A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer

作者：Chiappori A A^*; Schreeder M T; Moezi M M; Stephenson J J; Blakely J; Salgia R; Chu Q S; Ross H J; Subramaniam D S; Schnyder J; Berger M S

来源：British Journal of Cancer, 2012, 106(5): 839-845.

DOI：10.1038/bjc.2012.21

• small cell lung cancer
• apoptosis
• Bcl-2 gene family
• CNS symptoms

BACKGROUND: Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy. %26lt;br%26gt;METHODS: Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, %26lt;= 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m(-2), days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax. %26lt;br%26gt;RESULTS: Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts. %26lt;br%26gt;CONCLUSION: Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies. British Journal of Cancer (2012) 106, 839-845. doi:10.1038/bjc.2012.21 www.bjcancer.

• 出版日期2012-2-28