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 journalArticle

17 Citations (Scopus)

Abstract

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
Volume16
Issue number4
StatePublished - Apr 1998

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Aminopterin
Pharmacokinetics
Leucovorin
Neoplasms
Maximum Tolerated Dose
Biological Availability
Nerve Sheath Neoplasms
Folic Acid
Methotrexate
Area Under Curve
Oral Administration
Half-Life
Appointments and Schedules
Adenocarcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ratliff, A. F., Wilson, J., Hum, M., Marling-Cason, M., Rose, K., Winick, N., & Kamen, B. A. (1998). Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies. Journal of Clinical Oncology, 16(4), 1458-1464.

Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies. / Ratliff, Arleen F.; Wilson, Jennifer; Hum, Martina; Marling-Cason, Margaret; Rose, Kathy; Winick, Naomi; Kamen, Barton A.

In: Journal of Clinical Oncology, Vol. 16, No. 4, 04.1998, p. 1458-1464.

Research output: Contribution to journalArticle

Ratliff, AF, Wilson, J, Hum, M, Marling-Cason, M, Rose, K, Winick, N & Kamen, BA 1998, 'Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies', Journal of Clinical Oncology, vol. 16, no. 4, pp. 1458-1464.
Ratliff AF, Wilson J, Hum M, Marling-Cason M, Rose K, Winick N et al. Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies. Journal of Clinical Oncology. 1998 Apr;16(4):1458-1464.
Ratliff, Arleen F. ; Wilson, Jennifer ; Hum, Martina ; Marling-Cason, Margaret ; Rose, Kathy ; Winick, Naomi ; Kamen, Barton A. / Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies. In: Journal of Clinical Oncology. 1998 ; Vol. 16, No. 4. pp. 1458-1464.
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abstract = "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.",
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AU - Kamen, Barton A.

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