Hematopoietic Neoplasm
Conditions
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.
Interventions
DRUGSAR302503
Pharmaceutical form:capsule Route of administration: oral
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate: Percentage of Participants With >=35% Reduction From Baseline in Spleen Volume at End of Cycle 6 | Baseline, End of Cycle 6 | Spleen volume was measured by central imaging MRI (CT scan in participants with contraindications for MRI). Analysis was performed on Per Protocol (PP) population defined as all treated participants with a baseline and at least one post-baseline MRI/CT scan of spleen volume, and had no important protocol deviations that could impact on efficacy outcome. Last observation carried forward (LOCF) method was used to impute the missing data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Symptom Response Rate: Percentage of Participants With >=50% Reduction From Baseline in the Total Symptom Score Using MFSAF at End of Cycle 6 | Baseline, End of Cycle 6 | The key MF-associated symptoms were assessed using the modified Myelofibrosis Symptom Assessment Form (MFSAF) Diary: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain. These were measured on a scale from 0 (absent) to 10 (worst imaginable). Then Total symptom score (range 0 to 60) was defined as the sum of the scores for each of the 6 symptoms of MFSAF. Higher score indicated greater severity of symptoms. Analysis was performed on MFSAF analysis population defined as all treated participants with baseline and at least 1 post-baseline evaluable assessment of total symptom score. |
| Percentage of Participants With a ≥50% Reduction From Baseline in Length of Spleen by Palpation at End of Cycle 6 | Baseline, End of Cycle 6 | Percentage of Participants with a ≥50% Reduction From Baseline in Length of Spleen by Palpation at End of Cycle 6. |
| Response Rate: Percentage of Participants With ≥35% Reduction From Baseline in Spleen Volume Measured by MRI or CT Scan at End of Cycle 3 | Baseline, End of Cycle 3 | Percentage of Participants With ≥35% Reduction From Baseline in Spleen Volume Measured by MRI or CT Scan at End of Cycle 3. Analysis was performed on PP population. |
| Percent Change From Baseline in Spleen Volume Measured by MRI or CT Scan at End of Cycle 3 and Cycle 6. | Baseline, End of Cycle 3, 6 | Percent Change From Baseline in Spleen Volume Measured by MRI or CT Scan at End of Cycle 3 and Cycle 6. Analysis was performed on PP population. |
| Plasma Concentration of Fedratinib | Pre-dose (Hour 0), 0.5, 2.5 hours post-dose on Day 1 of Cycle 1, 2, pre-dose (Hour 0) on Day 1 of Cycle 4 | Analysis was performed on pharmacokinetic population defined as all participants who received at least 1 (even partial) cycle of study treatment and had evaluable drug concentration data. |
Countries
Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Participant flow
Recruitment details
The study was conducted at 36 sites in 10 countries. A total of 97 participants were enrolled between 30 April 2012 and 02 August 2013.
Pre-assignment details
All 97 enrolled participants were treated.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 44 Participants |
| Sex: Female, Male Male | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 97 |
| other Total, other adverse events | 95 / 97 |
| serious Total, serious adverse events | 33 / 97 |
Outcome results
None listed