Clinical trial NCT01758588
Conditions: Myelofibrosis
Keywords: Primary myelofibrosis PMF
Sponsor: Weill Medical College of Cornell University
Start date: 2013-01-01; Completion date: 2017-06-01
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to look at the effectiveness of giving patients who have been newly diagnosed with untreated early stage primary myelofibrosis (PMF) a study drug called PEGINTRON (also known as pegylated interferon alfa 2b). This intervention will be compared to the widely employed "watch and wait" (best supportive care) approach for early stage PMF, in which patients are followed closely and treatment initiated only if the disease progresses.

Detailed description:
Subjects will be randomized into one of the study groups: one in which subjects get treated with PEGINTRON and the other in which subjects are closely followed and get best supportive care until disease progression (the presently accepted standard approach for early disease). Subjects on the observation arm will be carefully monitored for clinical or laboratory progression of disease during scheduled study visits. However, they will not be treated with an active drug like Interferon alfa or others such as Hydroxyurea, Revlimid, Thalidomide, Pomalidomide, and the newly approved JAK2 (Janus Kinase 2) inhibitor Ruxolitinib (Jakafi). If their disease progresses, they will be eligible for cross-over into the treatment arm with PEGINTRON. Subjects randomized to the treatment arm will receive PEGINTRON once weekly.

Arms: arm 1: Subjects will be monitored closely for disease progression, however will receive no intervention. arm 2: Peginterferon alfa-2a will be administered at a dose of 50 micrograms once a week for up to 3 years.
Interventions: intervention 1: Peginterferon alfa-2a
Intervention descriptions: intervention 1: 50 mcg subcutaneous injection once per week

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB Protocol Number: 1202012178 
Version 4.0 dated: October 30, 2013 
Clinicaltrials.gov ID: NCT01758588 
 
 
TITLE: Phase II randomized controlled trial of pegylated interferon alpha-2b in 
early primary myelofibrosis 
 
Coordinating center: 
Weill Cornell Medical College 
Division of Hematology and Medical Oncology 
 
Principal Investigator: 
Richard T. Silver, MD 
Weill Greenberg Building 
1305 York Ave, Box 581 
New York, NY 10021 
Tel: 646-962-2255 
Fax: 646-962-1607 
E-mail: rtsilve@med.cornell.edu 
 
Weill Cornell Medical College Therapeutic/Diagnostic protocol 
Principal Investigator 
Richard T. Silver, MD 
Division of Hematology/Medical 
Oncology 
Weill Greenberg Building 
1305 York Ave, Box 581 
New York, NY 10021 
Tel: 646-962-2255 
Fax: 646-962-1607 
E-mail: rtsilve@med.cornell.edu 
Co-investigators 
Ellen K. Ritchie, MD 
Eric J. Feldman, MD 
Gail J. Roboz, MD 
Joseph M. Scandura, MD, PhD 
Pinkal Desai, MD MPH 
Sangmin Lee, MD 
Andrew I. Schafer, MD 
Attilio Orazi, MD 
Division of Hematopathology 
525 East 68th Street 
Starr Pavilion, 715 
New York, NY 10065 
Tel: 212-746-2050 
Email: ato9002@med.cornell.edu 
Collaborating institution: Emory University 
Principal Investigator 
Elliott Winton, MD 
The Winship Cancer Institute of Emory 
University 
1365 Clifton Road North East 
Atlanta, GA 30322 
Tel: 1-888-946-7447 
E-mail: ewinton@emory.edu 
Collaborating institution: Georgetown University Hospital 
Principal Investigator 
Crag Kessler, MD 
Georgetown University Hospital 
3800 Reservoir Road North West 
Washington, DC 20007 
Tel: 202-444-8154 
E-mail: kesslerc@gunet.georgetown.edu 


ii 
 
 
 
 
Statistician: 
Regulatory Coordinator: 
 
Paul Christos, Dr. PH, MS 
Elizabeth Christopher, BS 
402 East 67th Street, Room 234 
425 East 61st Street, Suite 201 
New York, NY 10065 
New York, NY 10065 
Tel: 646-962-8018 
Tel: 646-962-9432 
Fax: 646-962-0281 
Fax: 646-962-1610 
E-mail: pac2001@med.cornell.edu 
E-mail: elc2025@med.cornell.edu 
 
Study Coordinator: 
Data Coordiantor: 
 
Elena Lascu, MA 
Stefani Gjoni, BS 
523 E. 70th Street, AN811 
523 E. 70th Street, AN811 
New York, NY 10021 
New York, NY 10021 
Tel: 212-746-2389 
Tel: 212-746-2389 
Fax: 212-746-8698 
Fax: 212-746-8698 
Email: ell2028@med.cornell.edu 
Email: stg9031@med.cornell.edu 
 
 
Protocol Version and Date: 
Original, Version 1 dated January 25, 2011 
Amendment 1, Version 2.0 dated December 19, 2012 
Amendment 2, Version 3.0 dated February 13, 2013 
Amendment 2, Version 3.1 dated July 19, 2013 
Amendment 3, Version 4 dated October 30, 2013 


i 
 
 
i 
 
SCHEMA 
 
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by 
the monoclonal proliferation of a multipotent hematopoietictic stem cell (HSC), and its 
pathologic effects on bone marrow stroma leading to marrow fibrosis, osteosclerosis, 
neoangiogenesis, and eventual marrow failure. Morbidity and mortality result from 
profound cytopenias, massive splenomegaly (from extramedullary hematopoiesis), its 
consequences, and leukemic transformation. 
 
Current treatments for PMF attempt to target the abnormal HSC proliferation as well as 
the pathologic stromal reaction and fibrotic process. However, these are often 
irreversible once the disease is in intermediate to advanced stages, when patients 
commonly become symptomatic and start treatment. Although allogeneic bone marrow 
transplantation is often the only “curative” option, most patients are unable to undergo 
this procedure owing to advanced age or poor performance status due to advanced 
disease. 
 
Recombinant Interferon alpha (rIFNα) has shown substantial anti-tumor activity in bcr- 
abl 
negative 
MPNs, 
particularly 
in polycythemia 
vera 
(PV) 
and 
essential 
thrombocythemia (ET) 24. Recent observational evidence, including that from a pilot trial 
performed at our institution, suggests that when used as monotherapy in early PMF, 
rIFNα-2b resulted in clinical improvement, decreased spleen size, and improved bone 
marrow morphology, with overall response in nearly 80% of patients. 
 
Therefore, we plan to expand on this observation by conducting a randomized 
controlled phase II trial of pegylated interferon alpha 2b (Pegintron) in patients with early 
PMF, with the hypothesis that starting treatment in the early phase of the disease will 
result in symptomatic improvement, retardation of bone marrow fibrosis, and 
improvement in overall survival. 


ii 
 
 
TABLE OF CONTENTS 
 
Page 
SCHEMA .......................................................................................................................... i 
1. OBJECTIVES ............................................................................................................ 1 
1.1 
Primary Objectives ........................................................................................ 1 
1.2 
Secondary Objectives ................................................................................... 2 
2. BACKGROUND ......................................................................................................... 2 
2.1 
Disease .......................................................................................................... 2 
2.2 
Investigational Agent ....................................................................................... 4 
2.3 
Rationale ........................................................................................................ 6 
3. PATIENT SELECTION .............................................................................................. 7 
3.1 
Inclusion Criteria ........................................................................................... 7 
3.2 
Exclusion Criteria .......................................................................................... 8 
4. REGISTRATION PROCEDURES .............................................................................. 9 
4.1 
Central Patient Registration ......................................................................... 9 
5. TREATMENT PLAN ................................................................................................ 10 
5.1 
Agent Administration .................................................................................. 10 
5.2 
General Concomitant Medication and Supportive Care Guidelines ....... 10 
5.3 
Duration of Therapy and Criteria for Removal from Study ...................... 11 
5.4 
Duration of Follow Up ................................................................................. 11 
6. DOSING DELAYS/DOSE MODIFICATIONS ........................................................... 12 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ......................... 13 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ....... 13 
7.2 
Adverse Event Characteristics ................................................................... 13 
7.3 
Recording of Adverse Event ...................................................................... 14 
7.4 
Serious Adverse Event Reporting .............................................................. 14 
8. AGENT INFORMATION .......................................................................................... 15 
8.1 
Pegylated interferon alpha-2b .................................................................... 15 
8.2 
Availability ................................................................................................... 16 
8.3 
Agent Ordering ............................................................................................ 16 
8.4 
Agent Accountability................................................................................... 16 
9. CORRELATIVE/SPECIAL STUDIES ....................................................................... 17 
9.1 
Laboratory Correlative Studies .................................................................. 17 
9.2 
Special Studies ............................................................................................ 17 
ii 


i 
 
 
iii 
10. STUDY CALENDAR ................................................................................................ 18 
11. MEASUREMENT OF EFFECT ................................................................................ 19 
11.1 
Response Criteria ....................................................................................... 19 
11.2 
Duration of response .................................................................................. 19 
12. DATA REPORTING / REGULATORY CONSIDERATIONS .................................... 19 
12.1 Data Collection ............................................................................................ 19 
12.2 
Regulatory Considerations ........................................................................ 20 
12.3 
Data safety monitoring board ..................................................................... 20 
13. STATISTICAL CONSIDERATIONS ......................................................................... 22 
13.1 Study Design/Endpoints ................................................................................ 22 
13.2 Sample Size/Accrual Rate ............................................................................. 22 
13.3 Stratification Factors ..................................................................................... 23 
13.4 Analysis of Endpoints……………………………………………………………. 23 
13.5 Reporting and Exclusions……………………………………………………….. 23 
REFERENCES .............................................................................................................. 24 
APPENDICES 
APPENDIX A 
Performance Status Criteria ................................................................................ 28 
APPENDIX B 
WCMC SAE Reporting Forms… ......................................................................... 29 


 
1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
Primary efficacy objectives: 
1. The primary efficacy objective in patients treated with peginterferon alfa-2b, is 
improved clinical status, which is defined as clinical improvement (CI) in the response 
criteria of the International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT) 
 
Clinical improvement (CI) requires one of the following in the absence of both disease 
progression (as outlined below) and CR/PR assignment (CI response is validated only if 
it lasts for no less than 8 weeks): 
 
i. 
A minimum 20-g/L increase in hemoglobin level or becoming transfusion 
independent (applicable only for patients with baseline hemoglobin level of less 
than 100 g/L). ‡ 
 
ii. 
Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at 
least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline 
becomes not palpable.§ 
 
iii. 
A minimum 100% increase in platelet count and an absolute platelet count of at 
least 50,000 x 109/L (applicable only for patients with baseline platelet count 
below 50 x 109/L). 
 
iv. 
A minimum 100% increase in ANC and an ANC of at least 0.5 x 109/L (applicable 
only for patients with baseline absolute neutrophil count below 1 x 109/L). 
 
v. 
Normalization of bone marrow cellularity and architecture, including reduction in 
reticulin and collagen fibrosis, normalization of cellularity, and decreased 
megakaryocyte atypia 
 
vi. 
Complete or partial (> 50%) reduction in cytogenetic abnormalities, if present at 
diagnosis 
 
‡ Transfusion dependency is defined by a history of at least 2 units of red blood cell 
transfusions in the previous month for a hemoglobin level of less than 85 g/L, not 
associated with clinically overt bleeding. Similarly, during protocol therapy, transfusions 
for a hemoglobin level of 85 g/L or more is discouraged unless it is clinically indicated. (It 
is presumed that patients in this study will not have transfusion requirements, since it 
will primarily enroll those with early stage disease) 
 
§ In splenectomized patients, palpable hepatomegaly is substituted with the same 
measurements. 




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2 
 
 
 
1.2. 
Secondary Objectives 
1. Assessment of progression free survival and overall survival at study 
completion 
2. Decrease in myelofibrosis symptom burden (MF-SB) as assessed by a 50% 
reduction in MPN-SAF TSS51,54. 
 
2. BACKGROUND 
 
2.1 Disease 
 
A. Primary Myelofibrosis: Pathogenesis and pathophysiology 
 
The myeloproliferative neoplasms (MPNs) comprise a heterogeneous group of 
disorders that arises from the abnormal clonal expansion of a pluripotent 
hematopoietic stem cell 1-2. Of the three classical BCR-Abl negative MPNs (PV, ET 
and PMF), primary myelofibrosis (PMF) has the worst overall morbidity and 
mortality3. The quality of life for patients with PMF is compromised by progressive 
anemia, marked hepatosplenomegaly, severe constitutional symptoms including 
cachexia, and eventual leukemic transformation in up to 20% during their disease 
course 2-3. Median age at diagnosis is 60 years, and 10% of patients are less than 
45 years of age at diagnosis4. 
 
The clonal proliferation of a pluripotent hematopoietic stem cell (HSC) and its 
pathologic interaction with the bone marrow stroma (microenvironment) are thought 
to be the primary pathogenetic mechanisms of disease in PMF. Results of clonality 
studies, including X-chromosome inactivation studies in female patients with PMF6 
and G6PD isoenzyme analysis7, strongly suggest monoclonal expansion of a 
mutated HSC as the disease initiating factor. Furthermore, the presence of the clonal 
abnormality in terminally differentiated myeloid and lymphoid cells, suggests that the 
originating HSC clone retains the ability to fully mature into myeloid and lymphoid 
cell lines8, 9. Although cytogenetic studies have shown a variety of chromosomal 
abnormalities in PMF, including del(20)(q11;q13), del(13)(q12;q22), trisomy 8, 
trisomy 9, and others, there is no consistent cytogenetic pattern in this disease, 
analogous to BCR-Abl in CML5. Aside from the JAK2V617F mutation (seen in up to 
50% of patients) and mutations in MPL (8% of patients), there are few molecular 
abnormalities that are consistently seen in PMF10. 
 
The bone marrow stromal cells play a large role in the pathophysiology of PMF. 
These include cells derived from mesenchymal stem cells (MSCs), and endothelial 
cells1. Although the clonal abnormality in the HSC is not present in bone marrow 
stromal stem cells 11, 12, and they exhibit normal growth and function ex vivo 13, the 
bone marrow in PMF is characterized by increased collagen fibrosis, neo- 
angiogenesis, and abnormal bone formation (osteosclerosis) 1, 5. This supports the 
notion that a maladaptive interaction of the abnormal HSC clone and its progenitors 
with an otherwise normal bone marrow stroma, leads to the characteristic changes in 


3 
3 
 
 
 
bone marrow histology in PMF. This is further supported by the observation that the 
pathologic stromal changes in the marrow are reversed after allogeneic stem cell 
transplantation in patients with PMF 17. 
 
Several lines of evidence strongly implicate the megakaryocyte derived from the 
clonal HSC in altering the bone marrow stroma through elaboration of cytokines 
including transforming growth factor-beta (TGF-beta), vascular endothelial growth 
factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth 
factor (PDGF) 
1,5,14-16. As a result of the alteration in the bone marrow 
microenvironment, there is an egress of HSC stem cells from the bone marrow as 
the disease progresses, with a drastic increase in extramedullary hematopoiesis in 
the spleen, liver, and lungs 1,5, resulting in hepatosplenomegaly and pulmonary 
hypertension that are characteristic of the disease. 
 
The aforementioned disease mechanisms have important therapeutic implications. 
In order for meaningful clinical benefit, a drug should effectively target both the HSC 
clonal proliferation and retard or reverse the abnormal stromal reaction in the bone 
marrow and extramedullary sites of hematopoiesis. 
 
B. Diagnostic and Prognostic Criteria 
 
The WHO diagnostic criteria for PMF incorporate both bone marrow morphological 
and clinical features, and distinguish between early (pre-fibrotic) and advanced 
disease18,19. The WHO major bone marrow morphologic criterion is the presence of 
megakaryocyte proliferation and atypia with or without reticulin and/or collagen 
fibrosis 18. In the absence of reticulin fibrosis, megakaryocyte changes must be 
accompanied by an increased bone marrow cellularity characterized by granulocytic 
proliferation and often decreased erythropoiesis (i.e., prefibrotic cellular-phase 
disease) 18. Minor diagnostic criteria include palpable splenomegaly, anemia, 
leukoerythroblastosis, and elevated LDH 18,19. 
 
The IWG-MRT Dynamic International Prognostic Scoring System (DIPSS) stratifies 
PMF into four risk categories (low, intermediate 1, intermediate 2, and high risk), 
based on 5 clinical factors; Age>65, Hemoglobin <10gm/dL, WBC>25,000/uL, 
peripheral blasts>1%, and constitutional symptoms20,21. The median overall survival 
ranges from 135 months to 27 months for DIPPS low risk to high risk disease, 
respectively20,21. Risk factors independent of the DIPSS have also been identified 
and include platelet count<10047, and cytogenetic risk profile 48. 
 
Patients with pre-fibrotic and early fibrotic (reticulin fibrosis grade 0 to +1) PMF have 
hypercellular bone marrows with aforementioned atypical megakaryocytes in 
clusters, granulocytic proliferation, relative erythroid hypoplasia, and peripheral 
thrombocytosis18,19. This early phase of the disease, also referred to as the “cellular 
phase” of PMF, may be more responsive to treatment22,23. 


4 
4 
 
 
 
 
 
2.2 Pegylated Interferon alpha 2b (peg-IFNα-2b) 
 
A. Mechanism of Action 
 
Recombinant Interferon alpha (rIFNα) has shown substantial anti-tumor activity in 
bcr-abl negative MPNs, particularly in PV and ET24-26. The use of rIFNα in PMF is 
based upon its effectiveness in treating polycythemia vera with fibrosis,24,25, 27, 28 and 
on its biological  effects on megakaryopoiesis and hematopoietic stem cells.29-34 
Effects on megakaryopoiesis include decreasing megakaryocyte density and size,29 
inhibiting thrombopoietin-induced signaling,30 and antagonizing the action of platelet- 
derived growth factor,31 all of which play a major role in the pathogenesis of 
PMF.32,33 IFNα directly inhibits colony forming unit megakaryocyte proliferation and 
differentiation by blunting in vitro, possibly by inhibiting the JAK/STAT signaling 
responses that occur in response to thrombopoietin (TPO), and impairing TPO- 
induced intracellular signaling by up-regulating SOCS-1 expression45. Furthermore, 
IFNα 
directly 
inhibits 
cytoplasmic maturation 
and 
platelet 
production 
by 
megakaryocytes without affecting proliferation of megakaryocyte progenitor cells 
endomitosis of human megakaryocytes45. 
 
Recent evidence of the pro-apoptotic effects of rIFNα in a variety of tumor cells of 
diverse origin also indicated potential for treating patients with PMF.34 In vitro 
studies have shown that IFNα can reduce the colony-forming ability of myeloid 
progenitor cells in PV and PMF40, with suggestion of an increased sensitivity of the 
abnormal clone to IFNα compared to the normal counterpart41. In vivo studies from 
patients with PV have shown reconstitution of polyclonal hematopoiesis in patients 
treated with IFNα41. It is generally agreed that rIFNα has no beneficial effect in 
advanced PMF, when the marrow is extensively myelofibrotic and/or osteosclerotic 
without residual hematopoietic cells.22,35,36 
 
Pegylated interferon alfa 2b (peg-IFNα-2b) is produced by attaching a 12,000-Da 
monomethoxypolyethylene glycol (PEG12,000) polymer to the native IFN-a-2b37. 
This increases drug solubility and stability, thereby increasing serum half life, and 
allows weekly administration, instead of 2 to 3 times per week dosing of rIFNα-2b37. 
The toxicity profile is comparable to rIFNα-2b40. 
 
B. Clinical Studies 
In a pilot study which used rIFNα to treat patients with early PM, 17 patients meeting 
WHO PM diagnostic criteria received either rIFNα-2b 500,000-3,000,000 units thrice 
weekly, or peg-rIFNα-2a 45 or 90 mcg weekly38. Dose was adjusted based upon 
response and tolerance. IWG-MRT prognostic and response criteria were used. 
Eleven patients were women, and 6, men. The median age at diagnosis was 57 
years. Median baseline leukocyte, hematocrit, hemoglobin, and platelet values were 
8.7  K/uL,  35.5%,  11.7  g/dL,  and  404,000/uL,  respectively,  and  did  not  change 


5 
5 
 
 
 
substantially with treatment. Eleven patients were low risk, and 6, intermediate-1 
risk.  Two achieved complete remission, 7 partial remission, 1 clinical improvement, 
4 stable disease, and 3 progressive disease. Ten of 17 (58.8%) derived clinical 
benefit, and 4 (23.5%), disease stability. Thus, more than 80% derived clinical 
benefit or stability. Control of splenomegaly was maintained in 15 of 17. Reduction in 
myelofibrosis and improvement in megakaryocyte morphology occurred in 4. Toxicity 
was acceptable, and detailed below (see safety profile). 
 
A recent multicenter retrospective study of peg-IFNα-2a in 18 patients with primary 
and secondary myelofibrosis showed complete remission and/or major responses in 
44% of patients, with only 2 discontinuations due to loss of efficacy or symptomatic 
phase of disease46. Anemia improved in 80% of patients and, peg-IFNα-2a had a 
more specific and rapid response in those patients with leukocytosis or 
thrombocytosis at start of treatment, illustrating its anti-proliferative effects. The 
majority of hematologic responses were seen within 3 to 6 months46. 
 
A recent phase II trial of peg-IFNα-2b in 40 patients with various MPNs including PV, 
ET, PMF, hypereosinophilic syndrome, and unclassified MPN, showed variable 
response rates for each specific disease, with 1 of 11 patients with PMF achieving 
response37. However, the stage of PMF was unspecified in this study. Overall 
response was 45% with a median duration of response of 20 months and 3 
sustained responses (>24 months). Although toxicity was reported in 26% of 
patients, high starting doses of 3mcg/kg/week were used, a dose which can cause 
more adverse effects including decreased neutrophil counts39. Another phase II 
study of rIFNα-2b in MPNs reported objective responses and/or disease stabilization 
in PV, ET, and PMF, with reversal of splenomegaly and resorption of fibrosis in 
some patients40. 
 
C. Pharmacokinetics 
 
The 12kDa Peg-IFNα-2b is administered subcutaneously and has an absorption 
half-life of 4.3 hours (compared with 2.1 hours for rIFNα-2b), a volume of distribution 
of 0.99L/kg, a serum peak to trough ratio>10 (with multiple doses), and an 
elimination half-life of 40 hours42. This translates to relatively rapid absorption, and 
wide volume of distribution. The relatively large volume of distribution usually 
necessitates body weight-based dosing during the induction phase of treatment, in 
order to achieve reasonable drug levels42. Soon after injection, peg-IFNα-2b breaks 
down to  release free IFNα-2b, which is renally excreted. Therefore, dose 
modification is required in patients with impaired renal function (creatinine 
clearance<50mL/min), with 25% dose reduction for moderate renal dysfunction (CrCl 
30-50mL/min) and 50% dose reduction for severe renal dysfunction (CrCl 10-29 
mL/min). 
 
 
D. Safety profile in studies of rIFNα-2b in MPNs 


6 
6 
 
 
 
The side effects most commonly observed with peg-IFNα-2b are similar to those 
seen with rIFNα-2b, namely fever and flu-like symptoms, neuropsychiatric symptoms 
including depression, and peripheral cytopenias, including neutropenia and 
thrombocytopenia42. A summary analysis of 35 clinical trials of rIFNα-2b in ET and 
PV showed an average discontinuation rate of 25% with approximately half the 
withdrawals occurring during the first year of therapy41. In the pilot study of 17 
patients with PMF, toxicity was generally mild (grade 1 or 2) and included asthenia, 
fatigue, myalgias not requiring dose reduction. Eleven patients had hematologic 
toxicity including anemia (n=7: 6 grade 1-2,1 grade 4), thrombocytopenia (n=5: 4 
grade 1-2, 1 grade 3), and leukopenia (n=3: all grade 1). Ten patients had metabolic 
toxicity: 9 with grade 1-2 LFT abnormalities, 3 with grade 1 hypocalcemia, and 1 
patient with hyperthyroidism requiring discontinuation of rIFNα-2b38. 
 
E. Safety profile of peg-IFNα-2b in treatment of hepatitis C 
In a phase 3 randomized controlled trial with 1,210 patients comparing rIFNα-2b to 
peg-IFNα-2b as initial monotherapy for hepatitis C, the two drugs were similar with 
respect to safety and tolerability43. Three doses of peg-IFNα-2b (0.5mcg/kg/wk, 1.0 
mcg/kg/wk, and 1.5 mcg/kg/wk) were compared to 3 MIU rIFNα-2b TIW. The 
incidence of serious adverse reactions was similar (about 12%) in all treatment 
groups. The most common adverse events were flu-like symptoms, and a two-fold 
increase in injection site reactions with peg-IFNα-2b. Dose reduction due to 
neutropenia occurred infrequently for both drugs, with 5% requiring dose reduction in 
the 1.5mcg/kg group and 2-3% in the lower dosage groups. Incidence of dose 
reduction and adverse events was dose related and increased with higher doses43. 
2.3      Rationale 
 
Primary Myelofibrosis is characterized by stem cell-derived clonal myeloproliferation, 
ineffective 
erythropoiesis, 
abnormal 
leukocyte 
and 
platelet 
production, 
extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. 
Patients with PMF have shortened survival and their quality of life is compromised 
by progressive anemia, marked hepatosplenomegaly, and severe constitutional 
symptoms including cachexia. After decades of ineffective therapy, patients are now 
being treated earlier in their disease with approaches such as interferon alpha. 
Such progress calls for standardization of response criteria to accurately assess the 
value of new treatment modalities, to allow accurate comparison between studies, 
and to ensure that the definition of response reflects meaningful health outcome. 
Accordingly, the International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT), an international panel of experts, delineated 3 response 
categories:   complete   remission   (CR),   partial   remission   (PR),   and   clinical 
improvement (CI) 
44. These criteria address improvement in all of the 
aforementioned characteristic features of PMF. Bone marrow histologic and 
hematologic remissions characterize CR and CR/PR, respectively. CI reflects an 
improvement in quality of life, as measured by improvement in anemia, 
thrombocytopenia, neutropenia, and hepatosplenomegaly. 


7 
7 
 
 
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
3.1.1 Patients must meet laboratory, and bone marrow histological criteria 
for primary myelofibrosis based on the WHO diagnostic criteria as 
outlined in Table 118. 
 
Table 1: Proposed Criteria for PMF 
 
 
3.1.2 Patients must have Low or Intermediate 1 stage of disease as defined 
by International Working Group (IWG) risk stratification of primary 
myelofibrosis in the dynamic international prognostic scoring system 
(DIPSS). Patients must have >15% of marrow biopsy area showing 
hematopoietic marrow, irrespective of degree of fibrosis (reticulin 
and/or collagen)as defined by Manoharan criteria49. 
 
3.1.3 Patients should NOT have had prior therapy for primary myelofibrosis. 
This includes treatment with cytoreductive drugs (Hydroxyurea), 
immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), 
JAK2 inhibitors, or other therapies specifically for myelofibrosis. If they 
received these classes of drugs for indications other than PMF, 
treatment should be discontinued at least 6 weeks prior to 
randomization. 
 
3.1.4 Age >18 years. 
 
3.1.5 performance status < 2 
Major Criteria (must meet both major critieria) 
1. 
Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin 
and/or collagen fibrosis, or, in the absence of significant reticulin fibrosis, the megakaryocyte 
changes must be accompanied by an increased bone marrow cellularity characterized by 
granulocytic proliferation and often decreased erythropoiesis (ie. prefibrotic cellular-phase 
disease) 
2. 
Not meeting WHO criteria for PV, CML. MDS, or other myeloid neoplasm 
Minor Criteria (must meet at least two minor criteria) 
1. 
Leukoerythroblastosis 
2. 
increase in serum LDH 
3. 
Anemia 
4. 
Palpable splenomegaly 
5. 
Platelet count > 450,000/µL* 
*This  criterion  is  based  on  clinical  observations of  early,  pre-fibrotic  cases  of 
myelofibrosis in the absence of any of the 4 minor criteria proposed by WHO in 2008. 


8 
8 
 
 
 
 
3.1.6 Patients  must  have  normal  organ  and  marrow  function  as  defined 
below: 
 
o WBC 
>3,000/L 
o ANC 
>1,500/L 
o Platelets 
>100,000/L 
o Total bilirubin 
within normal limits 
o AST(SGOT)/ALT(SGPT) 2.5 X upper limit of normal 
o Creatinine Clearance 
≥50 ml/min 
 
3.1.7 The effects of peg-IFNα-2b on the developing human fetus at the 
recommended therapeutic dose are unknown. For this reason, women 
of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation. Should a 
woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician 
immediately. 
 
3.1.8 Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 6 weeks 
prior to entering the study or those who have not recovered from 
adverse events due to agents administered more than 6 weeks earlier. 
 
3.2.2 Patients with Intermediate 2 or High risk stage of disease as defined by 
International Working Group (IWG) risk stratification of primary 
myelofibrosis in the dynamic international prognostic scoring system 
(DIPSS) and/or less than 15% of bone marrow biopsy area showing 
hematopoietic marrow, irrespective of degree of reticulin fibrosis (by 
Manoharan criteria49), or collagen fibrosis, or osteosclerosis.. 
 
3.2.3 Patients may not be receiving any other investigational agents. 
 
3.2.4 History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to peg-IFNα-2b 
 
3.2.5 
Other Exclusion Criteria 
o Female patients who are pregnant or breast feeding 
o History of depression or active treatment for depression 
o History of non-compliance to medical regimens 


9 
9 
 
 
 
o History of autoimmune diseases 
o History of hypothyroidism or hyperthyroidism 
o Clinical evidence of neuropathy 
 
3.2.6 Uncontrolled illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart 
failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.2.7 Pregnant and lactating women are excluded from the study because 
the risks to an unborn fetus or potential risks in nursing infants are 
unknown. 
 
4. REGISTRATION PROCEDURES 
 
4.1 Central Patient Registration 
 
Patients will be centrally registered with the Department of Medicine, Joint 
Clinical Trials Office (JCTO). To register a patient, email the following 
documents 
to 
the 
JCTO 
at 
raa2017@med.cornell.edu 
and  
nec2006@med.cornell.edu (registrations can also be faxed to 646-962-1610 
but an email/phone call should accompany the fax to confirm receipt of 
registration packet): 
 
 WCMC Patient registration form 
 First and last page of the fully executed informed consent form, plus 
additional pages if checkboxes for correlative studies are required. 
 Fully executed HIPAA research authorization form 
 Eligibility  checklist  signed  and  dated  by  investigator  and research 
nurse/study coordinator 
 Documentation of any eligibility waivers granted 
 De-identified source documentation to confirm eligibility 
 For inpatients, signed consent documentation template (WCMC only) 
 
Central registration information is reviewed and entered into the Hem/Onc 
centralized research database. (For WCMC only) Documentation of patient 
registration will be faxed to the Investigational Pharmacy to allow for release 
of study agent. Patient is eligible to begin treatment once a confirmation email 
has been sent to study team. (For sub-sites) Once email confirmation from 
WCMC is received, follow your institutional pharmacy guidelines on releasing 
drug. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 


10 
10 
 
 
 
 
Treatment will be administered on an outpatient basis. Patients will be 
randomized to either the treatment arm or the control arm of the study with a 
2:1 allocation ratio. There will be a total of 47 patients in the study. Thirty-one 
patients will be in the peg-interferon alfa-2b arm and 16 patients in the control 
arm. 
 
Starting dose in the treatment arm will be 50 micrograms (mcg) of 
peginterferon alfa-2b subcutaneously (SC) per week. If a partial response 
(PR) or clinical improvement (CI) (as defined by IWG-MRT criteria) is not 
seen in the first 8 weeks, and toxicity (hematologic and non-hematologic) is 
no more than Grade 2, dose will be increased to the next defined dose level 
as outlined in section 6.2. The dose will be escalated every 8 weeks until at 
least PR or  CI is  achieved, at which point the dose will be maintained, 
provided toxicity does not exceed Grade 2 in severity. The maximum dose of 
peg-IFNα-2b will be 150 mcg Qweek. 
 
Given that observation until disease progression is a generally accepted 
standard of care for low and intermediate 1 stage PMF53, patients in the 
observation arm will be followed closely at 4 to 8 week intervals. If patients in 
the observation arm develop disease progression to the next higher DIPSS 
stage from diagnosis or have an increase in marrow fibrosis detectable by 
reticulin stain on sequential bone marrow biopsies, they will cross over to the 
treatment arm. 
 
Reported adverse events and potential risks are described in Section 7. 
Appropriate dose modifications for peg-IFNα-2b are described in Section 6. 
No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient’s 
malignancy. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
In general, concomitant medications and therapies deemed necessary for the 
supportive care and safety of the patient are allowed, provided their use is 
documented in the patient’s medical records. The administration of anticancer 
agents including chemotherapy and biologic agents are NOT permitted. 
 
Once on study, if cytoreductive therapy is required for patients randomized 
to the observation arm, only hydroxyurea may be used. Other cytoreductive 
drugs are not allowed. 
 
 
5.3 
Duration of Therapy and Criteria for Removal From Study 


11 
11 
 
 
 
In the absence of treatment delays due to adverse event(s), treatment may 
continue for 3 years or until one of the following criteria applies: 
 
o Disease progression55 defined as: 
 
Appearance of a new splenomegaly that is palpable at least 5 cm 
below the LCM, OR 
 
A ≥100% increase in palpable distance, below LCM, for baseline 
splenomegaly of 5 to 10 cm, OR 
 
A 50% increase in palpable distance, below LCM, for baseline 
splenomegaly of >10 cm, OR 
 
Leukemic transformation confirmed by a bone marrow blast count 
of ≥20%, OR 
 
A peripheral blood blast content of ≥20% associated with an 
absolute blast count of ≥1 x 10(9)/L that lasts for at least two 
weeks, OR 
 
Painful splenomegaly 
o Intercurrent illness that prevents further administration of treatment, 
 
o Unacceptable adverse event(s), 
 
o Patient decides to withdraw from the study, or 
 
o General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator 
 
o Patient becomes pregnant 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for a minimum of 3 years or study completion (to be 
defined). Patients will be followed at regular 4 to 8 week intervals during the 
study and after removal from study or until death, whichever occurs first. 
Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. 
 
Bone marrow biopsy from the posterior iliac crest will be performed once 
yearly during study follow up period. Bone marrow biopsies will undergo 
blinded hematopathologic evaluation by Dr. Attilio Orazi, Chief of the Division 
of Hematopathology at Weill Cornell Medical College. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
All interruptions, reductions, or any changes in study drug administration will 
be captured on the flow sheets. 


12 
12 
 
 
 
 
6.2 
With the exception of grade 3 or 4 non-hematologic toxicity, any patient 
receiving a reduced dose and who does not achieve or maintain a partial 
response (PR), complete response (CR), or clinical improvement (CI), may 
have the dose re-escalated to the preceding dose after a minimum of 6 
weeks of therapy provided no toxicities > grade 2 were observed at the 
reduced dose. 
 
 
Treatment Dose Levels 
Dose Level* 
Peg-IFNα-2b  Dose 
-2 
25 mcg SC Qweek 
-1 
40 mcg SC Qweek 
0 
50 mcg SC Qweek 
+1 
80 mcg SC Qweek 
+2 
96 mcg SC Qweek 
+3 
120 mcg SC Qweek 
+4 
150 mcg SC Qweek 
 
 
6.3 
Grade 2 Non-hematologic toxicity 
If a patient experiences grade 2 non-hematologic toxicity lasting for more than 
3 days at a specific dose level, peg-IFNα-2b must be withheld until the toxicity 
has resolved to less than grade 1. Peg-IFNα-2b may then be restarted at the 
same dose level. If grade 2 toxicity recurs, peg-IFNα-2b may be resumed at 
the next lower dose level as outlined in the table above. 
 
6.4 
Grade 3-4 Non-Hematologic Toxicity 
If a patient experiences grade 3-4 non-hematologic toxicity at a specific dose 
level, peg-IFNα-2b must be withheld until the toxicity has resolved to less 
than grade 1. Peg-IFNα-2b may then be restarted at the next lower dose level 
as outlined in the table above. If grade 3-4 toxicity recurs again, treatment will 
be stopped, and further treatment after any interruptions of more than 2 
weeks is not permitted. The subject will go off study and alternative treatment 
may be pursed if deemed appropriate. 
 
6.5 
Grade 1 or 2 Hematologic Toxicity 
No dose reductions or interruptions in treatment will occur for grade 1 or 2 
hematologic toxicity 
 
6.6 
Grade 3 or 4 Hematologic toxicity 


13 
13 
 
 
 
If a patient experiences grade 3 or 4 hematologic toxicity, defined as an 
ANC<1.0x109/L or a platelet count <50x109/L, peg-IFNα-2b must be withheld 
until the toxicity has resolved to < grade 2. ANC will take precedence over a 
WBC count in the determining the degree of neutropenia (doses should be 
interrupted  for  a  patient  with  a  WBC  count  <  2.0x109/L  even  if  ANC 
>1.0x109/L). If the toxicity resolves within 2 weeks, treatment may be 
resumed at the same dose level. If the grade 3 or 4 toxicity recurs or persists 
for longer than 2 weeks, peg-IFNα-2b must be withheld and reduced to the 
next lower dose level once toxicity has resolved to < grade 2. 
 
7. ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. 
The investigator will be required to provide appropriate information concerning any 
findings that suggest significant hazards, contraindications, side effects, or 
precautions pertinent to the safe use of the drug under investigation. Safety will be 
monitored by evaluation of adverse events reported by patients or observed by 
investigators or research staff, as well as by other investigations such as clinical 
laboratory tests, x-rays, electrocardiographs, etc. 
 
7.1 Pegylated IFN-alfa 2b Risks 
 
Common adverse events associated with the dosage range for peg-IFN-alfa 2b that 
will be used in this study include flu-like symptoms, gastrointestinal symptoms, 
psychiatric symptoms, and dermatologic symptoms. The relative frequency of these 
adverse events that were seen in a phase III randomized controlled trial of 1,299 
patients comparing peg-IFN-alfa 2b to Interferon alfa 2b in hepatitis C, are shown in 
table 2. 
 
Table 2: Adverse Event Frequency observed in phase III trial of Peg-IFNα-alfa 2b 
monotherapy in hepatitis C 43 
Toxicity 
Peg-IFN-alfa 2b 
0.5mcg/kg QW 
Peg-IFN-alfa 2b 
1.0mcg/kg QW 
Peg-IFN-alfa 2b 
1.5mcg/kg QW 
Influenza like symptoms 
Headache 
Fatigue 
Chills 
Fever 
Myalgia 
Muskuloskeletal pain 
61 
43 
34 
31 
48 
19 
64 
51 
40 
45 
54 
28 
58 
50 
33 
30 
53 
22 
Gastrointestinal 
symptoms 
Nausea 
Anorexia 
21 
10 
26 
20 
20 
17 
Psychiatric Symtpoms 
Irritability 
Insomnia 
19 
17 
18 
23 
24 
23 
Dermatologic Symptoms 
Alopecia 
Injection site reactions 
20 
44 
22 
42 
22 
16 


14 
14 
 
 
 
 
7.2 
Adverse Event Characteristics 
 
 
CTCAE term (AE description) and grade: The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific adverse event log. 
The AE log will be maintained by the research staff and kept in the patient’s 
research chart. 
 
7.4 Serious Adverse Event (SAE) Reporting 
 
7.4.1. Definition of SAE 
 
SERIOUS ADVERSE EVENTS include death, life threatening adverse 
experiences, 
hospitalization 
or 
prolongation 
of 
hospitalization, 
diagnosis of a new malignancy, disability or incapacitation, overdose, 
congenital anomalies and any other serious events that may 
jeopardize the subject or require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
7.4.2. Reporting of SAE to WCMC IRB 
 
All SAEs occurring on this study will be reported to the WCMC IRB 
according to the WCMC IRB policy. The WCMC IRB requires 
immediate reporting (within 48 hours) of all unexpected and study- 
related (definite or probable) adverse events that results in an 
increased harm or risk to study participants. The following procedure 
will be utilized for reporting SAEs to the WCMC IRB: 
 
 
Complete the WCMC SAE Cover Sheet, the WCMC IRB 
Immediate Reporting Form, and the Voluntary MedWatch 
Form (Form FDA 3500). 


15 
15 
 
 
 
 
Submit this form within 48 hours of investigator notification of 
the event. 
 
Sub-sites: Follow local IRB guidelines for reporting to your 
IRB. If your IRB requires a revision to the consent form, 
notify WCMC immediately. 
 
SAEs that do not meet the immediate reporting criteria listed 
above should still be reported to the WCMC IRB within 48 
hours. For these SAEs, only send the WCMC SAE Cover 
Sheet and the Voluntary MedWatch Form (Form FDA 3500). 
 
A request for SAE forms or questions regarding SAEs may be 
directed 
to 
Elizabeth 
Christopher 
via 
email 
at  
elc2025@med.cornell.edu. 
 
 
7.4.3. Reporting of SAE to FDA 
If an SAE occurs on this study, the event will be filed on a MedWatch 
form and sent to Merck. 
 
7.4.4. Reporting of SAE to Merck 
 
Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) will 
be provided with copies of all serious adverse experiences, within two 
working days. Additionally, any pregnancy occurring in association with use 
of a Merck Product will be reported to Merck & Co., Inc. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) regardless of drug relationship. 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted by 
the investigator as required by FDA, European Union (EU), Pharmaceutical 
and Medical Devices agency (PMDA) or other local regulators. This 
submission will be cross-referenced according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of 
submission.  Additionally, a  copy of these reports will be submitted to Merck 
& Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time 
of submission to FDA. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with pegylated IFN-alfa 2b 
can be found in Section 7.1. 
 
8.1 
Pegylated Interferon-alfa 2b 
PegIntron, peginterferon alfa-2b, is a covalent conjugate of recombinant alfa-2b 
interferon with monomethoxy polyethylene glycol (PEG). The average molecular 
weight of the PEG portion of the molecule is 12,000 daltons. The average molecular 


16 
16 
 
 
 
weight of the PegIntron molecule is approximately 31,000 daltons. The specific 
activity of  pegylated interferon alfa-2b is approximately 0.7 × 108 international 
units/mg protein. Interferon alfa-2b is a protein with a molecular weight of 19,271 
daltons produced by recombinant DNA techniques. It is obtained from the bacterial 
fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid 
containing an interferon gene from human leukocytes. 
 
8.2 Availability 
Peg-IFNα-2b is an investigational agent supplied to investigators by Merck to 
WCMC and all other sub-sites. It will be shipped in 50 microgram pre-filled syringes 
or the REDIPEN formulation. Upon receipt of the of the study treatment supplies, an 
inventory must be performed and a drug receipt log filled out and signed by the 
pharmacist or designee accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory. Any damaged or unusable study drug in a given shipment 
should be documented in the study files. The investigator must notify Merck and 
WCMC of any damaged or unusable study treatments supplied to the investigator’s 
site. 
 
The study drug should be stored, under adequate security, in the pharmacy at the 
study center in a refrigerator at a temperature of 2C to 8C (36F to 46F) until taken 
by the study patients. 
 
8.3 Pegylated Interferon alfa 2b Ordering 
The study drug may be requested from MERCK by the Principal Investigator (or their 
authorized designee) at each participating site. Transfer of drugs between 
institutions is not permitted. 
 
To order drug, fill out the drug supply request form and fax it to Michael Gregor 
@ 267-305-6534 or send the request via e-mail at michael.gregor@merck.com 
 
8.4 Pegylated Interferon alfa 2b Accountability 
 
Pegylated Interferon-alfa 2b Inventory Records – The investigator, or a responsible 
party designated by the investigator, will maintain a careful record of the inventory 
and disposition of all agents received from Sponsor on a Drug Accountability Record 
Form (DARF). If the study drug expires, each site will destroy the drug following their 
Institution's SOP and will document the drug destruction. Copies of this log must 
then be sent to MERCK for drug accountability. Send all accountability documents to 
Michael Gregor. 
 
At the completion of the study, there will be a final account of drug shipped, drug 
consumed, and drug remaining. This accounting process will be logged on the drug 
accounting form, signed and dated. Any discrepancies noted will be investigated, 
resolved, and documented prior to return or destruction of unused study drug. Drug 


17 
17 
 
 
 
destroyed on site will be documented in the study files. 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Study 
 
9.1.1 Testing for JAK2V617F: Blood samples, at least 30mL, from all patients 
will be collected and stored in the Hematology and Medical Oncology 
Translational Core lab in Weill Cornell Medical College. The samples will 
be stored for  potential future research  testing that may include JAK2 
quantitative testing, along with other mutation analysis. 
 
Instructions on collection and specimen shipment will be provided in a 
specimen instruction form. 
 
 
 
 
9.2 
Special Studies 
 
9.2.1 Quality of life assessment using MPN-SAF 
Measure changes in quality of life (QOL) of patients in treatment and non- 
treatment arms using the Myeloproliferative Neoplasm Symptom Assessment 
Form 
(MPN-SAF), 
a 
validated 
patient 
reported 
outcome 
(PRO) 
instrument51,54. This will be completed by the patient and reviewed by the trial 
coordinator on follow up visits every 4 weeks 


18 
18 
 
 
 
10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 4 weeks prior to administration of 
protocol therapy, with the exception of the bone marrow procedure which must be 
completed within 12 weeks. The pregnancy results should be confirmed if performed 
more than 14 days from the start of treatment; a urine pregnancy test may be 
performed for confirmation. The following study calendar outlines study visit intervals 
for a period of 1 year during the study. The schedule will apply for the entire 3 year 
duration of the study. 
 
Pre- 
Study 
Wk 
1 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Wk 
29 
Wk 
33 
Wk 
37 
Wk 
41 
Wk 
45 
Wk 
49 
Wk 
53 
Pegylated IFNα-2ba 
X ---------------------------------------------------------------------------------------------------------- X 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X ------------------------------------------------------------------------------------------------------------ X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
Pregnancy testc 
X 
Fundoscopic 
eye 
examd 
X 
Bone marrow 
aspiration & biopsy 
X 
X 
Adverse 
event 
evaluation 
X --------------------------------------------------------------------------------------------------------- X 
Thyroid function tests 
X 
X 
X 
Correlative Study 
X 
JAK2V617F 
Quatitative Mutational 
Analysis 
X 
X 
X 
Special 
study 
(MPNSAF) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a: 
Pegylated IFNα -2b: Starting dose of 50mcg SC Qweek 
b:   Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
c: 
Serum pregnancy test (women of childbearing potential); urine sample will be taken to confirm results within 7 
days of treatment start date. 
d: 
Full eye examination should be performed if subject complains of vision problems 


19 
19 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 Response Criteria 
 
Response will be evaluated according to the criteria of the International Working 
Group for Myelofibrosis Research and Treatment (IWG-MRT). Responses are 
measured as complete response (CR), partial response (PR), stable disease (SD), 
clinical improvement (CI), progressive disease (PD), and relapse44. 
 
11.2 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until 
the first date that recurrent or progressive disease is objectively documented (taking 
as reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started. 
 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
12.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, and efficacy data for all enrolled patients. 
 
12.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC. It is a tool 
for the creation of customized, secure data management systems that include Web- 
based data-entry forms, reporting tools, and a full array of security features including 
user and group based privileges, authentication using institution LDAP system, with 
a full audit trail of data manipulation and export procedures. REDCap is maintained 
on CTSC-owned servers that are backed up nightly and support encrypted (SSL- 
based) connections. Nationally, the software is developed, enhanced and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA. 


20 
20 
 
 
 
12.2 Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the 
Principal Investigator. Merck will have the opportunity to review and approve the 
changes prior to submission of these changes to the local IRB and distribution to 
participating sites. 
 
Prior to implementing this protocol at WCMC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be 
approved by the WCMC Institutional Review Board (IRB). Prior to implementing this 
protocol at the participating sites, approval for the WCMC IRB approved protocol 
must be obtained from the participating site’s IRB. 
 
The following documents must be provided to WCMC before the participating site 
can be initiated and begin enrolling participants: 
• 
Original FDA form 1572 
• 
Administrative guidelines for participating site participation 
• 
Letter/memo from participating sites’ Conflicts Management Office stating that 
they manage their conflicts 
• 
Participating Site IRB approval letter, approved consent form, and HIPAA 
authorization 
• 
CV and medical license of site delegated Principal Investigator 
 
Upon receipt of the required documents, WCMC will formally contact the site and 
arrange for a teleconference site initiation visit (SIV). Once the SIV is performed, the 
site will receive an activation letter granting permission to proceed with enrollment. 
The participating sites are responsible to maintain all participating site IRB 
correspondence (IRB approval letters referencing protocol version date and 
amendment number, IRB approved protocol, appendices, informed consent forms, 
deviations, violations, and approval of continuing reviews) in the regulatory binder on 
site. 
 
12.3 Data Safety Monitoring Board 
 
This study will utilize the Weill Cornell Medical College (WCMC) Institutional Data 
Safety Monitoring Board (DSMB) and follow its policies and procedures for 
monitoring this study for safety concerns, with ongoing updates from the Study Chair 
on an ongoing basis. The interim analysis will be performed by the DSMB and the 
decision to proceed or stop the trial will be provided to the Study Chair. In addition, 
an independent safety monitor, Dr. Steven Allen at The North Shore University 
Hospital-Monter Cancer Center (450 Lakeville Road, Lake Success, NY 11042) will 
perform annual monitoring of the safety of subjects throughout the trial including 
risks and benefits, as well as efficacy of the study. 


21 
21 
 
 
 
The WCMC DSMB is comprised of medical specialists and advisors on human rights 
issues in human subjects research. The DSMB currently has 9 members, meets at 
quarterly intervals during the year, and carries out ongoing review of protocols 
submitted throughout the year. Once a protocol has been submitted and approved 
by the Institutional Review Board (IRB) and is recommended for oversight by the 
DSMB, the Board determines if the protocol will be reviewed quarterly, semi- 
annually, or annually. 
 
The DSMB evaluates the accumulated data from the study in order to monitor the 
safety of subjects throughout the trial and reviews the risks and benefits, as well as 
the efficacy, of the study. The DSMB will also evaluate the overall trial conduct and 
progress. Ultimately, the DSMB validates the continuation of the trial or determines if 
a study needs modification or termination. 
 
Reports to the DSMB will include the following items for review: 
1. Completed DSMB Periodic Review Form. 
2. Synopsis of the study to date. 
3. IRB approved consent form. 
4. IRB current protocol. 
5. Summary table of study results, compromised of enrollment and response data 
6. Adverse  event  table  outlining  all  grade  3  and  4  toxicities,  including  serious 
adverse events 
7. Data safety monitoring plan. 
 
After the first six months of the study, the Principal Investigator will provide the 
WCMC DSMB with a list of grade 3 and 4 toxicities, a summary of all serious 
adverse events, and a summary of the study results, including enrollment and 
response data. The DSMB will review the data from WCMC and all participating sub- 
sites and determine if the study can continue to operate as is or if the study needs 
modification or termination. From here on out, the DSMB will review all the 
aforementioned items on a yearly basis. 
 
Safety monitoring is carried out to ensure and maintain the scientific integrity of 
human subject research projects and to protect the safety of human subjects. Safety 
monitoring can be viewed as any process during a clinical trial that involves the 
review of accumulated outcome data for groups of patient-subjects to determine if 
any of the treatment procedures practiced should be altered or stopped. NIH 
Guidelines (1998, 2000) specify that all clinical trials should have a system in place 
for appropriate oversight and monitoring to ensure the safety of participants and the 
validity of the data. 
 
Monitoring activities will be commensurate with the nature, size, and complexity of 
the trial in accordance with institutional policies and will be determined after IRB and 
DSMB review of the protocol immediately prior to study activation. For a small, 
single-center  study,  the  monitoring  is  usually  performed  by  a  statistician  in 


22 
22 
 
 
 
conjunction with a Safety Officer. For those single-site, high risk trials, a DSMB may 
be appropriate. For larger, single or multi-site studies, the monitoring is usually 
performed by a committee, often called a Data Safety Monitoring Board (DSMB). 
Ongoing review of the data by an independent individual or committee assures the 
investigators, the IRB, the study’s sponsor, and the funding agency that the trial can 
continue without jeopardizing subjects’ safety. 
 
Weill Cornell Medical College requires that all research approved by the WCMC IRB 
include an appropriate plan for the monitoring of data to ensure the safety of human 
subjects. Research supported by Federal agencies will be monitored according to all 
regulations and guidelines of the relevant Federal agency. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
This prospective, randomized, controlled, multi-center, phase II study will be 
designed to determine the safety and efficacy of peg-interferon alfa-2b in treating 
patients with early primary myelofibrosis (PMF). The primary objective of this study 
is to compare the clinical improvement rate between patients treated with 
peginterferon alfa-2b [Arm A] and untreated patients (clinical observation arm) [Arm 
B], in patients with early primary myelofibrosis. 
 
Patients will be randomized to either the treatment arm or the control arm of the 
study with a 2:1 allocation ratio. There will be a total of 47 patients in the study (31 
patients in the peginterferon alfa-2b arm and 16 patients in the control arm). 
 
13.2 Sample Size/Accrual Rate 
 
With a sample size of 31 patients in the peginterferon alfa-2b arm and 16 patients in 
the observation arm, (total sample size=47), the study is designed to have 
approximately 93% power to detect a difference in the clinical improvement rate of 
45% between the two groups (5% in observation arm vs. 50% in peginterferon alfa- 
2b arm), with a two-sided alpha level of 5%. The expected clinical improvement rate 
of 50% in the treatment arm is based on a pilot study that used rIFN to treat patients 
with early PM. In the pilot study, 10 of 17 patients (58.8%) achieved clinical 
improvement. 
 
A single interim analysis will be performed at 52 weeks for the purpose of assessing 
early efficacy (with statistical significance for the interim analysis set at P<0.0001); 
this will allow for patients in the observation arm to cross-over to the treatment arm if 
clear early efficacy is observed in the treatment arm. 


23 
23 
 
 
 
13.3 Stratification Factors 
 
Randomization Plan: 
 
A series of randomized blocks of 3 will be generated with a 2:1 allocation ratio. This 
will provide assurance that after three patients are enrolled, there will be two patients 
assigned to the peginterferon alfa-2b arm and one patient assigned to the 
observation arm. The blocked randomization will be stratified by participating 
institution. 
 
If patients in the observation arm develop disease progression to the next higher 
DIPSS stage from diagnosis or have an increase in marrow fibrosis detectable by 
reticulin stain on sequential bone marrow biopsies, they will cross over to the 
treatment arm. However, patients cannot switch over from the treatment arm to the 
observation arm. 
 
13.4 Analysis of Endpoints 
 
Fisher's exact test will be used to evaluate 1) the difference in the clinical 
improvement proportion between the treatment arm and the observation arm 
(primary efficacy endpoint) and 2) the difference in the toxicity proportions between 
the treatment arm and the observation arm (primary safety endpoint). Ninety-five 
percent confidence intervals (95% CI) for differences in the improvement and toxicity 
proportions between the two arms will be calculated to assess the precision of the 
obtained estimates. 
 
With adequate follow-up time, Kaplan-Meier survival analysis will be used to 
evaluate overall survival in the treatment/ observation arms and the log-rank test will 
be employed to compare overall survival between the treatment and observation 
arms. Overall survival will be defined as the time from first treatment day until death 
or until date of last follow-up. 
 
All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha 
level. All analyses will be performed in SAS Version 9.2 (SAS Institute Inc., Cary, 
NC). All statistical analyses will be performed by the Division of Biostatistics and 
Epidemiology in the Department of Public Health at Weill-Cornell Medical College. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from 
the time of their first treatment with peg-IFNα-2b 
 
13.5.2 Evaluation of response. All patients included in the study will be 
assessed for response to treatment if they have received at least 6 


24 
24 
 
 
 
months of treatment. 
Consultation with the Biostatistics Office will 
allow for completion of this section. 


25 
25 
 
 
 
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Paper not yet published. 


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29 
 
 
 
APPENDIX A 
 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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30 
 
 
 
APPENDIX B 
 
WCMC IRB SAE Reporting Forms 
 
The WCMC IRB SAE Reporting Forms can be obtained by contacting Ramsey Abdallah 
via email at raa2017@med.cornell.edu.