Study With SAR302503 in Patients With Polycythemia Vera or Essential Thrombocythemia

Study Overview
=================
Brief Summary
-----------------
Primary Objective: Dose Ranging Phase: To evaluate the efficacy of daily oral doses of 100, 200, and 400 mg SAR302503 in patients with PV and ET who are resistant or intolerant to hydroxyurea (per European LeukemiaNet criteria) for : Inducing absence of phlebotomy and a hematocrit below 45% for a minimum of 3 months in patients with polycythemia vera, and Reduction of platelet count to ≤400 x 10x9/L for a minimum of 3 months in patients with essential thrombocythemia. PV Dose Expansion Phase and ET Dose Ranging Phase (only 600 mg dose group): To evaluate the efficacy of daily oral SAR302503 in patients with PV and ET who are resistant or intolerant to hydroxyurea (per European LeukemiaNet criteria) for: Inducing absence of phlebotomy eligibility beginning at Day 1 of Cycle 4 visit and continuing through Day 1 of Cycle 6 visit in patients with PV, and Reduction of platelet count to ≤400 x 10x9/L beginning at Day 1 of Cycle 4 visit and continuing through Day 1 of Cycle 6 visit in patients with ET. Secondary Objectives: To evaluate the safety of SAR302503. To evaluate the efficacy of SAR302503 in patients with PV who are resistant or intolerant to hydroxyurea for inducing absence of phlebotomy eligibility. To evaluate the efficacy of SAR302503 in patients with ET who are resistant or intolerant to hydroxyurea for reduction of platelet counts. To evaluate the efficacy of SAR302503 in inducing complete and partial responses beginning at Day 1 of Cycle 6 visit through Cycle 8. To evaluate splenic response as measured by spleen volume using MRI or CT. To evaluate the pharmacokinetics of SAR302503 after single and repeat doses. To evaluate the pharmacodynamics of SAR302503 as measured by changes in JAK2V617F allele burden in patients with JAK2V617F mutation, and STAT3 phosphorylation inhibition. To measure improvement in baseline myeloproliferative neoplasm (MPN)-associated symptoms, as well as overall impact on quality of life. To measure generic health-related quality of life and utility value using the EuroQol Group (EQ-5DTM) questionnaire.

Detailed Description
-----------------
The duration of the study for an individual patient is at least 40 weeks and will include a period to assess eligibility (screening period) of up to 4 weeks (28 days), a treatment period of up to 8, 28-day cycles (32 weeks), and a follow-up visit 30 days following the last administration of study drug. Treatment may continue if the patient is deriving benefit and does not experience disease progression, unacceptable toxicity, or meet other study withdrawal criteria. Per Protocol Amendment No. 5, accrual of patients with essential thrombocythemia is closed.

Official Title
-----------------
A Randomized Phase II, Open-Label Study of the Efficacy and Safety of Orally Administered SAR302503 in Patients With Polycythemia Vera (PV) or Essential Thrombocythemia (ET) Who Are Resistant or Intolerant to Hydroxyurea

Conditions
-----------------
Hematopoietic Neoplasm

Intervention / Treatment
-----------------
* Drug: SAR302503


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Has had a diagnosis of hydroxyurea resistant or intolerant polycythemia vera (PV) or essential thrombocythemia (ET) documented at Screening. Polycythemia vera or essential thrombocythemia defined according to the revised WHO criteria. Polycythemia vera resistance or intolerance to hydroxyurea is defined as polycythemia vera patients on hydroxyurea with a hematocrit >45%, or phlebotomy twice in the last 6 months and at least once in the last 3 months. Essential thrombocythemia resistance or intolerance to hydroxurea is defined as essential thrombocythemia patients on HU with platelet count >600 x 10x9/L. Dose Expansion Phase (polycythemia vera) and 600 mg/day group (essential thrombocythemia): Has had a diagnosis of polycythemia vera or essential thrombocythemia according to the revised WHO 2008 criteria. PV patients must be resistant or intolerant to hydroxyurea. ET patients must be resistant or intolerant to hydroxyurea. Provide written informed consent to participate. Exclusion criteria: Less than 18 years of age. Participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to initiation of study drug, unless during non-treatment phase. (Prior treatment with another JAK2 inhibitor is allowed.) Unwilling to comply with scheduled visits, treatment plans, laboratory assessments, and other study-related procedures. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 or 4 at study entry. Splenectomy. Active malignancy other than polycythemia vera or essential thrombocythemia, except adequately treated basal cell carcinoma and squamous cell carcinoma of the skin, cervical carcinoma in situ, or other malignancies that have been stable and off therapy for ≥5 years. Major surgery within 28 days or radiation within 3 months prior to initiation of study drug. Active acute infection requiring antibiotics. Known human immunodeficiency virus or acquired immunodeficiency syndrome-related illness. Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of study drug. Any severe acute or chronic medical, neurological, or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with interpretation of study results and, in the Investigator's opinion, would make the patient inappropriate for entry into this study. Inadequate organ function. 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]). Concomitant treatment with or use of drugs or herbal agents known to be at least moderate inhibitors or inducers cytochrome P450 3A4 (CYP3A4). Presence of any gastric or other disorder that would inhibit absorption of oral medication. Known hypersensitivity to any excipients in the study drug formulation. Women of childbearing potential, unless using effective contraception while on study drug. Men who partner with a woman of childbearing potential, unless they agree to use effective contraception while on study drug. 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 100 mg<br>once daily X 28 days | Drug: SAR302503<br>* Pharmaceutical form:capsule Route of administration: oral<br>|
| Experimental: SAR302503 200 mg<br>once daily X 28 days | Drug: SAR302503<br>* Pharmaceutical form:capsule Route of administration: oral<br>|
| Experimental: SAR302503 400 mg<br>once daily X 28 days | Drug: SAR302503<br>* Pharmaceutical form:capsule Route of administration: oral<br>|
| Experimental: SAR302503 600 mg<br>once daily X 28 days | Drug: SAR302503<br>* Pharmaceutical form:capsule Route of administration: oral<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Ranging Phase: Proportion of PV patients with absence of phlebotomy and hematocrit below 45% and proportion of ET patients with a platelet count ≤ 400 x 10x9/L for a minimum of 3 months during the first 8 cycles of therapy. |  | 2 years | 
| PV Dose Expansion Phase: Proportion of PV patients with absence of phlebotomy eligibility beginning at Day 1 of Cycle 4 visit and continuing through Day 1 of Cycle 6 visit. |  | 2 years | 
| ET Dose Ranging Phase (only 600 mg dose group): Proportion of ET patients with a platelet count ≤400 x 10x9/L beginning at Day 1 of Cycle 4 visit and continuing through Day 1 of Cycle 6 visit. |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of PV patients with absence of phlebotomy eligibility beginning at Day 1 of Cycle 4 visit through Cycle 8 (for PV dose expansion phase only). |  | 2 years | 
| Proportion of ET patients with platelet count ≤400 x 10x9/L beginning at Day 1 of Cycle 4 visit and continuing through Cycle 8. |  | 2 years | 
| Characterization of clinicohematologic response (CR, PR, and no Response) defined by European LeukemiaNet beginning at Day 1 of Cycle 6 visit through Cycle 8. |  | 2 years | 
| Percent change in spleen volume (per Magnetic Resonance Imaging (MRI)) at the end of Cycles 4 and 8 or end of treatment (EOT) relative to baseline. |  | 2 years | 
| Proportion of patients with a ≥ 35% reduction in spleen volume (per Magnetic Resonance Imaging (MRI)) at the end of Cycles 4 and 8 or end of treatment (EOT) relative to baseline. |  | 2 years | 
| Number of participants who have changes in histological, cytogenetic, and molecular responses in bone marrow. |  | 2 years | 
| Response (defined as either a 2-point improvement in or resolution of a symptom present at baseline) at the end of Cycles 1, 4, and 8 or end of treatment (EOT), as measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). |  | 2 years | 
| Cumulative Distribution Function of responses between treatment groups at the end of Cycles 1, 4, and 8 or EOT on the MPN-SAF. |  | 2 years | 
| For each MPN-associated symptom present at baseline on the MPN-SAF, proportion of patients with resolution of that symptom at the end of Cycles 1, 4, and 8. |  | 2 years | 
| To measure generic health-related quality of life and utility values using the EQ-5D questionnaire after completion of 8 cycles of therapy. |  | 2 years | 
| Characterization of the safety profile of SAR302503, including the frequency, duration, and severity of adverse events graded using the National Cancer Institute (NCI) - CTCAE version 4.03, clinical laboratory parameters, ECG, and vital signs. |  | 2 years |