Phase I Trial of Fedratinib in Combination With Decitabine in Patients With Myeloproliferative Neoplasms in Accelerated and Blast Phase
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Decitabine and Fedratinib
研究概览
简要总结
The purpose of this research is to study the safety and tolerability and to establish the maximum tolerated dose (MTD) of the combination of two drugs, fedratinib and decitabine, for the treatment of advanced-phase MPNs.
详细描述
This is a single center phase I dose-escalation trial of Fedratinib in Combination with Decitabine in Patients with Myeloproliferative Neoplasms. The primary objective is to determine the maximum tolerated dose of the combination therapy, using a 3+3 dose escalation algorithm. Fedratinib will be administered at 2 dose levels: 300 mg and 400 mg by mouth, once daily. Fedratinib will be administered concomitantly with decitabine 20 mg/m2 intravenously over 1 hour per day for 5 days in 28-day cycles.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Subjects must have MPN-AP as defined by 10%-19% blasts in the peripheral blood or bone marrow and evidence of dysplastic marrow features with a concomitant diagnosis of essential thrombocythemia (ET), polycythemia vera (PV) or primary myelofibrosis (PMF) or a diagnosis of MPN-BP as defined by 20% blasts in the blood or bone marrow following a previous diagnosis of ET, PV or PMF.
- •Subjects must have adequate organ function documented within 14 days of study entry as follows:
- •Estimated creatinine clearance (by Cockcroft-Gault Equation) of ≥ 50 mL/min
- •Serum total bilirubin ≤ 1.5 × ULN (unless attributable to Gilbert's disease or hemolysis, in which case the direct bilirubin level must be ≤ 1.5 × upper limit of normal (ULN)).
- •Alkaline phosphatase, serum aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN.
- •≥ 18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) Performance status of 0-
- •Patients with ECOG performance status of 3 will be eligible if the lower performance status is deemed by the investigator to be due entirely to MPN-AP/BP and not due to another comorbidity.
排除标准
- •Receipt of chemotherapy or investigational therapy, with the exception of hydroxyurea, within 4 weeks of study entry. Previous treatment at any time with decitabine, fedratinib or ruxolitinib as single agents will not exclude eligibility. Previous stem cell transplant will not exclude eligibility as long as other inclusion/exclusion criteria have been met and subjects do not have Grade ≥ II graft-versus-host disease (GVHD) requiring systemic immunosuppressive therapy.
- •Subjects with an Human leukocyte antigen (HLA)-compatible donor or stem cell source who are immediate candidates for allogeneic hematopoietic cell transplantation (HCT).
- •Subjects who are receiving any concurrent treatment for acute myeloid leukemia (AML), including other investigational agents.
- •Diagnosis of acute myelofibrosis.
- •Uncontrolled intercurrent illness including, but not limited to hepatitis, human immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral therapy, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class 3 or 4), unstable angina pectoris, ventricular arrhythmia, Child-Pugh Class C cirrhosis, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Subjects with a prior history of Wernicke's encephalopathy (WE) will be excluded. If a subject has signs or symptoms of encephalopathy, including Wernicke's encephalopathy (e.g. severe ataxia, ocular paralysis or cerebellar signs), thiamine deficiency must be excluded and a brain MRI should be obtained prior to study initiation to evaluate for WE.
- •Other medications, severe acute/chronic medical or psychiatric conditions, or laboratory abnormalities that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, that in the judgment of the Investigator would make the subject inappropriate for entry into this study.
- •Pregnant women are excluded because of the potential for teratogenic or abortifacient effects.
研究组 & 干预措施
Fedratinib 300 mg
Cohort 1: 300 mg of Fedratinib by mouth, once daily during each 28-day cycle
干预措施: Fedratinib Oral Capsule 300 mg (Drug)
Fedratinib 300 mg
Cohort 1: 300 mg of Fedratinib by mouth, once daily during each 28-day cycle
干预措施: Decitabine 20 mg/m2 (Drug)
Fedratinib 400 mg
Cohort 2: 400 mg of Fedratinib by mouth, once daily during each 28-day cycle
干预措施: Decitabine 20 mg/m2 (Drug)
Fedratinib 400 mg
Cohort 2: 400 mg of Fedratinib by mouth, once daily during each 28-day cycle
干预措施: Fedratinib Oral Capsule 400 mg (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Decitabine and Fedratinib
时间窗: Up to 8 weeks for each dosing cohort
The MTD will be determined using a 3+3 algorithm. If \< 33% of the subjects enrolled at a dose level experience a dose-limiting toxicity (DLT), escalation to the next designated dose cohort will continue. If ≥ 33% of the subjects enrolled at a dose level experience a DLT, the previous dosing cohort will be considered the MTD. DLT is defined as: (1) Grade 3, 4, or 5 non-hematologic toxicity considered at least possibly related to the study drug, except for infection, bleeding, fever, fatigue, dyspnea, and (2) Grade 3, 4, or 5 anemia, neutropenia or thrombocytopenia with a hypocellular bone marrow and \< 5% marrow blasts lasting for 42 days or more.
次要结局
- Composite Complete Remission (CRc) Rate(Up to 3 years)
- Overall Survival (OS)(Up to 3 years)
- Complete Remission (CR) Rate(Up to 3 years)
- Partial Remission (PR) Rate(Up to 3 years)
- Progression Free Survival (PFS)(Up to 3 years)
研究者
Joseph Jurcic
Professor of Medicine
Columbia University