Phase II, Open Label, Single Arm Study of SAR302503 In Myelofibrosis Patients Previously Treated With Ruxolitinib

A Phase II, Multicenter, Open Label, Single Arm Study of SAR302503 in Subjects Previously Treated With Ruxolitinib and With a Current Diagnosis of Intermediate or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Primary Objective:

- To evaluate the efficacy of once daily dose of SAR302503 in subjects previously treated with ruxolitinib and with a current diagnosis of intermediate-1 with symptoms, Intermediate-2 or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV MF), or post-essential thrombocythemia myelofibrosis (Post-ET MF) based on the reduction of spleen volume at the end of 6 treatment cycles;

Secondary Objectives:

• To evaluate the effect of SAR302503 on Myelofibrosis (MF) associated symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary
• To evaluate the durability of splenic response
• To evaluate the splenic response to SAR302503 by palpation at the end of Cycle 6
• To evaluate the splenic response to SAR302503 at the end of Cycle 3
• To evaluate the effect of SAR302503 on the Janus kinase 2 (JAK2) V617F allele burden
• To evaluate the safety and tolerability of SAR302503 in this population
• To evaluate plasma concentrations of SAR302503 for population PK analysis, if warranted

The expected duration of the treatment in this study is approximately 8 months, based on a maximum 28-day screening period, followed by a 6-month (6-cycle) treatment period, and an EOT visit for subjects who will not continue the treatment after completing the 6 cycles of SAR302503, or discontinue the treatment early for any reasons as well as a follow-up visit which should occur 30 days after the last administration of SAR302503. Patients who continue to benefit clinically will be allowed to remain on study medication beyond the 6-month treatment period until the occurrence of disease progression or unacceptable toxicity.

Inclusion criteria:

• Diagnosis of PMF or Post-PV MF or Post-ET MF, according to the 2008 World Health Organization and IWG-MRT response criteria
• Subjects who previously received Ruxolitinib treatment for PMF or Post-PV MF or Post-ET MF or PV or ET for at least 14 days (exposure of <14 days is allowed for subjects who discontinued Ruxolitinib due to intolerability or allergy) and discontinued the treatment for at least 14 days prior to the first dose of SAR302503
• MF classified as Intermediate-1 with symptoms, Intermediate-2 or high-risk by Dynamic International Prognostic Scoring System (Passamonti et al., Blood 2010)
• Spleen ≥5 cm below costal margin as measured by palpation
• Male and female subjects ≥18 years of age
• Signed written informed consent

Exclusion criteria:

• Splenectomy

• Eastern Cooperative Oncology Group (ECOG) performance status of >2 before the first dose of SAR302503 at Cycle 1 Day1

• The following laboratory values within 14 days prior to the initiation of SAR302503:

  • Absolute Neutrophil Count (ANC) <1.0 x 10exp9/L
  • Platelet count <50 x 10exp9/L
  • Serum creatinine >1.5 x Upper limit of normal (ULN)
  • Serum amylase and lipase >1.5 x ULN

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN

• Total bilirubin ≥3.0 x ULN

• Subjects with total bilirubin between 1.5-3.0 x ULN must be excluded if the direct bilirubin fraction is ≥25% of the total

• Subjects with 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])

• Subjects with any other prior malignancies are not eligible, except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which subject has been disease-free for at least 5 years

• Any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), Anagrelide, immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin), or hormones (eg, androgens, danazol) within 14 days prior to initiation of SAR302503; darbepoetin use within 28 days prior to initiation of SAR302503.The only chemotherapy allowed will be hydroxyurea within 1 day prior to initiation of SAR302503

• 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 SAR302503

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.