(ASCO)
A Phase I Clinical and Pharmacokinetic Study of EPO906 (Epothilone B), Given Every Three Weeks, in Patients with Advanced Solid Tumors.
P M Calvert, V O'Neill, C Twelves, A Azzabi, A Hughes, C Bale, A Robinson, M Machan, S Dimitrijevic, D Moss, J Rothermel, P Cohen, T Chen, A Man, AH Calvert, NCCT, Newcastle upon Tyne, UK; Beatson Oncology Centre, Glasgow, UK; Novartis Oncology, Basel, Switzerland; Novartis Oncology, East Hanover, NJ.
EPO906 is a novel tubulin-interacting agent with greater potency than paclitaxel, and activity in paclitaxel-resistant tumors. The formulation of the drug obviates the need for pre-medication. We are conducting a Phase I trial of EPO906 in patients (pts) with advanced solid tumors, to determine the Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT), safety and pharmacokinetic profile of the drug. The study is a two-center, open-label trial, using a modified Fibonacchi design. 42 pts have been enrolled (19M:23F), median age 58 years (range 35-72), median number of prior chemotherapeutic regimens: 2 (range 0-6). Primary sites include: colorectal:13, breast:5, ovary:4, unknown primary:4, NSCLC:3 and a broad range of other tumor types. Starting dose was 0.3mg/m2 with the first 6 dose levels given as a 30 minute infusion every 21 days and subsequent dose levels as a 5-10 minute infusion every 21 days.11 dose levels have been tested. Median cycles per pt: 2 (range 1-9). DLT (diarrhea) was seen at 8mg/m2, de-escalation to 7mg/m2 with prophylactic loperamide is now being studied. Other grade 3 non-hematologic toxicity included fatigue (n=4) and nausea/vomiting (n=2). Grade 2 peripheral neuropathy was seen (n=3). No significant myelosuppression ( Grade 1) was seen. No hypersensitivity reactions were seen. The drug shows multiphasic clearance with long T1/2 ([approximately]3.5 days). Elimination is mainly non-renal. Dose proportionality is seen and there is no evidence of drug accumulation. Total body clearance is [approximately]200ml/min and volume of distribution at steady state is [approximately]1000L. Anti-tumor activity has been seen: of 36/42 evaluable pts: PR 1 pt (unknown primary), SD 11pts, significant responses (though not reaching criteria for PR) 4 pts (1 breast, 3 colorectal). We conclude that EPO906 can safely be given as a 5-10 minute infusion, with anti-diarrheal pre-medication in some patients. |
