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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 97
- 试验地点
- 82
- 主要终点
- 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)
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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
干预措施: SAR302503 (Drug)
结局指标
主要结局
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)
时间窗: 6 months
Response Rate: Percentage of Participants With >=35% Reduction From Baseline in Spleen Volume at End of Cycle 6
时间窗: 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.
次要结局
- 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)
- Proportion of subjects with a ≥50% reduction in length of spleen by palpation from baseline at the end of Cycle 6(6 months)
- Duration of spleen response, 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)
- 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)
- 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)
- Plasma concentrations of SAR302503(4 months)
- The effect of SAR302503 on the JAK2V617F allele burden(2 years)
- 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)
- 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)
- 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)
- 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)
- 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)