Phase 2 Study of Nivolumab in Patients With Primary Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis, or Post-Polycythemia Vera Myelofibrosis
Phase: PHASE2
Conditions: Hepatomegaly, Myelofibrosis Transformation in Essential Thrombocythemia, Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase, Primary Myelofibrosis, Splenomegaly
Sponsor: M.D. Anderson Cancer Center

2014-0962
August 11, 2016
Page 1
Protocol Page
Phase 2 Study of Nivolumab in Patients with Primary Myelofibrosis, Post-Essential 
Thrombocythemia Myelofibrosis, or Post-Polycythemia Vera Myelofibrosis 
2014-0962
Core Protocol Information
Short Title 
Phase 2 Study of Nivolumab in Patients with Myelofibrosis
Study Chair: 
Srdan Verstovsek
Additional Contact:
Paula J. Cooley
Sandra L. Rood
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7305
Unit:
428
Full Title: 
Phase 2 Study of Nivolumab in Patients with Primary Myelofibrosis, Post-Essential 
Thrombocythemia Myelofibrosis, or Post-Polycythemia Vera Myelofibrosis 
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 04/13/2018
Version:
09
Submitted by:
Sandra L. Rood--11/7/2017 3:54:25 PM
OPR Action:
Accepted by:  Inar Y. Graur -- 11/9/2017 10:46:56 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

2014-0962
August 11, 2016
Page 2
Protocol Body
 

 
 
 
 
 
Protocol 2014-0962 
 
 
August 11, 2016 
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Phase 2 Study of Nivolumab in Patients with Primary Myelofibrosis, 
Post-Essential Thrombocythemia Myelofibrosis, or Post-
Polycythemia Vera Myelofibrosis  
 
 
1.0 
HYPOTHESIS AND OBJECTIVES 
 
Hypothesis 
We hypothesize that blocking the PD-1/PD-L1 immune checkpoint with nivolumab may be an 
effective therapy for patients with Primary Myelofibrosis, Post-Essential Thrombocythemia 
Myelofibrosis, or Post-Polycythemia Vera Myelofibrosis (all collectively referred to as 
Myelofibrosis [MF]) 
 
Objectives 
Primary:   
 to determine the efficacy of nivolumab as therapy for MF 
Secondary: 
 to determine the safety of nivolumab as therapy for patients with MF  
 
Exploratory: 
 to explore time to response and duration of response 
 to assess changes in symptom burden 
 to explore changes in bone marrow fibrosis  
 to explore changes in JAK2V617F (or other molecular marker) allele burden or 
changes in cytogenetic abnormalities 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1  Myelofibrosis 
Myelofibrosis (MF) is a rare clonal proliferative disorder of a pluripotent stem cell.  This clone 
subsequently induces fibrogenic cytokines and/or growth factors in the marrow, which stimulate 
the deposition of extracellular matrix proteins by polyclonal fibroblasts.  Megakaryocytic 
hyperplasia-dysplasia is frequently observed.  Invasion of the blood stream and colonization of 
extramedullary sites ensues, resulting in organomegaly and splenomegaly. Extensive marrow 
fibrosis and osteosclerosis may be observed in advanced MF.  
 
The entity of MF can be either idiopathic (primary) or representative of end-stage 
myeloproliferative diseases such as polycythemia vera (PV) or essential thrombocythemia (ET).  
MF occurs in about 15-25% of patients with PV and in 5-10% of patients with ET. In the early 
cellular phase of MF with minimal marrow fibrosis, the differential diagnosis includes 
Philadelphia-positive chronic myeloid leukemia (CML), PV, and ET that must be distinguished 
based on cytogenetics and clinicopathologic features. Other entities that can induce 
myelophthisis include myelodysplastic syndrome (MDS), metastatic malignancies, lymphoma, 
Hodgkin’s disease, and plasma cell dyscrasias.  MF must be differentiated from acute 
megakaryocytic leukemia (AML, M7 of the French-American-British classification) and MDS 

 
 
 
 
 
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with fibrosis. In acute megakaryocytic leukemia patients usually present with severe 
constitutional symptoms and pancytopenia but without organomegaly or peripheral blood 
myelophthisis. 
 
The clinical picture of MF involves constitutional symptoms (e.g., cachexia, night sweats, 
fatigue, fever), splenomegaly, anisopoikilocytosis with teardrop erythrocytes, progressive 
anemia, immature myeloid and erythroid precursors in the peripheral blood, elevated lactate 
dehydrogenase (LDH) levels, and fibrosis of the marrow (as evaluated by reticulin and trichome 
[collagen] stains).  The leukoerythroblastic picture is postulated to be related to both the 
intramedullary sinusoidal marrow and splenic hematopoiesis.  
 
The disease generally occurs in adults, with the median age of 65 years.  In 40% of the patients, 
constitutional symptoms are present, including fever, weight loss, nocturnal sweating, pruritus, 
and bone pain.  Splenomegaly is present in 85% of the patients at diagnosis and is massive in 
10%.  Hematologic disease features include anemia in 50% to 70% at diagnosis and 25% will 
have severe anemia with hemoglobin level < 8.0 g/dL.  Approximately half of the patients 
present with an elevated white cell count (WBC), 28% with thrombocytosis (platelet count > 500 
x 109/L), and 37% with thrombocytopenia (platelet count < 150 x 109/L).  Circulating blast cells 
are present in one-third of the patients. 
 
Complications of MF are varied.  Thrombotic obliteration of intrahepatic veins and 
splenomegaly may lead to portal hypertension; severe cases may be associated with ascites 
and/or variceal bleeding.  Left upper quadrant pain may herald splenic infarction; episodes are 
usually self-limited and may persist for several days.  Supportive care measures such as 
analgesics and hydration are usually sufficient; refractory cases may require splenectomy or 
irradiation. Extramedullary hematopoiesis (EMH) may occur in locations other than the liver or 
spleen; involvement of such sites may be managed by low-dose irradiation.  Liver involvement is 
associated with increased levels of plasma alkaline phosphatase.  Clinical manifestations of 
EMH include cardiac tamponade, papular skin nodules, pleural effusions, and spinal cord 
compression. 
 
Autoimmune phenomena have been observed, including Coomb’s positive autoimmune 
hemolytic anemia, nephrotic syndrome, antinuclear antibodies, rheumatoid factor, and lupus-type 
anticoagulant. Postulated etiologies include clonality of the lymphoid population or activation by 
abnormal monocyte-macrophage interaction with the immune system. 
 
Adverse prognostic factors for survival include older age and anemia (hemoglobin < 10 g/dL).  
The etiology for the latter finding is usually multifactorial and related both to marrow failure and 
hypersplenism.  Poor prognosis has also been correlated with leukocytosis, leukopenia, 
circulating blasts, increased numbers of granulocyte precursors, thrombocytopenia, abnormal 
karyotype, and hypercatabolic symptoms. The course of the disease is highly variable.  Median 
survival from time of diagnosis ranges from 5 to 6 years.  Progressive marrow failure, 
transformation into acute myeloid leukemia, and portal hypertension lead to demise. 
 
Several therapies are available for MF, however no one therapy has demonstrated an ability to 
produce sustained remissions. In addition, currently available therapies are often limited by their 

 
 
 
 
 
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myelosuppressive effects. Ruxolitinib, a JAK1/2 inhibitor, produces symptom and spleen-size 
responses, but may result in anemia and/or thrombocytopenia in a significant proportion of 
patients.  Hydroxyurea is another commonly used agent in the proliferative phases of the disease.  
Interferon-alpha had yielded hematologic responses and reductions in splenomegaly (definitions 
varying among studies) especially those with proliferative phase; however, this agent tends to be 
poorly tolerated.  Agents used for the management of anemia include androgens and/or 
erythropoietin.  Splenectomy and/or splenic irradiation have been used to manage symptomatic 
splenomegaly.  Splenectomy has been associated with risk of leukemia transformation in some 
series, and splenic irradiation can result in severe myelosuppression. Patients with an intact 
quality of life and no threatening hematologic abnormalities, such as erythrocytosis or 
thrombocytosis, have usually been considered to not require any therapy. 
 
2.2 
Nivolumab 
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. 
 
2.3 
Rationale  
Expression of PD-L1 has been found in patients with myeloid malignancies (MDS, CMML), 
suggesting that nivolumab may be active in these patients (Yang et al. 2014). While expression 
of PD-L1 in MF has not yet been tested, dysregulated JAK-STAT signaling in hematopoietic 
cells and subsequent increased expression of cytokines in MF likely has downstream effects on 
T-cell development and differentiation. Furthermore, immunomodulatory drugs such as IFN-
alpha (Quintas-Cardama 2013) and lenalidomide (Quintas-Cardama 2009) are to date the only 
agents that have been shown to reduce the mutant clone in patients with myeloproliferative 
neoplasms (including MF), suggesting that modulation of the immune response has the potential 
to eradicate disease. The dose schedule proposed is based on previous safety data from in-human 
trials and protocols being developed for other hematological malignancies. 
 
 
3.0 
BACKGROUND DRUG INFORMATION 
 
The PK, clinical activity, and safety of nivolumab have been assessed in completed Phase 1 and 
ongoing Phase 2 and 3 studies sponsored by Bristol-Myers Squibb Company (BMS) in subjects 
with non-small cell lung cancer (NSCLC), melanoma, and clear-cell renal cell carcinoma (RCC) 
in addition to other tumor types. The current Phase 3 clinical program focuses on squamous and 
nonsquamous NSCLC, malignant melanoma, and RCC. Clinical activity and safety information 
presented in the Nivolumab Investigator Brochure (IB) (Appendix F) focuses primarily on that 
obtained from CA209063 (Phase 2 study in refractory squamous NSCLC), CA209037 (Phase 3 
study in melanoma), MDX1106-03 (also known as CA209003; Phase 1 study in metastatic 

 
 
 
 
 
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NSCLC, colorectal cancer (CRC), melanoma, RCC, or metastatic castrate-resistant prostate 
cancer [mCRPC]), CA209010 (Phase 2 study in advanced/metastatic clear-cell RCC). Data are 
also provided from Phase 1 studies CA209004 (also known as MDX1106-04), CA209012, 
CA209016, CA209038, and CA209039. Nivolumab is being investigated both as monotherapy 
and in combination with chemotherapy, targeted therapies, and other immunotherapies. 
 
3.1 Clinical Pharmacokinetics 
The single-dose pharmacokinetics (PK) of nivolumab was linear and dose-proportional in the 
range of 0.3 mg/kg to 10 mg/kg. The multiple-dose PK of nivolumab was linear with dose-
proportional increases in maximum serum concentration (Cmax) and area under the 
concentration-time curve over the dosing interval (AUC [TAU]) in the range of 0.1 mg/kg to 10 
mg/kg. Both elimination and distribution of nivolumab in the dose range studied appear to be 
independent of dose in the dose-ranging studies, while the end of infusion and minimum serum 
concentration (Cmin) after the first dose were approximately dose proportional. Based on 
population PK (PPK) results (preliminary data), clearance of nivolumab is independent of dose 
in the dose range (0.1 mg/kg to 10 mg/kg) and tumor types studied. Body weight normalized 
dosing showed approximately constant trough concentrations over a wide range of body weights 
and, therefore, is appropriate for future clinical trials with nivolumab. 
 
3.2 Clinical Efficacy 
Nivolumab has demonstrated clinical activity as monotherapy and as combination therapy with 
ipilimumab in several tumor types, including RCC, melanoma, NSCLC, and some lymphomas. 
The majority of responses were durable and exceeded 6 months (Please Refer to Section 5.4 of 
Nivolumab IB). 
 
3.3 Clinical Safety 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 4,000 subjects treated to date. For 
monotherapy, the safety profile is similar across tumor types. The only exception is pulmonary 
inflammation adverse events (AEs), which may be numerically greater in subjects with NSCLC, 
because in some cases, it can be difficult to distinguish between nivolumab-related and unrelated 
causes of pulmonary symptoms and radiographic changes. There is no pattern in the incidence, 
severity, or causality of AEs to nivolumab dose level. In several ongoing clinical trials, the safety 
of nivolumab in combination with other therapeutics such as ipilimumab, cytotoxic 
chemotherapy, anti-angiogenics, and targeted therapies is being explored. Most studies are 
ongoing and, as such, the safety profile of nivolumab combinations continues to evolve. The 
most advanced combination under development is nivolumab + ipilimumab in subjects with 
melanoma. Thus far, the combination of both agents results in a safety profile with similar types 
of AEs as either agent alone, but in some cases with a greater frequency. 
 
For a complete review of clinical information, please refer to the nivolumab Investigator 
Brochure (Appendix F). 
 
3.4 Rationale for Proposed Dose 
The 3 mg/kg dose is being carried forward in all hematologic malignancy trials. The rationale is 
based upon PD results in patients with solid tumors, including in ongoing Phase 1 study 

 
 
 
 
 
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CA209003 in NSCLC. Anti-tumor activity was observed in NSCLC subjects at dose levels of 1, 
3 and 10 mg/kg every 2 weeks. Anti-tumor activity appeared to approach a plateau at dose levels 
of 3 mg/kg and above. Consistent with these observations, the results of exposure response 
analyses showed that the probability of a tumor response tended to approach a plateau for trough 
concentrations produced by 3 and 10 mg/kg administered every 2 weeks. Nivolumab was 
adequately tolerated up to 10 mg/kg, the highest dose level tested, and no maximum tolerated 
dose (MTD) was identified. While the spectrum, frequency, and severity of -related AEs were 
generally similar across the dose levels tested, the 10 mg/kg dose level had numerically higher 
rates of Grade 3/4 drug-related SAEs and AEs leading to discontinuation. Based on these 
observations, a dose of 3 mg/kg every 2 weeks was chosen for further study. 
 
Specific clinical findings among the 306 subjects with melanoma treated in MDX1106-03 study 
that contributed to the selection of the Phase 2 dose were as follows:  
• 
Receptor occupancy was maintained at high levels across the dose range 0.1 to 10 mg/kg 
and over multiple cycles of drug administration. 
• 
In exposure-response analysis, the probability of response in melanoma, lung, and RCC 
subjects increased over the range of steady-state trough concentrations observed, but appeared to 
plateau at the ≥3 mg/kg Q2W dose. 
• 
There was a greater percent of objective responses observed in NSCLC subjects treated 
with 3 mg/kg (24.3%) and 10 mg/kg (20.3%) nivolumab than with 1 mg/kg (3%) nivolumab. 
• 
The nature, frequency, and severity of adverse events (AEs) were similar across the dose 
range 0.1 to 10 mg/kg and across tumor types. 
 
Integrated assessment of data from studies MDX1106-03 and CA209066 indicate that 3 mg/kg 
Q2W nivolumab offers an acceptable benefit-risk in this population, based on the consistency of 
ORR, DOR, other efficacy endpoints, and the safety profile. 
 
PRODUCT INFORMATION TABLE:  
*Nivolumab may be  labeled as BMS-936558-01 Solution for Injection 
 
Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1 
Product 
Description 
and Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab 
(BMS-
936558-01)* 
Injection drug 
product is a 
sterile, non-
pyrogenic, 
single-use, 
isotonic 
aqueous 
solution 
formulated at 
10 mg/mL   
100 
mg/Vial 
(10 
mg/mL). 
Carton of 5 
or 10 vials 
10-cc Type 1 
flint glass vials 
stoppered with 
butyl stoppers 
and sealed with 
aluminum 
seals. 
Clear to 
opalescent, 
colorless to pale 
yellow liquid.  May 
contain particles 
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 46 
degrees F) and 
protected from light 
and  freezing  

 
 
 
 
 
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August 11, 2016 
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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. Please see Appendix 1 
“sample of drug ordering and pharmacy reference material” for more details. Unused/expired 
study drug will be destroyed per institutional policy. 
 
4.0 
PATIENT ELIGIBILITY CRITERIA 
 
Inclusion criteria 
1. Diagnosis of MF (either primary or post essential thrombocythemia/polycythemia vera) 
requiring therapy, including those previously treated and relapsed or refractory, or if newly 
diagnosed, with intermediate-1 or -2 or high risk according to International Prognostic 
Scoring System (IPSS). 
2. Previously treated with ruxolitinib (unless not a good candidate for ruxolitinib therapy in the 
judgment of treating physician)^ 
3. Palpable splenomegaly or hepatomegaly of more than or equal to 5 cm below left or right, 
respectively, costal margin on physical exam 
4. Understanding and voluntary signing an IRB-approved informed consent form. 
5. No prior history of immune check point modulator therapy 
6. Age ≥ 18 years at the time of signing the informed consent. 
7. Disease-free of other malignancies. 
8. ECOG performance status 0 to 2. 
9. Negative pregnancy test in females of childbearing potential (FCBP)† Male patients with 
female partners of child-bearing potential and female patients of childbearing potential are 
required to use two forms of acceptable contraception, including one barrier method, during 
their participation in the study and for 23 weeks (for females) or 31 weeks (for males) 
following the last dose of study medication. Acceptable forms of contraception include 1 
highly effective method such as an intrauterine device (IUD), hormonal (birth control pills, 
injections, or implants), tubal ligation, or partner’s vasectomy and at least 1 additional 
approved barrier method such as a latex condom, diaphragm, or cervical cap plus 
spermicide. Female patients of childbearing potential must not be breast-feeding or planning 
to breast feed and must have a negative pregnancy test within 24 hours before first study 
treatment. 
10. Adequate organ function as demonstrated by the following: 
 Direct bilirubin < 1.5 x upper limit of normal (ULN) 
 Serum creatinine < 1.5 x ULN 
 AST (SGOT) and ALT (SGPT)   2.5 x ULN (unless considered to 
be related to MF or patient has known history of Gilberts, in which 
case it must be ≤5 x ULN)  
 
                                            
^ Must be documented in medical records (e.g. patient with grade 3 or 4 thrombocytopenia, or severe 
PRBC transfusion dependency) 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 

 
 
 
 
 
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Exclusion Criteria 
1. Use of any other standard or experimental therapy for MF within 14 days of starting study 
therapy.   
2. Lack of recovery from all toxicity from previous therapy to grade 1 or baseline. 
3. Any concurrent severe and/or uncontrolled medical conditions that could increase the 
patient’s risk for toxicity while in the study or that could confound discrimination 
between disease- and study treatment-related toxicities. 
4. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms consistent with New York 
Heart Association Class III-IV within 6 months prior to their first dose of the study drugs 
5. Patients who are currently receiving chronic (>14 days) treatment with corticosteroids at 
a dose ≥ 10 mg of prednisone (or its glucocorticoid equivalent) per day, or any other 
chronic immunosuppressive treatment that cannot be discontinued prior to starting study 
drug 
6. Patients with autoimmune diseases are excluded: Patients with a history of Inflammatory 
Bowel Disease (including Crohn’s disease and ulcerative colitis) are excluded from this 
study as are patients with a history of autoimmune disease (e.g., rheumatoid arthritis, 
systemic progressive 
sclerosis [scleroderma], Systemic 
Lupus 
Erythematosus, 
autoimmune vasculitis [e.g., Wegener’s Granulomatosis]). 
7. Pregnant or breast feeding (lactating) women, where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, confirmed by a positive 
β-HCG laboratory test. 
8. Known positive for HIV or infectious hepatitis, type A, B or C. 
9. The use of dietary supplements or herbal medications within 7 days of starting study 
therapy. 
 
5.0 
TREATMENT PLAN 
 
On this study 4 weeks of therapy is considered one cycle of therapy. Nivolumab will be given IV 
in outpatient setting at 3 mg/kg approximately every 2 weeks (every 14 days +/- 2 days; patients 
may be dosed no less than 12 days from the previous dose of drug) for 8 doses followed by a 
maintenance regimen of one dose every 12 weeks. Nivolumab should be administered as an IV 
infusion over 60 minutes through an intravenous line containing a sterile, nonpyrogenic in-line 
filter (0.2- to 1.2-micron, low-protein binding polyethersulfone membrane). Patients 
experiencing clinical benefit will continue therapy for 4 years unless progression of disease or 
toxicity warranting discontinuation of therapy is observed.  
 
5.1 Dose Modification  
 
Dose reductions or dose escalations are not permitted. 
 
5.2 Dose Delay Criteria 

 
 
 
 
 
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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.  Dose 
delays are also permitted for patient safety (e.g. unrelated medical issues, or life events) at the 
discretion of the PI.  
 
 
 
Nivolumab administration should be delayed for the following: 
 
 Grade 2 pneumonitis  
 Grade 2 or 3 colitis  
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and 
up to 5 times upper limit of normal (ULN) or direct bilirubin greater than 1.5 and up to 3 
times ULN  
 Creatinine greater than 1.5 and up to 6 times ULN or greater than 1.5 times baseline 
 Any other severe or Grade 3 treatment-related adverse reactions 
 
5.3 Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 
or baseline value. Subjects in whom a dose was held for a non-study drug-related AE may also 
resume treatment as acceptable and as indicated by the patient’s condition and at the discretion 
of the treating physician. 
 
 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is delayed past the next scheduled 
time point per protocol, the next scheduled time point 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. 
 
5.4 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 is considered an immuno-oncology 
agent 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. 
These algorithms are found in Appendix G of this protocol. The guidance provided in these 
algorithms should not replace the Investigator’s medical judgment but should complement it. 
 
5.5 Discontinuation Criteria 
Treatment should be permanently discontinued for the following study drug related events:  

 
 
 
 
 
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 Any life-threatening or Grade 4 adverse reaction 
 Grade 3 or 4 pneumonitis 
 Grade 4 colitis 
 AST or ALT greater than 5 times ULN or direct bilirubin greater than 3 times ULN 
 Creatinine greater than 6 times ULN  
 Any severe or Grade 3 treatment-related adverse reaction that recurs 
 Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per 
day within 12 weeks 
 Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to Grade 1 
or resolve within 12 weeks after last dose of therapy 
 Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing interruptions > 6 weeks but not exceeding 12 weeks 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 Principal 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 Principal Investigator. Prior to re-initiating treatment 
in a subject with a dosing interruption lasting > 6 weeks, the Principal 
Investigator must be consulted. Tumor assessments should continue as 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 
 
5.6 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 as an SAE if criteria are met. Infusion reactions should be graded according to NCI 
CTCAE (v4.03) guidelines. Treatment recommendations are provided below and may be 
modified based on local 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 paracetamol 325 to 1000 mg (acetaminophen) 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 [eg, antihistamines, non-steroidal anti inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated 
for  24 hours): Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 

 
 
 
 
 
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subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); 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 electronic case report form (eCRF). The following prophylactic premedications 
are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) 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 [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory 
support indicated): Immediately discontinue infusion of nivolumab. Begin an IV infusion of 
normal saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms will not recur. Nivolumab will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. In the case 
of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritis 
within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or 
corticosteroids). 
 
5.3 Concomitant Therapy 
Supportive measures consistent with optimal patient care may be given throughout the study. 
Concomitant medications will be captured in the medical record and will not be recorded on the 
case report form. 
 Therapies considered necessary for the patient’s well-being may be administered at the 
discretion of the investigator. These therapies include, but are not limited to antibiotics, 
analgesics, antihistamines, or other medications.  Guidance for growth factors and 
transfusions of red blood cells, platelets, or fresh frozen plasma are described below: 
 Packed red blood cells (RBCs): Transfusions of 2 units of packed RBCs should be 
considered for a decline in hemoglobin to <8 g/dl or symptoms of cardiovascular 
compromise. The following transfusion thresholds and guidelines are recommended for 
study participants: 
o hemoglobin <8 g/dl, 2 units of packed RBCs; hemoglobin <7, three units of 
packed RBCs 

 
 
 
 
 
Protocol 2014-0962 
 
 
August 11, 2016 
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o Platelets: Six to 10 units of random donor platelets or one cytopheresis unit of 
single donor platelets should be administered to all subjects with signs of 
hemostatic 
failure 
(i.e., 
bleeding 
or 
petechiae) 
or 
life-threatening 
thrombocytopenia (i.e., platelet count < 10,000/µ L) 
o Growth factor use with epoetin, darbepoetin, or granulocyte colony-stimulating 
factor must be terminated at least 14 days before initiation of study treatment and 
may not be used as part of supportive therapy while the patient is on study, except 
if in patients best interest after approval of PI (e.g., neutropenic fever) 
o Patients should not receive androgens or steroids for treatment of their anemia or 
thrombocytopenia as part of supportive therapy 
 Patients may receive hydrocortisone prophylactically to prevent 
transfusion reactions but chronic systemic steroid (≥10 mg/day 
prednisone) are not allowed. 
 Over-the-counter herbal preparations or dietary supplements, are not allowed throughout 
the trial.  Patients should stop using these herbal medications at least 7 days prior to the 
first dose of study medication. 
5.4 
Correlative studies 
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, 
under the supervision of the Immunotherapy Platform. Participation in this protocol is optional. 
In bone marrow biopsies immunohistochemical studies will be performed to evaluate disease and 
immunological cell markers such as CD4 and CD8 T cells. In peripheral blood, we will also 
evaluate malignant and immune cell populations including but not limited to CD4 and CD8 T 
cells in pre and post therapy samples.  
 
Peripheral blood will be collected under an IRB-approved laboratory protocol for testing of 
biomarkers described in this clinical protocol at the following time points:  
• At screening: 20cc  
• Prior to each dose of study drug 20cc 
• At progression/discontinuation of protocol participation 20cc 
  
  
5.5 
Pretreatment Evaluation  
 
History and physical exam including vital signs, body weight and height, and spleen and 
liver measurements. This also includes a transfusion history for 3 months prior to day 1 and 
concomitant medication notation (within 7 days of study day 1) 
 
CBC and differential, electrolytes (Na, K, Cl, HCO3), creatinine, uric acid, BUN, glucose, 
total and direct bilirubin, and amylase, lipase, SGPT and SGOT, PT/PTT, INR (within 7 
days of study day 1). 
 
Bone marrow biopsy and aspirate (within 1 month of study day 1, or within 3 months of 
study day 1 if patient was not on any therapy).  
 
Pregnancy test (for FCBP only) within 24 hours of study day 1 
 
Myeloproliferative Neoplasm - Symptom Assessment Form Total Symptom Score (MPN-
SAF TSS)  questionnaire (within 7 days of study day 1). 

 
 
 
 
 
Protocol 2014-0962 
 
 
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5.6 
Evaluation During Study 
 
Directed history and physical examination including vital signs, body weight, and spleen 
and liver measurements on Days 1, 7, and 14 of Cycle 1, then on Day 1 and Day 14 (+/- 2 
days) of Cycles 2 – 4, then on Day 1 of Cycle 5, and then on Day 1 (+/- 7 days) of every 3rd 
cycle after that (Cycles 8, 11, 14 and so on). This also includes a transfusion history and 
concomitant medication notation.  
 
CBC and differential, electrolytes (Na, K, Cl, HCO3), creatinine, BUN, glucose, total 
bilirubin, SGOT and SGPT, amylase and lipase on Days 1, 7, and 14 of Cycle 1, then on 
Day 1 and Day 14 of Cycles 2 – 4 (+/- 2 days), then on Day 1 of Cycle 5, and then on Day 1 
(+/- 7 days) of every 3rd cycle after that (Cycles 8, 11, 14 and so on). 
 
Bone marrow aspiration and biopsy after 4 cycles, and if deemed appropriate by the 
investigator, then every 12 weeks. 
 
Response assessment after 4 cycles of therapy, then every 12 weeks 
 
Pregnancy test after 2 and 4 cycles of therapy, then every 12 weeks 
 
Continuous assessment of AEs  
 
MPN-SAF TSS questionnaire on Day 1 and Day 14 (+/- 2 days), of cycles 1-4, then 
on Day 1 of Cycle 5 (+/- 7 days), then Day 1 (+/- 7 days) of every 3rd cycle after 
that. 
 
Every effort will be made to adhere to the schedule of events and all protocol requirements. 
Variations in schedule of events and other protocol requirements that do not affect the rights and 
safety of the patient will not be considered as deviations.  Such variations may include laboratory 
and history and physical exam assessments completed outside of schedule, occasional missed 
required research samples. 
 
The patient will be contacted by the PI and his staff approximately 30, 60 and 100 days after 
discontinuation of study drug to assess for AE’s, unless the patient receives further MF-directed 
treatment. Pregnancy test (for FCBP only) will be required approximately 30, 60 and 100 days 
after discontinuation of study drug. 
 
5.7 Criteria for Removal from the Study 
Treatment with study drugs is to be discontinued when any of the following occurs: 
 
Lack of therapeutic effect (any effort should be made to provide therapy to the patient in a 
safe way for at least 3-6 cycles for proper assessment of potential efficacy) 
 
Adverse event(s) that, in the judgment of the Investigator, may cause severe or permanent 
harm or which rule out continuation of study drug. 
 
Withdrawal of consent 
 
Lost to follow up 
 
Death 
 
Suspected pregnancy 
 
6.0 
CRITERIA FOR RESPONSE  

 
 
 
 
 
Protocol 2014-0962 
 
 
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Best overall response will be categorized according to the International Working Group Criteria 
(for all response categories, benefit must last at least for 12 weeks to qualify as a response) : 
Complete remission (CR): Requires all of the following in the absence of both transfusion and 
growth factor support:  
 Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† and 
 Peripheral blood: Hemoglobin ≥10 g/dL and <UNL; neutrophil count ≥ 1.0 × 109/L and 
<UNL; 
 Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells‡ and 
 Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH 
 
Partial remission (PR):  
 Peripheral blood: Hemoglobin ≥10 g/dL and <UNL; neutrophil count ≥1 × 109/L and 
<UNL; platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells  and 
 Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH or 
 Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†, and peripheral 
blood: Hemoglobin ≥8.5 but <10 g/dL and <UNL; neutrophil count ≥1 × 109/L and 
<UNL; platelet count ≥50, but <100 × 109/L and <UNL; <2% immature myeloid cells‡ 
and 
 Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH 
Clinical improvement (CI): The achievement of anemia, spleen or symptoms response without 
progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia§ 
   
Anemia response Transfusion-independent patients: a ≥2.0 g/dL increase in hemoglobin level|| 
Transfusion-dependent patients: becoming transfusion-independent¶ 
Spleen response# 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, 
becomes not palpable or 
A baseline splenomegaly that is palpable at >10 cm, below the LCM, 
decreases by ≥50% 
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not 
eligible for spleen response 
Symptoms 
response 
A ≥50% reduction in the MPN-SAF TSS†† 
 
Progressive disease:  
 Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or 
 A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 
5-10 cm or 
 A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 
cm or 

 
 
 
 
 
Protocol 2014-0962 
 
 
August 11, 2016 
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 Leukemic transformation confirmed by a bone marrow blast count of ≥20% or 
 A peripheral blood blast content of ≥20% associated with an absolute blast count of 
≥1 × 10(9)/L that lasts for at least 2 weeks 
 
Stable disease:  Belonging to none of the above listed response categories 
 
Relapse:  
 No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
 Loss of anemia response persisting for at least 1 month or 
 Loss of spleen response persisting for at least 1 month 
 Recommendations for assessing treatment-induced cytogenetic and molecular changes. 
 Cytogenetic remission  At least 10 metaphases must be analyzed for cytogenetic 
response evaluation and  
requires confirmation by repeat testing within 6 months 
window 
CR: eradication of a preexisting abnormality 
PR: ≥50% reduction in abnormal metaphases 
(partial response applies only to patients with at least ten 
abnormal metaphases at baseline) 
 
 
Molecular remission 
Molecular response evaluation must be analyzed in peripheral 
blood granulocytes and 
requires confirmation by repeat testing within 6 months 
window 
CR: Eradication of a pre-existing abnormality 
PR: ≥50% decrease in allele burden 
(partial response applies only to patients with at least 20% 
mutant allele burden at baseline) 
 
 
Cytogenetic/molecular 
relapse 
Re-emergence of a pre-existing cytogenetic or molecular 
abnormality that is confirmed by repeat testing 
 
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or 
imaging study-proven nonhepatosplenic EMH); LCM, left costal margin; UNL, upper normal 
limit.  
*Baseline and post treatment bone marrow slides are to be interpreted at one sitting by a 
central review process. Cytogenetic and molecular responses are not required for CR 
assignment.  
†Grading of MF is according to the European classification: Thiele et al. European 
consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 

 
 
 
 
 
Protocol 2014-0962 
 
 
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2005;90:1128. It is underscored that the consensus definition of a CR bone marrow is to 
be used only in those patients in which all other criteria are met, including resolution of 
leukoerythroblastosis. It should also be noted that it was a particularly difficult task for 
the working group to reach a consensus regarding what represents a complete histologic 
remission.  
‡Immature myeloid cells constitute blasts + promyelocytes + myelocytes + 
metamyelocytes + nucleated red blood cells. In splenectomized patients, <5% immature 
myeloid cells is allowed.  
§See above for definitions of anemia response, spleen response, and progressive disease. 
Increase in severity of anemia constitutes the occurrence of new transfusion dependency 
or a ≥20 g/L decrease in hemoglobin level from pretreatment baseline that lasts for at 
least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-
grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, 
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
In addition, assignment to CI requires a minimum platelet count of ≥25 000 × 10(9)/L and 
absolute neutrophil count of ≥0.5 × 10(9)/L.  
||Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting 
the strict criteria for transfusion dependency at the time of study enrollment (see as 
follows), but have received transfusions within the previous month, the pretransfusion 
hemoglobin level should be used as the baseline.  
¶Transfusion dependency before study enrollment is defined as transfusions of at least 6 
units of packed red blood cells (PRBC), in the 12 weeks prior to study enrollment, for a 
hemoglobin level of <85 g/L, in the absence of bleeding or treatment-induced anemia. In 
addition, the most recent transfusion episode must have occurred in the 28 days prior to 
study enrollment. Response in transfusion-dependent patients requires absence of any 
PRBC transfusions during any consecutive “rolling” 12-week interval during the 
treatment phase, capped by a hemoglobin level of ≥85 g/L.  
#In splenectomized patients, palpable hepatomegaly is substituted with the same 
measurement strategy.  
††Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS is assessed by the 
patients themselves and this includes fatigue, concentration, early satiety, inactivity, night 
sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 
0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. 
The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms 
response requires ≥50% reduction in the MPN-SAF TSS.  
‡‡ Baseline values for physical examination refer to pretreatment baseline  and not to post 
treatment measurements.  
 

 
 
 
 
 
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7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.1  Adverse Event Reporting for MD Anderson-Sponsored IND Protocols 
 
All adverse events that are possible, probably or definitely related to the study treatment will be 
captured on the case report form. Any grade 3 or higher adverse event that is considered 
unrelated or unlikely related to the study treatment will also be recorded. Adverse events will be 
defined using NCI CTCAE version 4.03. 
 
All adverse events occurring between the time the subject is consented and begins study drug 
will be considered a baseline event and recorded. Baseline adverse events will be recorded in the 
Clinical Oncology Research System (CORE). All baseline adverse events that increase in 
severity during the course of treatment will be captured as an adverse event in CORE. 
 
 
7.2  Serious Adverse Event Reporting (SAE) 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. 
 
Any serious adverse event that occurs during the study period (up through 100 days after the last 
day drug is administered) will be followed until clinical recovery is complete and laboratory tests 
have returned to normal, until progression of the event has been stabilized, or until the PI 
determines there has been acceptable resolution of the event. The PI or designee will be 
responsible for assigning attribution for all SAEs. 
 
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). 
Pregnancy, overdose and secondary malignancy will be handled as SAE. 
 

 
 
 
 
 
Protocol 2014-0962 
 
 
August 11, 2016 
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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 as per 
“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 IRB, 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 and MDACC IRB.  
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 100 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 100 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. It is the responsibility of the 
PI and the research team to ensure serious adverse events are reported according to the Code of 
Federal Regulations, Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
Reporting by investigator to BMS: 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 
 
The following SAEs are not subject to expedited reporting, but will be included in the annual 
report via the SAE log: Infection or cytopenias leading to hospitalization or prolongation of 
hospitalization; disease progression leading to death; life-threating AE, hospitalization or 
prolongation of hospitalization, or disability. 
 
Adverse events will be documented in the medical record and entered into the case report form. 
PDMS/CORe will be used as the electronic case report form for this protocol. Investigator or 
physician designee is responsible for verifying and providing source documentation for all 
adverse events and assigning the attribution for each event for all subjects enrolled on the trial. 
This form must be completed and supplied to BMS within 24 hours/1 business day at the latest on 

 
 
 
 
 
Protocol 2014-0962 
 
 
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the following working day.  The initial report must be as complete as possible, including details of 
the current illness and (serious) adverse event, and an assessment of the causal relationship 
between the event and the investigational product(s).  Information not available at the time of the 
initial report (e.g., an end date for the adverse event or laboratory values received after the report) 
must be documented on a follow-up MDACC SAE reporting form.  
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject or the female partner of a male subject occurring while the 
subject is on study drug, or within 30 days of the subject’s last dose of study drug, are considered 
immediately reportable events. Study drug is to be discontinued immediately in a female patient 
and the patient instructed to return any unused portion of the study drug to the investigator(s).  
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to BMS 
immediately by phone and facsimile using the MDACC AE report form. The female should be 
referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation 
and counseling. 
 
8.0 
DATA HANDLING 
 
PDMS will be used as the database for this study.  All adverse events will be reported in CORE. 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
This is a single-center phase II trial to determine the efficacy of nivolumab as a monotherapy in 
subjects with Primary, Post Polycythemia Vera, or Post Essential Thrombocythemia 
Myelofibrosis (PMF, post-PV MF, or post-ET MF). The primary endpoint is the objective 
response rate (ORR) after 8 doses of therapy (4 cycles), defined as CR (complete remission) + 
PR (partial remission) + CI (clinical improvement). Responses will be categorized according to 
the revised International Working Group-Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) and European LeukemiaNet (ELN) consensus criteria for myelofibrosis.   
An optimum two-stage design proposed by Simon will be implemented.  We assume a target 
ORR of 35%, and a response rate of 18% or lower will be considered not desirable. With a type I 
error rate of 7% and 80% power, we will enroll 16 patients in the first stage. If 3 or fewer 
patients achieve a response the trial will be stopped. If 4 or more out of the first 16 patients have 
a response, accrual will continue until a total of 40 patients have been enrolled. After the first 16 
patients have enrolled, the study will not enroll new patient until enough responses (at least 4 
responses out of 16 patients) are observed to warrant the continuation of the study. At the end of 
the study, if 11 or more out of these 40 patients achieve a response, the treatment of nivolumab 
will be considered efficacious and worth further investigation. Under this Simon’s Optimum 
two-stage design, the probability of early termination is 68% if the true ORR is 18% and the 
expected sample size is 23.7 patients. Patients will be enrolled from MDACC and patients will 
be registered through the Clinical Oncology Research System (CORE). The estimated accrual 
rate is 1-2 patients per month. An interim analysis (response summary) will be submitted to the 
IND Monitor following the treatment of 16 and 40 patients. 
 
The method of Thall, Simon and Estey will be used for toxicity monitoring for this study. 
Toxicity will be monitored among the 40 patients. Denote the probability of toxicity by p(T), 

 
 
 
 
 
Protocol 2014-0962 
 
 
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where toxicity is defined as Grade 3-4 clinically relevant non-hematologic toxicity or a serious 
adverse event that is at least possibly drug related (Common Terminology Criteria for Adverse 
Events CTCAE version 4.03) and occurs anytime during the treatment. We assume as a priori, 
p(T) ~ beta (0.6, 1.4).  We will stop treating patients if Pr(p(T)> 0.30 | data)  >0.9. That is, we 
will stop the trial for new patient enrollment if at any time during the study, we determine that 
there is more than 90% chance that the toxicity rate is more than 30%. This toxicity stopping rule 
will be applied by cohort size of 5, starting from the 5th patient. Stopping boundaries 
corresponding to this stopping rule are listed in table 8.a. The operating characteristics are 
summarized in Table 8.b. Multc Lean Desktop (version 2.0) was used to generate the toxicity 
stopping boundaries and the OC table.  
 
Table 8.a Boundary table for toxicity monitoring 
# of patients ( in 
cohort 
of 
5, 
starting from the 
5th patient) 
Stop the trial if 
there 
are 
this 
many 
patients 
with toxicities:  
5 
4-5 
10 
6-10 
15 
8-15 
20 
9-20 
25 
11-25 
30 
13-30 
35 
15-35 
 
Table 8.b. Operating characteristics for toxicity monitoring  
True toxicity rate 
Prob(stop the trial early) 
Average sample size 
0.1 
0.0006 
40 
0.2 
0.021 
39 
0.3 
0.186 
36 
0.4 
0.583 
27 
0.5 
0.905 
17 
 
Summary statistics will be provided for continuous variables.  Frequency tables will be used to 
summarize categorical variables.  The objective response rate (ORR) will be estimated along 
with the exact 95% confidence interval. Data from all subjects who receive any study drug will 
be included in the safety analyses. The severity of the toxicities will be graded according to the 
NCI CTCAE v4.03 whenever possible. We will follow standard reporting guidelines for adverse 

 
 
 
 
 
Protocol 2014-0962 
 
 
August 11, 2016 
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events. Safety data will be summarized by category, severity and frequency. The proportion of 
patients with AEs will be estimated, along with the Bayesian 95% credible intervals.  
Duration of response: Duration of response is defined as the date at which the subject’s 
objective status is first noted to be a CR, PR or CI to the date of progression (no longer meeting 
criteria for either CR, PR or CI) is documented (if one has occurred).  Patients who continue to 
respond as of the data cut-off date will be censored as of the date of their last assessment 
documenting continued response. 
Time to response: The time to response is defined as the time from study registration to the first 
date at which the subject’s objective status was classified as a response (CR, PR or CI). In 
subjects who do not achieve a response, time to response will be censored at the subject’s last 
evaluation date.  
The distribution for each of these event-time variables (duration of response and time to 
response) will be estimated by Kaplan-Meier curves.  
Anemia:  Descriptive statistics will be used to explore improvements in anemia and transfusion 
dependence.  The following outcomes will be summarized: mean changes in hemoglobin at 
monthly intervals. The proportion of transfusion independent patients not requiring transfusions 
on study who experience an increase of 2 g/dL in their hemoglobin relative to baseline, the 
proportion of transfusion dependent patients (defined as requiring a transfusion of 2 units PRBCs 
monthly for 3 months (12 weeks) prior to starting the trial) who become transfusion independent 
(not requiring a transfusion of PRBCs over a period of 3 months (12 weeks) while on study), the 
proportion of transfusion dependent patients who become transfusion independent and have a 1 
g/dL increase in hemoglobin relative to baseline, and the proportion of transfusion independent 
patients requiring a transfusion while on study. 
JAK2V617F Allele burden:  Change in JAK2V617 allele burden from baseline to each visit 
where it is measured. 
Correlative Studies: Descriptive statistics including plots, mean, median and standard 
deviations will be used to summarize data. For continuous outcomes, t-test and ANOVA will be 
used to compare outcome measures across patient characteristics. Dunnett’s and Tukey’s test that 
properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will 
be performed using pre- and post-therapy samples from each patient. The chi-square (c2) test or 
Fisher’s exact test will be used to test the association between two categorical variables such as 
disease state and performance status.  
 
9.0 
REFERENCES 
 
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and 
European LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395-1398. 
Yang H, Bueso-Ramos C, Dinardo C, et al (2014) Expression of PD-L1, PD-L2, PD-1, and 
CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. 
Leukemia 28:1280-1288 

 
 
 
 
 
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Quintas-Cardama A, Abdel-Whahab O, Manshouri T et al (2013) Molecular analysis of patients 
with polycythemia vera or essential thrombocythemia receiving pegylated interferon alpha-2a. 
Blood 122:893-901 
Quintas-Cardama A, Kantarjian HM, Manshouri T et al (2009) Lenalidomide plus prednisone 
results in durable clinical, histopathologic, and molecular responses in patients with 
myelofibrosis. J Clin Oncol 27:4760-4766 
Thall, PF, Simon, R, Estey, EH (1995)   Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes.  Statistics in Medicine 14:357-379 
Liakou, C. I. et al. CTLA-4 blockade increases IFNg-producing CD4+ICOShi cells to shift the 
ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci USA 105, 14987-
14992 (2008).   
  
Carthon, B. C. et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the 
setting of a presurgical clinical trial. Clinical cancer research : an official journal of the 
American Association for Cancer Research 16, 2861-2871, doi:10.1158/1078-0432.CCR-10-
0569 (2010).  
Tang, D. N. et al. Increased Frequency of ICOS+ CD4 T Cells as a Pharmacodynamic 
Biomarker for Anti-CTLA-4 Therapy Cancer Immunol Res 1, 229–234 (2013).  
Chen, H. et al. CD4 T Cells Require ICOS-Mediated PI3K Signaling to Increase T-Bet 
Expression in the Setting of Anti-CTLA-4 Therapy. Cancer Immunol Res 2, 1-10 (2014). 
  
 
 
 
  
 
 

 
 
 
 
 
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APPENDIX 1 
SAMPLE OF DRUG ORDERING  AND PHARMACY REFERENCE 
MATERIAL 
 
Nivolumab (BMS-936558) Pharmacy Reference Material 
 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five vials 
are provided in a carton. 
 
Initial Orders  
 
Following submission and approval of the required regulatory documents, a supply of 
nivolumab may be ordered from by completing a Drug Request Form provided by BMS for 
this specific trial. The first request may take place upon screening of the first patient  
 
The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug 
from BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient 
specific. All drug product will be shipped by courier in a temperature-controlled container. It 
is possible that sites may have more than one nivolumab clinical study ongoing at the same 
time. It is imperative that only drug product designated for this protocol number be used for 
this study. 
 
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents,  In-
line filters and infusion tubing 
Re-Supply 
 
Drug re-supply request form should be submitted electronically business days before the 
expected delivery date.  Deliveries will be made Tuesday through Friday. 
 
When assessing need for resupply, institutions should keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. Be sure to check with your pharmacy regarding existing 
investigational stock to assure optimal use of drug on hand. 
Drug Excursions 
 
Drug  excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form 
Please refer to the most recent version of the Investigator Brochure for additional 
information. 
 
Storage Conditions & Handling: 
 
Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
 
If any temperature excursions are encountered during storage, please report these to BMS 
for assessment via the Temperature Excursion Response Form.    

 
 
 
 
 
Protocol 2014-0962 
 
 
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 
As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of intravenous agents applying aseptic 
technique.  
 
Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs.  
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. For further information, please either discuss 
with your BMS CSR&O protocol manager or refer to your site IP Destruction policies and 
procedures  
 
Use Time/Stability: Please refer to section 3.2.3 of the current Investigator’s Brochure. The 
time of preparation should be noted in the Pharmacy Source documents [accountability logs] or 
in study files as required for investigator sponsored research [FDA and GCP] 
 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°-8°C, 
36-46°F) for up to 24 hours; and a maximum of 4 hours of the total 24 hours can be a room 
temperature (20°-25°C, 68°-77°F) and room light. The maximum 4-hour period under room 
temperature and room light conditions includes the product administration period. 
 
 
Preparation and Administration: 
1. Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution 
may have a pale-yellow color), or if there is foreign paticulate matter other than a few 
translucent-to-white, amorphous particles. 
Note: Mix by gently inverting several times.  Do not shake. 
2. Aseptically withdraw the required volume of nivolumab solution into a syringe, and dispense 
into an IV. bag.  If multiple vials are needed for a subject, it is important to use a separate 
sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, 
stopper coring, repeated friction of plunger against syringe barrel wall. Do not enter into each 
vial more than once.  Do not administer study drug as an IV push or bolus injection 
3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection  solution. It is acceptable to add nivolumab solution from the vials into an 
appropriate pre-filled bag of diluent. 
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 1 mg/mL.  
Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab. 
4. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
Nivolumab should be administered as an IV infusion over 60 minutes through an 
intravenous line containing a sterile, nonpyrogenic  in-line filter (0.2- to 1.2-micron, low-
protein binding polyethersulfone membrane). 
5. At the end of the infusion period, flush the line with a sufficient quantity of approved diluents. 
 
 

 
 
 
 
 
Protocol 2014-0962 
 
 
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Example Dose Calculation [at 3mg/kg]: 
Total dose should be calculated as follows  (assuming total dose volume of 210 mL, 70 
kg pt, dose of 3 mg/kg):  
 
 
Subject body weight in kg x 3 mg (for the 3 mg/kg cohort) = total dose (mg) 
70 kg x 3 mg/kg = 210 mg  
 
Total dose (mg) ÷ 10 mg/mL = Amount of solution to be withdrawn from vials 
210 mg ÷ 10 mg/mL = 21 mL 
 
Example of Total volume of solution to infuse (mL) for a minimum conc solution. – 
Volume of 10 mg/mL solution (mL) = Volume of Diluent (mL) to add 
                210 mL – 21 mL = 189 mL 
 
Please note it is perfectly acceptable to dose Nivolumab at a higher drug concentrations, as 
long as the total volume of diluted solution is at or above the minimum allowable 
concentration of 1 mg/mL, below is the calculation based on the above example. Please 
double check. 
Total dose in mg ÷ Total volume to infuse in mL = Overall drug concentration, mg/mL 
210 mg ÷  210mL = 1 mg/mL