A phase 1 and pharmacokinetic study of gemcitabine and oxaliplatin in patients with solid tumors

Cancer Chemotherapy and Pharmacology. 2005 Nov 19;:1-8 [Epub ahead of print]. [Link].

Hui K. Gan¹, Paul L. Mitchell¹, Peter Galettis², Ian D. Davis¹, Jonathan Cebon¹, Paul de Souza² and Matthew Links²

(1) Department of Medical Oncology and Ludwig Institute for Cancer Research, Austin Hospital, Level D, 3KZ Building, Studley Road, Heidelberg, Melbourne, VIC, Australia

(2) Department of Medical Oncology, St George Hospital and University of New South Wales, Gray Street, 2217 Kogarah, NSW, Australia

Abstract

Purpose: This dose escalation study aimed to determine the recommended doses, toxicity and pharmacokinetics of oxaliplatin and gemcitabine given on days 1 and 8 every 21 days. This schedule may maximize dose intensity of both drugs with acceptable or reduced toxicity.

Patient and methods: Eligible patients had solid malignancies, no more than two prior courses of chemotherapy, ECOG performance status 0–2, neurotoxicity ≤ NCI-CTC grade 1 and adequate organ function. Dose escalation commenced at oxaliplatin 40 mg/m² and gemcitabine 750 mg/m², both given on days 1 and 8 every 21 days, and reached oxaliplatin 80 mg/m² and gemcitabine 1,500 mg/m². The two highest dose levels were each expanded to six patients to gain additional toxicity data.

Results: There were no dose limiting toxicities related to treatment and an MTD was not reached. Five patients (24%) had grade 3 neutropenia, without associated infection, and seven patients (33%) had grade 3/4 thrombocytopenia. Neurotoxicity was mild and no worse than grade 1. Two patients with mesothelioma (10%) had partial responses and 11 patients (52%) had disease stabilization. No pharmacokinetic interaction between oxaliplatin and gemcitabine was detected. Dose intensity was maximal at level 4 (oxaliplatin 70 mg/m² and gemcitabine 1,250 mg/m²).

Conclusions: This schedule allows oxaliplatin and gemcitabine to be delivered at the full dose intensity of each drug with excellent tolerability and predictable pharmacokinetics. The recommended doses for phase II studies are oxaliplatin 70 mg/m² and gemcitabine 1,250 mg/m² on days 1 and 8 every 21 days.

Keywords: Gemcitabine – Oxaliplatin – Phase 1 – Neurotoxicity – Pharmacokinetics – Mesothelioma