Pegylated Interferon Alpha-2b in Early Primary Myelofibrosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Randomized Controlled Trial of Pegylated Interferon Alpha-2b in Early Primary Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Peginterferon alfa-2a


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Patients must meet laboratory, and bone marrow histological criteria for primary myelofibrosis as defined by World Health Organization (WHO) diagnostic criteria as follows: WHO diagnostic criteria for PMF Proposed Criteria for PMF Major Criteria 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) Not meeting WHO criteria for Polycythemia Vera (PV), Chronic Myeloid Leukemia (CML), Myledysplastic Syndrome (MDS), or other myeloid neoplasm Demonstration of JAK2617V>F or other clonal marker (e.g. MPL515W>L/K), or in the absence of a clonal marker, no evidence of bone marrow fibrosis due to underlying inflammatory or other neoplastic disease Minor Criteria Leukoerythroblastosis increase in serum Lactase Dehydrogenase (LDH) Anemia Palpable splenomegaly 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). In addition, they must show some active hematopoiesis with a cellularity of at least 15%, irrespective of the degree of reticulin and/or collagen fibrosis as defined by Manoharan criteria. 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. Eastern Cooperative Oncology Group (ECOG) performance status < 2 Patients must have normal organ and marrow function as defined below: White blood cell (WBC) ≥ 3,000/microL Absolute Neutrophil Count (ANC) ≥ 1,500/microL Platelets ≥ 100,000//microL Total bilirubin within normal limits Aspartate aminotransferase - serum glutamic oxaloacetic transaminase (AST(SGOT)) and alanine aminotransferase - serum glutamic pyruvic transaminase (ALT(SGPT)) less than or equal to 2.5 X upper limit of normal Creatinine Clearance ≥ 50 ml/min 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. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria 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. 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 bone marrow biopsy showing less than 15% cellularity in the presence +2 or more reticulin fibrosis (by Manoharan criteria), collagen fibrosis, or osteosclerosis. Patients may not be receiving any other investigational agents. History of allergic reactions attributed to compounds of similar chemical or biologic composition to peg-IFNα-2b Other Exclusion Criteria Female patients who are pregnant or breast feeding History of depression or active treatment for depression History of non-compliance to medical regimens History of autoimmune diseases History of hypothyroidism or hyperthyroidism Clinical evidence of neuropathy 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. Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Observation arm<br>Subjects will be monitored closely for disease progression, however will receive no intervention. | |
| Experimental: Peginterferon alfa-2a<br>Peginterferon alfa-2a will be administered at a dose of 50 micrograms once a week for up to 3 years. | Drug: Peginterferon alfa-2a<br>* 50 mcg subcutaneous injection once per week<br>* Other names: PEGINTRON, Interferon alfa, IFNα-2b;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Improvement | Clinical improvement (CI) Requires one of the following in the absence of both disease progression (as outlined below) and Complete Response (CR)/Partial Response (PR) assignment (CI response is validated only if it lasts for no fewer 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 50 000 109/L (applicable only for patients with baseline platelet count below 50 109/L). iv. A minimum 100% increase in Absolute Neutrophil Count (ANC) and an ANC of at least 0.5 109/L (applicable only for patients with baseline absolute neutrophil count below 1 109/L). | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression free survival is the measure of subject survival in the absence of disease progression. Disease progression is defined as progression to the next higher International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Dynamic International Prognostic Scoring System (DIPSS) stage from diagnosis. The IWG-MRT DIPSS stratifies primary myelofibrosis (PMF) into four risk categories (low, intermediate 1, intermediate 2, and high risk), based on 5 clinical factors; Age>65, Hemoglobin <10gm/dL, white blood cell (WBC)>25,000/uL, peripheral blasts>1%, and constitutional symptoms. Progression free survival will be assessed at 21 weeks from time of study entry. | Week 21 | 
| Overall Survival | Overall survival measures subject survival regardless of disease progression. Overall survival will be assessed at 21 weeks from time of study entry. | Week 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary myelofibrosis, PMF