Phase II, Open Label, Single Arm Study of SAR302503 In Myelofibrosis Patients Previously Treated With Ruxolitinib (JAKARTA2)

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

Study Overview

• Status: Completed
• Conditions: Hematopoietic Neoplasm
• Intervention / Treatment: Drug: SAR302503

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 5020
    • Investigational Site Number 040002
  • Wien, Austria, 1090
    • Investigational Site Number 040001
• Belgium
  • Antwerpen, Belgium, 2060
    • Investigational Site Number 056002
  • Leuven, Belgium, 3000
    • Investigational Site Number 056003
• Canada
  • Toronto, Canada, M5G 2M9
    • Investigational Site Number 124001
• France
  • Marseille, France, 13273
    • Investigational Site Number 250001
  • Nimes Cedex 9, France, 30029
    • Investigational Site Number 250003
  • Paris Cedex 10, France, 75475
    • Investigational Site Number 250002
  • Paris Cedex 12, France, 75571
    • Investigational Site Number 250006
  • Toulouse, France, 31000
    • Investigational Site Number 250004
• Germany
  • Frankfurt Am Main, Germany, 60590
    • Investigational Site Number 276003
  • Leipzig, Germany, 04103
    • Investigational Site Number 276007
  • Magdeburg, Germany, 39120
    • Investigational Site Number 276006
  • Mannheim, Germany, 68167
    • Investigational Site Number 276001
  • Ulm, Germany, 89081
    • Investigational Site Number 276005
• Italy
  • Firenze, Italy, 50134
    • Investigational Site Number 380004
  • Milano, Italy, 20122
    • Investigational Site Number 380001
  • Roma, Italy, 00161
    • Investigational Site Number 380002
  • Varese, Italy, 21100
    • Investigational Site Number 380003
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Investigational Site Number 528002
  • Maastricht, Netherlands, 6229 HX
    • Investigational Site Number 528003
  • Nijmegen, Netherlands, 6525 GA
    • Investigational Site Number 528001
• Spain
  • Barcelona, Spain, 08036
    • Investigational Site Number 724001
  • Majadahonda, Spain, 28222
    • Investigational Site Number 724003
  • Salamanca, Spain, 37007
    • Investigational Site Number 724002
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Investigational Site Number 826001
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Investigational Site Number 840007
  • California
    • San Francisco, California, United States, 94143
      • Investigational Site Number 840003
    • San Francisco, California, United States, 94143
      • Investigational Site Number 840004
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Investigational Site Number 840005
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Investigational Site Number 840014
  • Kansas
    • Kansas City, Kansas, United States, 66160-7321
      • Investigational Site Number 840001
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Investigational Site Number 840017
    • Baltimore, Maryland, United States, 21229
      • Investigational Site Number 840013
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0759
      • Investigational Site Number 840010
  • New York
    • New York, New York, United States, 10021
      • Investigational Site Number 840009
    • New York, New York, United States, 10032
      • Investigational Site Number 840018
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Investigational Site Number 840022
    • Middletown, Ohio, United States, 45042
      • Investigational Site Number 840019
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Investigational Site Number 840024
  • Texas
    • Houston, Texas, United States, 77030
      • Investigational Site Number 840002
  • Utah
    • Salt Lake City, Utah, United States, 84112-5550
      • Investigational Site Number 840015

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAR302503 400 mg; once daily in consecutive 28-day cycles, flexible dosing regimen (the starting dose is 400mg/day), orally, empty stomach, approximately 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 from baseline in volume of spleen at the end of Cycle 6 as measured by Magnetic Resonance Imaging (MRI) (or CT scan in subjects with contraindications for MRI)	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Symptom Response Rate (SRR): Proportion of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score using the modified MFSAF	6 months
Duration of spleen response, measured by MRI (or CT scan in subjects with contraindications for MRI)	6 months
Proportion of subjects with a ≥50% reduction in length of spleen by palpation from baseline at the end of Cycle 6	6 months
Response Rate at the end of Cycle 3, defined as the proportion of subjects who have a ≥35% reduction from baseline in volume of spleen at the end of Cycle 3 as measured by MRI (or CT scan in subjects with contraindications for MRI)	6 months
Percent change of spleen volume at the end of Cycles 3 and 6 from baseline as measured by MRI (or CT scan in subjects with contraindications for MRI)	6 months
Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03	approximately 5 years
Plasma concentrations of SAR302503	4 months
The effect of SAR302503 on the JAK2V617F allele burden	2 years

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, Jourdan E, Winton E, Silver RT, Schouten HC, Passamonti F, Zweegman S, Talpaz M, Lager J, Shun Z, Mesa RA. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017 Jul;4(7):e317-e324. doi: 10.1016/S2352-3026(17)30088-1. Epub 2017 Jun 8.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: January 27, 2012
• First Submitted That Met QC Criteria: January 31, 2012
• First Posted (Estimate): February 1, 2012

Study Record Updates

• Last Update Posted (Estimate): March 17, 2016
• Last Update Submitted That Met QC Criteria: February 17, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Hematologic Neoplasms; Primary Myelofibrosis
• Other Study ID Numbers: ARD12181; 2011-005226-21 (EudraCT Number); U1111-1124-0967 (Other Identifier: UTN)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No