Bortezomib (VELCADE), Cladribine and Rituximab (VCR) in Mantle Cell Lymphoma: A Phase I/II Study (PSHCI 10-011)
试验速览
- 阶段
- 1 期
- 入组人数
- 13
- 试验地点
- 2
- 主要终点
- Primary Outcome Dose Limiting Tolerability
研究概览
简要总结
This is a phase I/II trial of bortezomib, cladribine, and rituximab in newly diagnosed and relapsed mantle cell lymphoma (MCL). The phase I component has three dose levels of cladribine (3 mg/m2, 4 mg/m2, and 5 mg/m2) and is designed as a traditional dose-escalation study in which cohorts of 3 patients are evaluated for the incidence of dose-liming toxicity (DLT) at each dose level. Once the maximum tolerated dose (MTD) is determined, a phase II component with 2 arms will begin. One arm will enroll newly diagnosed MCL patients and one arm will enroll relapsed MCL patients. Each arm is a single-stage, fixed sample size study and will be accrued and analyzed separately. The phase I and II data will also be analyzed separately.
详细描述
The phase I portion of the study is a standard dose-escalation schemed designed to determine the maximum tolerated dose (MTD) of the combination of bortezomib, cladribine, and rituximab therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have dose-limiting toxicity (DLT). Three patients are enrolled on a dose level. If 0 out of 3 patients have DLT, then the next set of 3 patients are enrolled at the next highest dose level. If ≥2 out of 3 patients have DLT, then the MTD will have been exceeded and dose escalation will cease. Three additional patients will be enrolled at the next lowest dose level if only 3 were treated previously at that level. If 1 out of 3 patients have DLT, then the next set of 3 patients will be treated at the same dose level. If ≤1 out of 6 patients treated at that dose level have DLT, then the next set of patients will be treated at the next higher dose level. If ≥2 out of 6 patients treated at that dose level have DLT, then the MTD will have been exceeded and dose escalation will cease. Three additional patients will be treated at the next lowest dose level if only 3 were treated previously at that level. This phase I study will use 3 dose levels of cladribine (3 mg/m2, 4 mg/m2, and 5 mg/m2), with 3 mg/m2 being the starting dose level. DLTs will be assessed at the completion of the first 2 cycles of cladribine and rituximab.
Phase II Design: The phase II portion of the study is a two-arm, single-stage design with no interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue relapsed patients. In each arm, the progression-free survival rate at 2 years will be used as the primary endpoint for determining whether the treatment is sufficiently active in each arm. No comparisons will be made between the arms.
Due to difficulties with enrollment, this trial will not move into the intended Phase II of the proposed Phase I/II study. This study will only be Phase I.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Females that are postmenopausal for at least 1 year before the screening visit, surgically sterilized or if they are of childbearing potential agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose.
- •Male subjects must agree to practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse.
- •Patients with newly diagnosed and relapsed mantle cell lymphoma.
- •ECOG performance status grade 3 or higher.
排除标准
- •Patient has a platelet count of <50x10 9/L within 14 days before enrollment if not related to disease.
- •Patient has an absolute neutrophil count less than 100 within 14 days before enrollment if not related to disease.
- •Patient has a calculated or measured creatinine clearance of <20 mL/minute within 14 days before enrollment.
- •Patient has > Grade 2 peripheral neuropathy within 14 days before enrollment.
- •Patient has > 1.5 x ULN total bilirubin.
- •Myocardial infarction within 6 months prior to enrollment or has New York Heart Association Class II or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
- •Patient has hypersensitivity to bortezomib, boron or mannitol.
- •Female subject is pregnant or breast-feeding.
- •Patient has received other investigational drugs within 14 days before enrollment.
- •Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
- •Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
研究组 & 干预措施
Phase I
The phase I portion of the study is a standard dose-escalation schemed designed to determine the maximum tolerated dose (MTD) of cladribine in the combination of bortezomib, cladribine, and rituximab therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have dose-limiting toxicity (DLT). Rituximab 375 mg/m2 on day 5,12, 19, 26 for 1st cycle, then day 5 of cladribine for next 5 cycles and then every 2 months maintenance dose. Cladribine 3-5 mg/m2 days 1-5 for 6 cycles. Bortezomib 1.6 mg/m2 sub Q days 12,19,26 for 3 cycle, then every 2 weeks maintenance dose until toxicity or progression.
干预措施: Rituximab (Drug)
Phase I
The phase I portion of the study is a standard dose-escalation schemed designed to determine the maximum tolerated dose (MTD) of cladribine in the combination of bortezomib, cladribine, and rituximab therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have dose-limiting toxicity (DLT). Rituximab 375 mg/m2 on day 5,12, 19, 26 for 1st cycle, then day 5 of cladribine for next 5 cycles and then every 2 months maintenance dose. Cladribine 3-5 mg/m2 days 1-5 for 6 cycles. Bortezomib 1.6 mg/m2 sub Q days 12,19,26 for 3 cycle, then every 2 weeks maintenance dose until toxicity or progression.
干预措施: bortezomib (Drug)
Phase I
The phase I portion of the study is a standard dose-escalation schemed designed to determine the maximum tolerated dose (MTD) of cladribine in the combination of bortezomib, cladribine, and rituximab therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have dose-limiting toxicity (DLT). Rituximab 375 mg/m2 on day 5,12, 19, 26 for 1st cycle, then day 5 of cladribine for next 5 cycles and then every 2 months maintenance dose. Cladribine 3-5 mg/m2 days 1-5 for 6 cycles. Bortezomib 1.6 mg/m2 sub Q days 12,19,26 for 3 cycle, then every 2 weeks maintenance dose until toxicity or progression.
干预措施: Cladribine (Drug)
Phase II
The phase II portion of the study is a two-arm, single-stage design with no interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue relapsed patients. In each arm, the progression-free survival rate at 2 years will be used as the primary endpoint for determining whether the treatment is sufficiently active in each arm. No comparisons will be made between the arms. Rituximab 375 mg/m2 on day 5,12,19,26 for 1st cycles, then day 5 montly for next 5 cycles, then every 2 months maintenance dose. Cladribine 3-5 mg/m2 days for 6 cycles (dose determined from phase I). Bortezomib 1.6 mg/m2 weekly on day 12,19,26 for 3 cycles then every 2 weeks as maintenance dose until toxicity or progression.
干预措施: Rituximab (Drug)
Phase II
The phase II portion of the study is a two-arm, single-stage design with no interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue relapsed patients. In each arm, the progression-free survival rate at 2 years will be used as the primary endpoint for determining whether the treatment is sufficiently active in each arm. No comparisons will be made between the arms. Rituximab 375 mg/m2 on day 5,12,19,26 for 1st cycles, then day 5 montly for next 5 cycles, then every 2 months maintenance dose. Cladribine 3-5 mg/m2 days for 6 cycles (dose determined from phase I). Bortezomib 1.6 mg/m2 weekly on day 12,19,26 for 3 cycles then every 2 weeks as maintenance dose until toxicity or progression.
干预措施: bortezomib (Drug)
Phase II
The phase II portion of the study is a two-arm, single-stage design with no interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue relapsed patients. In each arm, the progression-free survival rate at 2 years will be used as the primary endpoint for determining whether the treatment is sufficiently active in each arm. No comparisons will be made between the arms. Rituximab 375 mg/m2 on day 5,12,19,26 for 1st cycles, then day 5 montly for next 5 cycles, then every 2 months maintenance dose. Cladribine 3-5 mg/m2 days for 6 cycles (dose determined from phase I). Bortezomib 1.6 mg/m2 weekly on day 12,19,26 for 3 cycles then every 2 weeks as maintenance dose until toxicity or progression.
干预措施: Cladribine (Drug)
结局指标
主要结局
Primary Outcome Dose Limiting Tolerability
时间窗: 2 years
Dose Limiting Tolerability as measured by CTCAEv.4 criteria and to evaluate progression free survival in patients treated with VCR in the Phase 1 portion .
次要结局
- Secondary Outcome objective response rates(7 months)
研究者
Jeffrey J. Pu, MD, PhD
Associate Professor of Medicine
Milton S. Hershey Medical Center