Advani Ranjana H, Lebovic Daniel, Chen Andy, Brunvand Mark, Goy Andre, Chang Julie E, Hochberg Ephraim, Yalamanchili Sreeni, Kahn Robert, Lu Dan, Agarwal Priya, Dere Randall C, Hsieh Hsin-Ju, Jones Surai, Chu Yu-Waye, Cheson Bruce D
Stanford University Medical Center, Stanford, California.
University of Michigan Medical School, Ann Arbor, Michigan.
Clin Cancer Res. 2017 Mar 1;23(5):1167-1176. doi: 10.1158/1078-0432.CCR-16-0772. Epub 2016 Sep 6.
Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. .
匹纳妥单抗维布妥昔是一种抗体药物偶联物，其强效抗微管药物单甲基奥瑞他汀E（MMAE）通过可被蛋白酶切割的连接子与抗CD22抗体偶联。这项I期研究确定了其推荐的II期剂量（RP2D），并评估了其单独使用以及与利妥昔单抗联合使用时，在复发/难治性（r/r）非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）中的安全性、耐受性和抗肿瘤活性。患者每21天接受递增剂量的匹纳妥单抗维布妥昔。在r/r弥漫性大B细胞淋巴瘤（DLBCL）和r/r惰性NHL（iNHL）患者中评估了单独使用RP2D或与利妥昔单抗联合使用时的临床活性。75例患者接受了单药匹纳妥单抗维布妥昔治疗。基于3例接受3.2mg/kg（最大评估剂量）治疗的患者中，有1例出现>7天的4级中性粒细胞减少和2例出现<7天的4级中性粒细胞减少的剂量限制性毒性（DLT），RP2D为2.4mg/kg。在2.4mg/kg时未发生DLT。在RP2D时，中性粒细胞减少是最常见的≥3级不良事件。外周神经病变相关的≥2级不良事件最常导致治疗中断。利妥昔单抗联合治疗不影响匹纳妥单抗维布妥昔的安全性、耐受性或药代动力学。未偶联的MMAE暴露远低于抗体偶联的MMAE暴露，且重复给药无蓄积。在RP2D时，在DLBCL（9/25）和iNHL（7/14）患者中观察到客观缓解；8例接受匹纳妥单抗维布妥昔（RP2D）和利妥昔单抗治疗的患者中有2例完全缓解。CLL患者未显示客观缓解。单独使用以及与利妥昔单抗联合使用时，匹纳妥单抗维布妥昔的RP2D均为2.4mg/kg，耐受性良好，在r/r NHL中具有令人鼓舞的临床活性。
