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Oral folic acid improves lometrexol toxicity profile: A phase I study

Lookup NU author(s): Lynsey Robson, Professor Alan Calvert

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Abstract

Lometrexol, the antipurine antifolate, has an MTD of 12 mg/m² when given as a single agent every 4 weeks. The dose limiting toxicities, myelosuppression and diarrhea, were substantially reduced in mice given a high folic acid diet. In an ongoing phase I dose escalation study of lometrexol coadministered with folic acid (5 mg/day for 14 days), 32 patients received lometrexol at doses of 12 mg/m² (3 pts), 16 mg/m² (4 pts), 30 mg/m² (5 pts), 45 mg/m² (11 pts), 60 mg/m² (6 pts) and 78 mg/m² (3 pts). Tumour types were: 6 breast, 5 ovary, 5 melanoma, 1 renal, 7 colorectal, 2 NSCLC, 2 pancreas, and 4 primary unknown. Initial doses were given at 28 day intervals with subsequent reduction to a 21 day cycle after 8 patients had been treated at 45 mg/m². A median of 2 courses was given (range 1-5). Haematological toxicity was mild. One patient experienced a grade 3 neutropenia and 2 patients grade thrombocytopenia (toxicities at 45 mg/m²). No grade haematological toxicity was seen at 60 mg/m² or 78 mg/m². Grade 3 diarrhea (45 mg/m²), nausea (45 mg/m²) and mucositis (60 mg/m²) were seen in 3 separate patients. We previously reported a 21-50% fall in GFR with repeated dosing. At 60 mg/m² the change in pretreatment GFR measured by ⁵¹Cr-EDTA was between −11.9% and +23.8%. No alteration in serum creatinine was seen at any dose level. One patient (30 mg/m², breast cancer) had a partial response of 6 weeks duration. The MTD has not been reached and the next dose escalation will be 100 mg/m². It is clear that coadministration of folic acid ameliorates the clinical toxicities seen with lometrexol.

Publication metadata

Author(s): Bailey, N., Humphreys, A., Laohavinij, S., Lind, M., Robson, L., Calvert, A. H.

Publication type: Article

Publication status: Published

Journal: European Journal of Cancer

Year: 1995

Volume: 31

Issue: Supplement 6

Pages: S931-934

Print publication date: 01/11/1995

ISSN (print): 0959-8049

ISSN (electronic): 1879-0852

URL: http://dx.doi.org/10.1016/0959-8049(95)96180-L

DOI: 10.1016/0959-8049(95)96180-L

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