NCT03755518终止3 期
A Phase 3b, Multicenter, Single-Arm, Open-Label Efficacy and Safety Study of Fedratinib in Subjects With DIPSS (Dynamic International Prognostic Scoring System)-Intermediate or High-Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF) and Previously Treated With Ruxolitinib
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- Celgene
- 入组人数
- 38
- 试验地点
- 35
- 主要终点
- Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6
研究概览
简要总结
This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib in Subjects with DIPSS (Dynamic International Prognostic Scoring System)-Intermediate or High- Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF), or Post-Essential Thrombocythemia Myelofibrosis (post-ET MF) and Previously Treated with Ruxolitinib.
The primary objective of the study is to evaluate the percentage of subjects with at least a 35% reduction in spleen size and one of the secondary objectives is to evaluate the safety of fedratinib.
详细描述
This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib in Subjects with DIPSS (Dynamic International Prognostic Scoring System)-Intermediate or High- Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF), or Post-Essential Thrombocythemia Myelofibrosis (post-ET MF) and Previously Treated with Ruxolitinib.
The spleen volume reduction at the end of Cycle 6 as the primary objective. The secondary objectives of the study are to further evaluate the safety and to assess and implement mitigation strategies for WE and for gastrointestinal (GI) adverse events.
The study will be at multiple centers to provide access to a broad population and have assurance the results are likely to have general applicability.
This is also conducted as an open-label study to collect efficacy and safety data with fedratinib use, no randomization or stratification will occur.
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
- •Main Study Inclusion Criteria
- •Subject is at least 18 years of age at the time of signing the informed consent form (ICF)
- •Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2
- •Subject has diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report
- •Subject has a DIPSS Risk score of Intermediate or High
- •Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥ 450 cm3 by MRI or CT-scan assessment or by palpable spleen measuring ≥ 5 cm below the left costal margin.
- •Subject has been previously exposed to ruxolitinib, while diagnosed with MF (PMF, post-ET MF or post-PV MF), and must meet at least one of the following criteria (a or b)
- •Treatment with ruxolitinib for ≥ 3 months
- •Treatment with ruxolitinib for ≥ 28 days complicated by any of the following:
- •Development of a red blood cell transfusion requirement (at least 2 units/month for 2 months) or
- •Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib
- •Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to fedratinib treatment.
- •Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
- •Subject is willing and able to adhere to the study visit schedule and other protocol requirements
- •Participants must agree to use effective contraception
排除标准
- •Main Study Exclusion Criteria
- •Any of the following laboratory abnormalities:
- •Platelets < 50,000/μL
- •Absolute neutrophil count (ANC) < 1.0 x 109/L
- •White blood count (WBC) > 100 x 10^9/L
- •Myeloblasts > 5 % in peripheral blood
- •Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per the Modification of Diet in Renal Disease [MDRD] formula)
- •Serum amylase or lipase > 1.5 x ULN (upper limit of normal)
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN
- •Total bilirubin > 1.5 x ULN, subject's total bilirubin between 1.5 - 3.0 x ULN are eligible if the direct bilirubin fraction is < 25% of the total bilirubin
- •Subject is pregnant or lactating female
- •Subject with previous splenectomy
- •Subject with previous or planned hematopoietic cell transplant
- •Subject with prior history of encephalopathy, including Wernicke's
- •Subject with signs or symptoms of encephalopathy including Wernicke's (eg, severe ataxia, ocular paralysis or cerebellar signs)
- •Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not corrected prior to enrollment on the study
- •Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), or dual CYP2C19 and CYP3A4 inhibitors
- •Subject on any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids > 10 mg/day prednisone or equivalent. Subjects who have had prior 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 the start of fedratinib treatment
- •Subject has received ruxolitinib within 14 days prior to the start of fedratinib
- •Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating factor [G-CSF]) within 14 days prior to the start of fedratinib treatment
- •Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1 cycle other than ruxolitinib treatment
- •Subject on treatment with aspirin with doses > 150 mg daily
- •Subject with major surgery within 28 days before starting fedratinib treatment
- •Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)
- •Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to enrollment.
- •However, subject with the following history/concurrent conditions provided successfully treated may enroll: non-invasive skin cancer, in situ cervical cancer, carcinoma in situ of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system), or is free of disease and on hormonal treatment only
- •Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
- •Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
- •Subject with serious active infection
- •Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
- •Subject is unable to swallow capsule
- •Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
- •Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
- •Subject has any condition that confounds the ability to interpret data from the study
- •Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to start of fedratinib treatment
- •Subject with life expectancy of less than 6 months.
研究组 & 干预措施
Administration of Fedratinib 400mg/day
Experimental
Self-administered Investigational Product (IP) (400 mg/day) on an outpatient basis, once daily preferably with food during an evening meal at the same time each day in consecutive 4-week (28-day) cycles.
干预措施: FEDRATINIB (Drug)
结局指标
主要结局
Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6
时间窗: From First Dose to end of Cycle 6 (approximately 168 days)
Percentage of participants who have a ≥ 35% SVR at end of Cycle 6 as compared to baseline. Participants with a missing MRI/CT spleen volume at the end of Cycle 6 including those who meet the criteria for progression of splenomegaly before the end of Cycle 6 will be considered non-responders. Baseline value is defined as the last value or measurement taken prior to the first dose in the study
次要结局
- Number of Participants of All Grade Adverse Events (AEs) and Grade 3/4 AEs(From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 128 weeks))
- Number of Participants and Severity of Treatment Related All Grade Adverse Events (AEs) and Grade 3/4 AEs(From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks))
- Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin(at Cycle 4 Day 1 and Cycle 7 Day 1)
- Mean Change From Baseline in Hematology Laboratory Analysis - Erythrocytes(at Cycle 4 Day 1 and Cycle 7 Day 1)
- Mean Change From Baseline in Hematology Laboratory Analysis - Platelets, Leukocytes and Neutrophils(at Cycle 4 Day 1 and Cycle 7 Day 1)
- Mean Change From Baseline in the Percentage of Blasts/Leukocytes in Hematology Laboratory Analysis(at Cycle 4 Day 1 and Cycle 7 Day 1)
- Mean Change From Baseline in Chemistry Parameters Analysis - ALT, AST, Amylase, Lipase(at Cycle 4 Day 1 and Cycle 7 Day 1)
- Mean Change From Baseline in Chemistry Parameters Analysis - Creatinine(at Cycle 4 Day 1 and Cycle 7 Day 1)
- Spleen Response Rate by Palpation(From First Dose to end of Cycle 6 (approximately 168 days))
- Symptom Response Rate(From First Dose to end of Cycle 6 (approximately 168 days))
- Durability of Spleen Response by Palpation (DRP)(From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.32 Weeks))
- Durability of Spleen Volume Response by MRI/CT (DR)(From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.40 Weeks))
- Durability of Symptom Response (DSR)(From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 31.33 Weeks))
- Number of Participants With Grade 3 or Higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy Including Wernicke's.(From first dose to end of treatment (an average of 50.3 weeks up to a maximum of 124 weeks))
- Number of Participants With Thiamine Levels < Lower Limit of Normal (LLN).(At Cycle 1, 2, 3, and every 3 cycles afterwards till End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks))
- Number of Participants With Thiamine Levels > Upper Limit of Normal (ULN).(At Cycle 1, 2, 3, and every 3 cycles afterwards till End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks))
- Number of Participants With Clinically Notable Laboratory Results, Grade 3 or 4(From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks))
研究者
研究点 (35)
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