Clinical trial NCT01523171: Phase II, Open Label, Single Arm Study of SAR302503 In Myelofibrosis Patients Previously Treated With Ruxolitinib
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hematopoietic Neoplasm
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2012-02-01
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: 6 months
Secondary outcomes:
measure: 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
timeFrame: 6 months
measure: Duration of spleen response, measured by MRI (or CT scan in subjects with contraindications for MRI)
timeFrame: 6 months
measure: Proportion of subjects with a ≥50% reduction in length of spleen by palpation from baseline at the end of Cycle 6
timeFrame: 6 months
measure: 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)
timeFrame: 6 months
measure: 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)
timeFrame: 6 months
measure: Safety, as assessed by clinical, laboratory, ECG, and vital sign events; graded by the NCI CTCAE v4.03
timeFrame: approximately 5 years
measure: Plasma concentrations of SAR302503
timeFrame: 4 months
measure: The effect of SAR302503 on the JAK2V617F allele burden
timeFrame: 2 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Investigational Site Number 840007
state: Arizona
city: San Francisco
country: United States
facility: Investigational Site Number 840003
state: California
city: San Francisco
country: United States
facility: Investigational Site Number 840004
state: California
city: Atlanta
country: United States
facility: Investigational Site Number 840005
state: Georgia
city: Chicago
country: United States
facility: Investigational Site Number 840014
state: Illinois
city: Kansas City
country: United States
facility: Investigational Site Number 840001
state: Kansas
city: Baltimore
country: United States
facility: Investigational Site Number 840017
state: Maryland
city: Baltimore
country: United States
facility: Investigational Site Number 840013
state: Maryland
city: Ann Arbor
country: United States
facility: Investigational Site Number 840010
state: Michigan
city: New York
country: United States
facility: Investigational Site Number 840009
state: New York
city: New York
country: United States
facility: Investigational Site Number 840018
state: New York
city: Cleveland
country: United States
facility: Investigational Site Number 840022
state: Ohio
city: Middletown
country: United States
facility: Investigational Site Number 840019
state: Ohio
city: Charleston
country: United States
facility: Investigational Site Number 840024
state: South Carolina
city: Houston
country: United States
facility: Investigational Site Number 840002
state: Texas
city: Salt Lake City
country: United States
facility: Investigational Site Number 840015
state: Utah
city: Salzburg
country: Austria
facility: Investigational Site Number 040002
city: Wien
country: Austria
facility: Investigational Site Number 040001
city: Antwerpen
country: Belgium
facility: Investigational Site Number 056002
city: Leuven
country: Belgium
facility: Investigational Site Number 056003
city: Toronto
country: Canada
facility: Investigational Site Number 124001
city: Marseille
country: France
facility: Investigational Site Number 250001
city: Nimes Cedex 9
country: France
facility: Investigational Site Number 250003
city: Paris Cedex 10
country: France
facility: Investigational Site Number 250002
city: Paris Cedex 12
country: France
facility: Investigational Site Number 250006
city: Toulouse
country: France
facility: Investigational Site Number 250004
city: Frankfurt Am Main
country: Germany
facility: Investigational Site Number 276003
city: Leipzig
country: Germany
facility: Investigational Site Number 276007
city: Magdeburg
country: Germany
facility: Investigational Site Number 276006
city: Mannheim
country: Germany
facility: Investigational Site Number 276001
city: Ulm
country: Germany
facility: Investigational Site Number 276005
city: Firenze
country: Italy
facility: Investigational Site Number 380004
city: Milano
country: Italy
facility: Investigational Site Number 380001
city: Roma
country: Italy
facility: Investigational Site Number 380002
city: Varese
country: Italy
facility: Investigational Site Number 380003
city: Amsterdam
country: Netherlands
facility: Investigational Site Number 528002
city: Maastricht
country: Netherlands
facility: Investigational Site Number 528003
city: Nijmegen
country: Netherlands
facility: Investigational Site Number 528001
city: Barcelona
country: Spain
facility: Investigational Site Number 724001
city: Majadahonda
country: Spain
facility: Investigational Site Number 724003
city: Salamanca
country: Spain
facility: Investigational Site Number 724002
city: London
country: United Kingdom
facility: Investigational Site Number 826001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.