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

14 Citations (Scopus)

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

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docetaxel
Mesylates
Non-Small Cell Lung Carcinoma
Febrile Neutropenia
Neutropenia
Maximum Tolerated Dose
obatoclax
Dyspnea
Disease-Free Survival

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Obatoclax mesylate, a pan-Bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer. / Chiappori, Alberto; Williams, Charles; Northfelt, Donald W; Adams, John W.; Malik, Shakun; Edelman, Martin J.; Rosen, Peter; Van Echo, David A.; Berger, Mark S.; Haura, Eric B.

In: Journal of Thoracic Oncology, Vol. 9, No. 1, 01.2014, p. 121-125.

Research output: Contribution to journalArticle

Chiappori, A, Williams, C, Northfelt, DW, Adams, JW, Malik, S, Edelman, MJ, Rosen, P, Van Echo, DA, Berger, MS & Haura, EB 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, vol. 9, no. 1, pp. 121-125. https://doi.org/10.1097/JTO.0000000000000027
Chiappori, Alberto ; Williams, Charles ; Northfelt, Donald W ; Adams, John W. ; Malik, Shakun ; Edelman, Martin J. ; Rosen, Peter ; Van Echo, David A. ; Berger, Mark S. ; Haura, Eric B. / Obatoclax mesylate, a pan-Bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer. In: Journal of Thoracic Oncology. 2014 ; Vol. 9, No. 1. pp. 121-125.
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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.",
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AU - Williams, Charles

AU - Northfelt, Donald W

AU - Adams, John W.

AU - Malik, Shakun

AU - Edelman, Martin J.

AU - Rosen, Peter

AU - Van Echo, David A.

AU - Berger, Mark S.

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N2 - 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.

AB - 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.

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