Cohen Steven J, Gallo James, Lewis Nancy L, Alpaugh R Katherine, Gentner Louis, Rogatko André, Yeslow Gwen, Schol Jessie, Verhaeghe Tom, Zannikos Peter, Palmer Peter A, Weiner Louis M, Meropol Neal J
Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
Cancer Chemother Pharmacol. 2004 Jun;53(6):513-8. doi: 10.1007/s00280-004-0764-7. Epub 2004 Feb 3.
R115777 is a selective, nonpeptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational modification of several proteins, including Ras. Given the high frequency of K-Ras mutations in malignancies commonly treated with irinotecan, the broad preclinical antiproliferative activity of R115777 and its largely non-overlapping toxicity profile with irinotecan, this phase I study of the combination of R115777 and irinotecan in patients with advanced cancer was undertaken.
Enrolled onto the study were 14 patients (eight male, six female; median age 63 years, range 48-72 years). Five patients had an ECOG performance status (PS) of 0, eight patients PS 1, and one patient PS 2. The patients were treated with R115777 orally twice daily for 28 days and irinotecan 100 mg/m(2) as an intravenous infusion on days 1, 8, 15, and 22 of each 42-day cycle. Seven patients received R115777 100 mg twice daily and seven received R115777 200 mg twice daily.
Dose-limiting toxicity (DLT) was experienced by one of seven patients treated with R115777 100 mg (grade 3 fatigue), and two of seven patients treated with R115777 200 mg (grade 3 diarrhea, grade 4 neutropenia lasting >5 days). The maximum tolerated dose (MTD) was R115777 100 mg twice daily and irinotecan 100 mg/m(2) weekly. Non-DLTs were primarily rash, fatigue, diarrhea, and neutropenia. R115777 demonstrated linear pharmacokinetics without interaction with irinotecan and achieved serum levels required for antitumor activity in vitro.
Serum levels of R115777 exceeded those necessary for FTase inhibition in vitro without evidence of interaction with irinotecan. However, the MTD of R115777 in this study was lower than that obtained with an alternate schedule. Thus, further development of this schedule is not recommended.
R115777是一种法尼基转移酶（FTase）的选择性非肽模拟抑制剂，FTase是一种负责多种蛋白质（包括Ras）翻译后修饰的酶。鉴于在常用伊立替康治疗的恶性肿瘤中K-Ras突变的高频率、R115777广泛的临床前抗增殖活性及其与伊立替康基本不重叠的毒性谱，开展了这项R115777与伊立替康联合用于晚期癌症患者的I期研究。
14例患者（8例男性，6例女性；中位年龄63岁，范围48 - 72岁）入组本研究。5例患者东部肿瘤协作组（ECOG）体能状态（PS）为0，8例患者PS为1，1例患者PS为2。患者接受R115777口服，每日2次，共28天，在每42天周期的第1、8、15和22天接受伊立替康100 mg/m²静脉输注。7例患者接受R115777每日2次，每次100 mg，7例患者接受R115777每日2次，每次200 mg。
在接受每日2次100 mg R115777治疗的7例患者中有1例出现剂量限制性毒性（DLT）（3级疲劳），在接受每日2次200 mg R115777治疗的7例患者中有2例出现DLT（3级腹泻、4级中性粒细胞减少持续>5天）。最大耐受剂量（MTD）为每日2次100 mg R115777和每周100 mg/m²伊立替康。非DLT主要为皮疹、疲劳、腹泻和中性粒细胞减少。R115777表现出线性药代动力学，与伊立替康无相互作用，并达到了体外抗肿瘤活性所需的血清水平。
R115777的血清水平超过了体外抑制FTase所需的水平，且无与伊立替康相互作用的证据。然而，本研究中R115777的MTD低于采用另一种给药方案时获得的MTD。因此，不建议进一步开发该给药方案。
