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

Purpose: 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 and methods: 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.

Results: 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.

Conclusion: 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.

Fig 1.

Platelet dynamics with different dosing schedules. (A) Dosing schema for intermittent dosing. (B) Platelet levels over time in six representative patients on intermittent dosing cohorts. Day 0 represented in this figure is study day −3. Patient 326 was a 60-year-old man with non–small-cell lung cancer (NSCLC); patient 327 was an 80-year-old man with pancreatic cancer; patient 328 was a 68-year-old man with NSCLC; patient 329 was a 64-year-old man with small-cell lung cancer (SCLC); patient 331 was a 60-year-old woman with neuroendocrine carcinoid; patient 332 was a 62-year-old man with SCLC. (C) Dosing schema for continuous dosing. (D) Platelet levels over time in six representative patients on continuous dosing cohorts. Day 0 represented in this figure is the lead-in period day 1. Red and orange lines represent the boundaries of a dose-limiting toxicity (grade 3, 25,000 to 50,000); 325 mg was chosen as a representative dose for comparing the two different dosing schedules. Patient 349 was a 65-year-old man with SCLC; patient 350 was a 67-year-old man with SCLC; patient 351 was a 57-year-old woman with SCLC; patient 353 was a 63-year-old man with SCLC; patient 354 was a 65-year-old woman with SCLC; patient 355 was a 60-year-old man with SCLC.

Fig 2.

Best overall percentage change from baseline in target lesion measurement by RECIST (Response Evaluation Criteria in Solid Tumors) guidelines for patients at different dose levels. The best tumor percent change is defined as the maximum reduction/minimum increase from baseline in tumor load. For patients who have the best percent change from baseline at multiple cycles, the earliest cycle is labeled. Best tumor percent change from baseline for the leftmost patient is truncated at 100%. Note that for some patients, a reduction in target lesions did not translate to response based on growth of new lesions. (*) Patients with small-cell carcinoma. (†) Patients with pulmonary carcinoid tumors.

Fig 3.

Biomarkers of navitoclax activity and tumor response. (A) Fluorescent in situ hybridization analysis of Bcl-2 in a patient with small-cell lung cancer demonstrating amplified signal (four copies) of Bcl-2 (orange) and three copies of CEP 18 (green) in circulating tumor cells (CTCs), but no amplification (two copies of both) in peripheral blood mononuclear cells (PBMC). (B) Pro-gastrin releasing peptide (pro-GRP) plasma concentration (pg/mL) plotted against mean Bcl-2 copy number. (C) Relative change in pro-GRP plasma concentration with different dose levels. (D) The relationship between best tumor percentage change is plotted against percentage change of pro-GRP from baseline to cycle 2 day 14. (E) Changes in circulating M30 levels with increasing dose as measured in cycle 1, 6 hours after first exposure.