Clinical trial NCT01437787: Phase III Study of SAR302503 in Intermediate-2 and High Risk Patients With Myelofibrosis
Official title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of SAR302503 in Patients With Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis With Splenomegaly
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hematopoietic Neoplasm
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2011-09-21
Enrollment: 289
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Response Rate (RR), defined as the proportion of patients who have a ≥35% reduction in volume of spleen size at the end of Cycle 6, and confirmed 4 weeks thereafter
timeFrame: 6 months
Secondary outcomes:
measure: Symptom Response Rate (SRR): Proportion of patients with ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score.
timeFrame: 6 months
measure: OS (overall survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo.
timeFrame: approximately 5 years
measure: PFS (progression free survival) of either 400 mg/day or 500 mg/day of IMP as compared to placebo.
timeFrame: approximately 5 years
measure: Proportion of patients who have ≥25% reduction in volume of spleen size at end of Cycle 6, and confirmed 4 weeks thereafter.
timeFrame: 6 months
measure: Duration of spleen response, measured by MRI (or CT scan in patients with contraindications for MRI.
timeFrame: 2 years
measure: Clinical and laboratory events graded by the NCI CTCAE v4.03.
timeFrame: approximately 5 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Investigational Site Number 840014
state: Arizona
city: La Jolla
country: United States
facility: Investigational Site Number 840001
state: California
city: La Jolla
country: United States
facility: Investigational Site Number 840012
state: California
city: Los Angeles
country: United States
facility: Investigational Site Number 840006
state: California
city: Baton Rouge
country: United States
facility: Investigational Site Number 840013
state: Louisiana
city: Rochester
country: United States
facility: Investigational Site Number 840008
state: Minnesota
city: Newark
country: United States
facility: Investigational Site Number 840009
state: New Jersey
city: Canton
country: United States
facility: Investigational Site Number 840002
state: Ohio
city: Houston
country: United States
facility: Investigational Site Number 840004
state: Texas
city: Box Hill
country: Australia
facility: Investigational Site Number 036001
city: Herston
country: Australia
facility: Investigational Site Number 036005
city: Randwick
country: Australia
facility: Investigational Site Number 036003
city: Tweed Heads
country: Australia
facility: Investigational Site Number 036004
city: Wodonga
country: Australia
facility: Investigational Site Number 036002
city: Wien
country: Austria
facility: Investigational Site Number 040001
city: Antwerpen
country: Belgium
facility: Investigational Site Number 056003
city: Leuven
country: Belgium
facility: Investigational Site Number 056001
city: Jau
country: Brazil
facility: Investigational Site Number 076002
city: Porto Alegre
country: Brazil
facility: Investigational Site Number 076004
city: Rio De Janeiro
country: Brazil
facility: Investigational Site Number 076001
city: Montreal
country: Canada
facility: Investigational Site Number 124001
city: Montreal
country: Canada
facility: Investigational Site Number 124003
city: Saint John
country: Canada
facility: Investigational Site Number 124002
city: Marseille
country: France
facility: Investigational Site Number 250006
city: Nantes Cedex 01
country: France
facility: Investigational Site Number 250005
city: Nimes
country: France
facility: Investigational Site Number 250004
city: Pierre Benite Cedex
country: France
facility: Investigational Site Number 250002
city: Poitiers
country: France
facility: Investigational Site Number 250007
city: Toulouse
country: France
facility: Investigational Site Number 250003
city: Villejuif Cedex
country: France
facility: Investigational Site Number 250001
city: Aachen
country: Germany
facility: Investigational Site Number 276006
city: Bonn
country: Germany
facility: Investigational Site Number 276007
city: Dresden
country: Germany
facility: Investigational Site Number 276008
city: Mannheim
country: Germany
facility: Investigational Site Number 276001
city: Budapest
country: Hungary
facility: Investigational Site Number 348002
city: Debrecen
country: Hungary
facility: Investigational Site Number 348001
city: Györ
country: Hungary
facility: Investigational Site Number 348007
city: Kecskemét
country: Hungary
facility: Investigational Site Number 348006
city: Miskolc
country: Hungary
facility: Investigational Site Number 348003
city: Dublin
country: Ireland
facility: Investigational Site Number 372002
city: Galway
country: Ireland
facility: Investigational Site Number 372001
city: Haifa
country: Israel
facility: Investigational Site Number 376003
city: Tel Hashomer
country: Israel
facility: Investigational Site Number 376002
city: Bergamo
country: Italy
facility: Investigational Site Number 380002
city: Bologna
country: Italy
facility: Investigational Site Number 380007
city: Firenze
country: Italy
facility: Investigational Site Number 380004
city: Pavia
country: Italy
facility: Investigational Site Number 380001
city: Pavia
country: Italy
facility: Investigational Site Number 380006
city: Varese
country: Italy
facility: Investigational Site Number 380003
city: Bundang-Gu
country: Korea, Republic of
facility: Investigational Site Number 410002
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410004
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410003
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410001
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410005
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410006
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410007
city: Kaunas
country: Lithuania
facility: Investigational Site Number 440001
city: Klaipeda
country: Lithuania
facility: Investigational Site Number 440002
city: Queretaro
country: Mexico
facility: Investigational Site Number 484001
city: Brzozow
country: Poland
facility: Investigational Site Number 616005
city: Gdansk
country: Poland
facility: Investigational Site Number 616002
city: Lodz
country: Poland
facility: Investigational Site Number 616006
city: Warszawa
country: Poland
facility: Investigational Site Number 616010
city: Wroclaw
country: Poland
facility: Investigational Site Number 616003
city: Coimbra
country: Portugal
facility: Investigational Site Number 620005
city: Lisboa
country: Portugal
facility: Investigational Site Number 620004
city: Lisboa
country: Portugal
facility: Investigational Site Number 620001
city: Porto
country: Portugal
facility: Investigational Site Number 620003
city: Brasov
country: Romania
facility: Investigational Site Number 642003
city: Bucharest
country: Romania
facility: Investigational Site Number 642004
city: Bucuresti
country: Romania
facility: Investigational Site Number 642002
city: Bucuresti
country: Romania
facility: Investigational Site Number 642006
city: Timisoara
country: Romania
facility: Investigational Site Number 642001
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643009
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643001
city: Nizhny Novgorod
country: Russian Federation
facility: Investigational Site Number 643010
city: Petrozavodsk
country: Russian Federation
facility: Investigational Site Number 643008
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643004
city: St.-Petersburg
country: Russian Federation
facility: Investigational Site Number 643005
city: Volgograd
country: Russian Federation
facility: Investigational Site Number 643007
city: Singapore
country: Singapore
facility: Investigational Site Number 702002
city: Singapore
country: Singapore
facility: Investigational Site Number 702001
city: Johannesburg
country: South Africa
facility: Investigational Site Number 710003
city: Parktown
country: South Africa
facility: Investigational Site Number 710002
city: Barcelona
country: Spain
facility: Investigational Site Number 724001
city: Madrid
country: Spain
facility: Investigational Site Number 724002
city: Stockholm
country: Sweden
facility: Investigational Site Number 752001
city: Uddevalla
country: Sweden
facility: Investigational Site Number 752002
city: Changhua
country: Taiwan
facility: Investigational Site Number 158002
city: Kaohsiung
country: Taiwan
facility: Investigational Site Number 158003
city: Taipei
country: Taiwan
facility: Investigational Site Number 158001
city: Belfast
country: United Kingdom
facility: Investigational Site Number 826006
city: Birmingham
country: United Kingdom
facility: Investigational Site Number 826003
city: Glasgow
country: United Kingdom
facility: Investigational Site Number 826002
city: Leeds
country: United Kingdom
facility: Investigational Site Number 826004
city: London
country: United Kingdom
facility: Investigational Site Number 826001
city: London
country: United Kingdom
facility: Investigational Site Number 826005
city: Manchester
country: United Kingdom
facility: Investigational Site Number 826007
city: Newcastle Upon Tyne
country: United Kingdom
facility: Investigational Site Number 826008
city: Oxford
country: United Kingdom
facility: Investigational Site Number 826009
city: Southampton
country: United Kingdom
facility: Investigational Site Number 826010
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, Masszi T, Mishchenko E, Jourdan E, Vannucchi AM, Drummond MW, Jurgutis M, Kuliczkowski K, Gheorghita E, Passamonti F, Neumann F, Patki A, Gao G, Tefferi A. Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2015 Aug;1(5):643-51. doi: 10.1001/jamaoncol.2015.1590.