A Phase I Study of Carfilzomib with Cyclophosphamide and Etoposide in Relapsed and Refractory Leukemia and Solid Tumors

Background: Novel therapies are needed for children, adolescents, and young adults with relapse/refractory leukemia or solid tumors. The proteasome inhibitor carfilzomib has demonstrated pre-clinical activity against several pediatric malignancies when used alone or in combination. Therefore, a multicenter dose-escalation phase 1 study of car-filzomib administered in combination with cyclophosphamide and etoposide was con-ducted. Methods: Study eligibility included age 6 months to < 30 years with re-lapsed/refractory leukemia (stratum A) or relapsed/refractory non-CNS solid tumor (stratum B), Karnofsky/Lansky score ≥ 50, and adequate organ function. A 5-day regimen of cyclophosphamide 440 mg/m2/day, etoposide 100 mg/m2/day, and carfilzomib was administered every 28 days with growth factor support. The carfilzomib starting dose was 11 mg/m2/day and dose escalation followed a rolling-six design, managed inde-pendently for each stratum. Dose-limiting toxicity (DLT) was assessed during the first cycle and disease response was assessed after one cycle (stratum A) or two cycles (stra-tum B). Results: Thirty-eight patients were treated (14 in stratum A; 24 in stratum B). For stratum A, the maximum tolerated dose (MTD) for carfilzomib was 11 mg/m2/day. Three DLTs were observed: thrombocytopenia, pericarditis, and posterior reversible enceph-alopathy syndrome (PRES). Most patients received one cycle. For stratum B, an MTD was not reached. The highest dose level administered and recommended phase 2 dose was 20 mg/m2/days 1-2 and 36 mg/m2/days 3-5 for cycle 1, then 36 mg/m2 for days 1-5 of all subsequent cycles. There was a single DLT of PRES. A dose expansion for additional toxicity data was conducted. Overall, twenty patients received > 2 cycles (range, 2–14). Conclusions: A 5-day schedule of carfilzomib/cyclophosphamide/etoposide was well tolerated in patients with solid tumors. Patients with sarcomas benefited most, war-ranting further evaluation.