A phase I trial and in vitro studies combining ABT-751 with carboplatin in previously treated non-small cell lung cancer patients

Abstract

Background: ABT-751 is a novel antimitotic agent that exerted cytotoxic effects in preclinical studies. Carboplatin has efficacy in treating advanced non-small cell lung cancer (NSCLC) in combination with other drugs.

Methods: Lung cancer cell lines were treated with ABT-751 and/or carboplatin to investigate their impact on cell growth. A phase I study with an expansion cohort was conducted in previously treated NSCLC patients. The primary objective was the maximum tolerated dose (MTD); secondary objectives were objective response rates, median survival, time to tumor progression, dose-limiting toxicities (DLTs), and pharmacodynamic evaluation of buccal swabs.

Results: Combining ABT-751 with carboplatin significantly reduced growth and induced apoptosis of lung cancer cell lines. Twenty advanced NSCLC patients were enrolled. MTD was ABT-751 125 mg orally twice daily for 7 days with carboplatin AUC 6. DLTs included fatigue, ileus, neutropenia and pneumonitis. Two patients had confirmed partial responses. Median overall survival was 11.7 months (95% CI 5.9-27.0). Time to tumor progression was 2.8 months (95% CI 2.0-2.7). Four of 6 patients showed decreased cyclin D1 protein in posttreatment versus pretreatment buccal swabs.

Conclusion: Combining ABT-751 with carboplatin suppressed growth of lung cancer cell lines and had modest clinical antitumor activity in advanced NSCLC previously treated predominantly with carboplatin. Further studies of this combination are not recommended while investigations of biomarkers in different patient populations, alternative schedules and combinations may be pursued.

Trial registration: ClinicalTrials.gov NCT00735878.

Conflict of interest statement

Disclosures: Anne E. Hagey and Gary B. Gordon are employees of Abbott Laboratories. Konstantin H. Dragnev received research funding from Abbott Laboratories. The other authors declare no conflicts of interest.

Copyright © 2012 S. Karger AG, Basel.

Figures

Figure 1

Effects of ABT-751 and carboplatin on cell growth in the indicated human lung cancer cell lines. Effects of individual and combined treatments of ABT-751 and carboplatin at the indicated dosages for 3 days on cell growth of human lung cancer cell lines HOP62, A549 and U1571. The symbols indicate P < 0.05 (*) and P < 0.01(**), respectively.

Figure 2

Relative cyclin D1 expression (normalized to actin as a loading control) in pre-treatment (day 0) versus post-treatment buccal swabs (days 4, 8, and 22).