Phase I study of vincristine and escalating doses of etoposide

Abstract

A phase I trial of vincristine and etoposide was designed following the identification of a potentially synergistic antitumor effect in a murine model. The dose of vincristine was fixed (0.5 mg daily for 3 days). Etoposide was given at 1 of 3 total dose levels (250, 500, or 750 mg/m2) per treatment. Each dose was given in 3 equal fractions and each fraction was given daily for 3 days, i.e., 83.3 mg/m2/d x 3d, 166.7 mg/m2/d x 3d, or 250 mg/m2/d x 3d. A total of 31 patients were entered into study including 10, 18, and 3 patients treated at the 250, 500, and 750 mg/m2 dose levels, respectively. Dose-limiting toxicity occurred at the 750 mg/m2 level, in which Grade 4 myelosuppression developed in all of the patients. Life-threatening gram negative sepsis occurred in two of these patients and both required platelet transfusions. Grade 3-4 WBC toxicity was observed in 9 of 16 (56%) evaluable patients treated at the 500 mg/m2 level, but reversal of toxicity was generally rapid with repeat courses given at 3 week intervals in most patients. Non-hematologic toxicity was negligible. Objective responses were observed in 2 of 4 patients with Hodgkin's disease. The starting dose of etoposide recommended for phase II trials of this agent in combination with vincristine is 500 mg/m2; dose escalation may be possible in some patients.

Combination high-dose etoposide and vincristine infusion

“…The current trial was designed after completing another trial of etoposide and vincristine in which vincristine was given by bolus injection rather than infusion [10]. The total dose of vincristine per course (1.5 mg) was identical to that used in the current study.…”

“…The initial dose levels of etoposide that were explored in that trial were the same as those in the current study. However, because of severe myelosuppression at the 750 mg/m 2 dose level in all 3 patients tested (2 of whom experienced sepsis), the $63 a Because of bone marrow involvement, one patient treated at the 250 mg/m 2 dose level and two patients treated at the 500 mg/m 2 dose level were not evaluable for hematologic toxicity in the trial employing bolus vincristine [10]. Therefore, the number of patients in the denominator of these groups changes accordingly.…”

“…Severe myelosuppression and frequent mucositis were the major side effects of the high-dose monotherapy. Having completed the animal experiments showing synergism between vincristine and etoposide, a trial $60 of conventional dose vincristine using a bolus injection in combination with progressively increasing doses of etoposide was explored in our institution [10]. Larger doses of etoposide than conventionally used were found to be surprisingly well tolerated, and in combination with vincristine, no unusual toxicities or compounded toxicity (such as neurotoxicity) were encountered.…”