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

Le résumé fourni par la source

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 carfilzomib administered in combination with cyclophosphamide and etoposide was conducted. Methods: Study eligibility included an age of 6 months to <30 years with relapsed/refractory leukemia (stratum A) or a 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 independently 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 (stratum 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 encephalopathy syndrome (PRES). Most patients received one cycle. For stratum B, an MTD was not reached. The highest dose level administered and recommended in phase 2 (RP2D) 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, warranting further evaluation.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.