Clinical trial NCT03065400
Conditions: Chronic Phase Myelofibrosis Primary Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Polycythemia Vera
Keywords: Myelofibrosis Acute Leukemia
Sponsor: John Mascarenhas
Start date: 2017-06-14; Completion date: 2020-05-28
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test the effectiveness of a drug called pembrolizumab in patients with Myeloproliferative Neoplasm (MPN); chronic phase (MF-CP), accelerated phase (MPN-AP), or blast phase (MF-BP). Myelofibrosis neoplasm (MPN) is a group of diseases of the bone marrow in which excessive cells are produced.

Pembrolizumab also known as Keytruda is a drug that has recently been approved in the United Stated by the Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma and disease progression. Pembrolizumab is experimental in the treatment of MPN. The researchers want to find out what effects, good and /or bad it has on participants and the disease.

Participants qualify to take part in this research study if have been diagnosed with a MPN blood disorder called myelofibrosis (MF). Accelerated (10-19% blasts in the blood or bone marrow) and blast phase (\>20% blasts in the blood or bone marrow) MPN has been a difficult disease to treat. The term "blasts" refers to immature cells found in the bone marrow. They are not fully developed, and therefore, do not yet carry out any particular function within the body.

Funds for conducting this research are provided by Merck and Company, the manufacturer of the study drug pembrolizumab.

Detailed description:
The researchers propose a Simon-two stage design for this study. The researchers will test pembrolizumab at the FDA approved dose (in head and neck cancer) of 200mg dose administered via intravenous infusion over 30 minutes given every 3 weeks. Nine patients will be enrolled in the first stage of the Simon-two stage design, and 15 in the second stage. A treatment cycle is 3 weeks and the core study period is 6 cycles. Response assessment by established consensus criteria will be used to assess response after 6 cycles in order to determine if the trial will progress to the second stage and for the purpose of determining the primary endpoint. In addition, allowed will be a maximum of ten patients with accelerated or blast phase disease (MPN-AP/BP) who are refractory or intolerant to conventional therapies such as decitabine, and in which hematopoietic stem cell transplant is not a therapeutic option (exploratory cohort), to enroll in the study as a separate exploratory cohort. These patients can be enrolled during stage 1 or 2 and will be analyzed separately from the primary cohort population.

Exploratory biomarkers will be obtained from enrolled patients at baseline, cycle 3 and cycle 7 and at 1 year of therapy. Patients that obtain at least a clinical improvement after 6 cycles of therapy can continue receiving pembrolizumab until evidence of disease progression, unacceptable toxicity, and patient or physician decision for a maximum of 2 years.

Arms: arm 1: None
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: 200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
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Title: PD-1 Inhibition in Advanced Myeloproliferative Neoplasms  
PI: John Mascarenhas, MD 
NCT03065400 
Document Date: 10/30/2018 
 


 
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PD-1 inhibition in advanced myeloproliferative neoplasms 
 
 
SPONSOR:   John Mascarenhas, MD 
Associate Professor of Medicine 
Tisch Cancer Institute  
Icahn School of Medicine at Mount Sinai  
New York, New York 10029 
 
IND NUMBER: pending 
 
Study Co-Chairs: 
 
 
 
 
 
 
 
 
John Mascarenhas, MD 
Icahn School of Medicine at Mount Sinai 
Tisch Cancer Institute,  
Division of Hematology/Oncology, Box 1079 
One Gustave L. Levy Place 
New York, New York 10029 
Tel: 212-241-3417 
Fax: 212-876-5276 
Email: john.mascarenhas@mssm.edu 
Camelia Iancu-Rubin, PhD 
Icahn School of Medicine at Mount Sinai 
Tisch Cancer Institute,  
Division of Hematology/Oncology, Box 1079 
One Gustave L. Levy Place 
New York, New York 10029 
Tel: 212-241-8589 
Fax: 212-876-5276 
Email: camelia.iancu-rubin@mssm.edu 
Co-Investigators: 
 
Gabriela Hobbs, MD 
Harvard Medical School  
Massachusetts General Hospital 
100 Blossom Street, Cox-1  
Office 110, Suite 107 
Boston, MA 02114 
Tel: 617-643-1754 
Fax: 617-724-2525 
Email: ghobbs@partners.edu 
Swati Goel, MD 
Division of Hematology, Department of 
Oncology 
Montefiore Medical Center 
3411 Wayne Ave, Ground Floor 
Bronx, NY, 10467 
718-920-4137 Office 
718-882-8698 Fax 
Email: swgoel@montefiore.org 
 
 
Co-Investigator: Pathology 
Dr. Mohamed Salama 
Attention:  Hematopathology 
Mayo Medical Laboratories 
3050 Superior Drive NW 
Rochester, MN  55901-1195 
Lab phone: 507-284-1143 
 
 
Co-Investigator: Statistician 
Erin Moshier, MS  
TCI Biostatistics Shared Resource 
Institute for Healthcare Delivery Science 
Dept of Population Health Science & Policy 
Icahn School of Medicine at Mount Sinai 
1425 Madison Avenue 
New York, NY 10029 
Tel: 212-659-9669 
Email: erin.moshier@mountsinai.org 
  


 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
PD-1 inhibition in MPN 
Trial Phase 
2 
Clinical Indication 
Myelofibrosis 
Trial Type 
Interventional therapeutic  
Type of control 
None 
Route of administration Intravenous 
Trial Blinding 
None 
Treatment Groups  
Single arm 
Number of trial subjects 34 patients 
Estimated Accrual Rate 17 patients per year (6 patients per year in each center) 
Estimated 
enrollment 
period 
24 months 
Estimated duration of 
trial 
36 months 
Duration of Participation Core study period of 18 weeks 
Last Revision Date 
05/04/16 
BSRF Approval Date 
05/05/16 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a multicenter, open-label, Phase 2 study to assess the efficacy, safety and tolerability 
of pembrolizumab in patients with chronic phase myelofibrosis (MF-CP) defined as either 
patients with primary myelofibrosis (PMF), post essential thrombocythemia (post-ET) or 
polycythemia vera (post-PV) myelofibrosis (primary cohort). We propose a Simon-two stage 
design for this study. We will test pembrolizumab at the FDA approved dose (in head and neck 
cancer) of 200mg dose administered via intravenous infusion over 30 minutes given every 3 
weeks. Nine patients will be enrolled in the first stage of the Simon-two stage design, and 15 
in the second stage. A treatment cycle is 3 weeks and the core study period is 6 cycles. 
Response assessment by established consensus criteria will be used to assess response after 6 
cycles in order to determine if the trial will progress to the second stage and for the purpose of 
determining the primary endpoint. In addition, we will allow a maximum of ten patients with 
accelerated or blast phase disease (MPN-AP/BP) who are refractory or intolerant to 
conventional therapies such as decitabine, and in which hematopoietic stem cell transplant is 
not a therapeutic option (exploratory cohort), to enroll in the study as a separate exploratory 
cohort. These patients can be enrolled during stage 1 or 2 and they will be analyzed separately 
from the primary cohort population. The study will therefore enroll a maximum of 34 patients. 


 
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The study will enroll at 3 centers (Mount Sinai, NY; Montefiore, NY; Massachusetts General 
Hospital, MA).  
Exploratory biomarkers will be obtained from enrolled patients at baseline, cycle 3 and cycle 
7 and at 1 year of therapy. Patients that obtain at least a clinical improvement after 6 cycles of 
therapy can continue receiving pembrolizumab until evidence of disease progression, 
unacceptable toxicity, and patient or physician decision for a maximum of 2 years.  
2.2 
Trial Diagram 
 
 
 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives & Hypotheses 
1. Objective: To assess the efficacy of single agent pembrolizumab in patients with  
chronic phase myelofibrosis (MF-CP) comprising our primary cohort. 
Hypothesis:  Deregulated immune checkpoint inhibition allows for progression of 
myeloproliferative neoplasm cells and serves as a therapeutic target. 


 
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3.2 
Secondary Objectives & Hypotheses 
1. Objective:  To assess the efficacy of single agent pembrolizumab in patients with 
accelerated or blast phase myelofibrosis (MPN-AP/BP) comprising our exploratory 
cohort.  
Hypothesis:  Deregulated immune checkpoint inhibition allows for evolution of the 
myeloproliferative neoplasm clone into acute leukemia. 
3.3 
Exploratory Objectives 
1. Objective: To assess the expression of PD-1, PD-L1 on MPN cells and supporting 
stromal cells in the bone marrow and blood of patients being treated with 
pembrolizumab. 
2. Objective: to evaluate whether treatment with pembrolizumab affects various immune 
pathways in the bone marrow of patients with advanced forms of myeloproliferative 
neoplasms.   
3.4 
Safety Objectives 
1. Objective:  To assess the safety and feasibility of single agent pembrolizumab in 
patients with chronic phase myelofibrosis (MF-CP) comprising our primary cohort and 
in patients with accelerated and or blast phase myelofibrosis (MPN-AP/BP) 
comprising our exploratory cohort. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 


 
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including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 


 
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4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
The Philadelphia chromosome (Ph) negative myeloproliferative neoplasms (MPNs) are a 
heterogeneous group of myeloid malignancies involving the hematopoietic stem/progenitor 
cell and resulting in a hyper-cellular bone marrow with a tendency to develop reticulin/collagen 
fibrosis, increased risk of thrombotic and hemorrhagic complications, organomegaly 
secondary to extramedullary hematopoiesis, and evolution to acute leukemia. Myelofibrosis 
(MF) is the most concerning of the Ph-negative MPNs due to the significant symptom burden, 
consequences of bone marrow failure, rate of leukemic transformation, and resultant shortened 
median overall survival of 5-6 years. Hematopoietic stem cell transplantation is the only 
therapeutic option that offers the potential for cure but is limited in application by advanced 
patient age and competing comorbid conditions, lack of appropriate donor options, and often 
patient willingness. Treatment for MF is most often based on risk stratification by various 
systems including the Dynamic International Prognostic Scoring System (DIPSS) which 
allows a physician to a determine a treatment plan based on the specific clinical issues at hand 
(e.g. anemia, constitutional symptoms, symptomatic splenomegaly) considering the competing 
risks of treatment risk and disease risk 1. Ruxolitinib (Jakafi, Incyte) a selective JAK1/2 oral 
tyrosine kinase inhibitor is the only FDA-approved therapy for intermediate/high risk MF 
patients with a relatively safe toxicity profile and proven efficacy in reducing splenomegaly 
and improving symptoms 2,3. However, due to dose limiting thrombocytopenia, inability to 
alleviate anemia, loss of initial response, and failure to halt progression to acute leukemia, 
other therapies are desperately needed. A growing appreciation of the complex genetic 
(JAK2V617F, MPL, CALR, TET2, ASXL1, EZH2, IDH1/2) and epigenetic alterations 
[(p14/p16 hypermethylation, overexpression of histone deacetylase (HDAC)] contribute to the 
pathogenesis of the chronic phase (CP) of MF as well as the evolution to accelerated (AP) and 
blast phase (BP) 4. Current experimental approaches include signaling pathway inhibition 
(JAK-STAT), histone deacetylase inhibition, DNMT1 inhibition, and telomerase inhibition 
and are moving ultimately towards combination therapy5.  
The role of deregulated immune function in the pathogenesis and maintenance of the malignant 
MPN clone has more recently been demonstrated. Elevation of circulating inflammatory 
cytokines (e.g. IL-6, TNFa) have been implicated in mediating MF symptoms and ruxolitinib 
treatment mostly through JAK1 inhibition leads to reduction of these levels and amelioration 
of constitutional symptoms 6. Increased TGFb expression has also been linked to production 
of pathologic bone marrow fibrosis and promotion of the MF clone 7. Recent reports in a related 
myeloid malignancy, myelodysplastic syndrome (MDS), show a potential role of programmed 
death 1 (PD-1) signaling (expression of PD-1 in bone marrow stromal cells and PD-L1 in MDS 
CD34+ cells) and gene expression of PD-1/PD-L1/CTLA4 was noted to be up-regulated in the 
setting of azacitdine therapy 8. In fact, PD-L1 expression was more pronounced in patients 
with loss of response to this particular therapy providing a possible mechanism for resistance.  
Additionally, PD-L1 expression has been documented on myeloid cell lines, expression 


 
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appears to correlate with disease progression to acute leukemia from antecedent MDS, as well 
as provide prognostic significance in de novo AML 9-11. 
The loss of anti-tumor immunity mediated by PD-1/PD-L1 signaling through aberrant 
expression of PD-L1 by the malignant cells has been well documented in solid tumors and 
serves as a novel and potent therapeutic target in many malignant disease types such as 
melanoma, lung cancer, lymphoma and others. The role of PD-1/PD-L1 pathway in myeloid 
derived malignancies remains poorly understood, but may offer an innovative approach at 
targeting the MPN hematopoietic stem cell and disrupting supporting signals from the stromal 
niche. Ongoing pre-clinical studies assessing the expression and function of PD-1 pathway in 
MPN primary cells is ongoing as a collaboration between the PI of this trial and Merck. These 
laboratory studies will provide insight into the role of PD-1 in escape of immune suppression 
of the malignant clone as well as progression and evolution of the malignant clone and the role 
the supporting bone marrow and splenic stroma may provide. However, it remains unclear at 
present if expression of PD-1 or PD-L1 by MPN cells or supporting stromal cells will predict 
response to pembrolizumab. Correlative studies within this trial will measure levels of 
expression of PD-1 and PD-L1 at baseline, after treatment with pembrolizumab at time or 
response assessment or at time of treatment discontinuation for any reason.  
Currently, ruxolitnib is the only FDA-approved therapy for the treatment of MF and patients 
that have either primary or secondary resistance or intolerance to this agent have been shown 
to have a particularly poor outcome. No established standard of care exists for these patients. 
Additionally, patients with MPN-AP/BP have a dismal prognosis and there is no standard of 
care therapy for these patients. Outside of hematopoietic stem cell transplantation (HSCT), 
which is only a viable therapeutic option for a fraction of these patients, no other therapies 
have demonstrated clear disease course modification. Therefore, effective treatment options 
for these patients with advanced MPN are urgently needed. This is the subset of MPN patients 
that will be included in this phase II trial of pembrolizumab with a primary objective of disease 
response assessment after 6 cycles.  
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg 
Q2W, the highest dose tested in PN001, determined the dose and schedule utilized in Cohorts 
A, B, C and D of this protocol to test for initial tumor activity.  Recent data from other clinical 
studies within the pembrolizumab program has shown that a lower dose of pembrolizumab and 
a less frequent schedule may be sufficient for target engagement and clinical activity. 
 


 
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PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  
This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  pembrolizumab has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well 
within the established exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma 
indication. The exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher 
dose and exposure). The population PK evaluation revealed that there was no significant 
impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC 
and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
4.2.3 Study Design and Statistical Methods: 
This is an open-label phase II trial to assess the efficacy, safety and tolerability of 
pembrolizumab in patients with PMF, post-PV MF, and post-ET MF. We propose a Simon 


 
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Two-Stage design for this study; the first 9 MF patients will be enrolled to confirm a signal of 
activity and safety of pembrolizumab at the FDA approved dose (in head and neck cancer) of 
200mg administered via intravenous infusion over 30 minutes given every 3 weeks for six 
cycles.  
In stage 1, if at least one response (out of 9 subjects in the primary cohort) is observed after six 
cycles of treatment at week 18, 15 additional patients will be accrued in the second stage (total 
of 24 evaluable patients in the primary cohort). If however, fewer than 3 of 24 patients respond 
to therapy, pembrolizumab will be deemed not worthy of any further investigation in this 
patient population. If response is seen in greater than or equal to 3 of 24 patients, 
pembrolizumab will be considered to have activity in this patient population and will be 
recommended for further study. For this study we define inactivity as a response rate of 5%, 
and activity as a response rate of 25%, which is comparable to that seen with ruxolitinib in a 
mixed population. The probability of erroneously concluding that the drug has activity if the 
true but unknown response rate is 5% is 0.10.  The power to detect a response rate of 25% with 
this design is 0.90. 
In addition, a separate exploratory cohort of 10 patients with MPN in accelerated/blast phase 
diseases that are refractory or intolerant to conventional therapies will be eligible for the study 
as well. 
 
See Section 11.3 for Safety Stopping Rules. 
 
4.2.4 Rationale for Endpoints 
4.2.4.1 Efficacy Endpoint 
Primary endpoint:  
1. The proportion of treated MF-CP patients (primary cohort) that achieve at least a 
clinical improvement (CI, PR, CR) by combined European Leukemia Net –
International Working Group (ELN-IWG) criteria (Table 5) after 6 cycles of 
pembrolizumab therapy.  
Secondary endpoint:  
1. The proportion of treated MPN-AP/BP patients (exploratory cohort) that achieve at 
least a complete morphologic remission of the leukemic blasts (CR, Cri) by Acute 
Myeloid Leukemia Response Criteria (Table 6A) within 6 cycles of pembrolizumab 
therapy.  
2. The proportion of treated MPN-AP/BP patients (exploratory cohort) that achieve at 
least an acute leukemia response-partial (ALR-P, ALR-C, CCR, CMR) using 
published consensus criteria by Mascarenhas et al. (Table 6B) within 6 cycles of 
pembrolizumab therapy. 
 


 
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4.2.4.2     Exploratory Endpoints:  
1. Assess expression of PD-1/PD-L1 on peripheral blood PB-MNCs, T-cells and CD34+ 
cells by flow cytometry  
2. Assess expression of PD-1/PD-L1 on bone marrow CD34+cells and supporting 
stromal cells by immunohistochemical staining  
3. Assess PD-1/PD-L1 DNA methylation status by bisulfite-sequencing assay 
4. Assess status and change in PD-1/PD-L1 expression with response to therapy. 
5. Assess changes in driver mutation burden (JAK2V617F, MPLW515L/K, CALR) in 
granulocytes from treated patients at diagnosis, after 6 cycles and at 1 year of 
pembrolizumab therapy using the rapid heme panel for next generation sequencing at 
Brigham and Women’s hospital and correlate with response to therapy. 
6. Evaluate changes in immune response gene expression profile as well as tumor 
microenvironment in bone marrow biopsy specimens using nanostring technology 
after 6 cycles of treatment with pembrolizumab. 
4.2.4.3    Safety Endpoints 
1. Assess treatment emergent CTCAE v4.0 hematological and non-hematological 
adverse events  
2. Clinical Laboratory test values including hematology, biochemistry and urinanlysis 
3. Vital Signs 
 
 
4.2.4.4 Biomarker Research 
Immunotherapy as a target in MPN has not been extensively studied. As such, an important 
component of this study will be to gain better understanding of markers that predict outcome 
and response to PD-1 therapy.  
1. Biomarker: Assess expression of PD-1/PD-L1 on peripheral blood PB-MNCs, T-cells 
and CD34+cells by flow cytometry: 
Up-regulated PD-1 expression on peripheral blood MNCs and PD-L1 on MPN CD34+cells 
provides an inappropriate immune tolerance signal allowing for disease progression. Pre-
clinical data suggests that PD-1 and PD-L1 are upregulated in patients with MDS and AML, 
especially in those who have received prior treatment. As part of this clinical trial we will test 
PD-1 and PD-L1 expression in circulating T-cells and tumor cells, respectively, to evaluate if 
expression of these molecules correlates with disease status and response to treatment.  
Expected result: PD-1 expression is up-regulated on PB MNC and T-cells and PD-L1 is up-
regulated on MPN HSC from patients enrolled on this trial at baseline. 
Assay: Expression of PD-1 and PD-L1 will be measured by flow cytometry on cells from the 
peripheral blood of treated patients at baseline and at the start of cycle 3 (9 weeks). 
 


 
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2. Biomarker: Assess expression of PD-1/PD-L1 on bone marrow CD34+cells and 
supporting stromal cells by immunohistochemical staining  
Up-regulated PD-1 expression on peripheral blood MNCs and PD-L1 on MPN CD34+cells 
provides an inappropriate immune tolerance signal allowing for disease progression. Pre-
clinical data suggests that PD-1 and PD-L1 are upregulated in patients with MDS and AML, 
especially in those who have received prior treatment. As part of this clinical trial we will test 
PD-1 and PD-L1 expression in circulating T-cells and tumor cells, respectively, to evaluate if 
expression of these molecules correlates with disease status and response to treatment. 
Expression of CD45 surface marker will be evaluated in parallel with PD-1 and/or PD-L1 
expression to differentiate between stromal (CD45 positive) and hematopoietic cells (CD45 
positive) within the bone marrow. 
Expected result: PD-1 expression is up-regulated on PB MNC and T-cells and PD-L1 is up-
regulated on MPN HSC from patients enrolled on this trial at baseline. 
Assay: Expression of PD-1 and PD-L1 will be measured by immunohistochemistry on bone 
marrow. 
 
 
3. Biomarker: Assess PD-1/PD-L1 DNA methylation status by bisulfite-sequencing 
assay 
Changes in gene methylation status correlate with protein expression. Little is known about 
the significance of methylation status and PD-1/PD-L1 expression in MPN. Differences in 
methylation status in MDS have been used to characterize different MDS risk groups as a result 
of epigenetic dysregulation.  
Assay: We will measure PD-1/PD-L1 gene methylation status by bisulfite-sequencing assay. 
Expected result: Differential methylation will correlate with expression levels of PD-1/PD-L1, 
which in turn will correlate with disease status and response to PD-1 antibody therapy. These 
results will be instrumental in determining treatment strategies after hypomethylating agent 
failure in MPN-AP/BP based on their PD-1 expression status and additionally may suggest a 
role for hypomethylating agent priming prior to PD-1 inhibition in MF-CP patients.  
 
4. Biomarker: Assess status and change in PD-1/PD-L1 expression with response to 
therapy. 
 
PD-1/PD-L1 expression has been investigated in a variety of malignancies as biomarkers of 
response to therapy, little is known about the significance of PD-1 and PD-L1 expression in 
MPN and if these markers are surrogates for disease response.  
 
Expected result: Changes in PD-1 and PD-L1 expression, as measured in exploratory aims 1-
3, will correlate with disease response assessed by conventional response criteria (IWG-
ELN).  


 
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5. Biomarker: Assess changes in driver mutation burden (JAK2V617F, MPLW515L/K, 
CALR) in granulocytes from treated patients at diagnosis, after 6 cycles and at 1 year of 
pembrolizumab therapy and correlate with response to therapy. 
  
Changes in mutational status allele burden may correlate with disease response. In addition, it 
is unknown if patients with different mutations will respond preferentially to PD-1 therapy. 
We will correlate mutational status as well as change in allele burden with disease status and 
response to therapy and with expression of PD-1 and PD-L1.  
Expected Result: Driver mutation burden will decrease in response to pembrolizumab therapy.  
Assay: In order to assess changes in driver mutation burden we will use the rapid heme panel 
for next generation sequencing at Brigham and Women’s hospital. 
 
6. Biomarker: Evaluate changes in Immune response gene expression profile as well as 
tumor microenvironment in bone marrow biopsy specimens using nanostring technology 
after 6 cycles of treatment with pembrolizumab 
Immune dysregulation leads to upregulation of PD-L1 on tumor cells and contributes to tumor 
initiation and disease progression. These changes may also occur in the tumor 
microenvironment leading to inactivation of tumor infiltrating lymphocytes. Little is known 
about the changes in genes related to immune regulation in myeloproliferative neoplasms and 
how these change with treatment. To this end, we will correlate changes in immune gene 
expression before and after PD-1 antibody therapy. 
We will applyenzyme-free nanostring technology, using the The nCounter® PanCancer 
Immune Profiling Panel system, for identification of immune cells and assesing immunological 
function in the local microienvironement of the bone marrow samples from patients with 
MPNs. We will use archival formalin-fixed, paraffin embedded (FFPE) samples. The 
nCounter® system uses enzyme-free nanostring technology and provides an excellent 
platform, to guide identification of microenvironment cell types and inform pathway activation 
patterns in these samples. 
The nCounter Analysis System utilizes a novel digital technology that is based on direct 
multiplexed measurement of gene expression and offers high levels of precision and sensitivity 
(<1 copy per cell). The technology uses molecular "barcodes" and single molecule imaging to 
detect and count hundreds of unique transcripts in a single reaction. Each color-coded barcode 
is attached to a single target-specific probe corresponding to a gene or a fusion gene of interest. 
Mixed together with controls, they form a multiplexed CodeSet 
Expected result: PD-1 blockade leads to changes in immune gene profile expression that 
promotes tumor tolerance and this is reversed with anti-PD-1 therapy 


 
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Assay: 500ng of RNA (at 100ng/ul) will be isolated from PMF bone marrow specimens for 
digital expression profilling that will be performed according to the standard nCounter Gene 
Expression Protocol as we recently reported (Liew et al 2015).  Nanostring tecnilogy will be 
briefly dscribed in three simple steps as follows: i) Hybridization: NanoString’s Technology 
employs two ~50 base probes per mRNA that hybridize in solution. The Reporter Probe carries 
the signal; the Capture Probe allows the complex to be immobilized for data collection. ii) 
Purification and Immobilization: After hybridization, the excess probes are removed and the 
probe/target complexes aligned and immobilized in the nCounter Cartridge. iii) Count:Sample 
Cartridges are placed in the Digital Analyzer for data collection. Color codes on the surface of 
the cartridge are counted and tabulated for each target molecule. 
The immune profiling panel that we will apply, is designed to quantitate expression of enriched 
genes that fall into functional categories that allow identification of immune cell types, and 
measure gene expression associated biological process such as cytokines, complement and 
cytotoxicity etc. The panel will include also housekeeping genes that facilitate sample-to-
sample normalization. A list of genes found in the PanCancer Immune Profiling Panel that we 
utilized in our preliminary data acquisition and their annotated functions is documented and 
available at www.nanostring.com. In addition to functional annotations, the HUGO Gene 
Nomenclature Committee (www.genenames.org) name and commonly used aliases are 
described.  
The nanostring experiment and data analysis will be performed at ARUP by co-investigator 
Dr. Salama. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
This trial is targeting patients with advanced forms of myeloproliferative neoplasms (MPNs). 
This will include patients with myelofibrosis (MF) in chronic (CP), accelerated (AP), and blast 
phase (BP) disease. Patients with other MPNs such as essential thrombocythemia (ET) or 
polycythemia vera (PV) will be eligible if they have AP/BP disease. Patients with MF will 
include those with primary myelofibrosis (PMF) as well as post essential thrombocythemia 
(post-ET) or polycythemia vera (post-PV) myelofibrosis. MF-CP patients will be required to 
have survival risk scores associated with advanced disease (intermediate-2/high) by the 
established Dynamic International Prognostic Scoring System (DIPSS). Patients with MF-CP 
will have had to have been previously treated with ruxolitinib and either had a suboptimal 
response or been intolerant as determined by the investigator, or be ineligible for ruxolitinib 
treatment as determined by the treating investigator. Patients with MPN-AP/BP will have had 
to have been previously treated with a hypomethylating agent such as decitabine or azacytidine 
and have progressive or resistant disease as determined by the treating investigator.  In all cases 
the subject must either not be eligible for hematopoietic stem cell transplant option or be 
unwilling to pursue this potentially curative treatment option.  


 
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5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Must have a diagnosis of chronic phase (CP) (defined as peripheral blood and bone 
marrow <10% blasts) primary myelofibrosis (PMF) or post essential thrombocythemia 
(post-ET) or polycythemia vera (post-PV) myelofibrosis by World Health Organization 
(WHO) criteria OR a diagnosis of a myeloproliferative neoplasm in accelerated/blast 
phase (MPN-AP/BP) defined as either a peripheral blood or bone marrow with ≥10% 
blasts  
4. If the diagnosis is MF-CP, must have Dynamic International Prognostic Scoring 
System (DIPSS) intermediate-2/high risk disease and either be intolerant/resistant to 
ruxolitinib as determined by the treating investigator or ineligible for ruxolitinib 
therapy as determined by the treating investigator (see Appendix 12.3) 
5. If the diagnosis is MPN-AP/BP, must have progressive/resistant disease after treatment 
with a DNMT1 inhibitor therapy (azacytidine, decitabine) as determined by the treating 
investigator  
6. Either not eligible or unwilling to proceed with hematopoietic stem cell transplantation  
(HSCT) 
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 28 days of treatment initiation.   
Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) ≥500 /mcL 
Platelets 
≥25,000 / mcL 
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubinb 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 


 
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AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
b unless due to Gilbert’s disease or hemolysis 
 
9. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
10. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
11. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or 
child) who is investigational site or sponsor staff directly involved with this trial, unless 
prospective IRB approval (by chair or designee) is given allowing exception to this 
criterion for a specific subject 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
4. Has a known history of active TB   (Bacillus Tuberculosis) 


 
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5. Hypersensitivity to pembrolizumab or any of its excipients. 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
7. Has had prior chemotherapy (except hydroxyurea), targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
10. Has known history of, or any evidence of active, non-infectious pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. "Anti-
CD137 or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 


 
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(including ipilimumab or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways)  
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
Pembrolizumab 
200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimenta
l 
 
Trial treatment should begin on the day of registration or as close as possible to the date on 
which treatment is available. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 
5.6.1 and Events of Clinical Interest Guidance Document for supportive care guidelines, 


 
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including use of corticosteroids. Although leukopenia, anemia, and thrombocytopenia are 
expected as a natural consequence of the disease being treated and will be present at baseline 
for the majority of enrolled subjects, grade 4 treatment emergent hematologic toxicity will 
require drug treatment interruption regardless of attribution and can be re-started once the 
hematologic toxicity has resolved to baseline or at least grade 3. Treatment emergent grade 
3/4 anemia and thrombocytopenia will be managed with red blood cell and platelet 
transfusional support as pre treating investigators discretion.   


 
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Table 3.Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatm
ent For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Co
litis 
2-3 
 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 3 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, 
or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 3 weeks of 
last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 
diabetes 
mellitus (if 
new onset) 
or 
Hyperglyce
mia 
T1DM 
or  
3-4 
Hold 
pembrolizumab 
for 
new onset Type 1 diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated 
with evidence of beta cell 
failure.  
 
Resume pembrolizumab when patients are 
clinically and metabolically stable. 
Hypophysiti
s 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 3 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 


 
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Toxicity 
Hold 
Treatm
ent For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Hyperthyroi
dism  
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 3 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 3 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Hypothyroid
ism 
2-4 
Therapy with 
pembrolizumab can be 
continued while treatment 
for the thyroid disorder is 
instituted 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumoniti
s 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 3 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 3 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal 
Failure or 
Nephritis 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 3 weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 3 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other 
Drug-
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 3 weeks of 
last dose or inability to reduce 


 
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Toxicity 
Hold 
Treatm
ent For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Related 
Toxicity2 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 3 
weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or 
any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then 
patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at 
physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse 
reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 
within 3 weeks of the last dose.   


 
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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
Subjects should be monitored after each infusion for 30 minutes. Vitals should be done pre-
infusin and post-infusion, and after the 30 minute monitoring period. 
In addition, the investigator or designee should conduct a safety follow-up phone call the day 
after the first infusion of study drug and weekly during the first cycle.  These telephone 
encounters should be documented in the MD or nursing note. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Randomization or Treatment Allocation 
There is no randomization in this single arm trial.  
5.4 
Stratification 
There is no formal stratification in this trial.  
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 


 
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or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 


 
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The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 


 
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o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 


 
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taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4. Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs       
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 


 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be 
held until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration. 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
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 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 


 
Version 2.0 Oct 30, 2018 
Page 29 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
 
 
In addition, the investigator or designee should conduct a safety follow-up phone call the day 
after the first infusion of study drug and weekly during the first cycle.  These telephone 
encounters should be documented in the MD or nursing note. 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   


 
Version 2.0 Oct 30, 2018 
Page 30 
 
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female subject’s male partner  
• contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, symptom-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 


 
Version 2.0 Oct 30, 2018 
Page 31 
 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study.  The subjects who meet this criteria will be contacted every 30 days for 
the 120 day period and pregnancy status will be documented at these intervals by the 
investigator or designee. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Subject did not achieve at least a CI response per Table 5 for the MF-CP cohort or at 
least PR for the MPN-AP/BP cohort per Table 6A at response assessment. 


 
Version 2.0 Oct 30, 2018 
Page 32 
 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).   
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR by IWG/ELN criteria for chronic phase MF and by IWG-AML criteria for AP/BP patients 
that have been treated for at least 6 cycles with pembrolizumab and had at least two treatments 
with pembrolizumab beyond the date when the initial CR was declared. Additional details are 
provided in Section 7.1.5.5.  The investigator or designee will contact patients weekly to 
monitor for SAEs during the 60 day period following the 30 day adverse event monitoring 
period.  These should be documented in an RN or MD note.   
5.9 
Subject Replacement Strategy 
Patients who do not complete at least one cycle of therapy will be replaced. 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 


 
V ersi o n 1 . 4  Oct 0 9 , 2 0 1 6 
P a g e 3 3  
 
6. 0  T RI A L F L O W C H A R T  
6. 1  
St u d y Fl o w C h art  
Tri al P eri o d:  
S cr e e ni n g  
Tr e at m e nt C y cl e s a  
C or e st u d y p eri o d  
Tr e at m e
nt 
c y cl e s b  
E xt 
p eri o d  
E n d of 
Tr e at m e
nt h 
E n d of 
St u d y  
Tr e at m e nt C y cl e/ Titl e : 
M ai n 
St u d y 
S cr e e ni n g  1 
2  
3 
4 
5 
6 
7 +  
 
3 0 d a y s 
p o st 
di s c o n  
S c h e d uli n g Wi n d o w ( D a y s):  
-2 8 t o - 1 
 
± 3  ± 3  ± 3  ± 3  ± 3  
+/ - 5 
+/ - 5 
+/ - 5 
I nf or m e d C o n s e nt 
X  
 
 
 
 
 
 
 
 
 
I n cl u si o n/ E x cl u si o n Crit eri a 
X  
 
 
 
 
 
 
 
 
 
D e m o gr a p hi c s a n d M e di c al 
Hi st or y  
X  
 
 
 
 
 
 
 
 
 
Pri or a n d C o n M e di c ati o n 
R e vi e w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Tri al Tr e at m e nt A d mi ni str ati o n  
 
X  
X  
X  
X  
X  
X  
X  
 
 
R e vi e w A d v er s e E v e nt s  
 
X  
X  
X  
X  
X  
X  
X  
X  
x  
F ull P h y si c al E x a mi n ati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vit al Si g n s a n d W ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
X  
x  
E C O G P erf or m a n c e St at u s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
x  
Pr e g n a n c y T e st –  Uri n e or 
S er u m r e g n 
X  
 
 
 
 
 
 
 
 
 
P T/I N R a n d a P T T  
X  
 
 
 
 
 
 
 
 
 
C B C wit h Diff er e nti al  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  


 
Version 1.4  Oct 09, 2016 
Page 34 
 
Trial Period: 
Screening 
Treatment Cyclesa 
Core study period 
Treatme
nt 
cyclesb 
Ext 
period 
End of 
Treatme
nth 
End of 
Study 
Treatment Cycle/Title: 
Main 
Study 
Screening 1 
2  
3 
4 
5 
6 
7+ 
 
30 days 
post 
discon 
Scheduling Window (Days): 
-28 to -1 
 
± 3 ± 3 ± 3 ± 3 ± 3 
+/-5 
+/-5 
+/-5 
Comprehensive Serum 
Chemistry Panelf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
X 
 
 
X 
 
 
 
X 
 
X 
Chest X ray (PA and lateral) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram-12 lead 
X 
 
 
 
 
 
 
 
 
 
Bone marrow (BM) evaluationc 
X 
 
 
 
 
 
 
X 
 
 
Flow cytometry g 
X 
 
 
 
 
 
 
X 
 
 
Cytogenenticsd,g 
X 
 
 
 
 
 
 
X 
 
 
Correlative Studies BM Collectione 
X 
 
 
 
 
 
 
X 
 
 
Correlative Studies Blood Collectione 
X 
 
 
X 
 
 
 
X 
 
X 
a core study period will be 6 cycles of therapy with pembrolizumab for primary response assessment  
b ext= extension phase will include those that go on to receive additional cycles of therapy after cycle 6, this will include cycle 7 and 
each subsequent cycle until the patient is discontinued from treatment for reasons outlined in the previous section  
c bone marrow evaluation consists of bone marrow biopsy and aspiration for pathology review done at screening and at C7D1 (after 
completion of 6 cycles of therapy).  Outside bone marrow may be used if biopsy is done within 3 months prior to screening—peripheral 
blood should be collected at screening instead for correlative studies. 


 
Version 1.4  Oct 09, 2016 
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d conventional metaphase cytogenetics to be performed locally at study site  
e Refer to biomarker table for blood and bone marrow collection in section 7.1.2.6 Table 8 
f Comprehensive Serum Chemistry Panel should include the following: Albumin, Alkaline phosphatase, Glucose, Alanine 
aminotransferase (ALT),  Aspartate aminotransferase (AST), Lactate dehydrogenase (LDH),(CO2 or bicarbonate),Uric Acid, Calcium, 
Chloride, Glucose, Phosphorus, Potassium, Sodium, Magnesium, Total Bilirubin, Direct Bilirubin (If total bilirubin is elevated above 
the upper limit of normal), Total protein, Blood Urea Nitrogen 
g Flow cytometry for acute leukemia panel and cytogenetics will be sent from the bone marrow aspirate, if this is not obtainable then 
will be sent from the peripheral blood to be performed locally at study site 
 h If it is known, prior to C7D1, that the patient will not achieve the required response, CI, for continuation,  the C7D1 and End of 
Treatment visit will be combined.  All study activities for C7D1 will be done except dosing of the study medication.  


 
Version 1.4  Oct 09, 2016 
Page 36 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these procedures 
at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially sensitive in 
nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed 
consent be obtained from the subject.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating in a 
clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person conducting 
the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation in the 
trial. 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the subject must receive the IRB/ERC’s approval/favorable opinion in advance 
of use.  The subject or his/her legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial.  The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the subject’s dated signature 
or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and Sponsor 
requirements. 
 


 
Version 1.4  Oct 09, 2016 
Page 37 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will include 
all active conditions, and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the Investigator.  Details regarding the disease for which the subject has enrolled 
in this study will be recorded separately and not listed as medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the subject within 28 days before starting the 
trial.  Treatment for the disease for which the subject has enrolled in this study will be recorded separately 
and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during the trial.  
All medications related to reportable SAEs and ECIs should be recorded as defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
Not applicable.  
7.1.1.6 Assignment of Screening Number 
Not applicable. 
7.1.1.7 Assignment of Randomization Number 
Not applicable.  


 
Version 1.4  Oct 09, 2016 
Page 38 
 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Patients will be instructed to comply to study visits and concomitant medications by the research staff and 
compliance. 
7.1.2 Clinical Procedures/Assessments 
Response assessment will formally be conducted after 6 cycles of pembrolizumab therapy, This will 
include assessment of symptoms, hematologic profile, bone marrow histomorphologic abnormalities, 
spleen length by manual palpation on physical exam, cytogenetics, and changes in mutational burden from 
baseline measurement.  These established consensus criteria (ELN-IWG) shown in TABLE 5 will allow 
for uniformity in response assessment and are standardized.  
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or worsening 
AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse experiences 
will be graded and recorded throughout the study and during the follow-up period according to NCI 
CTCAE Version 4.0 (see Section 11.2).  Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated with 
pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical interest 
(ECI) of a potentially immunologic etiology (termed immune-related adverse events, or irAEs).   
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening period.  
Clinically significant abnormal findings should be recorded as medical history.  A full physical exam 
should be performed during screening, and at each study visit as indicated in the trial flow chart.  
 
7.1.2.2.1 
MPN-SAF TSS 
The investigator or qualified designee will use the MPN-SAF TSS measure at every study visit to 
assess constitutional symptoms as part of the interval history assessment. 
7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of each 
dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 6.0).  
Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be 
measured at screening only. 


 
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7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment as specified in the 
Trial Flow Chart.   
7.1.2.5 Assessment of Disease Response 
Clinical response for patients with MF-CP in the primary cohort will be evaluated using the Revised IWG-
MRT and ELN response criteria for Myelofibrosis12 as follows (patients must achieve at least CI to 
continue in the extension phase): 
 


 
Version 1.4  Oct 09, 2016 
Page 40 
 
TABLE 5. International Working Group for Myelofibrosis Research and Treatment and European 
leukemiaNet (IWG-ELN) response criteria for myelofibrosis  
 


 
Version 1.4  Oct 09, 2016 
Page 41 
 
 
Response assessment for patients with MPN-BP disease will follow the standard response assessment for 
AML defined by Cheson et al13 as shown in Table 6A (patients must achieve at least a PR to continue to 
extension phase). 
Table 6A. Acute Myeloid Leukemia Response Assessment Criteria  
Complete Response (CR) 
The subject must be free of all symptoms related to leukemia and have an absolute 
neutrophil count of greater than 1 x 109/L, no need for red blood cell transfusion, 
platelet count greater than 100x 109/L, and normal marrow differential (<5% blasts) in 
a normo- or hypercellular marrow 
Cri 
As per CR but incomplete count recovery 
Partial Response 
CR with 6-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts 
 
Additionally, response assessment for patients with accelerated or blast phase disease will be measured 
by published consensus criteria by Mascarenhas et al. specifically designed for MPN-AP/BP as shown in 
Table 6B. These criteria will also be utilized as there are no current standardized response criteria for 
MPN-AP or BP. These criteria are based on hematological, pathological, clinical, cytogenetic and 
molecular responses. These criteria incorporate established response criteria for AML, MDS and MPN. 
TABLE 6B.  Formal response assessment categories for MPN-AP/BP  


 
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Version 1.4  Oct 09, 2016 
Page 43 
 
 
 
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood and Bone Marrow Sampling 
Both blood and bone marrow tissue will be collected and stored at time points indicated in Table 8 for the 
purposes of fulfilling the exploratory objectives of this trial. These samples will be collected as the 
protocol directs and then shipped to the central repository at Mount Sinai Under the supervision of Dr. 
Camelia Iancu Rubin.  
 


 
Version 1.4  Oct 09, 2016 
Page 44 
 
Table 8.  Correlative tissue banking of blood and bone marrow samples   
 
*At EOS or study discontinuation for any reason, collect peripheral blood for biomarkers (2 green top tubes). Biopsy is not required. 
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided below. Laboratory Safety 
Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.  
Baseline (at 
screening)
Start of 
Cycle 3 
End of 
Cycle 6 
End of 
Cycle 
12/EOS* 
BM aspirate -1 
green top tube 
Yes - remaining 
tissue
BM-MNCs 
X 
__ 
X 
X 
Flow cytometry 
ISMMS/Dr. Iancu-Rubin 
BM (biopsy) 
N/A Recover from 
Pathology
Paraffin embeded 
BM biopsy core 
X 
__ 
X 
X 
Immunohistochemistry 
ISMMS & Mayo Clinic/ 
Dr. Salama 
3
PB 1-green top 
or 1 PaxGene 
PB 
PB-MNCs
X 
X 
X 
X 
Bisulfite-sequencing assay 
(methylation)
TBD
PB - 1 green top 
tube 
PB - 1 green top 
tube 
PB-MNCs
X 
X 
X 
X* 
Flow Cytometry 
ISMMS/Iancu-Rubin 
BM (biopsy) 
N/A Recover from 
Pathology
Paraffin embeded 
BM biopsy core 
X 
__ 
X 
X 
Immunochesmisty 
ISMMS & Mayo Clinic/ 
Dr. Salama 
5
PB - 1 PaxGene 
DNA tube 
PB - 1 PaxGene 
DNA tube
Whole blood 
X 
X 
X 
Heme Panel NSG
MGH/Dr. Borger
6
BM (biopsy) 
N/A Recover from 
Pathology
Paraffin embeded 
BM biopsy core 
X 
__ 
X 
X 
Nanostring Technology 
Mayo Clinic/Dr. Salama 
Assess changes in driver mutation burden 
( JAK2V617F, MPLW515L/K, CALR) in granulocytes 
from treated patients at diagnosis, after 6 cycles and  
at 1 year of pembrolizumab therapy and 
correlate  with response to therapy. 
Evaluate changes in Immune response gene 
expression profile as well as tumor microenvironment 
in bone marrow biopsy specimens 
Assess expression of PD-1/PD-L1 on peripheral blood  
PB-MNCs, T-cells and CD34+cells 
Performed at Site/Laboratory 
ISMMS/Dr. Iancu-Rubin 
X 
X 
X* 
Table 1. Tissue Collection 
ASSAY 
2
Tissue to be 
analyzed 
Assay employed 
4
Time of collection/banking/analysis 
1
PB-MNCs
Assess status and change in PD-1/PD-L1 expression  
with response to therapy. 
Assess PD-1/PD-L1 DNA methylation status
Tissue collection 
PB - 1 green top 
tube 
Tissue banking 
(not HMTB) 
Yes - 1 green top 
tubes 
Assess expression of PD-1/PD-L1 on bone marrow 
CD34+cells and supporting stromal cells 
Flow cytometry 
X 


 
Version 1.4  Oct 09, 2016 
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Table 9.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If 
abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
  (CO2 or biocarbonate) 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte 
Count₸ 
Creatinine 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
MCV 
Uric Acid 
 
Blood for correlative studies 
NRBC 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper 
limit of normal) 
 
 
 
Total protein 
 
 


 
Version 1.4  Oct 09, 2016 
Page 46 
 
Hematology 
Chemistry 
Urinalysis 
Other 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy 
test will be required.   
‡ If considered standard of care in your region. 
₸ This value may be manually calculated. 
 
 
 


 
Version 1.4  Oct 09, 2016 
Page 47 
 
Laboratory tests for screening or entry into the Core Treatment Phase should be performed 
within 28 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.3.1 Pharmacodynamic Evaluations 
The pharmacodynamic studies performed in this trial are incorporated in the exploratory 
objectives and listed in TABLE 8. These include assessing PD-1/L1 expression levels in 
different cellular compartments in the blood and bone marrow as discussed above as well as 
determining treatment effect on the malignant clone by assessment of changes in driver 
mutation levels and histomorphologic changes in the bone marrow of treated patients.   
7.1.3.1.1 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in the 
Laboratory Manual. 
This will not be assayed in this trial. 
7.1.3.1.2 Blood Collection for Anti-Pembrolizumab Antibodies  
This will not be assayed in this trial.  
7.1.4 Other Procedures 
No other intended procedures.  
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who do not attain at least CI (MF-CP) or PR (MPN AP/BP). Subjects 
who attain a CR by IWG-ELN criteria after 6 cycles of therapy with pembrolizumab may 
discontinue treatment. After discontinuing treatment following assessment of CR, these 
subjects should return to the site for a Safety Follow-up Visit 30 days post last dose.  (described 
in Section 7.1.5.3.1). 
7.1.4.2 Blinding/Unblinding 
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7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
Subjects who are candidates for enrollment into the study will be evaluated for eligibility by 
the Investigator to ensure that the inclusion and exclusion criteria have been satisfied and that 
the subject is eligible for participation in this clinical study. The Study Chairs will confirm 
eligibility for all subjects prior to receipt of the first dose of pembrolizumab. 
7.1.5.1.1 Screening Period 
The screening period will begin after signed consent is obtained and will last for 28 days (Day 
-28 to day -1). During this period Inclusion and exclusion criteria will be reviewed by the PI 
and this will include the following tests and procedures to be completed: demographics and 
medical history, prior con med review, physical exam with attention to spleen length in 
craniocaudal direction measured by a ruler at the mid clavicular line from the costal margin, 
vitals, ECOG, CBC and comprehensive serum chemistry, PT/PTT, serum or urine HCG,  
urinalysis, thyroid function tests, Chest X ray (PA and lateral), bone marrow biopsy and 
aspiration, flow cytometry and cytogenetics (if aspirate is not obtained then will be done from 
the peripheral blood). Biomarkers from the peripheral blood and aspirate will also be collected 
as outlined in the biomarker section of this protocol and delineated in the Biomarker table.  
7.1.5.2 Treatment Period 
The treatment period will consist of 3 week cycles in which the study drug will be given on 
day 1 of each cycle and the following tests and procedures will be obtained: prior con med 
review, adverse event review, physical exam with attention to spleen length in craniocaudal 
direction measured by a ruler at the mid clavicular line from the costal margin, vitals, ECOG, 
CBC and comprehensive serum chemistry, and thyroid function tests (on C3D1).  
The core study period is a total of 6 cycles (study visits and drug administration will take place 
on day 1 of each cycle and the window is +/- days).  Response assessment visit will take place 
on cycle 7 day 1 which will include the addition of a bone marrow biopsy and aspiration and 
biomarker evaluation from the aspirate and peripheral blood. The PI will decide if the subject 
will continue receiving therapy in the extension phase (Cycle 7+) of the trial as long the 
following is true: at least a clinical improvement by IWG-ELN criteria (Table 5) for chronic 
phase patients and at least a partial response by Table 6A and 6B (secondary objective) for 
accelerated and blast phase patients; the absence of unacceptable toxicity; both patient and 
treating physician are in favor of continued treatment on protocol. Patients can continue 
receiving study drug in the extension phase as long as they do not meet criteria for 
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7.1.5.3 Post-Treatment Visits 
There will be a protocol driven 30 day follow up visit (see section 7.1.5.3.1) after the last dose 
of pembrolizumab. Visits to manage toxicity or disease related issues during this period will 
be scheduled as per the treating physician. The 30 day follow up visit (+/- 5 days) will include 
prior con med review, adverse event review, exam, vitals, ECOG, CBC and comprehensive 
serum chemistry, and thyroid function tests.   
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first. 
If it is known, prior to C7D1, that the patient will not achieve the required response, CI, for 
continuation,  the C7D1 and End of Treatment visit will be combined.  All study activities for 
C7D1 will be done except dosing of the study medication.  The patient should return 30 days 
later for the safety follow-up visit. 
7.2 
Assessing and Recording Adverse Events  
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
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Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
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Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
Refer to Table 10 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 30 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and the Sponsor will report to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
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7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220)Events of clinical interest for this trial 
include: 
1.  An overdose of Merck product, as defined in Section 7.1.6 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


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Table 10.  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused 
death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not worsened does not 
constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest 
and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the 
adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the 
source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment 
of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 


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intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug 
and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the 
greater the correlation with the components and their respective elements (in number and/or intensity), the more likely the 
Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), 
or other host or environmental factors 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug trial); or (4) 
Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the 
trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK 
PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck 
product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according 
to his/her best clinical judgment, including consideration of the above elements. 


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Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck 
product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the 
administration of the Merck product is reasonable.  The AE is more likely explained by the Merck product than 
by another cause. 
No, there is not a 
reasonable possibility 
Merck product relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of 
the Merck product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject 
with overdose without an associated AE.) 


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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
Data analyses will be performed after the study is completed and the database is released. All 
statistical programming and analyses will be performed using SAS Version 9.4. Data from 
participating centers in this protocol will be combined, so that an adequate number of 
patients will be available for analysis.  
 
For all analyses, data from patients with MPN-AP-BP  (exploratory cohort) will be 
summarized separately, unless otherwise stated. 
 
8.1.1 Analysis Populations 
8.1.1.1 Definition of Populations 
Full Analysis 
The Full Analysis (FA) population includes all patients who received at least one cycle of 
pembrolizumab and had at least one valid post-baseline efficacy assessment. The FA 
population will be used for all listings of raw data. Unless otherwise specified, the FA 
population will be the default analysis set used for all analyses. 
Safety 
The safety population includes all patients (primary and exploratory cohorts) who received at 
least one cycle of pembrolizumab and have at least one valid post-baseline safety assessment. 
Per Protocol 
The Per-Protocol (PP) population will consist of a subset of patients in the FA population who 
completed 6 treatment cycles and did not have major protocol violations or deviations. This 
population will be the secondary population for the analysis of the primary efficacy endpoint. 
8.1.1.2 Applicability of Population Efficacy analyses 
• The primary efficacy analysis of clinical improvement (CI) or better (partial response 
(PR) or complete response (CR)) as shown in TABLE 5, will be based on the FA 
population. A secondary analysis of CI or better (PR or CR) will be performed on the 
PP population. 
• All secondary efficacy analyses will be performed for the FA population. 


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Safety analyses 
All safety analyses will be based on the safety population. In addition, specific assessments of 
late toxicity will be performed for patients in the safety population who are followed for safety 
for at least one year from treatment initiation. 
Exploratory analyses 
Biomarker analyses will be performed in patients for the FA population.  
8.2 
Statistical Analysis Methods 
Description of Data 
Data will be presented in patient data listings by patient and according to visit. Continuous 
variables will be summarized using standard summary statistics such as number of 
observations (n), mean value, standard deviation (SD), minimum and maximum values, 
median value, and 1st and 3rd quartiles. Categorical variables will be summarized in frequency 
tables as counts and percentages. All individual data collected in the CRFs will be presented 
in data listings. Patients screened but not included in the study (i.e. screen failures) will not be 
presented in any tables or listings. 
 
8.2.1 Patient demographics and other baseline characteristics 
 
Demographic data and other baseline characteristics (including medical and disease history) 
will be summarized using descriptive statistics.  
 
8.2.2 Analysis of Efficacy Endpoints 
 
8.2.2.1 8.2.3.1 Primary Endpoint 
 
The primary efficacy endpoint, CI or better (PR,CR) after 6 cycles of treatment as defined by 
the combined European Leukemia Net –International Working Group (ELN-IWG)) (Table 5) 
in patients with MF-CP (primary cohort) will be reported as a percentage of the total number 
of subjects enrolled for both FA and PP populations. A two-sided 90% exact confidence 
interval for the percentage will be computed using the Clopper and Pearson method.  
8.2.2.2 8.2.3.2 Secondary Endpoints 
The secondary efficacy endpoint, CRi or better (CR), after 6 cycles of treatment as defined by 
Acute Myeloid Leukemia Response criteria (Table 6A) in patients with MPN-AP/BP) 
(exploratory cohort) will be reported as a percentage of the total number of subjects enrolled 
for the FA population.  


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The secondary endpoint, ALR-P or better (ALR-C, CCR, CMR), after 6 cycles of treatment as 
defined using published consensus criteria by Mascarenhas et al. (Table 6B) in patients with 
MPN-AP/BP (exploratory cohort) will be reported as a percentage of the total number of 
subjects enrolled for the FA population.  
8.2.3 Analysis of Safety Endpoints 
All safety summaries will be presented for the safety population. No formal statistical analysis 
of safety endpoints will be performed. Safety data to be evaluated includes AEs, physical 
examination and clinical laboratory results. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose of 
study medication. 
2. On-treatment period: from day of first dose of study medication to 30 days after last dose of 
study medication.  
3. Post-treatment period: starting at day 31 after last dose of study medication. 
 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period. 
8.2.3.1 Adverse Events (AEs) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relationship to study treatment. 
 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event. 
 
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). 
 
For each specified SEC, number and percentage of patients with at least one event within the 
SEC will be reported. 
 
8.2.3.2  Laboratory abnormalities 
Descriptive statistics (number of observations, mean, standard deviation, minimum, median 


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and maximum values) will be presented for clinical laboratory tests (hematology, 
biochemistry, urinalysis), and their changes from baseline, at applicable visits. 
 
For laboratory data, summary statistics will be presented for each parameter, together with 
their changes from baseline, by visit. In addition, changes from baseline will be summarized 
in shift tables according to severity during treatment and baseline grade. Graphical 
presentations of the mean value (± 2 SD) at each visit will be generated for each laboratory 
parameter. 
 
8.2.3.3  Other safety data 
Data from other tests (e.g., vital signs) will be listed, notable values will be flagged, and any 
other information collected will be listed as appropriate. Any statistical tests performed to 
explore the data will be used only to highlight any interesting comparisons that may warrant 
further consideration. Additionally, the following outputs will be produced: 
 
Vital signs 
• Shift table baseline to worst on-treatment result 
• Table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
 
8.2.4 Analysis of Exploratory Endpoints 
 
8.2.4.1 Biomarker: Assess expression of PD-1/PD-L1 on peripheral blood PB-MNCs, 
T-cells and CD34+cells by flow cytometry: 
To assess expression of PD-1/PD-L1 on peripheral blood PB-MNCs, T-cells and CD34+cells, 
median fluorescence intensity (MFI) and the percentage of cells expressing each antigen within 
a gate will be estimated for each sample by flow cytometry. If there are no expression levels 
equal to 0 among the samples, geometric means of MFIs and percentage of cells will be 
reported at baseline and at the start of cycle 6. The change in geometric mean MFIs/percentage 
of cells from baseline to end of cycle 6 will be reported as the ratio of geometric means and 
tested for difference from one using a paired t-test on log transformed data. If, however, there 
are expression levels equal to 0, median and interquartile range of MFIs/percentage of cells 
will be reported at baseline and end of cycle 6 treatment. Difference between median 
MFIs/percentage of cells from baseline to end of cycle 6 will be tested using a Wilcoxon Signed 
Rank test.  
 
 
8.2.4.2  Biomarker: Assess expression of PD-1/PD-L1 on bone marrow CD34+cells and 
supporting stromal cells by immunohistochemical staining: 
To assess expression of PD-1/PD-L1 on bone marrow CD34+ cells and supporting stromal 
cells by immunohistochemical staining, percentages of PD-L1 and PD-1 positive tumor cells 
and staining intensity will be evaluated for each sample. Staining intensity will be scored 


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considering 0 as negative or trace, 1 as weak, 2 as moderate and 3 as high. A semi-quantitative 
approach will be used to generate an H-score for each tissue core defined as the percentage of 
stained cells (0–100%) multiplied by the dominant intensity pattern of staining ranging from 0 
to 3. The overall semi-quantitative H-score will range from 0 to 300. If there are no H-scores 
of 0 among the samples, geometric means of H-scores will be reported at baseline and at the 
end of cycle 6 treatment. The change in geometric mean H-scores from baseline to end of cycle 
6 will be reported as the ratio of geometric means and tested for difference from one using a 
paired t-test on log transformed data. If, however, there are H-scores of 0, median and 
interquartile range of H-scores will be reported at baseline and following cycle 2 treatment. 
Difference between median H-scores from baseline to end of cycle 6 will be tested using a 
Wilcoxon Signed Rank test. In addition to the semi-quantitative H-score approach, a 
dichotomous variable indicating expression positivity will be created. In the absence of any 
standardized scoring system, all cases with staining intensity ≥ 2 in more than 5% of tumor 
cells will be considered as positive, similarly to previous studies (Antonia et al, 
2013; Grosso et al, 2013; Soria et al, 2013). McNemar’s test will be used to test for a change 
in the percentage of patients with positive PD-1/PD-L1 expression from baseline to the start 
of cycle 6 follow-up.  
 
8.2.4.3  Biomarker: Assess PD-1/PD-L1 DNA methylation status by bisulfite-
sequencing assay 
To assess PD-1/PD0L1 DNA methylation status geometric means of PD-1/PD-L1 
methylation levels (expressed as percentage) will be reported at baseline and at the start of 
cycle 3. The change in geometric mean methylation levels from baseline to start of cycle 6 
will be reported as the ratio of geometric means and tested for difference from one using a 
paired t-test on log transformed data.  
 
8.2.4.4  Biomarker: Assess status and change in PD-1/PD-L1 expression with response 
to therapy. 
To assess status and change in PD-1/PD-L1 expression with response to therapy, the proportion 
of patients responsive to treatment following their 6th cycle will be computed and compared 
between PD-1/PD-L1 positive and negative patient groups, with positivity based on 3rd cycle 
expression levels, using a Fisher’s exact test of association. 
 
8.2.4.5  Biomarker: Assess changes in driver mutation burden (JAK2V617F, 
MPLW515L/K, CALR) in granulocytes from treated patients at diagnosis, after 
6 cycles and at 1 year of pembrolizumab therapy and correlate with response 
to therapy. 
To assess the correlation between changes in driver mutation burden from diagnosis to 1 year 
of pembrolizumab therapy and response to therapy, the median JAK2V617F, MPLW515L/K 
and CALR allele burden (expressed as a percentage) will be computed at baseline, after 6 
cycles of treatment and at 1 year, with significant changes from baseline evaluated using the 
Wilcoxon signed rank test at each of the two follow-ups.  Among patients positive for each 
mutation, a linear mixed-effects model will be fit to log-transformed allele burden data with 


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patient as the random effect and time points as the fixed effect. The mean changes from 
baseline in PD-1 and PD-L1 and their standard errors will be derived at each time point from 
the model. 
 
8.2.4.6  Biomarker: Evaluate changes in Immune response gene expression profile as 
well as tumor microenvironment in bone marrow biopsy specimens using 
nanostring technology after 6 cycles of treatment with pembrolizumab. 
To evaluate changes in immune response, we will identify and characterize the gene expression 
signatures of both the global immune status as well as for each of the functional biological 
processes before therapy as well as at 6 cycles and 1 year post therapy. The regulation of these 
complex immunological processes involves hundreds of genes, many of which function in 
multiple biological processes. We anticipate that cases with different molecular make-up or 
outcome may have different immune response / microenvironment gene expression signature 
either in the global immune response level or at the level of selective functional biological 
process such as T-cell functions, cytokines or possible exctracellular matrix constituents, 
thereby could propose relevant immune response and potential resistance mechanisms to 
therapy. 
 
8.3 
 Interim Analysis 
In addition to periodic safety monitoring, a formal interim analysis will be performed after 9 
patients (from the primary cohort) have been assessed at the post cycle six assessments or at 
the time of withdrawal for those patients not completing six cycles of treatment. If at least one 
response is observed after six cycles of treatment, 15 additional patients will be accrued in the 
second stage. If no responses are observed the trial will be terminated. 
 
8.4 
   Sample Size Calculation 
Refer to Section 4.2.3: Study Design and Statistical Methods. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7.  Product Descriptions 


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Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
Icahn School of Medicine at Mount Sinai in New York, NY will serve as the Central Office 
for the management of this trial.  Under the guidance of Principal Investigator, Dr. John 
Mascarenhas, a Clinical Trials, will provide oversight and guidance on regulatory issues and 
trial management.  This trial will be monitored closely by a Clinical Research Coordinator who 


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will also be located at Icahn School of Medicine at Mount Sinai.  Biweekly meetings will be 
held to discuss this trial with the participating Sites andMerck.   
Lonette Sandy 
Clinical Trials Manager 
Icahn School of Medicine at Mount Sinai  
One Gustave L. Levy Place, Box  
New York, NY 10029 
212-241-4546(work) 
212-876-5276 (fax) 
 
10.1 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.2 Quality Management System 
10.3  Data Management Plan 
10.4  ELECTRONIC Data CAPTURE (edc) SYSTEM 
All computerized data entry will be performed by the Sponsor’s representative. All CRFs 
will be logged electronically and the data entered into a web-based electronic research 
application portal known as eRAP. eRAP’s role-based access control security and audit 
capability ensures that the research data is protected from unauthorized access, modification, 
and exposure. Key features of this web-based database system include allowing access and 
data entry from multiple sites, with each site having a separate pool of data as necessary. All 
data stored in the eRAP system is backed up daily. Detailed audit services include any data 
field level changes, who made the changes, when the changes were made, the old value and 
the new value. Data from eRAP can easily be extracted to excel or flat text file formats for 
easy import into SAS or other statistical software packages. 
 
 
11.0  DATA AND SAFETY MONITORING PLAN 
The site principal investigator (PI) will be responsible for ensuring participants’ safety on a 
daily basis. The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity 
to monitor participant safety, evaluate the progress of the study, to review procedures for 


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maintaining the confidentiality of data, the quality of data collection, and data management 
and analyses for all subjects. 
11.1 Frequency of Data and Safety Monitoring 
The Sponsor will be informed of serious adverse events as soon as they occur and will notify 
Merck within 24 hours of notification. The frequency of data review for this study differs 
according to the type of data and can be summarized in the following table. 
Data Type 
Frequency 
of 
Review 
Reviewer 
Stopping Rules 
(Treatment Response) 
Biweekly 
Quarterly 
Conference Call among 
sites 
PI, Sponsor,DSMB 
Subject 
accrual 
(including 
compliance 
with 
protocol 
enrollment criteria) 
Quarterly 
,Sponsor, DSMB 
Status of all enrolled subjects, 
as of date of reporting 
Quarterly 
Sponsor,  DSMB 
Adherence 
data 
regarding 
visits and intervention 
Quarterly 
Sponsor, DSMB 
AEs and rates (including out-of-
range lab values) 
Quarterly 
Sponsor, DSMB 
SAEs 
Per occurrence 
PI, Merck 
 
11.2  Contents of Data and Safety Monitory Report 
The content of the data and safety monitoring report will include study status, participant 
descriptive information, safety information and measures of study quality. See DSMR 
document for table templates. 
11.3  Safety Stopping Rules 
Sponsor and DBMB will meet quarterly to review the patient data for safety as related 
to the stopping rules as defined in this section. 
If a patient experiences grade 3 or higher toxicities (excluding grade 3/4 hematologic 
toxicity) deemed at least possibly related to the study drug (and not clearly disease related), 
or if grade 2 laboratory (excluding grade 2 hematologic toxicity) or clinical toxicities deemed 
at least possibly related to the study drug (and not clearly disease related) do not resolve 
within 3 weeks in spite of treatment, we will stop study drug administration.  
 
If, among the MF-CP (primary cohort) patients, 3 or more of the first 5, 4 or more of the first 
10, 6 or more of the first 15, or 7 or more of the first 24 patients stop study drug within the 
first 3 cycles due to toxicity as defined above in the previous paragraph, we will stop 


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enrolling patients to the primary cohort. The probability of stopping early if the true toxicity 
rate is 20%, 30%, 40% or 45% is 0.18, 0.51, 0.81, 0.91, respectively.  
 
If, among the MPN-AP/BP (exploratory cohort) patients, 2 or more of the first 5 or 3 or more 
of the first 10 patients, stop study drug within the first 3 cycles due to toxicity as defined above 
in the previous paragraph, we will stop enrolling patients to the exploratory cohort. The 
probability of stopping early if the true toxicity rate is 20%, 30%, 40% or 50% is 0.26, 0.48, 
0.66, 0.81, respectively. 
11.4  Efficacy Stopping Rules 
Sponsor and DBMB will meet quarterly to review data for efficacy as related to the stopping 
rules as defined in this section.     
 
Based on Simon’s optimal two stage design, 9 patients (among primary cohort patients only) 
will be enrolled at stage one. If no patient shows response, the study will be terminated.  
 


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12.0 APPENDICES 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
12.3 
Dynamic International Prognostic Scoring System (DIPSS) for primary 
myelofibrosis  
Values from anytime after diagnosis are acceptable to achieve score. 
DIPSS score 
The DIPSS score assigns points for the following five variables: 
 
Age >65 years: 1 point  
 
Leukocyte count >25,000/microL (>25 x 109/L): 1 point  
 
Hemoglobin <10 g/dL (<100 g/L): 2 points  


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 
Circulating blast cells ≥1%: 1 point  
 
Constitutional symptoms*: 1 point  
The resulting score is interpreted as follows: 
 
0 points – low risk  
 
1 to 2 points – intermediate-1 risk  
 
3 to 4 points – intermediate-2 risk  
 
5 to 6 points – high risk  
PMF: primary myelofibrosis; DIPSS: Dynamic International Prognostic Scoring System. 
* Constitutional symptoms include: Weight loss >10% of the baseline value in the year 
preceding PMF diagnosis, and/or unexplained fever or excessive sweats persisting for more 
than one month. 
Source: Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic 
International Prognostic Scoring System for primary myelofibrosis that incorporates 
prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 
2011; 29:392 
12.3 MPN-SAF TSS 
Medical History 
Modified Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) 
Fatigue (weariness, tiredness) in the past 24 hours 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Circle the one number that describes how, during the past week how much difficulty you have had with each 
of the following symptoms: 
Filling up quickly when you eat (Early satiety)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Abdominal discomfort  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Inactivity  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Problems with concentration - Compared to prior to 
my MPD 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Night sweats  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Itching (pruritus)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Bone pain (diffuse not joint pain or arthritis)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Pain under ribs on the left side  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Fever (>100 F)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)  
Unintentional weight loss last 6 months  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 


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References 
 
1. 
Passamonti F, Cervantes F, Vannucchi AM, et al: A dynamic prognostic model 
to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working 
Group for Myeloproliferative Neoplasms Research and Treatment). Blood 115:1703-8, 2010 
 
2. 
Harrison C, Kiladjian JJ, Al-Ali HK, et al: JAK inhibition with ruxolitinib 
versus best available therapy for myelofibrosis. N Engl J Med 366:787-98, 2012 
 
3. 
Verstovsek S, Mesa RA, Gotlib J, et al: A double-blind, placebo-controlled trial 
of ruxolitinib for myelofibrosis. N Engl J Med 366:799-807, 2012 
 
4. 
Rampal R, Levine RL: A primer on genomic and epigenomic alterations in the 
myeloproliferative neoplasms. Best Pract Res Clin Haematol 27:83-93, 2014 
 
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Mascarenhas J: Rationale for combination therapy in myelofibrosis. Best Pract 
Res Clin Haematol 27:197-208, 2014 
 
6. 
Quintas-Cardama A, Vaddi K, Liu P, et al: Preclinical characterization of the 
selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of 
myeloproliferative neoplasms. Blood 115:3109-17, 2010 
 
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Ciurea SO, Merchant D, Mahmud N, et al: Pivotal contributions of 
megakaryocytes to the biology of idiopathic myelofibrosis. Blood 110:986-93, 2007 
 
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Yang H, Bueso-Ramos C, DiNardo C, et al: Expression of PD-L1, PD-L2, PD-
1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating 
agents. Leukemia 28:1280-8, 2014 
 
9. 
Dolen Y, Esendagli G: Myeloid leukemia cells with a B7-2(+) subpopulation 
provoke Th-cell responses and become immuno-suppressive through the modulation of B7 
ligands. Eur J Immunol 43:747-57, 2013 
 
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Tamura H, Dan K, Tamada K, et al: Expression of functional B7-H2 and B7.2 
costimulatory molecules and their prognostic implications in de novo acute myeloid leukemia. 
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Ogata K, Kakumoto K, Matsuda A, et al: Differences in blast 
immunophenotypes among disease types in myelodysplastic syndromes: a multicenter 
validation study. Leuk Res 36:1229-36, 2012 
 
12. 
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 
122:1395-8, 2013 
 
13. 
Cheson BD, Bennett JM, Kopecky KJ, et al: Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin 
Oncol 21:4642-9, 2003 
 
14. 
Tefferi A, Barosi G, Mesa RA, et al: International Working Group (IWG) 
consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the 
IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood 108:1497-503, 2006