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/m2for 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.
背景：针对复发/难治性白血病或实体瘤的儿童、青少年及年轻成人患者，亟需新型治疗方案。蛋白酶体抑制剂卡非佐米在单独或联合用药时，已显示出对多种儿童恶性肿瘤的临床前活性。为此，我们开展了一项多中心剂量递增Ⅰ期研究，评估卡非佐米联合环磷酰胺与依托泊苷的用药方案。 方法：研究纳入年龄为6个月至<30岁、患有复发/难治性白血病（队列A）或复发/难治性非中枢神经系统实体瘤（队列B）的患者，要求卡氏/兰氏评分≥50分且器官功能良好。治疗方案为每28天一个周期，在生长因子支持下，连续5天给予环磷酰胺（440 mg/m²/天）、依托泊苷（100 mg/m²/天）及卡非佐米。卡非佐米起始剂量为11 mg/m²/天，剂量递增采用滚动六例设计，各队列独立管理。剂量限制性毒性在首个治疗周期内评估，疾病反应分别在1个周期（队列A）或2个周期（队列B）后评估。 结果：共38例患者接受治疗（队列A 14例；队列B 24例）。队列A中卡非佐米的最大耐受剂量为11 mg/m²/天，观察到3例剂量限制性毒性：血小板减少症、心包炎及可逆性后部脑病综合征。多数患者仅接受1个周期治疗。队列B未达到最大耐受剂量，所实施的最高剂量水平（亦推荐为Ⅱ期研究剂量）为：第1周期第1–2天20 mg/m²、第3–5天36 mg/m²，后续所有周期第1–5天均为36 mg/m²。该队列出现1例可逆性后部脑病综合征剂量限制性毒性。研究还进行了剂量扩展以收集更多毒性数据。总体而言，20例患者接受了≥2个周期治疗（范围2–14个周期）。 结论：卡非佐米/环磷酰胺/依托泊苷的5日给药方案在实体瘤患者中耐受性良好，其中肉瘤患者获益最为显著，值得进一步研究验证。
肿瘤(癌症)患者之家