NCT03386214终止1 期
Pevonedistat in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Safety and tolerability of pevonedistat in combination with ruxolitinib in patients with myelofibrosis as measured by the maximum tolerated dose (MTD)
研究概览
简要总结
Based on the investigators' preclinical data, the combination of pevonedistat and ruxolitinib may provide greater clinical responses in patients with myelofibrosis compared to ruxolitinib monotherapy via inhibition of NFκB in addition to JAK-STAT signaling.
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
- •Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/essential thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by IPSS.
- •On treatment with ruxolitinib for at least 3 months and have been on a stable dose for at least 8 weeks and have not achieved a CR by IWG criteria.
- •At least 18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- •Adequate bone marrow and organ function as defined below:
- •Absolute neutrophil count ≥ 500/mcL, and have not received any growth factor support for at least 4 weeks prior to screening
- •Platelets ≥ 50,000/mcL
- •Peripheral blood blasts ≤ 10%
- •Albumin > 2.7 g/dL
- •Total bilirubin ≤ institutional upper limit of normal (IULN); patients with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 x IULN
- •ALT and AST ≤ 2.5 x IULN
- •Creatinine clearance ≥ 50 mL/min
- •Female patients who:
- •Are postmenopausal for at least 1 year before the screening visit, OR
- •Are surgically sterile, OR
- •If they are of childbearing potential:
- •Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
- •Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
- •Male patients, even if surgically sterilized (ie, status postvasectomy), who:
- •Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
- •Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
- •Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)
排除标准
- •History of allogeneic stem cell transplant.
- •Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during the study period.
- •Received hydroxyurea therapy within 28 days (4 weeks) before the first dose of any study drug.
- •Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug.
- •Currently receiving any other investigational agents.
- •Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of study drug. Clinically significant metabolic enzyme inducers are not permitted during the study.
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pevonedistat, ruxolitinib, or other agents used in the study.
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures.
- •Diagnosis or treated for another malignancy within 2 years before enrollment, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any time are not excluded if they have undergone resection.
- •Ongoing or active infection.
- •Known cardiopulmonary disease defined as:
- •Unstable angina pectoris
- •Congestive heart failure (NYHA class III or IV)
- •Myocardial infarction within 6 months prior to first dose (patients who had ischemic heart disease such as ACS, MI, and/or revascularization more than 6 months prior to enrollment and who are without cardiac symptoms may enroll)
- •Symptomatic cardiomyopathy
- •Clinically significant cardiac arrhythmia
- •History of polymorphic ventricular fibrillation or Torsade de Pointes
- •Permanent atrial fibrillation (a fib), defined as continuous a fib for ≥ 6 months
- •Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening
- •Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker) or ablation. Patients with Paroxysmal a fib or < grade 3 a fib for a period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen.
- •Implantable cardioverter defibrillator
- •Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)
- •Clinically significant pulmonary hypertension requiring pharmacologic therapy
- •Uncontrolled coagulopathy or bleeding disorder.
- •Uncontrolled high blood pressure (i.e. systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg).
- •Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to institutional guidelines.
- •Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography.
- •Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis.
- •Known hepatic cirrhosis or severe pre-existing hepatic impairment.
- •Known CNS involvement.
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
- •Female patients who intend to donate eggs and male patients who intended to donate sperm during the course of this study or for 4 months after receiving the last dose of study treatment.
- •Female patients who are both lactating and breastfeeding or have positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug
- •Known HIV-positivity.
- •Chronic, active, or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier.
- •Life-threatening illness unrelated to cancer.
研究组 & 干预措施
Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Pevonedistat (Drug)
Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Ruxolitinib (Drug)
Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Peripheral blood draw (Procedure)
Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Skin biopsy (Procedure)
Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Pevonedistat (Drug)
Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Ruxolitinib (Drug)
Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Peripheral blood draw (Procedure)
Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Skin biopsy (Procedure)
Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Pevonedistat (Drug)
Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Ruxolitinib (Drug)
Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Peripheral blood draw (Procedure)
Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib
Experimental
- Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle.
- Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.
干预措施: Skin biopsy (Procedure)
结局指标
主要结局
Safety and tolerability of pevonedistat in combination with ruxolitinib in patients with myelofibrosis as measured by the maximum tolerated dose (MTD)
时间窗: 28 days after enrollment of last participant (estimated to be 25 months)
-MTD: The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. Dose escalations will proceed until the MTD has been reached.
Safety and tolerability of pevonedistat in combination with ruxolitinib in patients with myelofibrosis as measured by the frequency of adverse events
时间窗: Through 30 days after completion of treatment (estimated to be 42 weeks)
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
次要结局
- Hematologic response with the combination of pevonedistat and ruxolitinib as measured by anemia response(Through 12 weeks after completion of treatment (estimated to be 48 weeks))
- Hematologic response with the combination of pevonedistat and ruxolitinib as measured by platelet response(Through 12 weeks after completion of treatment (estimated to be 48 weeks))
- Pharmacokinetics of pevonedistat when co-administered with ruxolitinib as measured by the Tmax (time of maximum concentration observed)(Through Cycle 1 Day 5)
- Pharmacokinetics of pevonedistat when co-administered with ruxolitinib as measured by the area under the plasma drug concentration curve (AUC)(At 24 hours)
- Spleen response with the combination of pevonedistat and ruxolitinib(Through 12 weeks after completion of treatment (estimated to be 48 weeks))
- Pharmacokinetics of pevonedistat when co-administered with ruxolitinib as measured by the Cmax (peak serum concentration)(Through Cycle 1 Day 5)
- Improvement of constitutional symptoms with the combination of pevonedistat and ruxolitinib(Through completion of treatment (estimated to be 36 weeks))
研究者
研究点 (1)
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