Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and Graft-versus-host Disease in Allogeneic Hematopoietic Cell Transplantation for High-risk Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 53
- 试验地点
- 1
- 主要终点
- Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib
研究概览
简要总结
The investigators hypothesize that adding carfilzomib to standard conditioning regimen for allo-HCT for advanced or high-risk hematologic malignancies will decrease post-transplant relapse and treatment-related mortality by decreasing severe GVHD, leading to overall improvement in transplant outcomes.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Lymphoid or Myeloid malignancy requiring allogeneic hematopoietic cell transplantation
- •Pathology review by the study institution is required
- •Prior high-dose chemotherapy and autologous HCT(s) is (are) allowed
- •Disease status: Stable disease or better at the time of enrollment
- •Age: >18 and <70 years old at the time of transplant (< 71 years at transplant admission)
- •Life expectancy ≥ 6 months after transplant
- •A 8/8 or 7/8 HLA-matched donor is available
- •Karnofsky Performance Status >70% (A measure of quality of life that ranges from 0 to 100 where 100 equals perfect health and 0 is death.)
- •Adequate cardiac [LVEF (Left Ventricular Ejection Fraction) >0.4], pulmonary [FEV1 (Forced Expiratory Volume in 1 Second), FVC (Forced Vital Capacity), corrected DLCO (Diffusing Capacity) ≥ 50% predicted], hepatic [DB (Direct Bilirubin) <1.5xULN, AST (Aspartate Aminotransferase) / ALT (Alanine transaminase) ≤3xULN] and renal function [GFR (Glomerular Filtration Rate) ≥ 60 mL/min/1.73 m2]
排除标准
- •Progressive disease
- •Active central nervous system involvement by malignancy
- •Non compliance to medications or medical instructions
- •Lack of appropriate caregivers
- •Life expectancy <6 months
- •Pregnant or lactating females
- •Uncontrolled infection requiring active treatment (systemic antibiotics, anti-virals, or anti-fungals) within 14 days
- •HIV-1/HIV-2 or HTLV-1/HTLV-2 seropositivity
- •Active hepatitis A, B or C infection
- •Unstable angina or myocardial infarction within 6 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, uncontrolled or persistent atrial fibrillation/flutter, history of ventricular fibrillation, ventricular tachycardia/torsade de pointes, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
- •History of pulmonary hypertension
- •Uncontrolled hypertension or uncontrolled diabetes mellitus
- •Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen (PSA) levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
- •Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
- •Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all available anti-microbial drugs or intolerance to IV hydration due to pre-existing pulmonary or cardiac impairment
- •Subjects with pleural effusion requiring thoracentesis or ascites requiring paracentesis within 14 days prior to admission
- •Uncontrolled psychiatric condition
- •Any other clinically significant medical or psychiatric disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
研究组 & 干预措施
Carfilzomib
Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2 IV) on Day +1, +2, +6 and +7.
干预措施: Carfilzomib (Drug)
Carfilzomib
Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2 IV) on Day +1, +2, +6 and +7.
干预措施: Tacrolimus (Drug)
结局指标
主要结局
Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib
时间窗: Up to day 28
Subjects were enrolled on the first dose level (20 mg/m\^2), following a standard 3+3 dose escalation. For any given dose level, if none of the 3 subjects developed a treatment-related dose limiting toxicity (DLT), defined per protocol, dose escalation would follow. If a DLT occurred in any given dose level, the cohort would be expanded to 6. Further dose escalation would be made only if DLTs occurred in \<2 out of 6 subjects. If \>=2 of 6 develop DLTs, dose de-escalation would be made to the previous level. The highest dose level at which no more than one of six participants experience a DLT defines the MTD.
Phase II: Kaplan-Meier Estimate of the Percentage of Patients Who Are Alive and Have Not Developed Any "Event"
时间窗: 1 year
Kaplan-Meier estimate of the percentage of patients who are alive and have not developed relapse/progression of primary disease or clinical grade III-IV acute graft-versus- host disease (GVHD) or chronic GVHD requiring systemic treatment. Subjects who receive all 4 doses of carfilzomib at the maximum tolerated dose level will be considered evaluable for endpoint analysis.
次要结局
- Number of Regimen Related Toxicities (RRTs)(Up to 30 days post treatment)
- Phase II: Cumulative Incidence of Chronic GVHD(Up to 3 years)
- Phase II: Cumulative Incidence of Non-relapse Mortality(Up to 3 years)
- Phase II: Kaplan-Meier Estimate for Overall Survival Time(Up to 3 years)
- Phase II: Kaplan-Meier Estimate for Progression/Relapse-free Survival Time(Up to 3 years)
- Phase II: Cumulative Incidence of Acute GVHD(At day 180 post-transplant; data collected up to 3 years)