一项评估伏立诺他（丁酰苯丙胺羟肟酸，NSC 701852）联合多西他赛治疗晚期和复发性实体瘤患者的 I 期研究。

Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies.

机构信息

Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, 525 East 68th Street, 3rd floor, New York, NY 10065, USA.

出版信息

Invest New Drugs. 2012 Feb;30(1):249-57. doi: 10.1007/s10637-010-9503-6. Epub 2010 Aug 5.

DOI:10.1007/s10637-010-9503-6

PMID:20686817

Abstract

INTRODUCTION

Vorinostat is an inhibitor of histone deacetylase 6, which acetylates tubulin and stabilizes microtubules. Since taxanes also stabilize microtubules, we hypothesized that the administration of vorinostat followed by docetaxel should result in synergistic cytotoxicity. We conducted a phase I trial to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤30% of patients.

METHODS

Eligible patients had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, performance status of 0-2, and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle, with docetaxel given intravenously over 1 h on day 4. The time-to-event continuous reassessment method (TITE-CRM) guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m(2), respectively. Pharmacokinetic studies were performed on days 1 and 4 of cycle 1.

RESULTS

Twelve patients were enrolled: median age 65 years (range 49-74); 9 male, 3 female; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles administered was 2. Two patients were treated at DL -1, 4 at DL 0, 5 at DL 1 and 1 at DL 2. Five DLTs occurred in 5 patients: neutropenic fever/sepsis (2), anaphylactic reaction (1), myocardial infarction (1) and gastrointestinal bleed (1). Other toxicities included grade 3/4 neutropenia (4), peripheral neuropathy (1), and gastrointestinal bleed (n = 1). The estimated probability of DLT for DL -1 was 0.32 (90% posterior probability interval [PI], 0.11 to 0.53) for DL 0, 0.38 (90% PI, 0.16 to 0.58) and for DL 1, 0.43 (90% PI, 0.23 to 0.64). The trial was stopped due to excessive toxicity. No responses were noted.

CONCLUSIONS

The combination of vorinostat and docetaxel was poorly tolerated with excessive DLTs that required early study termination. No responses were identified. Vorinostat and docetaxel pharmacokinetics were comparable to previous reports in the literature, without obvious drug-drug interactions.

摘要

简介

伏立诺他是组蛋白去乙酰化酶 6 的抑制剂，可乙酰化微管蛋白并稳定微管。由于紫杉烷类药物也能稳定微管，我们假设伏立诺他联合多西他赛治疗会产生协同细胞毒性。我们进行了一项 I 期试验，以确定导致≤30%患者出现剂量限制性毒性（DLT）的伏立诺他联合多西他赛的剂量水平。

方法

符合条件的患者患有去势抵抗性前列腺癌（CRPC）或复发的尿路上皮癌或非小细胞肺癌（NSCLC），这些患者在接受不包含多西他赛的至少 1 种化疗方案后出现疾病进展，表现状态为 0-2 级，且器官功能正常。伏立诺他在 21 天周期的第 1 天开始口服 14 天，多西他赛在第 4 天静脉输注 1 小时。采用时间事件连续评估方法（TITE-CRM）指导剂量递增。剂量水平（DL）-1、0、1 和 2 分别对应于伏立诺他 100、100、200 和 200mg 加多西他赛 50、60、60 和 75mg/m2。在第 1 天和第 1 周期的第 4 天进行药代动力学研究。

结果

共纳入 12 例患者：中位年龄 65 岁（范围 49-74 岁）；9 例男性，3 例女性；4 例 CRPC，5 例尿路上皮癌，3 例 NSCLC。中位治疗周期数为 2 个。2 例患者接受 DL-1 治疗，4 例接受 DL 0 治疗，5 例接受 DL 1 治疗，1 例接受 DL 2 治疗。5 例患者发生 5 例 DLT：中性粒细胞减少性发热/败血症（2 例）、过敏反应（1 例）、心肌梗死（1 例）和胃肠道出血（1 例）。其他毒性包括 3/4 级中性粒细胞减少（4 例）、周围神经病（1 例）和胃肠道出血（1 例）。DL-1 的 DLT 估计概率为 0.32（90%后验概率区间[PI]，0.11 至 0.53），DL 0 的概率为 0.38（90%PI，0.16 至 0.58），DL 1 的概率为 0.43（90%PI，0.23 至 0.64）。由于毒性过大，试验提前终止。未观察到缓解。