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

Charles M. Rudin, Christine 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 & 4 others Andrew P. Krivoshik, Rod A. Humerickhouse, Geoffrey I. Shapiro, Leena Gandhi

Research output: Contribution to journalArticle

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-xL. 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, neuronspecific 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. Preclinicalmodels support that navitoclaxmay enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.

Original languageEnglish (US)
Pages (from-to)3163-3169
Number of pages7
JournalClinical Cancer Research
Volume18
Issue number11
DOIs
StatePublished - Jun 1 2012

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Small Cell Lung Carcinoma
Biomarkers
Gastrin-Releasing Peptide
Keratin-19
Circulating Neoplastic Cells
Safety
Phosphopyruvate Hydratase
Thrombocytopenia
Disease-Free Survival
Neoplasms
Research Design
Cell Count
navitoclax
Apoptosis
Antigens
Therapeutics
big gastrin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. / Rudin, Charles M.; Hann, Christine; Garon, Edward B.; Ribeiro De Oliveira, Moacyr; Bonomi, Philip D.; Camidge, D. Ross; Chu, Quincy; Giaccone, Giuseppe; Khaira, Divis; Ramalingam, Suresh S.; 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.; Krivoshik, Andrew P.; Humerickhouse, Rod A.; Shapiro, Geoffrey I.; Gandhi, Leena.

In: Clinical Cancer Research, Vol. 18, No. 11, 01.06.2012, p. 3163-3169.

Research output: Contribution to journalArticle

Rudin, CM, Hann, C, Garon, EB, Ribeiro De Oliveira, M, Bonomi, PD, Camidge, DR, Chu, Q, Giaccone, G, Khaira, D, Ramalingam, SS, Ranson, MR, Dive, C, McKeegan, EM, Chyla, BJ, Dowell, BL, Chakravartty, A, Nolan, CE, Rudersdorf, N, Busman, TA, Mabry, MH, Krivoshik, AP, Humerickhouse, RA, Shapiro, GI & Gandhi, L 2012, 'Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer', Clinical Cancer Research, vol. 18, no. 11, pp. 3163-3169. https://doi.org/10.1158/1078-0432.CCR-11-3090
Rudin, Charles M. ; Hann, Christine ; Garon, Edward B. ; Ribeiro De Oliveira, Moacyr ; Bonomi, Philip D. ; Camidge, D. Ross ; Chu, Quincy ; Giaccone, Giuseppe ; Khaira, Divis ; Ramalingam, Suresh S. ; 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. ; Krivoshik, Andrew P. ; Humerickhouse, Rod A. ; Shapiro, Geoffrey I. ; Gandhi, Leena. / Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 11. pp. 3163-3169.
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T1 - Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer

AU - Rudin, Charles M.

AU - Hann, Christine

AU - Garon, Edward B.

AU - Ribeiro De Oliveira, Moacyr

AU - Bonomi, Philip D.

AU - Camidge, D. Ross

AU - Chu, Quincy

AU - Giaccone, Giuseppe

AU - Khaira, Divis

AU - Ramalingam, Suresh S.

AU - Ranson, Malcolm R.

AU - Dive, Caroline

AU - McKeegan, Evelyn M.

AU - Chyla, Brenda J.

AU - Dowell, Barry L.

AU - Chakravartty, Arunava

AU - Nolan, Cathy E.

AU - Rudersdorf, Niki

AU - Busman, Todd A.

AU - Mabry, Mack H.

AU - Krivoshik, Andrew P.

AU - Humerickhouse, Rod A.

AU - Shapiro, Geoffrey I.

AU - Gandhi, Leena

PY - 2012/6/1

Y1 - 2012/6/1

N2 - 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-xL. 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, neuronspecific 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. Preclinicalmodels support that navitoclaxmay enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.

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