Original Article

Cancer Chemotherapy and Pharmacology

, Volume 58, Issue 2, pp 157-164

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

  • Hui K. GanAffiliated withDepartment of Medical Oncology and Ludwig Institute for Cancer Research, Austin Hospital Email author 
  • , Paul L. MitchellAffiliated withDepartment of Medical Oncology and Ludwig Institute for Cancer Research, Austin Hospital
  • , Peter GalettisAffiliated withDepartment of Medical Oncology, St George Hospital and University of New South Wales
  • , Ian D. DavisAffiliated withDepartment of Medical Oncology and Ludwig Institute for Cancer Research, Austin Hospital
  • , Jonathan CebonAffiliated withDepartment of Medical Oncology and Ludwig Institute for Cancer Research, Austin Hospital
  • , Paul de SouzaAffiliated withDepartment of Medical Oncology, St George Hospital and University of New South Wales
  • , Matthew LinksAffiliated withDepartment of Medical Oncology, St George Hospital and University of New South Wales

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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