Phase II Combination of Lirilumab and Nivolumab With 5-Azacitidine in Patients With Myelodysplastic Syndromes (MDS)
Phase: PHASE2
Conditions: Leukemia
Sponsor: M.D. Anderson Cancer Center

2014-0934
June 30, 2016
Page 1
Protocol Page
Phase II combination of lirilumab and nivolumab with 5-azacitidine in patients with 
myelodysplastic syndromes (MDS)
2014-0934
Core Protocol Information
Short Title 
Lirilumab and nivolumab with 5-azacitidine in patients with MDS
Study Chair: 
Guillermo Garcia-Manero
Additional Contact:
Shannon L. Bailey
Shunice Edwards-Harris
Department:
Leukemia
Phone:
713-745-3428
Unit:
428
Full Title: 
Phase II combination of lirilumab and nivolumab with 5-azacitidine in patients with 
myelodysplastic syndromes (MDS)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 01/30/2019
Version:
08
Submitted by:
Shunice Edwards-Harris--1/2/2018 2:02:42 PM
OPR Action:
Accepted by:  Melinda E. Gordon -- 1/4/2018 8:23:10 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

2014-0934
June 30, 2016
Page 2
Protocol Body
 

 
 
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Phase II Combination of Lirilumab and Nivolumab with 5-azacitidine in Patients 
with Myelodysplastic Syndromes (MDS) 
 
Guillermo Garcia-Manero MD 
Department of Leukemia  
MD Anderson Cancer Center 
 
 

 
 
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Table of Contents 
1.0 
OBJECTIVES ...................................................................................................... 33 
2.0 
BACKGROUND AND HYPOTHESIS ................................................................. 33 
3.0 
NIVOLUMAB (BMS-936558, MDX1106) ............................................................ 44 
4.0 
LIRILUMAB (IPH2102/BMS-986015) ............................................................. 1111 
5.0 
5-AZACYTIDINE (VIDAZA) ............................................................................ 1314 
6.0 
STUDY POPULATION .................................................................................... 1718 
7.0 
TREATMENT PLAN........................................................................................ 2021 
8.0  
STUDY MEDICATIONS .................................................................................. 2728 
8.1 
Nivolumab (Anti-PD1) ................................................................................................................. 2728 
8.2 
Lirilumab (BMS-986015) ........................................................................................................... 3234 
8.3 
Azacitidine ......................................................................................................................................... 3335 
9.0 
PATIENT EVALUATION ................................................................................. 3839 
10.0  EVALUATION DURING TREATMENT ........................................................... 3940 
11.0 CRITERIA FOR RESPONSE .......................................................................... 3941 
12.0 REPORTING OF ADVERSE EVENTS ............................................................ 3941 
13.0 INFORMED CONSENT ................................................................................... 4446 
14.0 CORRELATIVE STUDIES .............................................................................. 4446 
15.0 STATISTICAL CONSIDERATIONS ................................................................ 4647 
16. 
CONFIDENTIALITY PLAN ............................................................................. 5153 
17.0 REFERENCES ................................................................................................ 5254 
 
 
 

 
 
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Combination of Lirilumab and Nivolumab with 5-azacitidine in Patients  
with Myelodysplastic Syndromes (MDS) 
 
1.0 
Objectives 
 
Primary:  To determine the safety of nivolumab and lirilumab, as single agents or in 
combination and with 5-azacitidine, in patients with MDS. 
 
Secondary: 
1. 
To explore the clinical activity of nivolumab and lirilumab, as single agents 
or in combination and with 5-azacitidine, in patients with MDS including 
response, overall survival and progression free survival 
 
2. 
To explore the biological activity of these compounds 
in patients with MDS. 
 
2.0 
Background and hypothesis 
 
MDS consists of an heterogeneous group of myeloid malignancies characterized by 
bone marrow failure and increased risk of transformation to acute myelogenous 
leukemia (AML) 1. In general, patients are classified using IPSS criteria2, and more 
recently IPSS-R3, into a lower risk (low, int-1) and higher risk (int-2, high risk) category. 
The standard of care for most patients with MDS, except for those with an alteration of 
chromosome 5, is a hypomethylating agent such as 5-azacitdine1. Although this class of 
agents has significant activity in MDS and has been shown to improve survival 1, 
duration of response is usually limited and the prognosis of patients with HMA failure is 
extremely poor4. Therefore, the need for new therapies and combinations for this group 
of patients.  
 

 
 
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Several groups have reported on the expression of Kir ligands and receptors in myeloid 
leukemias5. Our group has also reported up regulation of innate immunity signals and 
the PD1/PDL1 axis in MDS and the fact that expression is up regulated by treatment 
with a hypomethylating agent6,7. We therefore hypothesized that immune checkpoints 
maybe involved in resistance to HMA agents and therefore maybe clinically synergistic 
with HMAs ref. To test these concepts, we propose a study where different cohorts of 
patients with MDS are treated either with single agent immune checkpoint inhibitor 
(nivolumab) in combination with an antibody against KIR (lirilumab) and with 5-
azacitidine. Data from this pilot trial will allow us to determine the toxicity profile of these 
agents in MDS and the potential for clinical activity that could then guide larger definitive 
clinical trials for more specific subsets of patients. 
 
3.0 
Nivolumab (BMS-936558, MDX1106) 
 
Mechanism of Action Immune activation is tightly regulated by co-stimulatory 
(e.g.  CD28 and ICOS) and co-inhibitory (e.g. CTLA-4 and PD-1) receptors 
expressed on T cells. Agonistic antibodies against co-stimulatory T cell receptors 
and blocking antibodies against co-inhibitory T cell surface receptors have both 
been shown to potentiate T cell activation for tumor cell killing. PD-1 is mainly 
expressed by activated CD4+ and CD8+ T cells, as well as antigen presenting 
cells (APCs). It has two ligands, PD-L1 and PD-L2, with distinct expression 
profiles. PD-L1 is expressed not only on APCs, but also on non- hematopoietic 
cells, including tumor cells. Expression of PD-L2 is largely restricted to APCs 
including macrophages and myeloid dendritic cells, as well as mast cells. The role 
of PD-1 as a negative regulator of T cells was best demonstrated by the finding 
that PD-1 deficient mice developed significant autoimmunity with high titers of 
autoantibodies. Subsequently, blocking antibodies against PD-1 were shown to 
activate immune responses that resulted in reduction of tumor metastasis and 
tumor growth in a number of experimental tumor models. Consistent with the 
immune inhibitory role of PD-1/PD-L1/2 signaling, forced expression of PD-L1 in 

 
 
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murine tumor cell lines allowed increased tumor growth in vivo, which was 
otherwise kept in check by T cells. The inciting effect of PD-L1 on tumor growth 
was reversed by blocking PD-L1 with antiPD-L1 antibodies.  
 
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype, monoclonal antibody 
that binds PD-1. Blockade of the PD-1 pathway by nivolumab was studied using the 
mixed lymphocyte reaction (MLR). PD-1 blockade resulted in a reproducible 
enhancement of both proliferation and IFN-γ release in the MLR. The effect of 
nivolumab on antigen-specific recall response was investigated using a CMV-
restimulation assay with human peripheral blood mononuclear cells (PBMCs), and was 
evaluated by ELISA. These data indicated that nivolumab, versus an isotype-matched 
control antibody, augmented IFN-γ secretion from CMV-specific memory T cells in a 
dose-dependent manner. PD-1 blockade by nivolumab is therefore considered a 
promising immunotherapeutic strategy. 
 
Summary of Safety Results from Nivolumab Program 
For a complete review of clinical information, please refer to the nivolumab Investigator 
Brochure. 
 
Summary of Safety 
The monitoring of subject safety during and after a clinical study with nivolumab, 
including any special monitoring precautions, tests, or observations, and the proper 
means of recording and reporting adverse safety information [including adverse 
events (AEs) and abnormal laboratory values] will follow the procedures outlined in 
the specific study protocol.  
 
The overall safety experience with nivolumab is based on experience in 
approximately 1500 subjects as either a monotherapy or in combination with other 
therapeutics. In general for monotherapy, the safety profile is similar across tumor 
types. The one exception is pulmonary inflammation AEs which may be numerically 

 
 
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greater in subjects with non-small cell lung cancer (NSCLC) possibly because in 
some cases it can be difficult to distinguish between nivolumab-related and unrelated 
causes of pulmonary symptoms and radiographic changes. The most frequently 
reported treatment-related AE is fatigue, which is almost always low grade.  
 
The safety profile is generally consistent across completed and ongoing clinical trials 
with no maximum tolerated dose (MTD) reached at any dose tested up to 10 mg/kg. 
There was no pattern in the incidence, severity, or causality of AEs to nivolumab dose 
level. Most related AEs are thought to be due to the effects of inflammatory cells on 
specific tissues. Most AEs were low-grade (Grade 1 to Grade 2) with relatively few 
related high-grade (Grade 3 to Grade 4) AEs. Most high-grade events were 
manageable with use of corticosteroids or hormone replacement therapy 
(endocrinopathies).  
 
Clinical Safety in Advanced Malignancies (Nivolumab Monotherapy) 
A total of 306 subjects with treatment-refractory malignancies have been treated in an 
ongoing, Phase 1 multidose study (MDX1106-03, CA209003). This is an ongoing 
phase I dose-escalation study of nivolumab monotherapy in patients with advanced 
cancers; 1, 3, or 10 mg/kg nivolumab and 0.1 and 0.3 mg/kg (included as part of 
Amendment 4) administered by IV Q2W; treatment up to 2 years. Results were 
published by Topalian et al. (NEJM 2012). The baseline disease diagnosis by 
treatment for MDX1106-03 is provided in Table 1. A review of the safety data by 
tumor type (RCC, NSCLC, mCRPC, CRC, and melanoma) did not show any 
clinically meaningful differences in the proportion of subjects with AEs noted across 
tumor type. 
 
Table 1: Baseline Disease Diagnosis by Treatment - MDX1106-03 
 
No. of Subjects 
Nivolumab (mg/kg) 
0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg TOTAL 
MDX1106-03, Total N 
17 
18 
86 
54 
131 
306 

 
 
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NSCLC 
0 
0 
33 
37 
58 
128 
Melanoma 
 
 
 
 
 
 
RCC 
0 
0 
18 
0 
16 
34 
mCRPC 
0 
0 
0 
0 
17 
17 
CRC 
0 
0 
0 
0 
19 
19 
Abbreviations: CRC: colorectal adenocarcinoma; mCRPC: metastatic castration-
resistant prostate cancer; NSCLC: non-small cell lung cancer; RCC: renal cell 
carcinoma;  
Source: Preliminary data, CA209003. Clinical data cut-off date 18 Mar-2013. 
 
Adverse Events 
There was no pattern in the incidence, severity, or causality of AEs related to 
the dose of nivolumab, between 1 and 10 mg/kg, in MDX1106-03. Of the 306 treated 
subjects in MDX1106-03, 303 (99.0%) subjects have at least 1 reported AE 
regardless of causality (Table 2). The most frequently reported AEs were fatigue 
(54.9%), decreased appetite (35.0%), diarrhea (34.3%), nausea (30.1%), and 
cough (29.4%). Treatment-related AEs were reported in 230 (75.2%) of the 306 
subjects. The most frequently reported treatment-related AEs were fatigue (28.1%), 
rash (14.7%), diarrhea (13.4%), and pruritus (10.5%). Most treatment-related AEs 
were low grade. Treatment-related Grade 3-4 AEs were reported in 52 (17.0%) 
of subjects. The most frequently reported treatment-related high grade AE was 
fatigue (6.5%). 
 
Table 2: Summary of Adverse Events Reported in ≥15% of All Treated Subjects- 
MDX1106-03 
Preferred Term 
No. of Subjects (%) 
AEs regardless of causality 
Treatment-related AEs 
Any Grade 
N=306 
Grade 3-4 
N=306 
Any Grade 
N=306 
Grade 3-4 
N=306 
Any AE 
303 (99) 
127 (42) 
230 (75) 
52 (17) 
Fatigue 
168 (55) 
20 (7) 
86 (28) 
7 (2) 
Decreased appetite 
107 (35) 
3 (1) 
28 (9) 
1(0.3) 

 
 
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Diarrhea 
105 (34) 
3 (1) 
41 (13) 
3 (1) 
Nausea 
92 (30) 
9 (3) 
27 (9) 
2 (1) 
Cough 
90 (29) 
4 (1) 
11 (4) 
1 (0.3) 
Dyspnea 
80 (26) 
27 (9) 
11 (4) 
0 
Constipation 
78 (26) 
2 (1) 
5 (2) 
0 
Rash 
74 (24) 
0 
45 (15) 
0 
Vomiting 
70 (23) 
7 (2) 
10 (3) 
1 (0.3) 
Back pain 
68 (22) 
7 (2) 
3 (1) 
1 (0.3) 
Arthralgia 
63 (21) 
4 (1) 
15 (5) 
0 
Pyrexia 
61 (20) 
1 (0.3) 
17 (6) 
0 
Headache 
59 (19) 
1 (0.3) 
8 (3) 
0 
Edema peripheral 
59 (19) 
1 (0.3) 
3 (1) 
0 
Dizziness 
56 (18) 
1 (0.3) 
10 (3) 
0 
Pruritus 
56 (18) 
1 (0.3) 
32 (11) 
1 (0.3) 
Weight decreased 
48 (16) 
1 (0.3) 
11 (4) 
0 
Malignant neoplasm progression 
4 (1) 
1 (0.3) 
 
 
 
Select Adverse Events 
Select AE categories (events with a potential inflammatory mechanism requiring more 
frequent monitoring and/or unique intervention such as immunosuppressant’s and/or 
endocrine replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic AEs, 
skin AEs, and endocrinopathies. In addition, Select AEs include a category for infusion 
reactions. Each category is composed of a discrete set of preferred terms, including those 
of greatest clinical relevance. These Select AEs are considered events of interest based on 
the mechanism of action and were previously referred to as immune-related AEs or immune-
mediated AEs. The frequencies of these events are summarized in investigator 
brochure (Appendix A). The 10-mg/kg cohort had numerically greater frequency of 
high-grade select AEs including the subcategories of endocrinopathies, GI, pulmonary, 
and infusion reactions.  
 
Adverse Events Leading to Discontinuation 
At least 1 treatment-related AE leading to discontinuation was reported in 32 (10.5%) of 

 
 
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the 306 treated subjects. Grade 3-4 treatment-related events were reported in 14 (4.6%) 
subjects. The frequency of treatment-related AEs leading to discontinuation was not 
associated with the dose of nivolumab. Pneumonitis was the most common treatment-
related AE leading to discontinuation (8 subjects, 2.6%); pneumonitis reported in 3 (1.0%) 
subjects was Grade 3-4.  Treatment-related AEs reported in at least 2 subjects included 
pneumonitis (8 subjects, 2.6%), colitis (3 subjects, 1.0%) and myalgia, hepatitis, 
hypersensitivity, and infusion-related r e a c t i o n s  ( each r e p o r t e d  i n  2 subjects, 0.7%). 
One event of Grade 5 sepsis was reported for 1 subject, a 62-year-old male treated with 1 
mg/kg nivolumab. 
 
Deaths 
As of 18-Mar-2013, 195 deaths have been reported in MDX1106-03 during the course of 
the study or within 30 days of last dose of study drug. The majority of the deaths were 
considered secondary to disease progression and malignant disease. 
 
Three subjects in MDX1106-03 died after developing pneumonitis. A 62-year-old male 
(MDX1106-03-1-699) with NSCLC (adenocarcinoma) in the 1 mg/kg treatment group and 
a 59-year old male (MDX1106-03-1-3582) with CRC in the 10 mg/kg treatment group both 
died due to Grade 5 sepsis after having developed Grade 4 pneumonitis. Sepsis and 
pneumonitis were considered related to study drug by the investigator in both of these cases. 
In addition, a 40-year- old female (MDX1106-03-5-710) with NSCLC (adenocarcinoma) in 
the 1 mg/kg treatment group died due to respiratory failure after having developed Grade 
4 pneumonitis and tumor progression. In this case, respiratory failure and pneumonitis 
were considered related to study drug by the investigator. 
 
Additional deaths reported as due to “other” in MDX1106-03 included: 
 
 MDX1106-03-2-3436 (10 mg/kg): Ischemic cardiomyopathy 
 MDX1106-03-4-3484  (10 mg/kg):  Death due to abdominal pain c a u s e d  b y  
superior mesenteric vein thrombosis 

 
 
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 MDX1106-03-3-674 (1 mg/kg): Progressive lung cancer 
 
Summary of Efficacy (Nivolumab monotherapy) 
The clinical activity data presented below are from MDX1106-03 (nivolumab 
monotherapy). 
 
Table 3:  Objective Response Rate and Progression Free Survival 24 Weeks Rate 
in Melanoma Subjects - MDX1106-03 
Dose (mg/kg) 
N 
ORR 
PFSR at 24 weeks (%) 
All Melanoma 
107 
33 (31) 
44 
0.1 
17 
6 (35) 
39 
0.3 
18 
5 (28) 
33 
1.0 
35 
11 (31) 
51 
3.0 
17 
7 (41) 
55 
10.0 
20 
4 (20) 
35 
Abbreviations: ORR: objective response rate, PFSR: progression-free survival rate  
Source: Preliminary data, MDX1106-03. Clinical cut-off date: 18-Mar-201 
 
Table 4: Objective Response Rate per RECIST 1.0 and Progression Free Survival 
24 Weeks Rate by Histology in Non-small Cell Lung Cancer Subjects - 
MDX1106-03 
Dose (mg/kg) 
N 
Histology 
ORR 
No. of Subjects (%)
PFSR at 24 
weeks (%) 
All NSCLC 
129 
NA 
22 (17) 
34 
1.0 
15 
SQ 
0 
36 
 
18 
NSQ 
1 (6) 
19 
3.0 
18 
SQ 
4 (22) 
45 
 
19 
NSQ 
5 (26) 
42 
10.0 
21 
SQ 
5 (24) 
45 
 
37 
NSQ 
7 (19) 
25 
Abbreviations: NA: not applicable, NSCLC: non-small cell lung cancer; NSQ: non-
squamous, ORR: objective response rate; PFSR: progression free survival rate, SQ: 
squamous 
Source: Preliminary data, MDX1106-03. Clinical cut-off date 18- Mar-2013. 
 

 
 
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4.0 
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 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 response8. 
 
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. 

 
 
2 0 1 4‐ 0 9 3 4 
 
 
J u n e  3 0,  2 0 1 6 
 
 
P a g e  1 2   of 5 4 
 
S urf a c e pl a s m o n r e s o n a n c e a n al y si s d e m o n str at e d t h at t h e m e a n ( st a n d ar d d e vi ati o n 
[ S D]) m o n o v al e nt affi nit y of liril u m a b f or r e c o m bi n a nt s ol u bl e KI R 2 D L 1 w a s 2. 0 4 
 1 0- 8 
( 0. 3 1  1 0- 8) M a n d f or KI R 2 D L 3 w a s 3. 0 1 x 1 0 - 1 0( 0. 4 1 x 1 0- 1 0) M. 
 
T h e s ci e ntifi c r ati o n al e f or t h e cli ni c al d e v el o p m e nt of liril u m a b w a s b a s e d o n t h e 
f oll o wi n g fi n di n g s: 
1)  Bl o c k a d e of i n hi bit or y KI R r e s ult e d i n killi n g of A M L bl a st s  b y KI R- mi s m at c h e d 
N K c ell s b ut n ot b y KI R- m at c h e d N K c ell s i n vitr o. 
2)  N O D/ S CI D mi c e i nf u s e d wit h A M L c ell s a n d N K c ell s di e d of di s e a s e wit hi n † 6 0 
d a y s. I n c o ntr a st, all mi c e tr e at e d  wit h KI R bl o c k a d e s ur vi v e d at D a y 7 5 ( p < 
0. 0 1) 9 . 
 
Liril u m a b al s o i s b ei n g d e v el o p e d i n c o m bi n ati o n wit h t h e T- c ell c h e c k p oi nt i n hi bit or s, 
i pili m u m a b a n d ni v ol u ma b. N o n cli ni c al st u di e s c o m bi ni n g a nti- L y 4 9 ( 5 E 6 F( a b’) 2), t h e 
m uri n e f u n cti o n al h o m ol o g of liril u m a b, wit h t h e m A b s s p e cifi c f or t h e m uri n e v er si o n s of 
eit h er c yt ot o xi c T-l y m p h o c yt e a nt i g e n 4 ( C T L A- 4) or pr o gr a m m e d c ell d e at h 1 ( P D- 1) 
d e m o n str at e d e n h a n c e d a nti-t u m or effi c a c y. 
 
Liril u m a b d o e s n ot bi n d t o N K c ell s fr o m n o n- h u m a n pri m at e or o t h er s p e ci e s 
tr a diti o n all y u s e d f or s af et y t e sti n g. S af et y t e sti n g w a s p erf or m e d i n mi c e b e c a u s e 
L y 4 9 C/I, t h e m uri n e i n hi bit or y r e c e pt or s, ar e f u n cti o n all y h o m o l o g o u s t o h u m a n KI R. 
Mi c e tr e at e d wit h liril u m a b at 1 0 m g/ k g o n c e w e e kl y f or 4 w e e k s , or t h e s urr o g at e a nti-
L y 4 9 ( 5 E 6 F( a b’) 2) at u p t o 1 0 m g/ k g t wi c e w e e kl y f or 1 3 w e e k s,  s h o w e d n o si g n s of 
t o xi cit y. 
 
Liril u m a b i s b ei n g d e v el o p e d f o r i m m u n ot h er a p y in p ati e nt s wit h  v ari o u s h e m at ol o gi c 
m ali g n a n ci e s a n d s oli d t u m or s. A  t ot al of 1 0 0 s u bj e ct s h a v e b e en tr e at e d i n 4 o n g oi n g 
cli ni c al tri al s a s s e s si n g s af et y,  p h ar m a c o ki n eti c s, bi o m ar k er mo d ul ati o n, a n d cli ni c al 
a cti vit y. T h e fir st (I P H 2 1 0 2- 1 0 1) i s a m o n ot h er a p y, d o s e e s c al a ti o n, P h a s e 1 tri al t o 
d et er mi n e t h e m a xi m u m t ol er at e d d o s e ( M T D). T h e s e c o n d i s a d o u bl e- bli n d, pl a c e b o-

 
 
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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 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. 
 
As of 29-Jul-2013, the majority of adverse events (AEs) in these 4 ongoing trials were 
mild or moderate (Grade 1 or 2), self-limiting, and manageable. The most common 
related AEs were asthenia, fatigue, pruritus, infusion-related reaction, chills, and 
headache. Only 2 serious adverse events (SAEs) (abnormal liver function tests and 
iridocyclitis) that were related to study treatment were reported. Blockade of inhibitory 
KIR by lirilumab is thus a promising mechanism to promote killing of tumor cells by the 
innate immune system. 
 
5.0 
5-azacytidine (Vidaza) 
 
5-azacytidine, an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and 
metabolism. Since the early 1970s, 5-azacytidine has been investigated primarily in the 
US for the treatment of acute leukemia. Clinical studies have focused mainly on patients 
with disease refractory to conventional chemotherapy. Results of these investigations 
demonstrated activity of 5-azacytidine in the treatment of AML. Clinical studies 
subsequently evaluated the effects of 5-azacytidine in a variety of other malignant and 
hematologic disorders, including solid tumors, hemoglobinopathies (eg, thalassemia 
and sickle cell anemia), and MDS. In 1984, the Cancer and Leukemia Group B 
(CALGB) began a series of clinical studies with 5-azacytidine in patients with MDS. 
These studies, in addition to other supportive data, led to the approval of Vidaza® (5-
azacytidine) in May 2004 for the treatment of MDS.  
 

 
 
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5-azacytidine inhibits the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase (DNMT). 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. It is now widely recognized 
that hypermethylation of DNA is frequently associated with myelodysplastic syndromes 
and other cancers, such as renal, melanoma, breast, colorectal, non-small cell lung and  
hematologic malignancies. 5-azacytidine is believed to exert its antineoplastic effects 
through hypomethylation and cytotoxicity on abnormal hematopoietic cells in the bone 
marrow.10-14 Hypomethylation may restore normal function to genes that are critical for 
differentiation and proliferation. 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.  
 
The cytotoxicity of 5-azacytidine is proportional to dose and exposure time. 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. Cytotoxicity is greatest in cells that are 
proliferating (S phase) and metabolically active.10 Cytotoxic effects may also be 
mediated through induction of the DNA damage response pathways. Nonproliferating 
cells are relatively insensitive to 5-azacytidine.  
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus monkeys. 
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.15 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. The genotoxicity of 5-azacytidine is consistent 

 
 
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with that of other nucleoside analogs that interact with nucleic acids. Likewise, similar to 
other agents with cytostatic properties, 5-azacytidine was embryotoxic and reduced the 
reproductive performance in mice and rats.  
 
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.15 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. A single dose (75 mg/m2) SC 
versus IV crossover study in 6 MDS subjects 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.  
 
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.  
 
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 

 
 
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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.16 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.16 
 
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.17 Patients were randomized to 5-azacytidine 
(75 mg/m2/day x 7days in 28 day cycles) or conventional care regimens (CCR), where 
CCR was pre-selected by the Investigator as best supportive care (transfusions, 
antibiotics, and G-CSF for neutropenic infection), low-dose cytarabine (20 mg/m2/day x 
14 days in 28 day cycles); or standard chemotherapy (conventional 
induction/consolidation). Patients were stratified by FAB/IPSS and randomized 1:1 to 5-
azacytidine or CCR. This trial did not allow erythropoietin. Three hundred fifty eight 
patients (70% male) were randomized at 79 centers to 5-azacytidine (N=179) or CCR 
(N=179): best supportive care only (N=105, 59%), low-dose cytarabine (N=49, 27%), or 
standard chemotherapy (N=25, 14%). Median age was 69 years (range 38-88 years). 
The 5-azacytidine and CCR groups were comparable for baseline patient 
characteristics. At baseline, 95% of patients were higher risk: RAEB (58%), RAEB-
T/WHO AML (34%), CMML (3%), and other (5%). By IPSS, 87% were higher risk: 
Intermediate -2 (40%), High (47%), and 13% Indeterminate/other. 5-azacytidine was 
administered for a median of 9 cycles; low-dose cytarabine for 4 cycles. Median follow-
up for the survival analysis was 21.1 months. 5-azacytidine demonstrated statistically 

 
 
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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 Investigator’s Brochure (Appendix B), 
which 
contains 
comprehensive 
pharmacology, 
toxicology, 
pharmacokinetics, 
pharmacodynamics, metabolism, preclinical, and clinical efficacy and safety data 
information.  
 
6.0 
Study Population 
 
Inclusion Criteria  
1. Patients with MDS (up to 20% blasts) of any risk. Patients with lower risk MDS 
(low and int-1 by IPSS) could have received prior non-hypomethylating agent 
therapy (ie growth factors or lenalidomide). Patients with higher risk MDS (int-2 
or high by IPSS) should not have received prior therapy with a hypomethylating 
agent. 
 
2. Age 18 years or older. 
 
3. Adequate organ function: creatinine ≤2.5 x ULN; serum bilirubin ≤2.5 x ULN; AST 
and ALT ≤2.5 x ULN.  
 
4. ECOG performance status ≤2   
 
5. Females of childbearing potential must have a negative serum or urine beta 
human chorionic gonadotrophin (β-hCG) pregnancy test result within 24 hours 
prior to the first dose of treatment and must agree to use an effective 

 
 
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contraception to avoid pregnancy for 23 weeks (30 days plus the time required 
for nivolumab to undergo five half-lives) after the last dose of investigational drug. 
Females of non- childbearing potential are those who are postmenopausal 
greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. 
 
6. Males who have partners of childbearing potential must agree to use an effective 
contraceptive method during the study and for 31 weeks after the last dose of 
nivolumab. 
 
7. Patients or their legally authorized representative must provide written informed 
consent. 
 
Exclusion Criteria 
1. History of another primary invasive malignancy that has not been definitively 
treated or in remission for at least 2 years. Patients with non-melanoma skin 
cancers or with carcinomas in situ are eligible regardless of the time from 
diagnosis (including concomitant diagnoses).  
 
2.  Any major surgery, radiotherapy, chemotherapy, biologic therapy, 
immunotherapy, experimental therapy within 2 weeks prior to the first dose of the 
study drugs.  
 
3. Patients with any other known concurrent severe and/or uncontrolled medical 
condition 
(e.g. 
uncontrolled 
diabetes; 
cardiovascular 
disease 
including 
congestive heart failure NYHA Class III or IV, myocardial infarction within 6 
months, and poorly controlled hypertension; chronic renal failure; or active 
uncontrolled infection) which, in the opinion of the investigator could compromise 
participation in the study. 
 
4. Patients unwilling or unable to comply with the protocol. 

 
 
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5. Patients who are on high dose steroid (ie prednisone or equivalent more than 10 
mg a day) or immune suppression medications. 
 
6.  Patients with autoimmune diseases (e.g., rheumatoid arthritis, systemic 
progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, 
autoimmune vasculitis [e.g., Wegener’s Granulomatosis]). 
 
7.  Patients with a history of Inflammatory Bowel Disease such as Crohn’s disease 
and ulcerative colitis  
 
8. Patients known to be positive for hepatitis B surface antigen expression or with 
active hepatitis C infection (positive by polymerase chain reaction or on antiviral 
therapy for hepatitis C within the last 6 months) or with a history of HIV disease. 
 
9. Current therapy with other systemic anti-neoplastic or anti-neoplastic 
investigational agents.   
 
10. Females who are pregnant or lactating 
 
11. Prior treatment with stem cell transplantation. 
 
12. Prohibited Prior Treatments and/or Therapies: 
a. Prior therapy with an anti-KIR, anti-PD-1, or anti-PD-L1, antibody. 
b. Prior treatment regimens with any immune cell modulating antibody such as 
anti-CD137 and anti-OX40. However, prior anti-CTLA4 therapy is allowed if 
the last dose is 101 days or more from the first dose of study drug. 
c. Exposure to any other investigational drug within 2 weeks prior to the first 
dose of study drug (within 101 days for anti-CTLA4 therapy). 

 
 
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d. Any anti-cancer therapy (e.g., chemotherapy, biologics, vaccines, 
radiotherapy with curative intent, or hormonal treatment) within 2 weeks prior 
to the first dose of study drug administration (within 101 days for anti-CTLA4 
therapy administration. 
e. Use of non-oncology vaccines containing live virus for prevention of infectious 
diseases within 4 weeks prior to study drug. The use of the inactivated 
seasonal influenza vaccine (Fluzone®) is allowed. 
f. Systemic corticosteroid at immunosuppressive doses (> 10 mg/day of 
prednisone or equivalent), must be discontinued at least 2 weeks prior to 
enrollment 
 
7.0 
Treatment Plan 
 
We plan to study 2 different patient groups (lower risk MDS [defined as low and int-1 by 
IPSS] and higher risk [defined as int-2 and high risk by IPSS]) with 2 cohorts each.  
Each cohort will be composed of N=20 patients. Accrual to cohort will be sequential in 
each patient group. Accrual will be parallel for each patient group.  
 
All treatments can vary +/- 3 days. 
 
1. Lower Risk  MDS cohorts (Low and Int-1): 
o Cohort 1: Lirilumab single agent Q4 wks.  
o Cohort 2: Lirilumab Q4 weeks+ Nivolumab, Q2 wks X 9 cycles then both 
Q4 wks. 
2. Higher Risk MDS cohorts (Int-2 and High):  
o Cohort 3: 5-azacitidine IV, D1-7 of 28 day cycle, in combination with 
Lirilumab IV on  D7 

 
 
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o Cohort 4: 5-azacitidine IV, D1-7 of 28 day cycle, in combination with 
Lirilumab IV Day 7 and Nivolumab IV  D7 & D21 X 9 cycles then D7 only 
on Cycle 10 +  
Specific cohorts can be closed based on ongoing experience with this trial or other 
relevant information. 
Patients will receive study drug(s) according to the following treatment plan. Individual 
minor variations in the initiation of therapy, are acceptable as indicated by patient 
condition and physician judgment. These variations should be documented in the 
patient’s medical record. 
 
Dosing calculations for Nivolumab and 5-Azacitidine will be based actual body weight.  
 
Single agent:  
 
Lirilumab:  Patient will receive lirilumab 3 mg/kg IV over approximately 60 minutes 
every 4 weeks.  One cycle is defined as 4 weeks. 
 
Combination: 
 
Lirilumab and Nivolumab: Patient will receive Nivolumab 3 mg/kg IV over 
approximately 60 minutes every 2 weeks for 9 cycles. Lirilumab will be administered at 
3 mg/kg IV over approximately 60 minutes once every 4 weeks. One cycle will be 
defined as 4 weeks. 
 
Azacitidine+ lirilumab: Azacitidine 75 mg/m2 IV daily x 7 days and lirilumab 3 mg/kg IV 
over approximately 60 minutes on day 7. A cycle will be considered 4 weeks. 
 
Azacitidine+ lirilumab + Nivolumab: Azacitidine 75 mg/m2 IV daily x 7 days followed 
on day 7 by nivolumab and lirilumab and nivolumab also on day 21. A cycle will be 

 
 
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considered 4 weeks. Doses of nivolumab and lirilumab are 3 mg/kg IV each over 
approximately 60 minutes. 
 
Dose Adjustments 
Based on the adverse effect profiles of the 3 agents, the following dose adjustments are 
recommended.  Hematological toxicities will be attributed primarily to Azacitidine and 
preferentially will be dose reduced (Table 1).  Specific non-hematological toxicities will 
be attributed primarily to NIVOLUMAB OR LIRILUMAB. No dose reductions of these 
two agents are allowed, see below. 
 
Table 1: Dose Adjustments for Grade 3 – 4 Hematological Toxicity 
 
Azacitidine IV (x 7 days) 
Level – 1  
50 mg/m2/day 
Level – 2 
25 mg/m2/day 
 
Nivolumab and Lirilumab Dose Modification  
Nivolumab/ Lirilumab Dose reductions or dose escalations are not permitted. 
 
Dose Delay Criteria: 
Because of the potential for clinically meaningful nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for 
suspected AEs of selected categories.  
 
Dose delay criteria apply for all drug-related adverse events   
 
Nivolumab & Lirilumab administration should be delayed for the following: 
 Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 
o However, dose delays should occur for the following laboratory 

 
 
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abnormalities: 
 G2 Creatinine, or 
 G2 ALT, AST or total bilirubin 
 Any Grade 3 skin, drug-related AE 
 Any Grade 3 drug-related laboratory abnormality, with the following exceptions 
for lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase 
or lipase: 
o Grade 3 lymphopenia or leukopenia does not require dose delay. 
o Grade 3 AST, ALT or total bilirubin requires permanent discontinuation of 
nivolumab 
 Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. 
 
Criteria to Resume Treatment: 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 
 Subjects may resume treatment in the presence of Grade 2 fatigue  
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
 Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed 
 Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment 
 
If the criteria to resume treatment are met, the subject should restart treatment at the 
next scheduled timepoint per protocol. However, if the treatment is delayed past the 
next scheduled timepoint per protocol, the next scheduled timepoint will be delayed 
until dosing resumes. 
 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued 
from study therapy, except as specified in discontinuation section. 
 

 
 
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Management Algorithms: 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity 
and duration than AEs caused by other therapeutic classes. Nivolumab & Lirilumab 
are considered immuno-oncology agents in this protocol. Early recognition and 
management of AEs associated with immuno-oncology agents may mitigate severe 
toxicity. Management algorithms have been developed to assist investigators in 
assessing and managing the following groups of AEs: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, 
Neurological. 
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the 
algorithms. The guidance provided in these algorithms should not replace the 
Investigator’s medical judgment but should complement it. 
 
Discontinuation Criteria: 
Treatment should be permanently discontinued for the following: 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the 
re-treatment period OR requires systemic treatment  
 
 Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, diarrhea, colitis, neurologic adverse event, 
hypersensitivity reactions, and infusion reactions: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic adverse event, hypersensitivity reaction, or infusion 
reaction of any duration requires discontinuation 
 
o Grade 3 drug-related laboratory abnormalities do not require treatment 

 
 
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discontinuation except those noted below: 
 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
 
 Grade 3 drug-related ALT, AST, or total bilirubin require 
discontinuation  
 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated 
with symptoms or clinical manifestations of pancreatitis and decrease to < 
Grade 4 within 1 week of onset.  
 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72 hours of their onset 
 
 Any dosing interruption lasting > 6 weeks with the following exceptions: 
 
o Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Investigator must 
be consulted. Tumor assessments should continue as per protocol even if 
dosing is interrupted 
 
o Dosing interruptions > 6 weeks that occur for non-drug-related reasons 
may be allowed if approved by the Investigator. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 6 weeks, the 
Investigator must be consulted. Tumor assessments should continue as 

 
 
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per protocol even if dosing is interrupted 
 
 Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
 
Supportive Care 
Patients will receive a 5-HT3 antagonist, or any other antiemetics at the discretion of the 
treating physician, prior to each dose of Azacitidine to prevent nausea and emesis. 
 
Routine supportive measures for leukemia patients such as analgesics, blood 
transfusions, and antimicrobials are permitted.  Prophylactic antimicrobials may be 
prescribed at the discretion of the treating physician.   
 
Patients aged 50 or older may receive their first course of therapy in the Protected 
Environment if preferred by the treating physician. 
 
Hematopoietic colony stimulating factors may be used at the discretion of the treating 
physician to provide optimal patient care. 
 
The administration of other anticancer therapies, other investigational agents, or 
erythropoetic agents is not permitted.  
 
Hydroxyurea can be used in patients with rapidly proliferative disease at the discretion 
of the treating physician.  That said, concomitant use of hydroxyurea with 5-azacitidine 
will not be recommended. 
 
Treatment may continue until:  
 
1. Clinically significant progressive disease, or 

 
 
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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. 
 
8.0  
Study Medications 
 
For treatment visits where both Lirilumab and Nivolumab are administered, Nivolumab 
will be administered first followed by Lirilumab within 30 minutes after completion of the 
Nivolumab. 
 
8.1 Nivolumab (Anti-PD1) 
Nivolumab is a fully human, IgG4 (kappa) isotype, monoclonal antibody that binds 
PD-1. Nivolumab will be supplied in vials of 100 mg (10 mg/mL) and packaged in an 
open-label fashion. Ten nivolumab vials (each 10 mL) will be packaged within a 
carton. The vials are not subject specific although there will be specific vial 
assignments by subject distributed by the Pharmacy in order to track drug usage 
and re-supply. 
 
PRODUCT INFORMATION TABLE:  
Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1) 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Secondary 
Packaging 
(Qty)/Label Type 
Appearance Storage 
Conditions 
(per label) 

 
 
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*Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
8.1.1 Dose Calculation of nivolumab 
Total dose should be calculated as in the following example: 
 
Subject’s actual body weight in kg x 3 mg = total dose in mg 
 
Therefore, a subject weighing 70 kg who is to receive a dose of 3 mg/kg would 
be administered 210 mg of nivolumab (70 kg x 3 mg/kg = 210 mg). 
 
8.1.2 Preparation and Dispensing of Nivolumab 
The product storage manager should ensure that the study drug is stored in 
accordance with the environmental conditions (temperature, light, and humidity) 
as determined by the Investigator Brochure. If concerns regarding the quality or 
appearance of the study drug arise, do not dispense the study drug and contact 
the sponsor immediately. 
 
Investigational product documentation must be maintained that includes all 
processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage 
temperatures, reconstitution, and use of required processes (e.g. required 
diluents, administration sets). 
 
Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be 
protected from light. If stored in a glass front refrigerator, vials should be stored in 
Nivolumab (BMS-
936558-01)* 
Injection drug 
product is a sterile, 
non-pyrogenic, 
single-use, 
isotonic aqueous 
solution formulated 
at 10 mg/mL   
100 mg/Vial 
(10 mg/mL) 
Carton of 5 
or 10 vials 
10-cc Type 1 flint 
glass vials 
stoppered with 
butyl stoppers and 
sealed with 
aluminum seals. 
Clear to 
opalescent, 
colorless to 
pale yellow 
liquid.  May 
contain 
particles 
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 
46 degrees F) and 
protected from 
light and  freezing  

 
 
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the carton. Recommended safety measures for preparation and handling of 
nivolumab include laboratory coats and gloves. 
 
For details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the Investigator Brochure 
section for “Recommended Storage and Use Conditions”. Care must be taken to 
assure sterility of the prepared solution as the product does not contain any anti-
microbial preservative or bacteriostatic agent. No incompatibilities between 
nivolumab and polyolefin bags have been observed. 
 
Nivolumab is to be administered as a 60 minute IV infusion, using a volumetric 
pump with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug 
can be diluted with 0.9% normal saline for delivery but the total drug 
concentration of the solution cannot be below 0.35 mg/ml. It is not to be 
administered as an IV push or bolus injection. At the end of the infusion, flush the 
line with a sufficient quantity of normal saline. 
 
8.1.3 Administration of nivolumab 
Patients will receive nivolumab as a 60 minute IV. Dosing calculations should be 
based on the body weight assessed at the start of each cycle as described 
above. All doses should be rounded to the nearest milligram. The screening body 
weight may be used for dosing of cycle 1.  
 
Patients may be dosed no less than 12 days from the previous dose of drug.  
The dosing calculations should be based on the actual body weight. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to 
calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram. There will be no dose modifications allowed 
 
8.1.4  Patient Monitoring During Infusion 

 
 
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Patient vital signs should be monitored prior to dosing, about 15 minutes after 
initiation of the infusion (then every 15-20 minutes as indicated), at 60 and 120 
minutes after completion of the infusion, or longer if indicated, until the vital signs 
normalize or return to baseline. For subsequent infusions, vital signs should be 
collected prior to dosing, every 30 minutes during dosing, and 1 hour post 
dosing.  All vital sign times will be +/- 10 mins. 
 
8.1.5 Treatment of nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, 
bronchospasm,  or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the BMS Medical 
Monitor and reported as an SAE if criteria are met. Infusion reactions should be 
graded according to NCI CTCAE (version 4.0) guidelines. 
 
Treatment recommendations for nivolumab related infusion reactions are 
provided below and may be modified based on MD Anderson treatment 
standards and guidelines, as appropriate: 
 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; 
intervention not indicated):Remain at bedside and monitor subject until recovery 
from symptoms. The following prophylactic premedications are recommended for 
future infusions: diphenhydramine 50 mg (or equivalent) and/or acetaminophen 
325 to 1000 mg at least 30 minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms (Moderate reaction requires therapy or infusion 
interruption but responds promptly to symptomatic treatment [e.g. antihistamines, 

 
 
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non-steroidal anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, 
IV fluids]; prophylactic medications indicated for ≤ 24 hours): 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 
325 to 1000 mg; remain at bedside and monitor subject until resolution of 
symptoms. Corticosteroid or bronchodilator therapy may also be administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the 
original infusion rate when symptoms resolve; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor subject closely. If symptoms recur then no further nivolumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at 
bedside and monitor the subject until resolution of symptoms. The amount of 
study drug infused must be recorded on the case report form (CRF). The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg 
should be administered at least 30 minutes before additional nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg 
of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms [Severe reaction, Grade 3: prolonged (i.e. 
not rapidly responsive to symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial improvement; hospitalization 
indicated for other clinical sequelae (e.g. renal impairment, pulmonary infiltrates), 
Grade 4: life- threatening; pressor or ventilatory support indicated]: 
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline, and treat the subject as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 

 
 
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diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), 
as needed. Subject should be monitored until the investigator is comfortable that 
the symptoms will not recur. Nivolumab will be permanently discontinued. 
Institutional guidelines will be followed for the treatment of anaphylaxis. Remain 
at bedside and monitor subject until recovery from symptoms. In the case of late-
occurring hypersensitivity symptoms (e.g. appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may 
be given (e.g. oral antihistamine or corticosteroids). 
 
8.1.6 Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary 
for patient supportive care and safety are permitted. Other anticancer agents, 
specifically systemic chemotherapy, radiation therapy, or biologic response 
modifiers are not permitted during the study.  Intrathecal chemotherapy is 
allowed if intended for prophylaxis.  No other investigational drug is allowed 
during the study. Prophylaxis may be used for the prevention of infections or 
nausea and vomiting.  Concomitant medications data will not be collected or 
entered into the case report form other than hydrea; however, the subject’s 
medication record will contain a list of concomitant medications. 
 
8.2 Lirilumab (BMS-986015) 
Lirilumab injection has been developed to be used as an intravenous (IV) infusion for 
clinical studies. The drug product is a clear to opalescent, colorless liquid, which 
may contain few particles. It is a sterile, non-pyrogenic, single-use, preservative-free, 
ready-to-use solution containing 10 mg/mL lirilumab. The 50-mg/Vial and 100-
mg/Vial presentations are contained in 6-cc and 10-cc Type I flint glass vials, 
respectively, closed with 20-mm stoppers, and sealed with aluminum seals. The 
formulation composition is identical for these two presentations. Each vial of drug 
product contains the labeled amount of lirilumab drug substance, sucrose, sodium 
phosphate monobasic, sodium phosphate dibasic, polysorbate 80, and water for 

 
 
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injection. Diluted sodium hydroxide and/or hydrochloric acid solution may be added 
to adjust the pH to 7.0. A sufficient overfill is included in each vial to account for vial, 
needle, and syringe holdup. The placebo for lirilumab injection is composed of 0.9% 
sodium chloride injection (normalsaline; NS).  
 
Drug Product Preparation 
Lirilumab injection is administered intravenously either undiluted (10 mg/mL) or 
diluted in NS to lirilumab concentrations as low as 0.5 mg/mL. The dosing solution is 
to be infused over 60 minutes through a non-di-2-ethylhexyl phthalate (DEHP) or 
DEHP IV infusion set with a 0.2-micron polyethersulfone (PES) in-line filter. The drug 
product is not to be administered as an IV push or bolus injection. Care must be 
taken to ensure the sterility of the prepared solutions as the drug product does not 
contain anti-microbial preservatives or bacteriostatic agents. The placebo is 
administered in a similar fashion. 
 
Recommended Storage and Use Conditions 
Lirilumab injection should be stored refrigerated at 2º-8ºC and protected from light 
and freezing. After dilution with NS or transfer from the original vial to an IV bag, the 
infusion solution must be administered within 4 hours, including the time for infusion, 
if stored at room temperature, 20º-25ºC/ambient light. If not dosed immediately, the 
infusion solution may be stored in a refrigerator, 2º-8ºC, for up to 24 hours, and a 
maximum of 4 hours, including the time for infusion, of the total 24 hours can be at 
room temperature, 20º-25ºC/ambient light  
 
8.3 Azacitidine 
Chemical Name: 4-amino-1-(2-deoxy-ß-D-erythro-pentofuranosyl)-1,3,5-triazin-
2(1H)-one 
 

 
 
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Other Names: 4-Amino-1-ß-D-ribofuranosyl-1,3,5-triazin-2(1H)-one, 5 AZC, 5-AC, 
5- AzaC, 5-azacytidine, 5-AZCR, Antibiotic U 18496, Azacytidine, ladakamycin, 
Mylosar, NSC-102816, U-18496, WR-183027, Azacitidine 
 
Classification: Antimetabolite, DNA hypomethylating agent 
 
CAS Registry Number: 320-67-2 
 
Molecular Formula: C8H12N4O5       M.W.: 244.21 
 
Approximate Solubility: soluble (soluble in caustic soda) 
 
Mode of Action: 
Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation 
of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. 
The concentration of azacitidine required for maximum inhibition of DNA methylation 
in vitro does not cause major suppression of DNA synthesis. Hypomethylation may 
restore normal function to genes that are critical for differentiation and proliferation. 
The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including 
cancer cells that are no longer responsive to normal growth control mechanisms. 
Non-proliferating cells are relatively insensitive to azacitidine. 
 
Pharmacokinetics: 
The pharmacokinetics of azacitidine were studied in six MDS patients following a 
single 75 mg/m2 subcutaneous (SC) dose and a single 75 mg/m2 intravenous (IV) 
dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma 
azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability 
of SC azacitidine relative to IV azacitidine is approximately 89%, based on area 
under the curve. Mean volume of distribution following IV dosing is 76 ± 26 L. Mean 
apparent SC clearance is 167 ± 49 L/hour and mean half-life 

 
 
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after SC administration is 41 ± 8 minutes. 
 
Published studies indicate that urinary excretion is the primary route of elimination of 
azacitidine and its metabolites. Following IV administration of radioactive azacitidine 
to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive 
dose. Fecal excretion accounted for <1% of administered radioactivity over three 
days. Mean excretion of radioactivity in urine following SC administration of 14C-
azacitidine was 50%. The mean elimination half-lives of total radioactivity 
(azacitidine and its metabolites) were similar after IV and SC administrations, about 
4 hours. 
 
Drug-Drug Interactions: 
Drug interaction studies with 5-azacitidine have not been conducted.  An in vitro 
study of 5-azacitidine incubation in human liver fractions indicated that azacitidine 
may be metabolized by the liver. Whether azacitidine metabolism may be affected 
by known microsomal enzyme inhibitors or inducers has not been studied.  The 
potential of azacitidine to inhibit cytochrome P450 (CYP) enzymes is not known.  In 
vitro studies with human cultured hepatocytes indicate that azacitidine at 
concentrations of 1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5.  
Hydroxurea is known to inhibit ribonuclease reducatase, a key enzyme required for 
the incorporation of 5-azacytidine residues into DNA.  Therefore, hydroxyurea may 
potentially limit the clinical activity of 5-azacytidine and its use during this clinical trial 
should be avoided. 
 
Route of Administration: Intravenous  
 
Preparation:  Azacitidine is a cytotoxic drug and, as with other potentially toxic 
compounds, caution should be exercised when handling and preparing suspensions.  
If reconstituted azacitidine comes into contact with the skin, immediately and 

 
 
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thoroughly wash with soap and water. If it comes into contact with mucous 
membranes, flush thoroughly with water. 
 
How Supplied: Azacitidine is supplied as 100 mg vials of lyophilized powder. 
 
Storage:  Store un-reconstituted 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 azacitidine from exposure to light. 
 
Handling and Disposal:  Procedures for proper handling and disposal of anticancer 
drugs should be applied. 
 
Reported Adverse Events and Potential Risks: 
In clinical studies, the most commonly occurring adverse reactions were nausea 
(70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia 
(51.8%), leucopenia (48.2%), diarrhea (36.4%), fatigue (35.9%), injection site 
erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis 
(30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), 
febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), 
aggravated fatigue (12.7%) and malaise (10.9%). 
 
Because treatment with Azacitidine is associated with neutropenia and 
thrombocytopenia, complete blood counts should be performed as needed to 
monitor response and toxicity, but at a minimum, prior to each dosing cycle. 
 
Because azacitidine is potentially hepatotoxic in patients with pre-existing hepatic 
impairment, caution is needed in patients with liver disease. In addition, azacitidine 
and its metabolites are substantially excreted by the kidneys and the risk of toxic 
reactions to this drug may be greater in patients with impaired renal function. 
Because elderly patients are more likely to have decreased renal function, it may be 
useful to monitor renal function. 

 
 
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Azacitidine may cause fetal harm. While receiving treatment with Azacitidine, women 
of childbearing potential should avoid becoming pregnant, and men should avoid 
fathering a child. In addition, women treated with Azacitidine should not nurse. 
 
Reconstitution Recommendations for Azacitidine for IV Administration 
 
General Cautions: 
Azacitidine’s active agent, azacitidine, is hydrolytically unstable. Administration of 
reconstituted drug product must be completed within one hour of reconstitution. 
Azacitidine is incompatible with 5% Dextrose solutions, Hespan, or solutions 
containing Bicarbonate.  At no time should diluents with a pH below 6.0 be used. 
 
Procedure: 
1. Reconstitute each Azacitidine drug product vial with 10mL of Sterile Water for 
Injection, USP (SWFI).  
2. Shake/roll the vial until all solids are dissolved as determined by visual 
inspection.  Vigorous shaking is allowed if required to ensure complete 
dissolution.  The reconstituted solution should be clear. 
3. The concentration of the reconstituted drug product is 10 mg/mL Azacitidine. 
4. Withdraw and dilute the required amount of reconstituted drug product in an 
appropriate container with either 0.9% Sodium Chloride Injection, USP, or 
Lactated Ringer’s Injection, USP.  The final volume of the diluted drug product 
should be no greater than 100mL. 
5. If a patient requires more than one vial of Azacitidine, reconstitute each vial 
as described above and dilute all required, reconstituted Azacitidine into a 
single container with a total volume not to exceed 100mL. (Final 
concentration should be <10 mg/mL). 

 
 
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6. The reconstituted and diluted Azacitidine should be administered 
intravenously over a 10 - 40 minute period. The administration must be 
completed within one hour of the reconstitution time. 
7. Follow the administration with a 10 mL normal saline flush. 
 
8.4 Study Drug Destruction 
All expired or unused study drugs will be destroyed or returned as per institutional 
and investigational pharmacy standard operating procedures, with supplier 
agreement. 
 
9.0 
Patient Evaluation 
 
Pre-Treatment Evaluation: All pretreatment studies should be obtained within 14 days 
(±3 days) of entry into the trial, unless otherwise stated. 
 
1. A complete history and physical, including assessment of baseline adverse 
events. 
2. CBC, platelet count, differential (differential can be omitted if WBC is ≤0.5 
x109/L). 
3. Creatinine, total bilirubin, ALT, AST, amylase, lipase, and TSH.  
4. Pregnancy test (urine or plasma) in females of childbearing potential should be is required 
within 24 hrs of study enrollment or randomization, then every 6 weeks. After 
discontinuation from nivolumab these should be repeated at approximately 30 days 
and approximately 70 days [or more frequently if required by local standard]. 
5. Bone marrow aspirate during the last 14 days preceding study initiation. 
Cytogenetics will be obtained prior to therapy in patients known to have 
cytogenetic abnormalities at the time of diagnosis or relapse (results from 
prior analysis within 4 weeks can be used for this purpose). 
6. Chest x-ray.  
7. Pretreatment optional correlative studies. Every effort will be made to collect 
all samples at all time points for all patients; however, missing collection in 

 
 
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one or more of these time points in occasional patients will not be considered 
a protocol deviation/violation. 
 
10.0  Evaluation during Treatment 
 
All evaluations can vary +/- 3 days. 
 
Complete history and physical and assessments for toxicity should be performed weekly 
for the first course, then once per course. 
 
CBC, platelet count, differential, creatinine, albumin, SGPT, electrolytes, total bilirubin, 
and TSH weekly for the first course, then once per course at the discretion of the 
treating physician. 
 
Bone marrow aspiration with cytogenetics (if abnormal at baseline) on Day 28 of Course 
1 (+/- 3 days) and afterwards every 3 months or as indicated to document response or 
to decide on therapy administration.  Once a response is obtained, bone marrow 
sampling can be repeated at the discretion of the treating physician to confirm remission 
status or document loss of response. 
 
11.0 Criteria for Response 
 
For MDS, the International Working Group criteria will be use to assess response (11).   
 
Remission is calculated from date of first response until relapse. Survival is calculated 
from start of therapy until death from any cause. 
 
12.0 Reporting of Adverse Events 
 
Baseline events will be recorded in the medical history section of the case report form 
and will include the terminology event name, grade, and start date of the event. 

 
 
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Baseline events are any medical condition, symptom, or lab abnormality present before 
the informed consent is signed. If exact start date is unknown, month and year or year 
may be used as the start date of the baseline event. 
 
The maximum grade of the adverse event will be captured per cycle. 
 
Serious Adverse Event Reporting (SAE) Language for M. D. Anderson-sponsored 
IND Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 

 
 
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 Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office.   
 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  
 Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event.  Additionally, any serious adverse 
events that occur after the 30 day time period that are related to the study 
treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 

 
 
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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. 
 
Investigator Communication with Supporting Companies: 
 
Expedited reporting by investigator to BMS 
Serious adverse events (SAE) are defined above.  The investigator will inform BMS of 
any SAE within 24 hours of being aware of the event via email and/or fax.  
 All SAEs should be reported via confirmed facsimile (fax) transmission, or 
scanned and reported via electronic mail to:  
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
 
All pregnancies will also be reported.  
 
Reporting of adverse event information following study completion  
Collection of safety information following the end of investigational product 
administration is important in assisting in the identification of possible delayed toxicities 
or withdrawal effects.  All SAEs must be collected which occur within 100 days of 
discontinuation of dosing or completion of the patient’s participation in the study if the 
last scheduled visit occurs at a later time.   
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting 
purposes only.  ‘Expected’ AEs (the ASAEL) are bold and italicized in the CAEPR. 
 
Attribution of the AE: 
 
Definite – The AE is clearly related to the study treatment. 

 
 
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Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 Physician or designee will assign attributions. 
 Adverse events will be captured in CORe. 
 CTC version 4.03 will be used for this trial. 
 PDMS will be used as the case report form for this study. 
 
Pregnancy Statement  
 
All women of childbearing potential MUST have a negative pregnancy test within 24 
hours prior to receiving the investigational product.  If the pregnancy test is positive, the 
patient must not receive investigational product and must not be enrolled in the study.   
 
During the course of the trial, all patients of childbearing potential should be instructed 
to contact the treating physician immediately if they suspect they might have conceived 
a child.  In addition, a missed or late menstrual period should be reported to the treating 
physician.  If a female patient or the treating physician suspects that the female patient 
may be pregnant prior to administration of study drugs, the study drugs must be 
withheld until the results of a pregnancy test are available. If pregnancy is confirmed the 
patient must not receive study medications and must be withdrawn from the study.  
Throughout the entire pregnancy, additional contact should be made with the patient, 
and in some cases with the healthcare provider, to identify spontaneous abortions and 
elective terminations, as well as any medical reasons for elective termination. In 
addition, the study investigator should include perinatal and neonatal outcome. Infants 
should be followed for a minimum of 4 weeks. 
 
If a male patient is suspected of having fathered a child while on study drugs, the 
pregnant female partner must be notified and counseled regarding the risk to the fetus. 

 
 
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In addition, the treating physician must follow the course of the pregnancy, including 
prenatal and neonatal outcome. Infants should be followed for a minimum of eight 
weeks. 
 
Upon live-birth delivery, the minimum information that should be collected includes date 
of birth, length of pregnancy, sex of infant, major and minor anomalies identified at 
birth. Outcomes can be obtained via maternal interviews, medical record abstraction, or 
a combination of these methods. All serious adverse event reports relating to the 
pregnancy, including spontaneous abortion, elective abortion and congenital 
anomalies, should be forwarded to the FDA & BMS.  
 
13.0 Informed Consent 
 
The investigator is responsible for obtaining written, informed consent(s) from each 
patient interested in participating in this study prior to conducting any study-related 
procedures.  Written informed consent should be obtained after adequate, thorough and 
clear explanation of the aims, methods, objectives, and potential hazards of the study 
as well as any use of the patient’s genetic information from the study.  The investigator 
must use the most current IRB-approved consent form for documenting written informed 
consent.  Each informed consent will be appropriately signed and dated by the patient 
and the person obtaining consent.  The investigational site must retain the original 
signed consent and provide a copy to the patient. 
 
14.0 Correlative Studies 
 
Correlative studies will be considered exploratory and will be performed whenever 
possible.  Bone marrow and blood samples will only be collected on patients who 
consent to protocols: LAB01-473 and PA13-0291. If a patient’s baseline correlative 
bone marrow sample is not collected for any reason, no additional correlative bone 
marrow or blood samples will be collected on the patient.  Additionally, any samples that 

 
 
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are missed are not considered a protocol deviation. 
 
Gene sequencing. Patients not consented through the Apollo program (PI Futreal) will 
be offered consenting under protocol LAB03-473 at baseline and their genomes will be 
sequenced using that platform. 5 cc of blood in a green tube will be required for this 
analysis.  If the patient participates on LAB01-473, the following samples will be 
collected at the specified time points:  
 Bone Marrow aspirate: will be baseline, C1D28, thereafter every 3 cycles, at time 
of best morphological response and at progression.   
 Peripheral Blood: screening, prior to each dose of study drug during the first 3 
cycles, at time of best morphological response, and at progression.  
 
Immune assessment. Tumor tissue, blood samples and bone marrow aspirate will be 
collected on a separate IRB approved laboratory protocol (PA13-0291) for immune 
monitoring as previously published,18-21 under the supervision of the Immunotherapy 
Platform. In tumor tissues, immunohistochemical studies will be performed to evaluate 
tumor and immunological cell markers such as CD4 and CD8 T cells. In peripheral 
blood, we will also evaluate tumor and immune cell populations including but not limited 
to CD4 and CD8 T cells in pre and post therapy samples. 
  
Peripheral blood. Up to 150 mL (within 24 hours) of peripheral blood will be collected 
under an IRB-approved laboratory protocol (PA13-0291)for testing of biomarkers 
described in this clinical protocol at the following time points, if the patient agrees to 
participate on PA13-0291: 
 At screening 
 Prior to each dose of study drug during the first 3 cycles. On days when 
both Nivolumab and Lirilumab are administered, a blood sample will 
only be collected prior to the Nivolumab dose.  
 At time of best morphological response 
 At progression 

 
 
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The treating physician or designee will have the option to cancel the laboratory protocol 
collection for patient safety without protocol deviation. 
 
 
Because we will use a number of different assays, the variability of which is not 
necessarily established, the intention of the correlative studies is not to draw statistical 
conclusions in terms of the optimal biological dose of the agents studied here. Rather, 
they should be considered pilot studies that will help understand the in vivo mechanism 
of action of the agents studied, and may help in the development of future studies of this 
or other combinations.  
 
15.0 Statistical Considerations 
 
This is a Phase II open-label study designed to determine the safety and efficacy of 
nivolumab and lirilumab, as single agents or in combination and with 5-azacitidine, in 
patients with myelodysplastic syndromes (MDS). Two different patient groups (lower 
risk MDS and High MDS) with 2 cohorts each will be study.  Each cohort will be 
composed of N=20 patients. Accrual will be parallel for each patient group.  
The primary efficacy outcome for each cohort is the overall response rate (ORR) 
defined as CR + PR + hematological improvement (HI). Overall response will be 
assessed after 6 cycles of treatment; cycle length is 28 days. A maximum of 20 total 
evaluable patients will be enrolled in each cohort (N=80). 
 
Lower Risk MDS cohorts: cohorts (1 and 2): each cohort separately 
The target ORR with the experimental treatment (i.e. lirilumab alone or in combination 
with nivolumab) is 70%, assuming the standard treatment ORR is 50%. The regimen of 
the experimental treatment will be considered worthy of further investigation if it elicits 
an increase in ORR to 70% with acceptable toxicity.  A >30% therapy related non-
hematological grade 3/4 toxicity rate is considered unacceptable.  Thus, interim 

 
 
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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)  + 0.20 | data} > 0.95, or 
2) Stop if Prob{ p(TOX,E)>0.30| data}>0.975,  
3) 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 < 5.0%) that ORR rate of the experimental treatment is 
greater than the ORR rate of standard treatment by 20.0%. The second condition 
will stop the study early if excessive therapy-related non-hematological grade 3/4 
toxicity (>30.0%) is highly probable (i.e., probability >97.5%) for the experimental 
treatment.  Monitoring for toxicity and futility will start when the first patient has 
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 1.  For example, accrual will cease if 4 or more 
patients experience toxicities among the first 5 patients. 
 
Table 1. Stop accrual if the number of drug-related non-hematological grade 3/4 toxicities is greater than 
or equal to indicated (i.e., # patients with toxicities) among the number of patients evaluated 
# patients evaluated  
5 
10 
15 
20 
# patients with toxicities 
4-5 
7-10 
9-15 
Always stop with this many patients  
 
Monitoring the ORR rate, based on the above assumptions and monitoring conditions is 
found in Table 2.  For example, accrual will cease if 1 patient experience an overall 
response within 6 cycles in the first 5 patients treated. 
 
Table 2. 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 
# patients with overall response 
1 
4 
7 
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 3). In order to utilize the software for the 
design, a response constant rate of 50% and beta (1.0, 1.0) priors were assumed for 

 
 
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the standard treatment response distribution and experimental treatment response prior 
distribution, respectively. A delta 20% was assumed. 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 experimental treatment 
was 70% and the true toxicity rate was 30% was 12.4%.  Probabilities of stopping early 
for high true toxicity rates (i.e., 50%) were 72.6% when the true ORR was 50%, and 
43.2% when true ORR rate was 70%. 
 
Table 3.  Operating characteristics for simultaneous monitoring response and toxicity rates for patients 
treated with experimental treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.50 
0.5590 
 
0.60 
0.2739 
 
0.70 
0.0849 
 
0.80 
0.0137 
 
0.90 
0.0010 
0.20 
0.50 
0.5621 
 
0.60 
0.2790 
 
0.70 
0.0914 
 
0.80 
0.0207 
 
0.90 
0.0081 
0.30 
0.50 
0.5779 
 
0.60 
0.3050 
 
0.70 
0.1241 
 
0.80 
0.0560 
 
0.90 
0.0439 
0.40 
0.50 
0.6271 
 
0.60 
0.3861 
 
0.70 
0.2263 
 
0.80 
0.1661 
 
0.90 
0.1554 
0.50 
0.50 
0.7261 
 
0.60 
0.5490 
 
0.70 
0.4316 
 
0.80 
0.3874 
 
0.90 
0.3795 
 

 
 
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High Risk MDS cohorts (3 and 4): each cohort separately  
The target ORR with the experimental treatment (i.e. 5-azacitidine in combination with 
lirilumab, or combination of 5-azacitidine, Lirilumab and nivolumab) is 70%, assuming 
the standard treatment ORR is 50%. The regimen of the experimental treatment will be 
considered worthy of further investigation if it elicits an increase in ORR to 70% with 
acceptable toxicity.  A >30% therapy related non-hematological 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)  + 0.20 | data} > 0.95, or 
2) Stop if Prob{ p(TOX,E)>0.30| data}>0.975,  
3) 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 < 5.0%) that ORR rate of the experimental treatment is 
greater than the ORR rate of standard treatment by 20.0%. The second condition 
will stop the study early if excessive therapy-related non-hematological grade 3/4 
toxicity (>30.0%) is highly probable (i.e., probability >97.5%) for the experimental 
treatment.  Monitoring for toxicity and futility will start when the first patient has 
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 non-hematological grade 3/4 toxicities 
is greater than or equal to indicated (i.e., # patients with toxicities) among the number of 
patients evaluated 
# patients evaluated  
5 
10 
15 
20 
# patients with toxicities 
4-5 
7-10 
9-15 
Always stop with this many patients  
 

 
 
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Monitoring the ORR rate, based on the above assumptions and monitoring conditions is 
found in Table 5.  For example, accrual will cease if 0 patients experience an overall 
response within 6 cycles in the first 5 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 
# patients with overall response 
1 
4 
7 
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 response constant rate of 50% and beta (1.0, 1.0) priors were assumed for 
the standard treatment response distribution and experimental treatment response prior 
distribution, respectively. A delta 20% was assumed. 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 experimental treatment 
was 70% and the true toxicity rate was 30% was 12.4%.  Probabilities of stopping early 
for high true toxicity rates (i.e., 50%) were 72.6% when the true ORR was 50%, and 
43.2% when true ORR rate was 70%. 
 
Table 6.  Operating characteristics for simultaneous monitoring response and toxicity rates for patients 
treated with experimental treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.50 
0.5590 
 
0.60 
0.2739 
 
0.70 
0.0849 
 
0.80 
0.0137 
 
0.90 
0.0010 
0.20 
0.50 
0.5621 
 
0.60 
0.2790 
 
0.70 
0.0914 
 
0.80 
0.0207 
 
0.90 
0.0081 
0.30 
0.50 
0.5779 
 
0.60 
0.3050 

 
 
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0.70 
0.1241 
 
0.80 
0.0560 
 
0.90 
0.0439 
0.40 
0.50 
0.6271 
 
0.60 
0.3861 
 
0.70 
0.2263 
 
0.80 
0.1661 
 
0.90 
0.1554 
0.50 
0.50 
0.7261 
 
0.60 
0.5490 
 
0.70 
0.4316 
 
0.80 
0.3874 
 
0.90 
0.3795 
 
Statistical Analysis Plan 
All patients who received any dose of the study agent will be included in the analysis for 
efficacy and safety.  Demographic/clinical characteristics (i.e. 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 experimental treatments, along with the 95% credible 
intervals. 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 (PFS and OS) including overall 
survival and event 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.  
 
16. 
Confidentiality Plan 
 
Confidentiality will be maintained via codification of data collected and restriction of 
access to the data.  In particular, to be authorized to use the PDMS database, M. D. 

 
 
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Anderson employees must have an institutional USERID assigned through the 
Information Services Security Department.  State regulations for database computer 
access are followed.  ALL database analysts regularly log and monitor the system 
access and log-in activity.  All unsuccessful attempts to access the ALL database are 
logged to a file that is reviewed daily by the ALL database coordinator.  If the user has 
updated patient data, they will be prompted for the password upon exiting the ALL 
database.  If the password is not verified, an automated e-mail is sent to the ALL 
database coordinator, and a log is created.  Users are required to change their 
password every three months.  The passwords are stored in an encrypted format. 
 
Unless specifically described and explained to the clinical trial participants in the 
informed consent document, results of the study will not be shared with the patients.  
The profiles will be obtained on coded samples with no patient identifiers, and 
confidentiality will be maintained.  Results of the clinical trial will be entered in 
clinicaltrials.gov, but individual patient’s results will remain confidential information. 
 
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4. 
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5. 
Dawson MA, Spencer A: Successful use of haploidentical stem-cell 
transplantation with KIR mismatch as initial therapy for poor-risk myelodysplastic 
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6. 
Wei Y, Chen R, Dimicoli S, et al: Global H3K4me3 genome mapping 
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Li LH, Olin EJ, Fraser TJ, et al: Phase specificity of 5-azacytidine against 
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16. 
Silverman LR, McKenzie DR, Peterson BL, et al: Further analysis of trials 
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17. 
Fenaux P, Mufti G, Santini V, et al: Azacitidine (AZA) treatment prolongs 
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