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Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer

Clinical cancer research, 2012-06, Vol.18 (11), p.3163-3169 [Peer Reviewed Journal]

2015 INIST-CNRS ;2012 AACR. 2012 ;ISSN: 1078-0432 ;EISSN: 1557-3265 ;DOI: 10.1158/1078-0432.CCR-11-3090 ;PMID: 22496272 ;CODEN: CCREF4

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Title:
Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
Author: RUDIN, Charles M ; HANN, Christine L ; RANSON, Malcolm R ; DIVE, Caroline ; MCKEEGAN, Evelyn M ; CHYLA, Brenda J ; DOWELL, Barry L ; CHAKRAVARTTY, Arunava ; NOLAN, Cathy E ; RUDERSDORF, Niki ; BUSMAN, Todd A ; MABRY, Mack H ; GARON, Edward B ; KRIVOSHIK, Andrew P ; HUMERICKHOUSE, Rod A ; SHAPIRO, Geoffrey I ; GANDHI, Leena ; DE OLIVEIRA, Moacyr Ribeiro ; BONOMI, Philip D ; ROSS CAMIDGE, D ; CHU, Quincy ; GIACCONE, Giuseppe ; KHAIRA, Divis ; RAMALINGAM, Suresh S
Subjects: Aged ; Aniline Compounds - administration & dosage ; Aniline Compounds - adverse effects ; Aniline Compounds - therapeutic use ; Antineoplastic agents ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - therapeutic use ; Biological and medical sciences ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms - drug therapy ; Male ; Medical sciences ; Middle Aged ; Pharmacology. Drug treatments ; Pneumology ; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors ; Recurrence ; Small Cell Lung Carcinoma - drug therapy ; Sulfonamides - administration & dosage ; Sulfonamides - adverse effects ; Sulfonamides - therapeutic use ; Thrombocytopenia - chemically induced ; Tumors of the respiratory system and mediastinum
Is Part Of: Clinical cancer research, 2012-06, Vol.18 (11), p.3163-3169
Description: 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. 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. 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. 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.
Publisher: Philadelphia, PA: American Association for Cancer Research
Language: English
Identifier: ISSN: 1078-0432
EISSN: 1557-3265
DOI: 10.1158/1078-0432.CCR-11-3090
PMID: 22496272
CODEN: CCREF4
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
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Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer

2015 INIST-CNRS ;2012 AACR. 2012 ;ISSN: 1078-0432 ;EISSN: 1557-3265 ;DOI: 10.1158/1078-0432.CCR-11-3090 ;PMID: 22496272 ;CODEN: CCREF4

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