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
| Autor: | M. M. Moezi, J. Schnyder, Alberto Chiappori, M S Berger, M. T. Schreeder, J. Stephenson, Deepa S. Subramaniam, J. L. Blakely, Ravi Salgia, Helen J. Ross, Q. S. Chu |
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| Rok vydání: | 2012 |
| Předmět: |
Central Nervous System
Male Cancer Research Indoles Lung Neoplasms Maximum Tolerated Dose Clinical Trials and Supportive Activities Oncology and Carcinogenesis Pharmacology Drug Administration Schedule Bcl-2 gene family Carboplatin chemistry.chemical_compound Clinical Research Antineoplastic Combined Chemotherapy Protocols Medicine Humans In patient Pyrroles Oncology & Carcinogenesis Lung Etoposide Cancer Aged business.industry Lung Cancer Antagonist apoptosis Hematology Middle Aged Small Cell Lung Carcinoma Oncology chemistry Proto-Oncogene Proteins c-bcl-2 Apoptosis 6.1 Pharmaceuticals Public Health and Health Services Clinical Study Female Patient Safety small cell lung cancer business Extensive-stage small cell lung cancer CNS symptoms Obatoclax medicine.drug |
| Zdroj: | British Journal of Cancer British journal of cancer, vol 106, iss 5 |
| ISSN: | 1532-1827 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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