A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours
Paridaens, Robert × Uges, D R Barbet, N Choi, L Seeghers, M van der Graaf, W T Groen, H J Dumez, Herlinde Buuren, I V Muskiet, F Capdeville, R Oosterom, A T de Vries, E G #
British Journal of Cancer vol:83 issue:5 pages:594-601
Because tumour cell proliferation is highly dependent upon up-regulation of de-novo polyamine synthesis, inhibition of the polyamine synthesis pathway represents a potential target for anticancer therapy. SAM486A (CGP 48664) is a new inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), more potent and specific than the first-generation SAMDC inhibitor methylglyoxal (bis) guanylhydrazone (MGBG). Preclinical testing confirmed promising antiproliferative activity. In this phase I study, SAM486A was given 4-weekly as a 120 h infusion. 39 adult cancer patients were enrolled with advanced/refractory disease not amenable to established treatments, PS </= 2, adequate marrow, liver, renal and cardiac function. Doses were escalated in 100% increments without toxicity in 24 pts from 3 mg m(-2)cycle(-1)up to 400 mg m(-2)cycle(-1). At 550 and 700 mg m(-2)cycle(-1)reversible dose-limiting neutropenia occurred. Other toxicities included mild fatigue, nausea and vomiting. No objective remission was seen. Pharmakokinetic analysis showed a terminal half-life of approximately 2 days. AUC and Cmax were related to dose; neutropenia correlated with AUC. The recommended dose for further phase II studies on this schedule is 400 mg m(-2)cycle(-1).