South Texas Accelerated Research Therapeutics (START), 4383 Medical Dr, Room 4042, San Antonio, TX, 78229, USA,
Cancer Chemother Pharmacol. 2013 Oct;72(4):861-8. doi: 10.1007/s00280-013-2267-x. Epub 2013 Aug 25.
Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2-10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study.
Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m(2) in week 1 of cycle 1 and 20, 27, or 36 mg/m(2) thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts.
Fourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m(2) was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts.
Carfilzomib 20/36 mg/m(2) was well tolerated when administered twice weekly by 2-10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.
在这项 I/II 期研究中，评估蛋白酶体抑制剂卡非佐米在既往治疗后进展的晚期实体瘤患者中的耐受性、药代动力学（PK）、药效学和抗肿瘤活性。卡非佐米的给药方案为：在 28 天的周期中，每 2 周静脉输注 2-10 分钟，于第 1、2、8、9、15 和 16 天给药，剂量为第 1 周期的第 1 周 20mg/m2，此后为 20、27 或 36mg/m2。在剂量递增期间确定的最大耐受剂量或方案规定的最大计划剂量（MPD）用于扩展队列和小细胞肺癌、非小细胞肺癌、卵巢癌和肾癌的 II 期肿瘤特异性队列的患者。
入组标准为既往接受≥1 种治疗后进展的成年实体瘤患者。在 28 天的周期中，每 2 周静脉输注 2-10 分钟，于第 1、2、8、9、15 和 16 天给药，剂量为第 1 周期的第 1 周 20mg/m2，此后为 20、27 或 36mg/m2。在剂量递增期间确定的最大耐受剂量或方案规定的最大计划剂量（MPD）用于扩展队列和小细胞肺癌、非小细胞肺癌、卵巢癌和肾癌的 II 期肿瘤特异性队列的患者。
14 例患者在剂量递增期间接受了卡非佐米治疗。在 20/36mg/m2 时，唯一的剂量限制毒性为 3 级疲劳，确定 MPD 为扩展和 II 期剂量。65 例患者在 MPD 时接受了卡非佐米治疗。不良反应包括疲劳、恶心、厌食和呼吸困难。卡非佐米的 PK 呈剂量相关性，半衰期<1 小时。所有剂量均导致血液中至少 80%的蛋白酶体抑制。在 I 期有 2 例患者出现部分缓解，在扩展和 II 期队列中可评估的患者中，4 个周期后有 21.5%的患者疾病稳定。
每周两次静脉输注 2-10 分钟，卡非佐米 20/36mg/m2 时耐受性良好。在该剂量和输注速率下，卡非佐米抑制血液中的蛋白酶体，但在晚期实体瘤患者中抗肿瘤活性有限。
