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Phase III Double-Blind Placebo-Controlled Study of Farnesyl Transferase Inhibitor R115777 in Patients With Refractory Advanced Colorectal Cancer

From the Royal Marsden Hospital, London and Surrey; Southampton General Hospital, Southampton, United Kingdom; Hospital Saint Antoine; Hospital Tenon, Paris, France; Vienna University Medical School, Vienna, Austria; Johnson & Johnson Pharmaceutical Research and Development, Beerse; St Luc University Hospital, Brussels, Belgium; National Oncological Centre, Sofia, Bulgaria; Oncology Institute, Plesi; Oncology Centre, Pardubice, Czech Republic; Medical University, Debrecen, Hungary; Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ

Address reprint requests to David Cunningham, MD, FRCP, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; e-mail: david.cunningham{at}icr.ac.uk

PURPOSE: To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study.

PATIENTS AND METHODS: Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life.

RESULTS: The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P = .376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms.

CONCLUSION: Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.

Supported by Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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