Phase I trial of the sequential administration of pemetrexed (P) and docetaxel (D) in patients (pts) with advanced solid tumours

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Abstract
2108 Background: Pemetrexed and docetaxel have shown activity in a broad range of solid tumours. Combined in vitro administration of both drugs results in synergistic effect if P is given before taxane. Previous phase I trials (Mackay et al, 2002; Fyfe et al, 2003) revealed DLT at low doses of P and D given concomitantly. The current trial was designed to evaluate the toxicity profile and feasibility of a sequential schedule of P follows by D. Methods: Protocol design allowed 2 sequential schedules for dose escalation. In the first, pts received increasing doses of P (300–600 mg/m2, day 1) with a fixed dose of D (60 mg/m2, day 8). If MTD appeared, as happened at level 1(L1), a second escalation started at the same doses with a biweekly sequence of both drugs. Pts received in-label premedication with corticosteroids, folic acid and vitamin B12. Results: To date, 17 pts have received treatment (14 M, 3 F; PS 0–1). Cancer diagnoses were NSCLC (3), urothelial carcinoma (2), melanoma (3), unknown primary (3), and others (6). Two out of 5 pts in Level 1 (P 300 mg/m2 day 1, D 60 mg/m2 day 8) experienced DLT: 1 died from septicaemia, and 1 had grade 3 asthenia. As per protocol, schedule was modified to sequential biweekly administration starting at the same doses. 13 pts have been treated with this schedule: 3 in L1 (P 300/D 60); 6 in L2 (P 400/D 60); 3 in L3 (P 500/D 60); and 1 in L4 (P 600/D 60). One DLT (febrile neutropenia) occurred at L2. Other G3/4 toxicities included: neutropenia (7 pts), anaemia (2 pts), hepatic toxicity (2 pts), vomiting (2 pts), asthenia (1 pt), and rash (1 pt). Tumour response has been evaluated in 12 pts (7 stable disease, 5 progressive disease). Conclusions: Sequential administration of P (day 1) and D (day 15) is feasible and can be safely administered. At present, MTD has not been reached. Study enrolment is ongoing at the P 600/D 60 dose level.

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