A Phase II Study of Pomalidomide in Myelofibrosis With Myeloid Metaplasia

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety of and to select a treatment regimen of pomalidomide (CC-4047) either as single-agent or in combination with prednisone to study further in patients with myelofibrosis with myeloid metaplasia (MMM).

Detailed Description
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Participants received study treatment in the Double Blind Treatment Phase for up to 12 cycles (336 days; 12 cycles of 28 days each). Participants who completed the Double-Blind Treatment Phase were unblinded and, if receiving pomalidomide and determined to have a complete remission (CR), partial remission (PR) or clinical improvement (CI) using the International Working Group (IWG) Response Criteria in the study protocol, could have continued on their current dose of pomalidomide until disease progression. Participants receiving placebo were discontinued from the study.

Official Title
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A Phase 2, Prospective, Randomized, Multicenter, Double-blind, Active-control, Parallel-group Study to Determine the Safety of and to Select a Treatment Regimen of CC-4047 (Pomalidomide) Either as Single-agent or in Combination With Prednisone to Study Further in Subjects With Myelofibrosis With Myeloid Metaplasia

Conditions
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Myelofibrosis With Myeloid Metaplasia, Myeloid Metaplasia, Myelofibrosis

Intervention / Treatment
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* Drug: Pomalidomide
* Drug: Prednisone
* Drug: Placebo to pomalidomide
* Drug: Placebo to prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must sign an informed consent form Must be >18 years of age Must be diagnosed with myelofibrosis Eligibility is based on local pathology review of bone marrow aspirate and biopsy Screening total hemoglobin level < 10g/dL or transfusion-dependent anemia defined as per International Working Group (IWG) criteria. Must have adequate organ function as demonstrated by the following ≤ 14 days prior to starting study drug: Alanine aminotransferase (ALT; SGPT)/aspartate aminotransferase (AST; SGOT) ≤ 3 x upper limit of normal (ULN), [unless upon judgment of the treating physician, it is believed to be due to extra-medullary hematopoiesis (EMH)]. Total Bilirubin <3x ULN or Direct Bilirubin <2 x ULN Serum creatinine ≤ 2.0 mg/dL Absolute neutrophil count ≥ 1,000/μL (≥ 1 x 10^9/L). Platelet count ≥ 50,000 /μL (≥ 50 x 10^9/L). Patients must be willing to receive transfusion of blood products Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 at screening. Must be able to adhere to the study visit schedule and other protocol requirements. No active malignancies with the exception of controlled prostate cancer, basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. Must agree to follow pregnancy precautions as required per the protocol Exclusion Criteria: Known positive status for human immunodeficiency virus (HIV), hepatitis B carrier, or active hepatitis C infection. Previous untoward reaction to corticosteroid (specifically, prednisone) therapy that was severe enough, in the opinion of the treating physician, to preclude study participation. The use of any growth factors, cytotoxic chemotherapeutic agents (e.g. hydroxyurea and anagrelide), corticosteroids, or experimental drug or therapy within a minimum of 28 days of starting CC-4047 and/or lack of recovery from all toxicity from previous therapy to grade 1 or better (e.g. alpha interferon may require 84 days of longer or washout). Prior therapy with CC-4047 or, lenalidomide or thalidomide for Myelofibrosis with myeloid metaplasia (MMM). (Prior prednisone use as a therapy for MMM is allowed, but not within 28 days of starting CC-4047). History of deep vein thrombosis or pulmonary embolism within one year of starting study medication. Any serious medical condition or psychiatric illness that would prevent, (as judged by the treating physician) the subject from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Pregnant or lactating females

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisone<br>Participants received oral prednisone from Day 1-28 of each 28-day cycle for up to 3 cycles (84 days), 1st cycle = 30 mg daily, 2nd cycle = 15 mg daily, 3rd cycle = 15 mg every other day, and pomalidomide placebo tablets on Days 1-28 for up to 12 cycles in the Double-Blind Treatment Phase. After the completion of cycle 12 and upon unblinding, participants were discontinued from the study. | Drug: Prednisone<br>* Participants will take oral prednisone in the evening for 3 cycles of 28 days each (up to 84 days). The dose will be as follows: 1st cycle = 30 mg daily, 2nd cycle = 15 mg daily, 3rd cycle = 15 mg every other day.<br>Drug: Placebo to pomalidomide<br>* Matching pomalidomide placebo tablets<br>|
| Experimental: Pomalidomide<br>Participants received 2 mg oral pomalidomide daily from Day 1-28 of each 28-day cycle for up to 12 cycles (336 days), and prednisone placebo tablets on Days 1-28 for the first 3 cycles in the Double-Blind Treatment Phase. After the completion of Cycle 12 and upon unblinding, participants determined to have a complete remission (CR), partial remission (PR) or clinical improvement (CI) using the International Working Group (IWG) Response Criteria in the study protocol, were eligible to participate in the extension phase and continue to receive oral pomalidomide 2 mg daily, from Days 1-28 of each cycle, until disease progression, unacceptable toxicity or voluntary withdrawal. | Drug: Pomalidomide<br> <br> * Other names: Pomalyst;Drug: Placebo to prednisone<br>* Matching prednisone placebo tablets<br>|
| Experimental: Pomalidomide 2 mg + Prednisone<br>Participants received 2 mg oral pomalidomide daily from Day 1-28 of each 28-day cycle for up to 12 cycles (336 days), and oral prednisone tablets on Days 1-28 for the first 3 cycles, 1st cycle = 30 mg daily, 2nd cycle = 15 mg daily, 3rd cycle = 15 mg every other day in the Double-Blind Treatment Phase. After the completion of cycle 12 and upon unblinding, participants determined to have a complete remission (CR), partial remission (PR) or clinical improvement (CI) using the International Working Group (IWG) Response Criteria in the study protocol, were eligible to participate in the extension phase and continue to receive oral pomalidomide 2 mg daily, from Days 1-28 of each cycle, until disease progression, unacceptable toxicity or voluntary withdrawal. | Drug: Pomalidomide<br> <br> * Other names: Pomalyst;Drug: Prednisone<br>* Participants will take oral prednisone in the evening for 3 cycles of 28 days each (up to 84 days). The dose will be as follows: 1st cycle = 30 mg daily, 2nd cycle = 15 mg daily, 3rd cycle = 15 mg every other day.<br>|
| Experimental: Pomalidomide 0.5 mg + Prednisone<br>Participants received 0.5 mg oral pomalidomide daily from Day 1-28 of each 28-day cycle for up to 12 cycles (336 days), and oral prednisone tablets on Days 1-28 for the first 3 cycles, 1st cycle = 30 mg daily, 2nd cycle = 15 mg daily, 3rd cycle = 15 mg every other day in the Double-Blind Treatment Phase. After the completion of cycle 12 and upon unblinding, participants determined to have a complete remission (CR), partial remission (PR) or clinical improvement (CI) using the International Working Group (IWG) Response Criteria in the study protocol, were eligible to participate in the extension phase and continue to receive oral pomalidomide 0.5 mg daily, from Days 1-28 of each cycle, until disease progression, unacceptable toxicity or voluntary withdrawal. | Drug: Pomalidomide<br> <br> * Other names: Pomalyst;Drug: Prednisone<br>* Participants will take oral prednisone in the evening for 3 cycles of 28 days each (up to 84 days). The dose will be as follows: 1st cycle = 30 mg daily, 2nd cycle = 15 mg daily, 3rd cycle = 15 mg every other day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Clinical Response Within the First 6 Cycles of Treatment | A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable. Participants who discontinued the study early without achieving clinical response were counted as non-responders. | Up to 168 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Clinical Response Within the First 12 Cycles of Treatment | A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable. Participants who discontinued the study early without achieving clinical response were counted as non-responders. | Up to 336 days | 
| Time to the First Clinical Response | The time to the first clinical response achieved within 168 days after the first study drug dosing date was calculated for participants who achieved a clinical response as: Start date of the first clinical response - the first study drug date +1. A clinical responder was defined as either: A baseline red blood cell (RBC)-transfusion-dependent participant with a ≥ 56 consecutive day RBC transfusion-free period after the first dose of study drug, or A baseline RBC-transfusion-independent participant with an increase in hemoglobin of 2.0 g/dL or more from baseline for ≥ 56 consecutive days in the absence of RBC transfusions, or A participant with either a ≥ 50% reduction in palpable splenomegaly of a spleen that was ≥ 10 cm at baseline or a spleen that was palpable at > 5 cm and became not palpable. | Up to 168 days | 
| Duration of First Clinical Response | For RBC-transfusion-dependent patients, duration of response was calculated as the last day of response - first day of response +1, where the last day of response was the date of the first RBC-transfusion administrated at or more than 56 days after the response started. For patients who did not receive a subsequent transfusion after the response started, the end date of response was censored at the day of last hemoglobin assessment. For RBC-transfusion-independent patients, the duration of response was calculated as the last day of response - first day of response +1, where the last day of response was the earlier of the date of a hemoglobin increase of < 2.0 g/dL and the date of a RBC transfusion at ≥ 56 days after the response started. For patients whose hemoglobin measurements were always ≥ 2.0 g/dL and never received a RBC transfusion after response started, the end date of the response was censored at the date of last hemoglobin measurement. Kaplan-Meier methodology was used. | Up to 40 months | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Anemia (FACT-An) Subscale and Total Scores | The FACT-An comprises the four subscales of the 27-item FACT-General Scale (FACT-G), Physical Well-being, Social/Family Well-being, Emotion Well-being, Functional Well-Being, and the Additional Concerns Anemia subscale. Questions are rated on a scale from 0 to 4, where higher scores indicate more impact on quality of life. Physical Well-being consists of 7 questions, the subscale score ranges from 0-28; Social/Family Well-being consists of 7 questions, the subscale score ranges from 0-28; Emotion Well-being consists of 6 questions, the subscale score ranges from 0-24; Functional Well-Being consists of 7 questions, the subscale score ranges from 0-28; Anemia subscale consists of 20 questions, the subscale score ranges from 0-80; Total FACT-An score ranges from 0-188. | Baseline and Cycle 6 (168 days). | 
| Change From Baseline in Hemoglobin Concentration for Responders | Change from Baseline in hemoglobin for participants with a clinical response within the first 6 cycles of treatment. | Baseline, Cycle 6 (168 days) | 
| Change From Baseline in Hemoglobin Concentration for Non-Responders | Change from Baseline in hemoglobin for participants without a clinical response within the first 6 cycles of treatment. | Baseline, Cycle 6 (168 days) | 
| Change From Baseline in Likert Abdominal Pain Scale | Participants rated abdominal discomfort or pain over the previous week on a scale from zero to ten, where zero is no discomfort or pain and ten is the worst pain imaginable. | Baseline and Cycle 6 (168 days) | 
| Percentage of Participants With Clinical Response by Baseline JAK2 Assessment | Percentage of participants who achieved a clinical response, presented by participants with positive and negative janus kinase 2 (JAK2) V617F mutation results at Baseline. | Up to 336 days | 
| Number of Participants With Adverse Events (AEs) | A serious AE (SAE) was defined as any AE which resulted in death or was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or constituted an important medical event (events that may have jeopardized the patient or required intervention to prevent one of the outcomes listed above). The severity of AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) or according to the following scale: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Death. The Investigator determined the relationship between study drug and the occurrence of an AE as Not Related or Related (since the study was double-blinded, a patient receiving only prednisone could have an AE that was judged as related to pomalidomide, and vice-versa). | From date of the first dose of the study drug until discontinuation or the data cut-off date (up to approximately 45 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Celgene, CC-4047, Myelofibrosis, myelofibrosis with myeloid metaplasia, myeloid metaplasia, JAK2, CC-4047-MMM-001, Prednisone, Phase II, pomalidomide, bone marrow histology, imids, MMM, Ashkenazi Jewish Population, exposure to Thorotrast, exposure to solvents (benzene and toluene), acute megakaryocytic leukemia, history of polycythemia vera