Obatoclax mesylate, a pan-Bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer

Alberto Chiappori, Charles Williams, Donald W. Northfelt, John W. Adams, Shakun Malik, Martin J. Edelman, Peter Rosen, David A. Van Echo, Mark S. Berger, Eric B. Haura

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

INTRODUCTION: The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC). METHODS: Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC - docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2 - every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m × 1 and obatoclax 30 mg × 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated. RESULTS: Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed. CONCLUSIONS: Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event.

Original languageEnglish (US)
Pages (from-to)121-125
Number of pages5
JournalJournal of Thoracic Oncology
Volume9
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Apoptosis
  • Efficacy
  • Maximum tolerated dose
  • Non-small-cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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    Chiappori, A., Williams, C., Northfelt, D. W., Adams, J. W., Malik, S., Edelman, M. J., Rosen, P., Van Echo, D. A., Berger, M. S., & Haura, E. B. (2014). Obatoclax mesylate, a pan-Bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer. Journal of Thoracic Oncology, 9(1), 121-125. https://doi.org/10.1097/JTO.0000000000000027