Thirty-five patients with advanced refractory
cancer were enrolled on this phase I study of
menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients received alternating oral and IV doses of
menogaril (250 mg/m2 IV; 250-500 mg/m2 oral) with accompanying blood and urine sampling for pharmacokinetics analysis.
Nausea and
vomiting were the dose-limiting toxicities at the 625 mg/m2 dosage level;
vomiting was inadequately relieved by prophylactic
antiemetics at this dosage level. Other toxicities included sporadic
leukopenia at all dosage levels; at dosages of 500 mg/m2 and 625 mg/m2,
leukopenia < 3000/microliters occurred in 7 of 24 patients.
Anemia and
thrombocytopenia were much less frequent toxicities. Among the patients receiving IV
menogaril, peripheral vein
phlebitis,
leukopenia and
anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with
non-small cell lung cancer experienced a 30% reduction in metastatic
tumor nodules. For the patients receiving alternating oral and IV
menogaril, comparative pharmacokinetic analyses were performed by HPLC. After
oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after
intravenous administration. The harmonic mean (+/- SD) terminal disposition half-life after oral dosing was 29.3 +/- 9.2 hours; mean systemic bioavailability was 33.6 +/- 10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of
menogaril and the primary metabolite,
N-demethylmenogaril, were 4.00 +/- 0.96% and 0.44 +/- 0.16%, respectively. Because of the poor tolerance of oral
menogaril and minimal evidence of
biological activity, this schedule of
drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral
menogaril, frequent chronic low-intermediate dosages of the
drug may be given orally with potentially better tolerance and antitumor activity.