with poorly controlled 
CNS leukemia.  
 
4.2.10 
Active and uncontrolled disease/ (active uncontrolled infection, uncontrolled 
hypertension despite adequate medical therapy, active and uncontrolled 
congestive heart failure NYHA class III/IV, clinically significant and 
uncontrolled arrhythmia) as judged by the treating physician. 
 
4.2.11 
Patients with active and uncontrolled Human Immunodeficiency Virus 
(HIV) infection will be excluded. However, patients with well controlled 
HIV infection will be considered. 
 
4.2.12 
Patients known to be positive for hepatitis B by surface antigen expression. 
Patients known to have active hepatitis C infection (positive by polymerase 
chain reaction or on antiviral therapy for hepatitis C within the last 6 
months) 
 
4.2.13 
Any other medical, psychological, or social condition that may interfere with 
study participation or compliance, or compromise patient safety in the 
opinion of the investigator  
 
4.2.14 
Patients unwilling or unable to comply with the protocol. 
 
4.2.15 
Pregnant or breastfeeding 
 
4.2.16 
Acute promyelocytic leukemia (APL). 
 
 


 
 
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5 
TREATMENT PLAN 
 
5.1 
General 
 
All patients will be registered through CORe. The objective will be to administer 
lirilumab and 5-azacytidine at full dose. We will first treat 6 patients at dose level -1. 
Other dose levels will be used for dose adjustments for toxicity during therapy. 
 
5.2 
Schedule 
 
The Investigator is responsible for completing the cohort summary template and 
submitting to the IND office Medical Monitor for review and approval prior to 
advancing subjects to the next protocol specified cohort/dose level. A copy of the 
cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”.  This should be submitted after the first six patients. 
 
5.2.1 Patients will be treated according to the following schedule: 
 
x 5-azacytidine will be administered subcutaneously (SQ) or intravenously (IV) for 
7 days of every cycle (Days 1-7) as determined by treating physician.  Both SQ 
and IV forms of administration are FDA approved and considered 
interchangeable. Patients may start receiving 5-azacytidine by one route and 
changed to the other at any time as needed based on patient and/or physician 
preference. 
 
x Lirilumab will be administered as an approximately 60 minute IV infusion on 
Day 8 (+/-2 days) of each 5-azacyidine cycle. Lirilumab will be administered 
every cycle with no interruptions unless there are adverse events as described in 
Section 5.3. The dosing calculations should be based on the body weight. All 
doses should be rounded to the nearest milligram. There will be no dose 
reductions (only interruptions when indicated) allowed for lirilumab on this trial. 
 
x 5-azacytidine at a dose of 75 mg/m2 on days 1-7 has been shown to be safe in 
combination with multiple agents including lenalidomide[49], bortezomib[49], 
and vorinostat[50, 51]. IPH2101 is the first fully-human anti-KIR monoclonal 
antibody, and lirilumab is the second generation. Both products bind to the same 
KIR subtypes with similar affinities. Functionally and biologically, the 2 
antibodies are similar with the following exceptions: 1) IPH2101 is a non-
recombinant protein that is produced by a murine hybridoma cell line; whereas, 
lirilumab is a recombinant product produced in CHO cells. 2) Lirilumab has a 
single amino acid substitution of a serine to a proline in the IgG4 heavy chain, 
resulting in greater stability of the compound by reducing the formation of half 
antibodies. IPH2101 studies were done prior to lirilumab studies and safety, 
efficacy, PKs, and immunologic correlates of IPH2101 in a phase 1 trial in 
elderly AML in first remission have been published (Vey N, et al., Blood, 2012 
Nov 22;120(22):4317-23).  Patients received escalating doses (0.0003-3 mg/kg) 
of IPH2101 following a 3 + 3 design. The doses that elicited full occupancy 


 
 
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were: 1 week = 0.075 mg/kg, 2 weeks = 1 mg/kg, and for at least 4 weeks = 3 
mg/kg. There was a clear correlation between mAb exposure and KIR 
occupancy. The maximum tolerated dose was not reached, although full KIR 
saturation (> 90%) was sustained for 4 weeks only at the 3 mg/kg. Lirilumab 
dose of 3 mg/kg every 4 weeks is also the highest dose to be tested in BMS study 
of lirilumab in combination with elotuzumab for multiple myeloma: A Phase I 
Open Label Dose Escalation and Randomized Cohort Expansion Study of the 
Safety and Tolerability of Elotuzumab (BMS-901608) Administered in 
Combination With Either Lirilumab (BMS-986015) or Urelumab (BMS-663513) 
in Subjects With Multiple Myeloma” (study identifier: NCT02252263). Based on 
this data and the tolerability of lirilumab in combination with other agent 
(namely nivolumab) in the CA223001 the maximum dose for this trial of 
lirilumab 3.0 mg/kg every 4 weeks is the recommended phase 2 dose (RP2D) 
from ongoing Phase 2 study (IPH2102-101). We propose the starting dose level 
of 5-azacytidine 75 mg/m2 x 7 days and lirilumab 1.0 mg/kg on day 8 of each 28 
(+/- 7) day cycle to be escalated or de-escalated based on occurrence of DLTs as 
described below. The lead-in phase is to ensure that the combination is well 
tolerated with no unexpected side effects.  
 
5.2.1.1 The starting dose will be dose level -1. 
 
Table 1. Dose levels of 5-azacytidine and lirilumab during the lead-in phase (part 
a) 
 
 
 
 
5.2.1.2 The goal of the lead-in phase is to identify the dose at which <2/6 patients 
experience DLT. During the lead-in phase the dose’s of 5-azacytidine and 
lirilumab may be reduced if 2 or more patients experience DLT at any 
given dose. After the lead in phase the dose of lirilumab may not be 
reduced in the phase II portion of the study. For potential lirilumab related 
AEs in the phase II portion of the study only dose interruptions of 
lirilumab will be permitted. Dose reductions or escalations of 5-
azacytidine will continue to be permitted in the phase II portion of the 
study and dose reductions or escalations of 5-azacytidine beyond those 
mentioned in table 5 or different to the doses specified should be discussed 
with the PI and documentation of the justification recorded in the chart. 
 
Dose level 5-azacytidine 
(mg/m2/d, Days 1-
7) 
Lirilumab (mg/kg, 
day 8) 
-4 
25 
0.3 
-3 
50 
0.3 
-2 
75 
0.3  
-1 
75 
1.0 (Starting dose) 
0 
75 
3.0   


 
 
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5.2.1.3 The dose and /or schedule of administration is subject to modification 
pending information from ongoing clinical trials of lirilumab as a single 
agent and in combination with other drugs.  
 
DLT is defined as clinically significant non-hematologic adverse event or abnormal 
laboratory value assessed as unrelated to disease progression, intercurrent illness, or 
concomitant medications and occurring during the first cycle on study that meets 
any of the following criteria:  
 
x CTCAE Grade 3 AST (SGOT) or ALT (SGPT) for > 7 days 
 
x CTCAE Grade 4 AST (SGOT) or ALT (SGPT) of any duration 
 
x All other clinically significant non-hematological adverse event that is 
Grade 3 or 4 according to the NCI common terminology criteria 
version 4.0 with the following exceptions: 
 
x Grade 3 or 4 nausea, vomiting and diarrhea will be considered 
DLT only if not controlled by optimal therapy. 
 
x Grade 3 biochemical abnormalities (e.g., lipase or bilirubin 
elevation) will only be considered DLT if accompanied by clinical 
consequences.  Grade 3 or 4 electrolyte abnormalities will only be 
considered DLT if possibly related to study drug and not corrected 
by optimal replacement therapy. 
 
5.2.1.4 We will first treat 6 patients at dose level -1 in the lead-in phase. If DLT 
occurs in ≥2/6 patients, this dose level would exceed the MTD, and 6 
patients will be treated at the next lower dose level (i.e. dose level -2). If 
DLT is observed in the first 28 days of treatment in 0 or 1/6 at dose level -
1, then dose level 0 will be evaluated. The dose adjustment (Table 1) will 
continue in cohorts of 6 until we reach a dose level at which <2/6 patients 
experience a DLT in the first 28 days. The dose level at which 0-1/6 
patients experience a DLT in the first 28 days of treatment will be the 
MTD and will be used to treat an additional 34 patients in the phase II 
portion of the study. If ≥2/6 patients experience DLT at dose level -4, the 
study will be revised to consider additional lower dose levels (based on 
potential synergistic toxicity). 
 
5.2.1.5 
Patients that are removed from study before day 28 for any reason other 
than toxicity and have not experienced DLT will be replaced.  
 
5.2.2 One cycle of therapy is defined as 28 days. Patients will receive one cycle 
of therapy every 28 days (+/- 7 days).  
 


 
 
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5.2.2.1 In the phase II part of the study (once the MTD dose has been 
defined) cycles may be started early (but not earlier than day 21) 
for patients with active disease if judged in the best interest of the 
patient.  
             For the lead-in cohort, DLT defining period is 28 days. As such, 
cycle 2 should not be started before 28 days for the patients being 
treated on the lead-in cohort. 
 
5.2.2.2 Subsequent cycles may be delayed for recovery of toxicity or 
other medical conditions (e.g. infections). Delays in start of 
subsequent cycles greater than 8 weeks will be acceptable only for 
patients who are deriving clinical benefit and after discussion with 
the principal investigator of potential risk/benefit ratio.  
 
5.2.2.3 In instances where one drug has to be discontinued transiently 
because of safety, the administration of the other drug may 
continue as scheduled. If the drug that is held can resume at a later 
time, no doses will be made up and the administration will follow 
the originally defined schedule calendar according to the drug that 
was continued.   
 
5.2.2.4 Subsequent courses of 5-azacytidine and lirilumab may be 
administered regardless of peripheral blood counts during the first 
4 cycles and/or in the presence of residual leukemia. 
 
              If prolonged myelosuppression (more than 8 weeks) WITH 
evidence of a hypocellular marrow (marrow cellularity less than 
5% without evidence of leukemia) is observed, 5-azacytadine and 
lirilumab will be discontinued. Delays in start of subsequent cycles 
greater than 8 weeks will be acceptable only for patients who are 
deriving clinical benefit and after discussion with the principal 
investigator of potential risk/benefit ratio. If the peripheral counts 
do not recover (ANC <1 x109/L and/or platelets <30 x109/L) but 
there is evidence of residual leukemia in the bone marrow, 
subsequent cycles can be administered at the discretion of the 
treating physician not earlier than 21 days after the prior cycle. 
 
5.2.2.4 For patients who discontinue therapy, the reason for treatment 
discontinuation will be captured.   
 
5.3 Dose Adjustments 
 
5.3.1   Lirilumab and 5-azacytidine dose adjustments for drug-related hematological 
AEs: 
Dose reduction/interruption/discontinuation decisions should be based on the 
CTCAE version 4.0 (Appendix C) of the toxicity and the guidelines provided 
below. 


 
 
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x Patients with acute leukemia’s usually present with abnormal peripheral 
blood counts at the time therapy is started and myelosuppression is an 
expected event during the course of therapy for acute leukemias. Thus, no 
dose adjustments or treatment interruptions for myelosuppression will be 
planned for the first 4 cycles and/or in the presence of residual leukemia. 
After that, treatment interruptions and dose adjustments may be considered 
according to the following guidelines only when there is no evidence of 
active leukemia (e.g., only if <5% blasts in the bone marrow or cytopenias 
not considered to be related to leukemia).  
 
1. 
Patients with a response (e.g., only if <5% blasts in the bone 
marrow or cytopenias not considered to be related to leukemia) 
and pre-cycle counts of neutrophils >1x109/L and platelets >50 
x109/L who have sustained low counts of neutrophils <0.5 x109/L 
or a platelet count <20 x 109/L for more than 2 consecutive weeks 
in the current cycle, may have the treatment with 5-azacytidine 
interrupted at the discretion of the treating physician after 
discussing with the PI until neutrophils recover to ≥1 x109/L and 
platelets to ≥50 x109/L. Lirilumab has not been associated with 
neutropenia and/or thrombocytopenia in prior studies and should 
generally not be interrupted for myelosuppression. 
 
2. 
If there are persistent peripheral blood blasts, or the bone marrow 
shows >5% blasts or evidence of leukemia, treatment may be 
continued regardless of neutrophil and platelet count with 
supportive care as needed. Dose-interruptions of 5-azacytidine in 
these patients should be considered on an individual case and 
discussed with the PI.  
 
3. 
Patients with a response (no marrow evidence of leukemia) and 
pre-cycle counts of neutrophils <1x109/L and platelets <50 x109/L 
may be continued regardless of neutrophil and platelet count with 
supportive care as needed. Dose-interruptions in these patients 
should be considered on an individual case and discussed with the 
PI. 
 
4. 
Investigators should, whenever possible, determine which 
medication is causing the toxicity and interrupt or dose reduce 5-
azacytidine and/or interrupt lirilumab, as applicable. No dose 
reductions are permitted for lirilumab. Lirilumab has not been 
associated with neutropenia and/or thrombocytopenia in prior 
studies and should generally not be interrupted or discontinued for 
myelosuppression. 
 
    5.3.2  Lirilumab and 5-azacytidine dose adjustments for non-hematologic drug-related 
AEs 


 
 
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Investigators should, whenever possible, determine which medication is 
causing the toxicity and interrupt or dose reduce 5-azacytidine and/or 
interrupt lirilumab, as applicable. No dose reductionss (only interruptions) 
are permitted for lirilumab. Dose reductions of azacytidine will be as per 
Table 1. Thus, if dose level 0 is established as the MTD, one and two dose 
level reductions of azacytidine will be azacytidine 50 mg/m2 x 7 days and 
azacytidine 25 mg/m2 x 7 days, respectively. If the MTD is below dose 
level 0 further dose reduction levels of 5-azacytidine will be defined before 
moving to the phase II portion of the study. 
 
Table 2 Dose adjustments for non-hematologic drug-related adverse events, clinically 
significant in the opinion of the investigator 
 
Grade 
Occurrence 
Dose modification 
1 or 2 
Any time 
No dose reduction. 
3 or 4 
 
(Persistent 
grade 2: 
Consider 
similar dose 
adjustments if 
persistent and 
not 
responding to 
optimal 
management 
in the opinion 
of PI and 
treating 
physician) 
1st and 
2nd time 
Hold lirilumab and 5-azacytidine. 
Resume lirilumab and 5-azacytidine at prior dose if recovery to 
≤ Grade 1 occurs within 14 days. 
If toxicity persists for 15-28 days, hold therapy and resume at 
ONE dose level below current dose for 5-azacytidine and prior 
dose of lirilumab ONLY after recovery to ≤ Grade 2. 
Dose re-escalation to prior dose of 5-azacytidine is permitted in 
accordance with the dose-escalation guidelines in section 5.3.6. 
3rd and 4th 
time 
Hold lirilumab and 5-azacytidine. 
Follow until toxicity ≤ Grade 2.  
Resume lirilumab at prior dose and 5-azacytidine at ONE dose 
level below current dose. 
Dose re-escalation of 5-azacytidine to prior dose is permitted in 
accordance with the dose-escalation guidelines in section 5.3.6. 
5th time 
Hold lirilumab and 5-azacytidine. 
Follow until toxicity ≤ Grade 2.  
Resume lirlilumab at prior dose and 5-azacytidine at TWO dose 
levels below current dose. 
Dose re-escalation of 5-azacytidine by ONE dose level every 4 
weeks is permitted in accordance with the dose-escalation 
guidelines in section 5.3.6. 
 
5.3.3 Lirilumab dose delay/interruption for immune-oncology drug-related AEs, 
clinically significant in the opinion of the investigator 
 
Lirilumab administration should be delayed for the following drug-related AEs, 
clinically significant in the opinion of the investigator: 
x Any Grade >2 non -skin AE, except that  
 
Grade 2 fatigue or laboratory abnormalities do not require delay, however 
i 
For a subject with baseline AST, ALT, or total bilirubin within normal 
limits, delay dosing for drug-related Grade >2 values 
x Any Grade 3 skin AE, or Grade 3 laboratory abnormality, with the following 
exceptions: 


 
 
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 
   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 
x Any AE, laboratory abnormality, or intercurrent illness, which in the judgment 
of the investigator, warrants delaying the dose of study medication. 
x Lirilumab dose reductions are not permitted in this study (only dose delays 
when indicated).  
 
Subjects may resume treatment with study drug when the drug-related AE(s) 
resolve to Grade ≤1 or baseline value, with the following exceptions: 
x Subjects may resume treatment in the presence of Grade 2 fatigue  
x Subjects who have not experienced a Grade 3 drug-related skin AE may 
resume treatment in the presence of Grade 2 skin toxicity  
x 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 
x Subjects with combined Grade 2 AST/ALT AND total bilirubin values 
meeting discontinuation parameters (Discontinuation Section below) should 
have treatment permanently discontinued 
x Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed 
x 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 same dose at the next scheduled timepoint per protocol. The next scheduled 
time point for 5-azacytidine is the projected day 1 of the next cycle. The next 
scheduled time point for Lirilumab is the projected day 8 of the next cycle. These 
will be the next scheduled time points irrespective of the patients current dose 
level. However, if the treatment is delayed past the next scheduled timepoint per 
protocol, the next scheduled timepoint will be delayed until dosing resumes. 
Patients who receive combination therapy in whom continuation of 5-azacytidine 
is considered to be inadequate, or inappropriate (e.g., because of pancytopenia) 
can discontinue 5-azacytidine and continue with lirilumab only. 
 
If treatment is delayed > 8 weeks , the subject must be permanently discontinued 
from study therapy, except as specified in discontinuation section. 
 
5.3.4 Lirilumab Discontinuation Criteria 
Treatment should be permanently discontinued for the following: 
x Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the 
re-treatment period OR lasting > 7 days with systemic treatment  
 
x Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 


 
 
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pneumonitis, bronchospasm, diarrhea, colitis, neurologic adverse event, 
hypersensitivity reactions, and infusion reactions: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic adverse event, hypersensitivity reaction, or infusion 
reaction of any duration requires discontinuation 
 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below: 
 Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: AST or ALT > 8 x ULN 
 
 
x 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 
 
x Any dosing interruption lasting > 8 weeks  with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage 
drug-related adverse events are allowed. Prior to re-initiating treatment in 
a subject with a dosing interruption lasting  > 8 weeks  the Investigator 
must be consulted. Tumor/Leukemia assessments should continue as per 
protocol even if dosing is interrupted. 
 
o Dosing interruptions > 8 weeks that occur for non-drug-related reasons 
may be allowed if approved by the Investigator. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 8 weeks the 
Investigator must be consulted. Tumor/Leukemia assessments should 
continue as per protocol even if dosing is interrupted. 
 
            5.3.5    Detailed management algorithms for immune-oncology drug-related adverse events 
(including gastrointestinal, renal, pulmonary, hepatic, endocrine, skin and 
neurological) are provided in Appendix G. These general guidelines constitute 
guidance to the Investigator and may be supplemented by discussions with the 
Medical Monitor representing the Sponsor in specific cases.  
 
5.3.6     Intra-patient dose re-escalation of 5-azacytidine for patients who have had 
dose-reductions due to hematological or non-hematological toxicity: 
Once the MTD has been established in the lead-in, the lirilumab dose will not 
be reduced or escalated during the phase II. Intra-patient dose re-escalation of 
5-azacytidine (in accordance with the dosing schema in table 1) will be 
permitted provided: 
 


 
 
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 
Patient has completed ≥1 cycle at their current dose level  
 
 
Patient has not experienced any grade 3 or higher non-hematologic 
drug-related toxicity, and 
 
 
Patient has not experienced drug-related hematologic DLT, and 
 
 
At least 6 patients have been treated at the next higher dose level and 
followed for at least 28 days without experiencing DLT.  
 
 
The dose may be escalated by one dose level per cycle (per table 1) 
provided such dose level does not exceed the established MTD or 
dose level 0, whichever is lower. Dose level 0 is the maximum dose 
allowed on this study. No dose escalation beyond dose level 0 will be 
permitted. 
 
5.3.7     Modifications of dose schedules other than the above will be allowed within the 
following guidelines: 
 
5.3.7.1 Further dose reductions can be made to keep clinically significant toxicities grade 
< 2.  
 
5.3.7.2 Dose adjustments by more than 1 dose level at a time (e.g., from 5-azacytidine 75 
mg/m2 to 25 mg/m2) can be considered when judged in the best interest of the 
patient (e.g. severe myelosuppression) when toxicity has resolved. The reason for 
this reduction will be discussed with the PI or Co-PI and documented in the 
medical record. 
 
5.3.7.3 A patient who has had a dose reduction because of any of the reasons mentioned 
above may have their dose escalated provided the patient has remained free of 
toxicity requiring dose adjustments as defined above for at least 1 month. 
Escalation will be made by 1 dose-level increment only, and not more frequent 
than every month.  
 
5.3.7.4 Treatment interruptions and dose modifications other than the ones mentioned 
above for either study drug related toxicity and/or events that are unrelated to 
study drug, for example but not limited to hospitalization for reasons unrelated to 
study drug can be considered after discussion with the PI, and proper 
documentation of the rationale. Dose adjustment/delay of only one of the agents 
is permissible if the toxicity is most likely judged to be related to one of the 
agents by the investigator (e.g., in patients with autoimmune thyroiditis or 
autoimmune hepatitis this would be likely secondary to lirilumab and 5-
azacytidine dose could be escalated, in patients with cytopenia’s this would be 
likely secondary to 5-azacytidine and lirilumab dose could be escalated). 
 
5.4   Duration of Therapy 


 
 
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In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 
 
1. Clinically significant progressive disease, or 
 
2. Intercurrent illness that prevents further administration of treatment, or 
 
3. Patient request, or 
 
4. General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator, or 
 
5. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to 
continue therapy. 
 
5.4.1        It is planned that up to a total of 24 cycles of therapy will be administered for 
patients deriving benefit from this regimen. Continuation of therapy for 
patients completing 24 cycles of therapy may be considered on a case-by-
case basis after discussion with the principal investigator.  
 
5.4.2.      A minimum of 1 full course (defined as the administration of 5-azacytidine 
for 7 days and one dose of lirilumab) will be required for a patient to be 
considered as having received an adequate trial to evaluate efficacy. All 
patients receiving at least one dose of any of the two drugs will be 
considered evaluable for toxicity. 
 
 5.5   Supportive Care: 
           Supportive care measures including blood products, infection prophylaxis and 
growth factors will be administered according to institutional and Leukemia 
Department guidelines. 
 
           Supportive care measures including blood products, infection prophylaxis and 
growth factors will be administered according to institutional and Leukemia 
Department guidelines. 
Management Algorithms for Treatment of Lirilumab Related Adverse Events 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity 
and duration than AEs caused by other therapeutic classes. Lirilumab is 
considered an immuno-oncology agent in this protocol. Early recognition and 
management of AEs associated with immuno-oncology agents such as lirilumab 
may mitigate severe toxicity. Lirilumab has a known safety profile however, a 
general principle is that differential diagnoses should be diligently evaluated 
according to standard medical practice. Non-inflammatory etiologies should be 
considered and appropriately treated. Corticosteroids are a primary therapy for 
immuno-oncology drug-related adverse events, and lirilumab is no exception. 
The oral equivalent of the recommended IV doses may be considered for 


 
 
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ambulatory patients with low-grade toxicities. The lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent 
dose of oral corticosteroids.  
Management Algorithms have been developed to assist investigators in assessing 
and managing the following groups of adverse events: Endocrinopathy, 
Gastrointestinal, Hepatic, Neurological Pulmonary, Renal and Skin. These 
algorithms are found in the “Lirilumab Investigator Brochure” (Appendix E) and 
“Management algorithms for immuno-oncology drug-related adverse events” 
(Appendix G) of this protocol. The guidance provided in these algorithms should 
not replace the Investigator’s medical judgment but should complement it. 
Finally, consultation with a medical or surgical specialist, especially prior to an 
invasive diagnostic or therapeutic procedure, is highly recommended. 
 
5.6 Concomitant Medications: 
Consistent with subject safety and comfort, administration of any prescription or 
over-the-counter drug products other than study medication should be minimized 
during the study period. Subjects should be discouraged from use of street drugs, 
herbal remedies, self-prescribed drugs, tobacco products, or excessive alcohol 
during the clinical study. 
 
If considered necessary for the subject’s wellbeing, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the 
investigator. The investigator’s decision to authorize the use of any drug other 
than study drug should take into account subject safety, the medical need, the 
potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the 
outcome or integrity of the study. 
 
Subjects should be instructed about the importance of the need to inform the clinic 
staff of the use of any drugs or remedies (whether prescribed, over-the-counter, or 
illicit) before and during the course of the study.  
 
Recommendations with regard to specific types of concomitant therapies, 
supportive care, diet and other interventions are as follows:  
 
Concomitant medications are recommended as prophylaxis for nausea, vomiting, 
and infections, and are allowed for managing myelosuppression as shown in Table 
3. Myelosuppression is expected in patients with AML due to underlying disease, 
as well as due to chemotherapy (such as 5-azacytidine), or both. Most patients 
have neutropenia, thrombocytopenia, or both at study entry. Significant or life-
threatening myelosuppression may be managed with growth factor support 
including G-CSF, GM-CSF and platelet growth factors and 
erythropoeitn/darbopoetin/blood transfusion according to institutional standard of 


 
 
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care, American Society of Clinical Oncology (ASCO) Practice Guidelines, and/or 
NCCN Practice Guidelines.  
 
Infections secondary to myelosuppression are common in patients with AML, and 
may be related to underlying disease, chemotherapy, or both. Therefore, the use of 
prophylactic antibiotics, antifungal agents, and antiviral agents is recommended 
according to institutional standards.  
 
Since the effect of both lirilumab and 5-azacytidine may be delayed for up to 4 
weeks, patients with high WBC counts may receive hydroxyurea and up to 1 dose 
of cytarabine (up to 2 g/m2) prior to study entry. Hydroxyurea is allowed while 
the patient is on active study treatment, as needed, for clinical benefit and after 
discussion with the PI. Hydrea and cytarabine use would be recorded in the CRF. 
Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled 
CNS disease is permitted. With the exception of these agents, concomitant 
systemic chemotherapy or radiation therapy is not permitted. Subjects are not 
allowed to participate concurrently in any other therapeutic clinical study. 
 
 
Subjects may be receiving systemic corticosteroids (daily doses ≤10 mg of 
prednisone or equivalent if indicated for adrenal replacement or antiemetic 
therapy), topical, or inhaled corticosteroids at study enrollment. They may receive 
systemic, topical, inhaled, or enteric corticosteroids while on study without 
limitation if they develop conditions that require corticosteroid therapy; such 
subjects are not required to discontinue study participation. 
 
All ongoing medications and therapies (including herbal products, nutritional 
supplements, and nontraditional medications) at screening will be considered prior 
medications. Concomitant medication data will not be collected or entered into the 
case report form other than hydrea and cytarabine as mentioned above; however, 
the subject’s medication record will contain a list of concomitant medications. If a 
prohibited medication is inadvertently administered/ taken by the patient, the 
patient may remain on study as long as the prohibited medication is discontinued 
as soon as feasible. If a prohibited medication is considered essential for the 
patient well being, continuation on study with concomitant administration of such 
medication(s) will need to be discussed with and approved by principal 
investigator and medical monitor. Prohibited medications are shown in Table 3. 
 
Table 3: Instructions for the use of concomitant medications and therapies 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Prophylactic antibiotics, 
antifungal agents, and 
antiviral agents 
Strongly encouraged 
None 
 
Antiemetic agents 
According to standard of 
care at MDACC 
None 
Allowed 
Oral allopurinol or 
rasburicase 
At investigators discretion 
 
None 
 
Leukapheresis 
According to standard of 
Before induction 1 day 1 


 
 
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care at MDACC 
 
only 
 
Red blood cell transfusion 
None 
 
 
None 
 
Platelet transfusion 
None 
 
 
None 
 
White blood cell 
transfusion 
At investigators discretion 
according to standard of 
care at MDACC 
 
None 
 
Myeloid growth factors or 
platelet growth factor 
At investigators discretion 
according to standard of 
care at MDACC 
 
None 
 
Erythropoietin or 
darbepoetin 
 
At investigators discretion 
 
None 
 
Any other medication for 
supportive care 
At investigators discretion 
according to standard of 
care at MDACC  
None 
 
 
 
6.0      STUDY MEDICATIONS 
 
6.1 Lirilumab (Anti-KIR) 
            For details regarding dose-calculation of lirilumab, preparation and dispensing of lirilumab, 
administration of lirilumab, patient monitoring during infusion and treatment of lirilumab 
related infusion reactions please see the dosing procedure manual (Appendix I). 
 
6.2     Azacytidine:  
 
5-azacytidine is commercially available. Commercial supply will be used for purposes of 
this study. Standard procedures should be used for preparation and administration of 5-
azacytidine. The following guidelines are suggested: 
 
 
Vidaza® (5-azacytidine) (is a cytotoxic drug and, as with other potentially toxic 
compounds, caution should be exercised when handling and preparing Vidaza® (5-
azacytidine) suspensions. 
 
 
If reconstituted Vidaza® (5-azacytidine) comes into contact with the skin, 
immediately and thoroughly wash with soap and water.  If it comes into contact with 
mucous membranes, flush thoroughly with water. 
 
 
The Vidaza® (5-azacytidine) vial is single-use and does not contain any 
preservatives. Unused portions of each vial should be discarded properly. Do not save any 
unused portions for later administration.  
 
MDACC = MD Anderson Cancer Center 


 
 
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6.2.1 Preparation for Subcutaneous Administration: Vidaza® (5-azacytidine) 
should be reconstituted aseptically with 4 mL sterile water for injection.  The 
diluent should be injected slowly into the vial.  Vigorously shake or roll the 
vial until a uniform suspension is achieved.  The suspension will be cloudy. 
The resulting suspension will contain 5-azacytidine 25 mg/mL.  
 
6.2.1.1 Preparation for Immediate Subcutaneous Administration:  Doses 
greater than 4 mL should be divided equally into 2 syringes. The 
product may be held at room temperature for up to 1 hour, but 
must be administered within 1 hour after reconstitution.  
 
6.2.1.2 Preparation for Delayed Subcutaneous Administration:  The 
reconstituted product may be kept in the vial or drawn into a 
syringe. Doses greater than 4 mL should be divided equally into 
2 syringes. The product must be refrigerated immediately, and 
may be held under refrigerated conditions (2ºC–8ºC, 36ºF–46ºF) 
for up to 8 hours. After removal from refrigerated conditions, the 
suspension may be allowed to equilibrate to room temperature for 
up to 30 minutes prior to administration.  
 
6.2.1.3 Subcutaneous Administration: To provide a homogeneous 
suspension, the contents of the syringe must be re-suspended by 
inverting the syringe 2–3 times and vigorously rolling the syringe 
between the palms for approximately 30 seconds immediately 
prior to administration. Vidaza® (5-azacytidine) suspension is 
administered subcutaneously. Doses greater than 4 mL should be 
divided equally into 2 syringes and injected into 2 separate sites. 
Rotate sites for each injection (thigh, abdomen, or upper arm). 
New injections should be given at least 1 inch from an old site and 
never into areas where the site is tender, bruised, red, or hard.  
 
6.2.1.4 Suspension Stability: 5-azacytidine reconstituted for subcutaneous 
administration may be stored for up to 1 hour at 25°C (77°F) or 
for up to 8 hours between 2°C and 8°C (36°F and 46°F).   
 
6.2.2 Preparation for Intravenous Administration: Reconstitute the appropriate 
number of Vidaza® (5-azacytidine) vials to achieve the desired dose. 
Reconstitute each vial with 10 mL sterile water for injection.  Vigorously 
shake or roll the vial until all solids are dissolved.  The resulting solution will 
contain 5-azacytidine 10mg/mL. The solution should be clear. Parenteral 
drug product should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
 
Withdraw the required amount of Vidaza® (5-azacytidine) solution to deliver the desired 
dose and inject into a 50-100 mL infusion bag of either 0.9% Sodium Chloride Injection or 
Lactated Ringer’s Injection. 
 


 
 
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6.2.2.1 Intravenous Solution Incompatibility: Vidaza® (5-azacytidine) is 
incompatible with 5% Dextrose solutions, Hespan, or solutions 
that contain bicarbonate. These solutions have the potential to 
increase the rate of degradation of Vidaza® (5-azacytidine) and 
should therefore be avoided. 
 
6.2.2.2 Intravenous Administration: Vidaza® (5-azacytidine) solution is 
administered intravenously.  Administer the total dose over a 
period of 10-40 minutes. The administration must be completed 
within 1 hour of reconstitution of the VIDAZA vial. 
 
6.2.2.3 Solution Stability: Vidaza® (5-azacytidine) reconstituted for 
intravenous administration may be stored at 25°C (77°F), but 
administration must be completed within 1 hour of reconstitution. 
 
6.2.3 Storage: Store unreconstituted vials at 25º C (77º F); excursions permitted to 
15º-30º C (59º-86º F) (See USP Controlled Room Temperature).  There is no 
need to protect 5-azacytidine from exposure to light. 
 
6.2.4 Handling and Disposal: Procedures for proper handling and disposal of 
anticancer drugs should be applied.  
 
6.3 Variations in infusion times of lirilumab or 5-azacytidine due to minor differences in 
IV bag overfill/underfill and institutional procedure on flushing chemotherapy lines 
will not result in protocol deviation. All infusion times are considered approximate. 
 
 
7.0       PATIENT EVALUATION 
Every effort will be made to adhere to the schedule of events and all protocol requirements. 
Variations in schedule of events and other protocol requirements that do not affect the rights 
and safety of the patient will not be considered as deviations.  Such variations may include 
laboratory assessments completed outside of schedule, occasional missed required research 
samples such correlative assays. 
 
7.1 
Pre-Treatment Evaluation 
 
All pretreatment studies should be obtained within 14 days of entry into the trial, unless otherwise 
stated.  
 
7.1.1 A complete history and physical, documentation of all measurable disease, 
concomitant medications and performance status. 
 
7.1.2 CBC, platelet count, differential (differential can be omitted if WBC is ≤0.5 
x109/L). 
 
7.1.3 Creatinine, total bilirubin, ALT or AST.  
 


 
 
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7.1.4 Pregnancy test (urine or plasma) in females of childbearing potential should 
be performed within 72 hours before initiation of study. 
 
7.1.5 Bone marrow aspirate during the last 28 days preceding study initiation. 
Cytogenetics will be obtained prior to therapy (results from prior analysis can 
be used for this purpose). 
 
7.1.6 Pretreatment optional correlative studies (see below) 
 
7.2 
Evaluation During Treatment 
 
7.2.1 Physical exam at the start of each cycle (± 4 days) and documentation of all 
concomitant medications. 
 
7.2.2 CBC, platelet count, differential once weekly (r4 days) for the first 3 cycles, 
then every 2-4 weeks (differential can be omitted if WBC is ≤0.5 x109/L) 
 
7.2.3 Creatinine, total bilirubin, ALT once weekly (r4 days) for the first 3 cycles, 
then every 2-4 weeks. 
 
7.2.4 Bone marrow aspiration on day 28 (+/- 7 days), then every 1-3 cycles. Bone 
marrow tests can be ordered more frequently if mandated by development of 
peripheral blood counts. No repeat bone marrow is necessary if nonresponse 
or progressive disease can be unequivocally diagnosed from peripheral blood 
tests or, in patients with a WBC < 0.3 if the bone marrow test is considered 
noncontributory by the investigator at any time point. 
  
7.2.5 Concomitant medication data will not be collected or entered into the case 
report form except for concomitant hydroxyurea and cytarabine; however, the 
subject’s medication record will contain a list of concomitant medications. 
 
7.2.6 Correlative Studies relating to immunologic response: Tumor tissue, blood 
samples and bone marrow aspirate will be collected on a separate IRB 
approved laboratory protocol for immune monitoring as previously 
published[52-55], under the supervision of the Immunotherapy Platform 
(MDACC Protocol PA13-0291). Patients will be consented separately on the 
IRB approved consent for protocol PA 13-0291. Patients may participate in 
protocol 2014-0862 irrespective of whether they choose to participate on 
protocol PA 13-0291. In tumor tissues, immunohistochemical studies will be 
performed to evaluate tumor and immunological cell markers such as CD4 
and CD8 T cells. In peripheral blood, we will also evaluate tumor and 
immune cell populations including but not limited to CD4 and CD8 T cells in 
pre and post therapy samples.  
7.2.7  


 
 
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Peripheral blood up to 20 mL (within 24 hours) will be collected under an 
IRB-approved laboratory protocol for testing of biomarkers at the following 
time points 
-Baseline (prior to 5-azacytidine dose), on day 8 (prior to lirilumab dose), and 
between days 21 to 28 on cycle 1 (done at MD Anderson).  
-In each subsequent cycle blood samples will be obtained on day 1 (prior to 
5-azacytidine dose) and day 8 (prior to lirilumab dose) when possible.  
-Samples will be collected at progression whenever possible.  
 
Bone Marrow: 
-Bone marrow samples will be collected under an IRB-approved laboratory 
protocol for testing of biomarkers at baseline, at day 28 (+/-7 days), then 
every 1-3 cycles, and at progression whenever possible. 
 
All these samples can be obtained +/- 3 days. Missed samples for correlative 
studies will not constitute protocol deviations. All correlative samples are 
optional. 
 
7.2.8 For patients that remain on study with no significant toxicity for more than 6 
months, subsequent evaluations during study may be modified after 
discussion with the principal investigator.  These include a decrease in 
frequency of bone marrow aspirations to every 6-12 months (or as clinically 
indicated), correlative studies to every 6-12 months (or suspension of sample 
collection for correlative studies), other laboratory tests to once every cycle. 
 
7.2.9 ALL treatments with lirilumab must be administered at the MDACC 
outpatient clinic. The first  cycles of azacytidine must be administered at the 
MDACC outpatient clinic. Subsequently. patients will have the option of 
receiving 5-azacytidine injections or infusions at the MDACC outpatient 
clinic or local ambulatory treatment center. If the local treatment center 
cannot accommodate 7 consecutive day administration on Days 1-7 of 5-
azacytidine, it is allowable to be administered on a 5+2 (days off) + 
2 schedule (For example, Administer Monday through Friday, omit Saturday 
and Sunday, Resume/Administer Monday and Tuesday).  In the event that the 
5+2+2 schedule is utilized, the Lirilumab will be administered on Day 10, 
which is allowable by schedule window or +/- 2 days from Day 8. We do not 
intend for the subjects to receive lirilumab at an outside physician’s office.  
During the first cycle all the laboratory evaluations will be done at MDACC. 
Subsequently, the patient may have the laboratory work done at a local clinic 
and the results reported to the research nurse for the study. The laboratory 
work done at the local clinic will be forwarded to the patient’s attending 
physician at MDACC or PI of the study, who will sign off on the labs to 
verify that the results have been reviewed. 
 
      Outside Physician Participation During Treatment 
 


 
 
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1. MDACC Physician communication with the outside physician is required 
prior to the patient returning to the local physician.  
This will be documented in the patient record 
 
2. A letter to the local physician outlining the patient's participation in a 
clinical trial will request local physician agreement to supervise the patient's 
care (Appendix H) 
 
3. Protocol required evaluations outside MDACC will be documented by 
telephone, fax or e-mail. Fax and/or e-mail will be dated and signed by the 
MDACC physician, indicating that they have reviewed it. Changes in drug 
dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be 
documented in the patient record. 
 
4. A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician. 
 
5. Documentation to be provided by the local physician will include progress 
notes, reports of protocol required laboratory and diagnostic studies and 
documentation of any hospitalizations. 
 
6. The home physician will be requested to report to the MDACC physician 
investigator all life threatening events within 24 hours of documented 
occurrence. 
 
7. All follow-up visits will be performed at MDACC. Patients will return to 
MDACC for physical examination at the start of each cycle i.e. 
approximately every 28 days (+/-7).  
 
7.2.10 End of Treatment Visit to be completed 30 days (+/-7 days) after the last 
dose of study drug. Blood (about 2-3 teaspoons) will be drawn for CBC, 
platelet count, differential, creatinine, total bilirubin, ALT.  No other 
procedures or labs will be needed. 
 
7.2.11 Patients with an objective response at completion of active study treatment 
will be followed for survival at MD Anderson Cancer Center (MDACC) for 
up to 90 days after completion of active treatment and while still on study. If 
the patient is unable to return to MDACC the follow-up visits may be 
conducted via telephone. 
 
Data regarding adverse events will be collected during the study. Please see Appendix D 
regarding data capturing of adverse events and adverse events source documentation. 
Protocol specific data will be entered into PDMS/CORe. PDMS/CORe will be used as the 
electronic case report form for this protocol. Only unexpected AEs will be recorded in the 
Case Report Form (CRF). The Principal Investigator will sign and date the AE log per each 


 
 
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patient at the completion of each course. Following signature, the AE log will be used as 
source documentation for the adverse events for attribution.  
 
Treatment may be discontinued for a variety of reasons, including patient withdrawal, 
investigator decision, and reasons specified by the protocol. Reasons for discontinuation of 
treatments are described below. 
 
 
7 
CRITERIA FOR RESPONSE: 
 
Response Criteria for AML 
 
Response criteria will be modified from the International Working Group for AML 
(JCO 2003; 21: 4642-9)[56]. Responders are patients who obtain a CR, CRi, or PR, 
with or without cytogenetic response, hematologic improvements, and morphologic 
leukemia-free state. Briefly, criteria are as follows: 
 
8.1.1 
Complete remission (CR):  
 
i 
Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count ≥1.0 x109/L  
 
Platelet count ≥100 x109/L 
 
i 
Bone marrow aspirate and biopsy: 
 
≤5% blasts 
 
No Auer rods 
 
No extramedullary leukemia 
 
                         8.1.2     Complete Remission with Incomplete Platelet Recovery (CRp): 
 
For patients to be classified as being in CRp, they must achieve CR   
except for incomplete platelet recovery (< 100 × 109/L). 
 
8.1.3  
Complete remission with incomplete blood count recovery (CRi): 
 
i 
Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count <1.0 x109/L, or 
 
Platelet count <100 x109/L 
 
i 
Bone marrow aspirate and biopsy: 
 
≤ 5% blasts 
 
No Auer rods 
 
No extramedullary leukemia 
 


 
 
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8.1.4 
Partial remission:  
i 
All CR criteria if abnormal before treatment  except: 
i 
t50 % reduction in bone marrow blast but still >5% 
 
8.1.5 
Morphologic leukemia-free state:  
i 
Bone marrow: 5% myeloblasts   
 
8.1.6 
Hematologic Improvement (HI): Hematologic response must be    
described by the number of positively affected cell lines. 
 
i 
Erythroid response (E) (pretreatment Hgb <11 g/dL) 
 
Hgb increase by 1.5 g/dL 
 
i 
Platelet response (P) (pretreatment platelets <100 x109/L) 
 
Absolute increase of 30 x 109/L for patients starting with > 20 x 
109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
 
i 
Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
i 
Blast response (B) 
>/=50% reduction in peripheral blood or bone marrow blasts but still 
>5% 
 
9 
DISCONTINUATION OF TREATMENT: 
 
9.1 Discontinuation Criteria for Individual Patients 
 
9.1.1 Patient Withdrawal 
Patients may voluntarily withdraw consent to participate in the clinical study at any time 
and without giving any reason. Their withdrawal will not jeopardize their relationship 
with their healthcare providers or affect their future care. Patients may also choose to 
withdraw from study treatment, but agree to remain in the study for follow-up 
procedures.  
 
9.1.2 Investigator Discontinuation of Patient 
The investigator may exercise medical judgment to discontinue study treatment if 
clinically significant changes in clinical status or laboratory values are noted. 
 
9.1.3 Criteria for Protocol-Defined Required Discontinuation of Treatment 
The protocol requires discontinuation of study treatment for the following reasons: 
1.  Patient requests discontinuation. 
2.  Unacceptable toxicity that in the opinion of the investigator makes it unsafe to     
continue therapy.  
3. Clinically significant progressive disease.  


 
 
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4. Investigator discretion. 
 
9.1.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Patients who discontinue treatment for any reason should complete end-of-treatment 
procedures when possible. End of treatment procedures will include a physical examination, 
CBC with differential and platelets and a limited chemistry profile (total bilirubin, serum 
creatinine, SGPT or SGOT). A bone marrow aspiration may be recommended only if non-
response or progressive disease cannot be unequivocally diagnosed from peripheral blood. 
Although treatment will be discontinued at that time, all patients who do not withdraw 
consent for follow-up, die, or become lost to follow-up, will remain on study for follow-up 
evaluations. Subject will be followed for toxicity for at least 30 days after the last protocol 
treatment. The 30-day follow-up visit will be scheduled as a clinic visits for clinical 
evaluation and physical examinations. If the patient cannot make it to the MDACC clinic for 
this visit, the required follow up treatment procedures may be done with a local physician 
and the records forwarded to MDACC. The research nurse will contact the patient by 
telephone and get a verbal assessment of the patient’s condition. The phone conversation 
will then be documented in the patient’s charts.  
 
9.2 Study Stopping Rules 
The principal investigator and MDACC IND office have the right to terminate this clinical 
study at any time. The principal investigator and MDACC IND office, as appropriate, will 
be involved in any decisions regarding terminating the study, temporarily suspending 
enrollment, or stopping ongoing treatment with study treatment. 
Reasons for terminating the clinical study or a study site’s participation include, but are not 
limited to, the following: 
x 
The incidence or severity of an adverse reaction related to treatment in this study or 
other studies indicates a potential health hazard to patients 
x 
Data recording is significantly inaccurate or incomplete 
x 
Study site personnel are noncompliant with study procedures 
x 
Pattern of noncompliance is observed 
 
9.3 Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required processes or 
procedures that affect patient safety or benefit potential, or confound assessments of safety 
or clinical activity. A protocol deviation is a departure from the protocol that does not meet 
the above criteria. Protocol violations or deviations may be grouped into the following 
classes: 
x 
Enrollment criteria 
x 
Study activities (missed evaluations or visits) except for those allowed per protocol 
x 
Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay; or discontinuation criteria 
x 
Investigational product handling, including storage and accountability 
x 
Informed consent and ethical issues 
            
10 ADVERSE EVENT REPORTING 


 
 
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10.1 
Adverse event is any untoward medical occurrence that may present during   
treatment with a pharmaceutical product but which does not necessarily have a 
causal relationship with this treatment.  
 
 Adverse drug reaction is a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
disease or for the modification of physiologic function.  
 
 Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) the 
event would not have happened at all, 2) the event would have occurred later than it 
actually did, or 3) the event would have been less severe. 
 
 The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial. 
 
10.2 
Adverse Events (AEs) will be evaluated according to the latest CTC version 4 
(Appendix C) and documented in medical record.  Only unexpected AEs will be 
recorded in the Case Report Form (CRF).  Expected events during leukemia 
therapy are: 
 
10.2.6 Myelosuppression related events (due to disease or leukemia therapy) 
 
10.2.6.1 
febrile or infection episodes not requiring management in the 
intensive care unit 
 
10.2.6.2 
epistaxis or bleeding except for catastrophic CNS or 
pulmonary hemorrhage 
 
10.2.6.3 
anemia, neutropenia, lymphopenia, thrombocytopenia, 
leukopenia 
 
10.2.7 Disease related events 
 
10.2.7.1 
symptoms associated with anemia 
 
10.2.7.1.1 fatigue 
 
10.2.7.1.2 weakness 
 
10.2.7.1.3 shortness of breath 
 
10.2.7.2 
electrolyte abnormalities (sodium, potassium, bicarbonate, 
CO2, magnesium) 
 


 
 
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10.2.7.3 
chemistry abnormalities (LDH, phosphorus, calcium, BUN, 
protein, albumin, uric acid, alkaline phosphatase, glucose) 
 
10.2.7.4 
coagulation abnormalities 
 
10.2.7.5 
disease specific therapy (induction, maintenance, salvage, or 
stem cell therapy) 
 
10.2.7.6 
alopecia 
 
10.2.7.7 
bone,  joint, or muscle pain 
 
10.2.7.8 
liver function test abnormalities associated with infection or 
disease progression 
 
10.2.7.9 
disease progression 
 
10.2.7.10 
abnormal hematologic values  
 
10.2.8 General therapy related events 
 
10.2.8.1 
catheter related events 
 
10.2.8.2 
renal failure related to tumor lysis syndrome or antibiotic/ 
antifungal therapy 
 
10.2.8.3 
rash related to antibiotic use 
 
10.2.9 Hospitalization for the management of any of the above expected   events 
 
10.3 Abnormal hematologic values will not be 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. 
 
10.4  Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
x Death 
x 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. 
x Inpatient hospitalization or prolongation of existing hospitalization 


 
 
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x A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
x 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). 
 
x Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the IND 
Sponsor, IND Office. 
 
x 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). 
 
x 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.  
 
x Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB. 
 
x 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.  
 
x 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. 
 


 
 
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Reporting to FDA: 
x Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy 
 
10.5     Serious Adverse event Reporting to Bristol-Myers Squibb Inc. 
All Serious Adverse Events must be reported to BMS Worldwide Safety 
x All SAEs, whether related or unrelated to lirilumab and all pregnancies must 
be reported to BMS (by the investigator or designee) within 24 hours.  
x All SAEs should be reported via confirmed facsimile (fax) transmission. 
x  SAE Fax Number: 609-818-3804 
 
10.6 
Data Safety Plan 
The PI of this Clinical Protocol will be responsible for the management of the protocol 
and data safety. Confidentiality of personal health information (PHI) will be maintained 
throughout the study. The investigators do realize that a risk to patient PHI 
confidentiality exists whereby personal information could accidentally be released, 
however, all necessary precautions will be taken to prevent this from happening. 
Unique patient identifiers will be used to replace patient name and medical record 
number. Patient identifiers will be available only to the investigators for the study and 
will be kept in a password-protected database and locked file cabinet.  Paper records 
(data forms, list of patient names and unique identifiers, etc.) will be kept in a locked 
file cabinet with access granted only to study investigators. No identifying personal 
health information will be used in any publication from this study. Collected 
information (including patient identifiers) will be destroyed within 5 years after 
publication. The protected health information used in this study will not be reused or 
disclosed to any person or entity outside of the investigators nor will it be used for other 
research. 
 
11.0 
STATISTICAL CONSIDERATIONS 
This will be a single arm, single center, open label study of lirilumab in combination with 5-
azacytidine in patients with refractory, relapsed or untreated AML.  
 
11.1 
Sample Size 
 
Part a. Lead-in phase  
The primary objective of the lead-in phase is to determine the safety of lirilumab in 
combination with 5-azacytidine in patients with refractory/ relapsed AML. Up to 24 patients 
will be accrued into lead-in part of the study. 
        
       Part b. Phase II  
Up to 40 patients (including 6 patients treated at the MTD from the lead-in part) will be 
recruited for the Phase II part.  


 
 
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The primary objective of the phase II is to determine the efficacy of lirilumab in 
combination with 5-azacytidine in patients with refractory, relapsed or untreated AML. The 
efficacy of the combination will be measured by the overall response rate (ORR), defined as 
CR (complete remission) + CRp (complete remission with incomplete platelet recovery) + 
CRi (complete remission with incomplete count recovery) + PR (partial response) + marrow 
clearance of blasts + HI(Hematological improvement) within 3 months of treatment 
initiation among adult patients with refractory/ relapsed AML. ORR and toxicity will be 
monitored simultaneously using the Bayesian approach of Thall, Simon, Estey (1995, 1996) 
and the extension by Thall and Sung (1998).  
 
Once safety of the MTD has been established, any patients still on study at a dose lower 
than MTD can be dose escalated up to MTD. Patients treated in the lead-in phase at MTD 
will be included in the phase II portion of the study. 
 
11.2 
Statistical Design 
 
Part a. Lead-in phase 
The MTD is defined as the highest dose level with </= 1 out of 6 patients experience a DLT 
during the first 28 days of treatment. DLT is defined in section 5.2.2. The dosing schema for 
the combination treatment during the lead in phase is shown in Table 1 in section 5.2.1. 
 
Part b. Phase II 
Historical data on similar patients shows an ORR of 10-15%. The target ORR with the 
experimental treatment is 30%. This regimen of the combination treatment will be considered 
worthy of further investigation if it elicits an increase in ORR to 30% with acceptable toxicity.  
A >30% drug-related grade 3/4 toxicity rate is considered unacceptable.  Thus, interim 
monitoring rules, assuming the prior distributions above, were constructed that meet the 
following two conditions, 
1) Stop if   Prob{ p(ORR,E )<p(ORR,H)  + 0.15 | data> 0.975, or 
2) Stop if Prob{ p(TOX,E)>0.30| data}>0.975,  
where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the combination 
treatment, and p(ORR, H) is the true ORR rate of the standard treatment. The first rule provides 
for stopping the study if the data suggest that it is unlikely (i.e., probability < 2.5%) that ORR 
rate of the combination treatment is greater than the ORR rate of standard treatment by 15.0%. 
The second condition will stop the study early if excessive therapy-related grade 3/4 toxicity 
(>30%) is highly probable (i.e., probability >97.5%) for the combination treatment.  
Monitoring for toxicity and futility will not begin until 5 patients have been evaluated, and 
cohort size for future evaluations is 5. 
The monitoring rule for the toxicity rate, based on these assumptions and monitoring 
conditions above is found in Table 4. For example, accrual will cease if 4 or more patients 
experience toxicities among the first 5 patients. 
 
Table 4. Stop accrual if the number of drug-related grade 3/4 toxicities is greater than or equal 


 
 
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to indicated (i.e., # patients with toxicities) among the number of patients evaluated 
# 
patients 
evaluated  
5 
10 
15 
20 
25 
30 
35 
40 
# 
patients 
with 
toxicities 
4-
5 
6-
10 
8-
15 
10-
20 
12-
25 
14-
30 
16-
35 
Always 
stop with 
this many 
patients 
 
Monitoring the ORR rate, based on the above assumptions and monitoring conditions is found 
in Table 5.  For example, accrual will cease if less than 2 patients experience an overall 
response within 3 months of initiation of therapy in the first 10 patients treated. 
 
Table 5. Stop accrual if the number with overall response is less than or equal to indicated (i.e., 
# patients with overall response) among the number of patients evaluated 
# patients 
evaluated  
5 
10-
15 
20-
25 
30-
35 
40 
# patients with 
overall 
response 
Never stop 
with this many 
patients 
0-1 
0-2 
0-3 
Always stop  
with this many 
patients 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping 
boundaries and the OC table (Table 6). In order to utilize the software for the design, a beta 
(0.3, 1.7) and beta (0.4, 1.6) priors were assumed for the standard treatment response 
distribution and experimental treatment response prior distribution, respectively. In addition, a 
30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for the standard treatment 
toxicity constant rate and experimental treatment toxicity prior distribution, respectively. 
The probability of stopping the study early if the true ORR of the combination treatment was 
30% and the true toxicity rate was 30% was 15.1%.  Probabilities of stopping early for high 
true toxicity rates (i.e., 50%) were 84.0% when the true ORR was 30% and 83.6% when true 
ORR rate was 40%. 
 
Table 6.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.15 
0.3001 
 
0.20 
0.1479 
 
0.25 
0.0703 
 
0.30 
0.0328 


 
 
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Table 6.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
 
0.35 
0.0151 
 
0.40 
0.0069 
0.20 
0.15 
0.3101 
 
0.20 
0.1601 
 
0.25 
0.0836 
 
0.30 
0.0466 
 
0.35 
0.0292 
 
0.40 
0.0211 
0.30 
0.15 
0.3859 
 
0.20 
0.2523 
 
0.25 
0.1842 
 
0.30 
0.1514 
 
0.35 
0.1358 
 
0.40 
0.1286 
0.40 
0.15 
0.6194 
 
0.20 
0.5367 
 
0.20 
0.4945 
 
0.30 
0.4741 
 
0.35 
0.4645 
 
0.40 
0.4600 
0.50 
0.15 
0.8841 
 
0.20 
0.8589 
 
0.25 
0.8460 
 
0.30 
0.8398 
 
0.35 
0.8369 
 
0.40 
0.8355 
 
Statistical Analysis Plan 


 
 
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All patients who received any dose of the study agent will be included in the analysis for 
efficacy and safety.  Demographic/clinical characteristics (including duration of response) and 
safety data of the patients will be summarized using descriptive statistics such as mean, 
standard deviation, median and range. For the primary efficacy analysis, we will estimate the 
ORR for the combination treatment, along with the 95% confidence interval. Patients who drop 
out of the study before completing all the cycles will be treated as “failures” for the primary 
analysis. ORR during the study period will also be presented with the 95% confidence interval. 
The association between ORR and patient’s clinical characteristics will be examined by 
Wilcoxon’s rank sum test or Fisher’s exact test, as appropriate. Toxicity type, severity and 
attribution will be summarized for each patient using frequency tables.  
The distribution of time-to-event endpoints (DFS and OS) including overall survival and 
progression free survival will be estimated using the method of Kaplan and Meier. 
Comparisons of time-to-event endpoints by important subgroups will be made using the log-
rank tests. Paired t-tests will be used to determine the immunological and molecular changes in 
the peripheral blood and bone marrow from baseline to the time of response, and to the time of 
disease progression. Correlation analysis (such as logistic regression analysis) will be 
conducted to determine the relationship between induction of hypomethylation / DNA damage 
and clinical response.    
Statistical analysis of biomarker data: Descriptive statistics including plots, mean, median 
and standard deviations will be used to summarize data. For continuous outcomes, t-test and 
ANOVA will be used to compare outcome measures across patient characteristics. Dunnett’s 
and Tukey’s test that properly adjust for multiplicity in multiple tests will be implemented. 
Pair-wise comparisons will be performed using pre- and post-therapy samples from each 
patient . The chi-square test or Fisher’s exact test will be used to test the association between 
two categorical variables such as disease state and performance status. Both univariate and 
multivariate logistic regressions will be performed to model prognostic factors. 
 
12.0 
PROTOCOL ADMINISTRATION 
This study will be monitored by the MD Anderson IND Office and a protocol-
specific monitoring plan will be followed. 
 
 
Protocol amendments 
 
Changes to the protocol will be made only when protocol amendments have been 
signed by the principal investigator and approved by the sponsor and the IRB of the 
study center. 
 
Archival of data 
 
All patient data (including source data) generated in connection with this study will 
be kept in the archives of the MDACC for at least 15 years after the study has been 
completed. All data will be available for inspection by company representatives of 
the 
Medical 
Department 
and 
by 
regulatory 
authorities.


 
 
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44 
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14.0 APPENDICES 
Appendix A: Prioritization List – Priority List 
Appendix B: Protocol Checklist  
Appendix C: CTCAE version 4.0 
Appendix D: Leukemia specific AE recording and reporting guidelines 
Appendix E: Lirilumab BMS Investigator Brochure 
Appendix F: Vidaza Drug Information 
Appendix G: Management algorithms for immuno-oncology drug-related adverse events 
Appendix H: Outside Physician Form 
Appendix I: DOSING PROCEDURE MANUAL for Lirilumab and Nivolumab Version 
2.0