Details

Autor(en) / Beteiligte

• GANDHI, Leena
• CAMIDGE, D. Ross
• DIVE, Caroline
• ENSCHEDE, Sari H
• NOLAN, Cathy
• CHIU, Yi-Lin
• BUSMAN, Todd
• HAO XIONG
• KRIVOSHIK, Andrew P
• HUMERICKHOUSE, Rod
• SHAPIRO, Geoffrey I
• RUDIN, Charles M
• DE OLIVEIRA, Moacyr Ribeiro
• BONOMI, Philip
• GANDARA, David
• KHAIRA, Divis
• HANN, Christine L
• MCKEEGAN, Evelyn M
• LITVINOVICH, Elizabeth
• HEMKEN, Philip M

Titel

Phase I Study of Navitoclax (ABT-263), a Novel Bcl-2 Family Inhibitor, in Patients With Small-Cell Lung Cancer and Other Solid Tumors

Ist Teil von

• Journal of clinical oncology, 2011-03, Vol.29 (7), p.909-916

Ort / Verlag

Alexandria, VA: American Society of Clinical Oncology

Erscheinungsjahr

2011

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Resistance to chemotherapy-induced apoptosis represents a major obstacle to cancer control. Overexpression of Bcl-2 is seen in multiple tumor types and targeting Bcl-2 may provide therapeutic benefit. A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors. Patients enrolled to intermittent dosing cohorts received navitoclax on day -3, followed by dosing on days 1 to 14 of a 21-day cycle. Patients on continuous dosing received a 1-week lead-in dose of 150 mg followed by continuous daily administration. Blood samples were collected for pharmacokinetic analyses, biomarker analyses, and platelet monitoring. Forty-seven patients, including 29 with small-cell lung cancer (SCLC) or pulmonary carcinoid, were enrolled between 2007 and 2008, 35 on intermittent and 12 on continuous dosing cohorts. Primary toxicities included diarrhea (40%), nausea (34%), vomiting (36%), and fatigue (34%); most were grade 1 or 2. Dose- and schedule-dependent thrombocytopenia was seen in all patients. One patient with SCLC had a confirmed partial response lasting longer than 2 years, and eight patients with SCLC or carcinoid had stable disease (one remained on study for 13 months). Pro-gastrin releasing peptide (pro-GRP) was identified as a surrogate marker of Bcl-2 amplification and changes correlated with changes in tumor volume. Navitoclax is safe and well tolerated, with dose-dependent thrombocytopenia as the major adverse effect. Preliminary efficacy data are encouraging in SCLC. Efficacy in SCLC and the utility of pro-GRP as a marker of treatment response will be further evaluated in phase II studies.