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.
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.