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

Abstract

A B S T R A C T PurposeResistance 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 and MethodsPatients enrolled to intermittent dosing cohorts received navitoclax on day Ϫ3, 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. ResultsForty-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. ConclusionNavitoclax 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. J Clin

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

“…The present investigation provides the biological rationale for these future clinical trials to evaluate ABT-737 alone or in combination with Mcl-1-reducing agents in MCL patients. Indeed, ABT-263 (navitoclax; Abbott), which is an orally bioavailable BH3-mimetic compound of the same class as ABT-737 and currently under investigation in hematologic and solid malignancies, could also be used as ABT-737 (13,(43)(44)(45)(46).…”

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

“…We selected navitoclax, a dual Bcl-2/Bcl-x L inhibitor that is the subject of clinical trials (28)(29)(30)(31), and a novel MEK inhibitor, G-963 (Fig. 1B), to test the combination efficacy associated with targeting these proteins.…”

PI3K and Bcl-2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and Phospho-BAD

“…This class of molecules is more effective in tumors with high levels of bcl-2/bcl-xL. ABT-263 is currently under investigation in various malignancies, either as a single drug compound, or in combination with other antitumor reagents (8,9) and has already reached clinical trials (10). Specifically, preclinical studies, involving ABT-263, have shown that it has activity against small cell lung cancer (SCLC) as well as acute lymphoblastic leukemia (7).…”