Phase III Study of SAR302503 in Intermediate-2 and High Risk Patients With Myelofibrosis (JAKARTA)

• Symptom Response Rate (SRR): Proportion of patients with ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  This assessment will be conducted through the modified MFSAF diary, which will be completed during the week prior to Day 1 of each treatment cycle up to Cycle 6, and during the week prior to the end of Cycle 6.
• OS (overall survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo. [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• PFS (progression free survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo. [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• Proportion of patients who have ≥25% reduction in volume of spleen size at end of Cycle 6, and confirmed 4 weeks thereafter. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Duration of spleen response, measured by MRI (or CT scan in patients with contraindications for MRI. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Clinical and laboratory events graded by the NCI CTCAE v4.03. [ Time Frame: approximately 5 years ] [ Designated as safety issue: Yes ]

• Symptom Response Rate (SRR): Proportion of patients with ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  This assessment will be conducted through the modified MFSAF diary, which will be completed during the week prior to Day 1 of each treatment cycle up to Cycle 6, at end of Cycle 6, the EOT visit, and the 30-day follow-up visit.
• OS (overall survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo. [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• PFS (progression free survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo. [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• Proportion of patients who have ≥25% reduction in volume of spleen size at end of Cycle 6, and confirmed 4 weeks thereafter. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Duration of spleen response, measured by MRI (or CT scan in patients with contraindications for MRI. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Clinical and laboratory events graded by the NCI CTCAE v4.03. [ Time Frame: approximately 5 years ] [ Designated as safety issue: Yes ]
  Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03

Primary Objective:

• To evaluate the efficacy of daily oral doses of 400 mg or 500 mg of SAR302503 (Investigational Medicinal Product, IMP) compared to placebo in the reduction of spleen volume as determined by magnetic resonance imaging (MRI) (or computed tomography scan in patients with contraindications for MRI).

Secondary Objectives:

• To evaluate the effect on Myelofibrosis (MF)-associated symptoms (key MF symptoms) as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary.
• To evaluate the Overall Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo.
• To evaluate the Progression Free Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo.
• To evaluate the durability of splenic response.
• To evaluate the safety of IMP.

The expected duration of a patient's 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 End Of Treatment (EOT) visit, which should be performed at least 30 days following the last administration of IMP or placebo.

Patients who continue to benefit clinically will be allowed to remain on IMP or placebo beyond the 6-month treatment period until the occurrence of disease progression or unacceptable toxicity.

• Drug: SAR302503

  Pharmaceutical form:capsule

  Route of administration: oral

• Drug: Placebo

  Pharmaceutical form:capsule

  Route of administration: oral

• Placebo Comparator: Placebo comparator
  once daily X 28 days, orally, empty stomach, approximately same time each day
  Intervention: Drug: Placebo
• Experimental: SAR302503 400 mg
  once daily X 28 days, orally, empty stomach, approximately same time each day
  Intervention: Drug: SAR302503
• Experimental: SAR302503 500 mg
  once daily X 28 days, orally, empty stomach, approximately same time each day
  Intervention: Drug: SAR302503

Inclusion criteria:

• Diagnosis of Primary Myelofibrosis (MF) or Post-Polycythemia Vera MF or Post-Essential Thrombocythemia MF, according to the 2008 World Health Organization and International Working Group of Myelofibrosis Research and Treatment (IWG-MRT) criteria.
• MF classified as high-risk or intermediate-risk level 2, as defined by modified IWG-MRT criteria (IPSS) (according to Cervantes F. et. al.; at screening).
• Enlarged spleen, palpable at least 5 cm below costal margin.
• At least 18 years of age.
• Eastern Cooperative Oncology Group performance status of 0, 1, or 2 at study entry.
• The following laboratory values within 14 days prior to the initiation of IMP or placebo:
• 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

Exclusion criteria:

• Splenectomy.
• Any chemotherapy (eg, hydroxyurea), 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 IMP or placebo; darbepoetin use within 28 days prior to initiation of IMP or placebo. Patients who have had exposure to hydroxyurea (eg, hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to initiation of IMP or placebo.
• Major surgery within 28 days or radiation within 6 months prior to initiation of IMP or placebo.
• Prior treatment with a Janus Kinase 2 (JAK2) inhibitor.
• Known active (acute or chronic) Hepatitis A, B, or C; and hepatitis B and C carriers
• AST or ALT ≥2.5 x ULN
• Total Bilirubin:
• Exclude if ≥3.0 x ULN
• Patients with total bilirubin between 1.5-3.0 x ULN must be excluded if the direct bilirubin fraction is ≥25% of the total
• 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.