CLINICAL-PHASE-I AND PHARMACOKINETIC TRIAL OF VINORELBINE ADMINISTERED AS SINGLE INTRAVENOUS BOLUS EVERY 21 DAYS IN CANCER-PATIENTS

We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim w as to evaluate a schedule with longer treatment intervals than one wee k and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unk nown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thy roid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female , median age: 56 years (range: 37-69)]. Dose levels were 35, 40 and 45 mg/m(2) with a total of 26 cycles administered. At 40 mg/m(2), 2/6 pt s developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m(2) developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities wer e mild to moderate. Neurologic toxicity except for constipation was mi ld. Constipation occurred at 35 mg/m(2) in 1/6 pts WHO grade 4, at 40 mg/m(2) in 2/6 pts WHO grade 3 and at 45 mg/m(2) in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was obs erved. Vinorelbine pharmacokinetics were analysed in whole blood and p lasma and were similar to previously published studies using less than or equal to 30 mg/m(2). Our results confirm a high affinity of vinore lbine to corpuscular blood elements. We conclude that the MTD of vinor elbine administered once every 21 days as bolus injection is 40 mg/m(2 ), the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m(2).