A Phase 1 Study of Ipilimumab in relapsed and refractory high risk myelodysplastic syndrome and acute myeloid leukemia with minimal residual disease
B Douglas Smith
1) Evaluate the safety and toxicity associated with the administration of ipilimumab in terms of dose limiting toxicities (DLT), and maximally-tolerated dose (MTD) in a cohort of patients with high risk myelodysplastic syndrome who failed hypomethylating therapy, and patients with AML who underwent induction therapy but are not planned for further intensive chemotherapy. 2) Determine the optimal dose of ipilimumab for the dose-expansion phase of the trial.
This is a single-center open-label prospective phase I study with a dose expansion phase evaluating the use of CTLA-4 blocking antibody ipilimumab in 1) patients with MDS with high risk features as defined by INT-2 or high IPSS score, or INT-1 MDS with excess blasts ( greater than 5% blasts in BM) or RBC transfusion-dependency who have failed to respond or relapsed after an initial response to hypomethylating agents 5-azacitidine or decitabine, 2) patients with AML patients who have received one or 2 courses of induction chemotherapy or hypomethylating agent therapy AND no plans for further chemotherapy therapy, but remain with evidence of residual disease of less than 5% blasts in BM, by morphology, cytogenetics, FISH, PCR, or flow cytometry.
Treatment will be administered on an outpatient basis. Appropriate dose modifications are described in Section 6 of the protocol. No investigational or commercial agents or therapies other than ipilimumab will be used. Ipilimumab will be administered intravenously on day 1 of each cycle for 4 cycles of induction. The cycle duration will be 21 days each. In the dose-escalation part of the study, only patients with MDS will be enrolled, and there will be 2 dose levels (dose level 1 [DL1] with 3 mg/kg and DL2 with 10 mg/kg), with 2 additional dose levels to be only used if excessive toxicity noted at the DL1 or DL2. There will be no intra-patient dose escalation. The phase-expansion part of the study will have 2 arms using the optimal dose identified in the dose-escalation phase with 2 arms: one arm for MDS and another for AML patients, and each of these 2 arms will aim to recruit a total of 18 patients. All patients who do not experience significant toxicity or disease progression will continue on a maintenance phase of the study in which 4 more doses of ipilimumab will be administered every 12 weeks. The maintenance phase will use the same dose used in the induction phase for each individual patient.
09/17/2014 04:03 AM