Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cancer Chemother Pharmacol. 2011 Aug;68(2):539-45. doi: 10.1007/s00280-011-1671-3. Epub 2011 May 19.
PR-104 is activated by reductases under hypoxia or by aldo-keto reductase 1C3 (AKR1C3) to form cytotoxic nitrogen mustards. Hepatocellular carcinoma (HCC) displays extensive hypoxia and expresses AKR1C3. This study evaluated the safety and efficacy of PR-104 plus sorafenib in HCC.
Patients with advanced-stage HCC, Child-Pugh A cirrhosis, and adequate organ function, were assigned to dose escalating cohorts of monthly PR-104 in combination with twice daily sorafenib. The plasma pharmacokinetics (PK) of PR-104 and its metabolites were evaluated.
Fourteen (11 men, 3 women) HCC patients: median age 60 years, ECOG 0-1, received PR-104 at two dose levels plus sorafenib. Six patients were treated at starting cohort of 770 mg/m(2). In view of one DLT of febrile neutropenia and prolonged thrombocytopenia, a lower PR-104 dose cohort (550 mg/m(2)) was added and accrued 8 patients. One patient had a partial response and three had stable disease of ≥8 weeks in the 770 mg/m(2) cohort. Three patients at the 550 mg/m(2) had stable disease. There were no differences in PK of PR-104 or its metabolites with or without sorafenib, but the PR-104A AUC was twofold higher (P < 0.003) than in previous phase I studies at equivalent dose.
PR-104 plus sorafenib was poorly tolerated in patients with advanced HCC, possibly because of compromised clearance of PR-104A in this patient population. Thrombocytopenia mainly and neutropenia were the most clinically significant toxicities and led to discontinuation of the study. PR-104 plus sorafenib is unlikely to be suitable for development in this setting.
PR-104 在缺氧条件下或通过醛酮还原酶 1C3（AKR1C3）被还原酶激活，形成细胞毒性氮芥。肝细胞癌（HCC）表现出广泛的缺氧，并表达 AKR1C3。本研究评估了 PR-104 联合索拉非尼治疗 HCC 的安全性和疗效。
晚期 HCC、Child-Pugh A 肝硬化和足够的器官功能的患者被分配到每月接受 PR-104 联合每日两次索拉非尼的剂量递增队列。评估了 PR-104 及其代谢物的血浆药代动力学（PK）。
14 名（11 名男性，3 名女性）HCC 患者：中位年龄 60 岁，ECOG 0-1，接受了两种剂量水平的 PR-104 加索拉非尼治疗。6 名患者在起始队列接受 770mg/m²剂量。鉴于一例发热性中性粒细胞减少症和血小板减少症持续时间延长的 DLT，加入了较低的 PR-104 剂量队列（550mg/m²），并招募了 8 名患者。在 770mg/m² 队列中，1 名患者有部分缓解，3 名患者有≥8 周的稳定疾病。在 550mg/m² 队列中，有 3 名患者疾病稳定。有无索拉非尼时，PR-104 或其代谢物的 PK 没有差异，但 PR-104A AUC 比以前在等效剂量的 I 期研究中高两倍（P < 0.003）。
PR-104 联合索拉非尼在晚期 HCC 患者中耐受性差，可能是由于该患者人群中 PR-104A 的清除率降低所致。血小板减少症和中性粒细胞减少症主要是最具临床意义的毒性，导致研究中止。PR-104 联合索拉非尼不太可能在这种情况下适合开发。
