Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer.

Abstract

PURPOSE:

Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x(L). The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy.

EXPERIMENTAL DESIGN:

Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates.

RESULTS:

The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit.

CONCLUSION:

Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.

• Authors: Charles M Rudin, Christine L Hann, Edward B Garon, Moacyr Ribeiro de Oliveira, Philip D Bonomi, D Ross Camidge, Quincy Chu, Giuseppe Giaccone, Divis Khaira, Suresh S Ramalingam, Malcolm R Ranson, Caroline Dive, Evelyn M McKeegan, Brenda J Chyla, Barry L Dowell, Arunava Chakravartty, Cathy E Nolan, Niki Rudersdorf, Todd A Busman, Mack H Mabry, Andrew P Krivoshik, Rod A Humerickhouse, Geoffrey I Shapiro, Leena Gandhi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 11 Pg. 3163-9 (Jun 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22496272 (Publication Type: Clinical Trial, Phase II, Journal Article)

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• navitoclax

Topics

• Aged
• Aniline Compounds (administration & dosage, adverse effects, therapeutic use)
• Antineoplastic Agents (adverse effects, therapeutic use)
• Disease-Free Survival
• Female
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Middle Aged
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Recurrence
• Small Cell Lung Carcinoma (drug therapy)
• Sulfonamides (administration & dosage, adverse effects, therapeutic use)
• Thrombocytopenia (chemically induced)