Phase 2 Study in Japanese Patients With Intermediate-2 or High Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis With Splenomegaly

Study Overview
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Brief Summary
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Primary Objective: - To evaluate the efficacy of daily oral doses of 300 mg, 400 mg, and 500 mg SAR302503 and combined for the response rate defined with the ≥35% reduction of spleen volume as determined by magnetic resonance imaging (MRI or computed tomography scan [CT] in patients with contraindications for MRI). Secondary Objectives: To evaluate the safety of SAR302503 for both pooled (300, 400, and 500mg) and individual doses population. To evaluate the pharmacokinetics (PK) of SAR302503 after single and repeat-dose. To evaluate the effect on Myelofibrosis (MF)-associated symptoms (Key MF symptoms) as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF). To evaluate the durability of splenic response. To evaluate the effect of SAR302503 on bone marrow with regard to changes on reticulin fibrosis.

Detailed Description
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The duration of the study for an individual patient will include a period to assess eligibility (screening period 28 days), followed by a treatment period of at least 1 cycle (28 days) of study treatment, and an end-of-treatment visit at least 30 days following the last administration of study drug. However, treatment may continue if patients are deriving benefit and do not have unacceptable toxicity or meet study withdrawal criteria.

Official Title
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A Phase 2 Open-Label, Dose-Ranging Study of the Efficacy and Safety of Orally Administered SAR302503 in Japanese Patients With Intermediate-2 or High Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis With Splenomegaly

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: SAR302503


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Diagnosis of primary or post-polycythemia vera or post-essential thrombocythemia myelofibrosis Myelofibrosis classified as high-risk or intermediate-risk level 2 Enlarged spleen, palpable at least 5 cm below costal margin Active symptoms of myelofibrosis At least 20 years of age Eastern Collaborative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 at study entry Absence of active malignancy other than myelofibrosis Written informed consent to participate. Exclusion criteria: Splenectomy. Any recent chemotherapy (eg, hydroxyurea), immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin), hormones (eg, androgens, danazol) within 14 days prior to initiation of study drug. Major surgery therapy within 28 days or radiation including spleen radiation within 6 months prior to initiation of study drug. Concomitant treatment with or use of pharmaceutical or herbal agents known to be moderate or severe inhibitors or inducers CYP3A4. Active acute infection requiring antibiotics. Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of study drug. Participation in any study of an investigational agent (drug, biologic, device) within 30 days, unless during nontreatment phase. Prior treatment with a JAK 2 Inhibitor. Treatment with aspirin in doses >150 mg/day Known human immunodeficiency virus or acquired immunodeficiency syndrome-related illness. Pregnant or lactating female. Once the lactating female stop and participate in the study, she cannot re-start feeding the baby. Women of childbearing potential, unless using effective contraception while on study drug. Otherwise patients must be post-menopausal (at least 1 years from last menstruation without other medical reason), or surgically sterile. Known active (acute or chronic) Hepatitis A, B, or C; and hepatitis B and C carriers. Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis [NASH]) The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 20 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR302503 300mg<br>SAR302503 will be self-administered, orally, once daily, as a single agent, in consecutive, 28-day cycles at the dose level of 300mg. SAR302503 will be taken on an empty stomach at approximately the same time each day | Drug: SAR302503<br>* Pharmaceutical form:Capsule Route of administration: oral<br>|
| Experimental: SAR302503 400 mg<br>SAR302503 will be self-administered, orally, once daily, as a single agent, in consecutive, 28-day cycles at the dose level of 400 mg. SAR302503 will be taken on an empty stomach at approximately the same time each day | Drug: SAR302503<br>* Pharmaceutical form:Capsule Route of administration: oral<br>|
| Experimental: SAR302503 500 mg<br>SAR302503 will be self-administered, orally, once daily, as a single agent, in consecutive, 28-day cycles at the dose level of 500 mg. SAR302503 will be taken on an empty stomach at approximately the same time each day | Drug: SAR302503<br>* Pharmaceutical form:Capsule Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR), defined as the proportion of subjects who have a ≥35% reduction as measured by MRI (or CT scan in subjects with contraindications for MRI). - Time Frame: |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Serious Adverse events using NCI CTCAE v4.03, clinical parameters and vital signs |  | From baseline to the 30 days after last drug administration | 
| Measurements of SAR302503 pharmacokinetic endpoints including Cmax, Tmax, and AUC0-24 |  | SAR302503, pre-dose and post-dose plasma collections will be obtained on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 2, and Cycle 3 Day 1 | 
| Symptom Response Rate (SRR): Proportion of subjects with a ≥50% reduction in the total symptom score using the modified MFSAF |  | 24 weeks | 
| Duration of maintenance of ≥35% reduction in spleen volume |  | From baseline to the 30 days after last drug administration | 
| Percent change from baseline in spleen volume measured by MRI |  | 24 weeks | 
| Percent change from baseline in spleen size measured by palpation |  | 24 weeks | 
| Proportion of patients with any grade reduction in reticulin fibrosis |  | 24 weeks |