Ryan David P, O'Neil Bert H, Supko Jeffrey G, Rocha Lima Carlo M, Dees E Claire, Appleman Leonard J, Clark Jeffrey, Fidias Phinos, Orlowski Robert Z, Kashala Oscar, Eder Joseph P, Cusack James C
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
Cancer. 2006 Dec 1;107(11):2688-97. doi: 10.1002/cncr.22280.
The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients with advanced solid tumors.
Patients who had received >/=1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m(2), 1.3 mg/m(2), or 1.5 mg/m(2)) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m(2) to 125 mg/m(2)) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics.
Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients), gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received >/=1 dose of study drug. Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m(2) bortezomib and 125 mg/m(2) irinotecan. The most common grade >/=3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n = 4 episodes), and nausea (n = 4 episodes). grade >/=3 bortezomib-related hematologic adverse events included neutropenia (n = 6 episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration.
The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m(2) on Days 1, 4, 8, and 11 plus irinotecan at a dose of 125 mg/m(2) on Days 1 and 8 every 21 days were the recommended Phase II doses.
作者开展了一项I期剂量探索试验，以研究硼替佐米联合伊立替康在晚期实体瘤患者中的应用。
曾接受过≥1种既往化疗方案的患者符合入组条件。患者在每个21天周期的第1、4、8和11天接受硼替佐米（1.0mg/m²、1.3mg/m²或1.5mg/m²），并在每个21天周期的第1天和第8天接受伊立替康（剂量从50mg/m²至125mg/m²），最多8个周期。在第1周期以及第3至8周期的联合给药日，硼替佐米在伊立替康之后给药，但在第2周期中硼替佐米在伊立替康之前给药，以评估给药顺序对硼替佐米药效学的影响。
51例入组的恶性肿瘤患者，包括结直肠癌（23例）、肺癌（6例）、胃食管癌（6例）和胰腺癌（3例），接受了≥1剂研究药物。恶心、呕吐和腹泻是主要的剂量限制性毒性反应，由此确定硼替佐米的最大耐受剂量为1.3mg/m²，伊立替康的最大耐受剂量为125mg/m²。最常见的≥3级与硼替佐米相关的非血液学不良事件为疲劳（5例）、腹泻（4例）和恶心（4例）。≥3级与硼替佐米相关的血液学不良事件包括中性粒细胞减少（6例）和血小板减少（4例），且很少成为剂量限制性因素。在34例可评估患者中，根据实体瘤疗效评价标准未观察到客观缓解；10例患者病情稳定。全血中的蛋白酶体抑制程度表明，伊立替康联合给药不影响硼替佐米的生物活性。
这项针对实体瘤患者的I期研究结果表明，推荐的II期剂量为第1、4、8和11天给予1.3mg/m²的硼替佐米，每21天的第1天和第8天给予125mg/m²的伊立替康。
