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

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

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.

Study Overview

• Status: Completed
• Conditions: Myelofibrosis
• Intervention / Treatment: Drug: SAR302503

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Akita-Shi, Japan
    • Investigational Site Number 392010
  • Bunkyo-Ku, Japan
    • Investigational Site Number 392002
  • Bunkyo-Ku, Japan
    • Investigational Site Number 392006
  • Sendai-Shi, Japan
    • Investigational Site Number 392004
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392008
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392009
  • Suita-Shi, Japan
    • Investigational Site Number 392003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: SAR302503 300mg; 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; Pharmaceutical form:Capsule Route of administration: oral
EXPERIMENTAL: SAR302503 400 mg; 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; Pharmaceutical form:Capsule Route of administration: oral
EXPERIMENTAL: SAR302503 500 mg; 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; Pharmaceutical form:Capsule Route of administration: oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): March 1, 2014

Study Registration Dates

• First Submitted: September 10, 2012
• First Submitted That Met QC Criteria: September 20, 2012
• First Posted (ESTIMATE): September 25, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): September 22, 2014
• Last Update Submitted That Met QC Criteria: September 19, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Pathological Conditions, Anatomical; Blood Coagulation Disorders; Blood Platelet Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Hypertrophy; Primary Myelofibrosis; Thrombocytosis; Thrombocythemia, Essential; Polycythemia Vera; Polycythemia; Splenomegaly
• Other Study ID Numbers: ARD12888; U1111-1130-3710 (OTHER: UTN)