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Clinical Trial
. 2012 Feb 28;106(5):839-45.
doi: 10.1038/bjc.2012.21. Epub 2012 Feb 14.

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

A A Chiappori  1 , M T Schreeder, M M Moezi, J J Stephenson, J Blakely, R Salgia, Q S Chu, H J Ross, D S Subramaniam, J Schnyder, M S Berger
Affiliations
Clinical Trial

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

A A Chiappori et al. Br J Cancer. .

Abstract

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.

Methods: Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, ≤ 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.

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.

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.

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Figures

Figure 1
Figure 1
Enrolment into dosing cohorts. A total of 25 patients were enrolled, alternating between 3-h and 24-h infusion cohorts. †No DLT observed in five treatment-naïve patients in this cohort. Myelosuppressive DLT observed in two previously treated patients; protocol was amended to exclude previously treated patients and these DLTs were excluded from dose-escalation decision. *Safety data from one patient excluded from dose-escalation decision due to pump malfunction. §This cohort was discontinued after enrolment of one patient.
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