Journal of Clinical Oncology, Vol 21, Issue 13
(July), 2003: 2492-2499
© 2003 American Society for Clinical Oncology
Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer
Stephen R.D. Johnston,
Tamas Hickish,
Paul Ellis,
Stephen Houston,
Lloyd Kelland,
Mitch Dowsett,
Janine Salter,
Bart Michiels,
Juan Jose Perez-Ruixo,
Peter Palmer,
Angela Howes
From the Departments of Medicine and Academic Department of Biochemistry, Royal Marsden Hospital; Department of Medical Oncology, Guy’s Kings & St Thomas’ Cancer Centre, Guy’s Hospital, London; Department of Haematology & Oncology, Royal Bournemouth General Hospital, Bournemouth; St Luke’s Cancer Centre, Royal Surrey County Hospital, Guilford; CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton; Johnson & Johnson Pharmaceutical Research & Development, Saunderton, United Kingdom; and Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium.
Address reprint requests to Stephen R.D. Johnston, MD, PhD, Royal Marsden Hospital and Institute of Cancer Research, Fulham Road, London SW3 6JJ, United Kingdom; email: stephen.johnston{at}rmh.nthames.nhs.uk.
Purpose: R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor–dependent cell-signal–transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer.
Patients and Methods: Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]).
Results: In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at ≥ 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P = .016) and grade 3 to 4 thrombocytopenia (3% v 26%; P = .013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P = .0004).
Conclusion: The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.
Supported by Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ.
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