Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies

Arleen F. Ratliff, Jennifer Wilson, Martina Hum, Margaret Marling-Cason, Kathy Rose, Naomi Winick, Barton A. Kamen

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 (IV) 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 IV (n = 14) and oral (n = 13) doses were 1.20 ± 0.09 (SE) and 1.05 ± 0.14 μmol · 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.

Original languageEnglish (US)
Pages (from-to)1458-1464
Number of pages7
JournalJournal of Clinical Oncology
Issue number4
StatePublished - Apr 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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