Journal of Clinical Oncology, Vol 16, 1458-1464, Copyright © 1998 by American Society of Clinical Oncology
Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies
AF Ratliff, J Wilson, M Hum, M Marling-Cason, K Rose, N Winick and BA Kamen
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas 75235-9063, USA. aratli@mednet.swmed.edu
PURPOSE: Aminopterin (AMT) is a potent folate analog that is no longer in
routine clinical use. Because of laboratory data that suggests improved
metabolism of AMT versus methotrexate (MTX) in lymphoblasts, we developed a
phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting
toxicity (DLT), and pharmacokinetic profile of AMT. PATIENTS AND METHODS:
Twenty patients with refractory malignancies were treated. The starting
dose of AMT was 2.5 mg/m2 every 12 hours for two doses weekly: the dose of
AMT was decreased and leucovorin (LV) rescue was added after the DLT was
observed. Pharmacokinetics were performed after both intravenous (i.v.) and
oral AMT administration. RESULTS: Mucosal toxicity was dose-limiting and
resulted in the need for a dose reduction (dose level 2: AMT 2 mg/m2 every
12 hours for two doses weekly) and, subsequently, the addition of scheduled
LV rescue (dose level 3: AMT 2 mg/m2 every 12 hours for two doses followed
by LV 5 mg/m2 orally every 12 hours for two doses, starting 24 hours after
the second dose of AMT). The mean areas under the curve (AUC) for the i.v.
(n = 14) and oral (n = 13) doses were 1.20 +/- 0.09 (SE) and 1.05 +/- 0.14
micromol x h/L respectively. The half-life was 3.64 +/- 0.28 hours and the
oral bioavailability in 12 matched subjects was 83.5% +/- 8.3%. One patient
with endometrial adenocarcinoma achieved a complete response (CR) and
remains on therapy at 11+ months. Seven patients had stable disease (SD)
for 8 weeks or greater, which included one patient with a metastatic nerve
sheath tumor who was stable for 9 months. CONCLUSION: We conclude that AMT
has good oral bioavailability and that, when given on a q12 hour x two
weekly schedule, the MTD is 2 mg/m2 with delayed LV rescue.
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