Phase I study of Tomudex and Doxorubicin in patients with locally advanced, inoperable or metastatic cancer (IND.98)

Background: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) and recommended phase II dose for Tomudex and doxorubicin when given in combination to patients with advanced metastatic cancer. The secondary objective was to assess the toxicity profile. Patients and methods: Starting doses were Tomudex 2.5 mg/m2 i.v. bolus day 1 and Doxorubicin 30 mg/m2 i.v. bolus day 1, repeated every 3 weeks. Doxorubicin was escalated in increments of 10 mg/m2 to 60 mg/m2, followed by escalation of Tomudex in increments of 0.5 mg/m2 to 3.5 mg/m2, on six dose levels. Twenty-five patients received 127 cycles of therapy, with at least 3 patients treated at each dose level. Results: There was no dose limiting toxicity (DLT) observed in the first five dose levels. Three of six patients on dose level six had DLT. Further dose escalation was not warranted and this was declared the MTD. Grade 3 or 4 granulocytopenia was observed in 16/25 patients, with associated fever in 3/25 patients. Responses were seen in this study with one complete response (duration 12.8 months) and 3 partial responses (median duration 8 months) in 21 evaluable patients. Fourteen patients had stable disease (median duration 2.5 months). All 4 responding patients and 10 patients with stable disease had gastric cancer. Conclusions: The recommended phase-II dose for this combination in future studies is Tomudex 3 mg/m2 and doxorubicin 60 mg/m2 given every 3 weeks.