Hematopoietic Neoplasm
Conditions
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.
Interventions
DRUGSAR302503
Pharmaceutical form:capsule Route of administration: oral
DRUGPlacebo
Pharmaceutical form:capsule Route of administration: oral
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (RR): Percentage of Participants Who Had a >=35% Reduction From Baseline in Volume of Spleen Size at The End Cycle 6 | Baseline, Week 24 | Spleen volume was determined by magnetic resonance imaging (MRI) (or computed tomography scan in participants with contraindications for MRI) at baseline and at the end of cycle 6 with a confirmatory scan approximately 4 weeks after the end of Cycle 6. The MRI or CT imaging results reviewed in a blinded manner by an Independent Review Committee (IRC). Analysis was performed on intent-to-treat (ITT) population defined as all randomized participants who signed informed consent form (ICF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Symptom Response Rate (SRR): Percentage of Participants With >=50% Reduction From Baseline in the Total Symptom Score at End of Cycle 6 | Baseline, Week 24 | Total symptom score is the averaged value of the daily scores for each of 6 key Myelofibrosis (MF) associated Symptom items (night sweats, pruritus, abdominal discomfort, early satiety \[filling up quickly when you eat\], pain under ribs on left side, and bone or muscle pain), each item measured on a scale from 0 (absent) to 10 (worst imaginable). A higher score indicates worse symptoms. Analysis was performed on ITT population. Number of participants analysed= participants with available data at end of cycle 6. |
| Percentage of Participants Who Had >=25% Reduction From Baseline in Volume of Spleen Size at End of Cycle 6 | Baseline, Week 24 | Spleen volume was determined by magnetic resonance imaging (MRI) (or computed tomography scan in subjects with contraindications for MRI) at baseline and at the end of cycle 6 with a confirmatory scan approximately 4 weeks after the end of Cycle 6. Analysis was performed on ITT population. |
Countries
Australia, Austria, Belgium, Brazil, Canada, France, Germany, Hungary, Ireland, Israel, Italy, Lithuania, Mexico, Poland, Portugal, Romania, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Participant flow
Recruitment details
The study was conducted at 101 sites in 25 countries. A total of 351 participants were screened between 22 December 2011 and 24 August 2012.
Pre-assignment details
Of 351 screened participants, 62 were screen failures and 289 were randomized.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 119 Participants |
| Sex: Female, Male Male | 170 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 96 | 5 / 96 | 6 / 97 | 0 / 35 | 1 / 36 |
| other Total, other adverse events | 76 / 95 | 96 / 96 | 94 / 97 | 33 / 35 | 36 / 36 |
| serious Total, serious adverse events | 22 / 95 | 37 / 96 | 43 / 97 | 13 / 35 | 13 / 36 |
Outcome results
None listed