A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer

Robert A. Wolff, Martin Fuchs, Maria Di Bartolomeo, Anwar M. Hossain, Clemens Stoffregen, Steven Nicol, Volker Heinemann

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). Methods: Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m 2 intravenously [IV], 5-fluorouracil 400-mg/m 2 bolus, 5-fluorouracil 2400 mg/m 2 IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. Results: Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P =.896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P =.913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P =.008). One possibly enzastaurin-related death occurred because of arrhythmia. Conclusions: Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone.

Original languageEnglish
Pages (from-to)4132-4138
Number of pages7
JournalCancer
Volume118
Issue number17
DOIs
Publication statusPublished - Sep 1 2012

Keywords

  • 5-fluorouracil/leucovorin
  • bevacizumab
  • enzastaurin
  • maintenance therapy
  • metastatic colorectal cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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