Phase I and pharmacological study of two schedules of the antifolate edatrexate in combination with cisplatin Journal Article

Authors: Laurie, S. A.; Pfister, D. G.; Kris, M. G.; Tong, W. P.; Chrowowski, G.; Pisters, K. M. W.; Heelan, R. T.; Sirotnak, F. M.
Article Title: Phase I and pharmacological study of two schedules of the antifolate edatrexate in combination with cisplatin
Abstract: The antifolate edatrexate has shown moderate activity against cancers of the head and neck and non-small cell lung cancer, as has cisplatin. Edatrexate demonstrates synergy with cisplatin in transplanted tumor models. This Phase I study was designed to evaluate two schedules of administration of cisplatin in combination with escalating doses of edatrexate, in a population consisting mainly of patients with these two cancers. The starting dose of edatrexate was 40 mg/m2. Dose escalation was to occur in 10-mg/m2 increments; the planned maximum dose level for study was 80 mg/m2. A total of 39 patients were registered. Eleven were treated on schedule A: cisplatin 120 mg/m2 every 4 weeks, and edatrexate weekly. Twenty-eight patients were assigned to schedule B: cisplatin 60 mg/m2 and edatrexate, both given every 2 weeks. On schedule A, the maximum tolerated dose of weekly edatrexate was 40 mg/m2, with dose-limiting toxicities of leukopenia, mucositis, and renal insufficiency. On schedule B, the maximum tolerated dose of biweekly edatrexate was 80 mg/m2, with leukopenia and mucositis as dose limiting. For schedule A, pharmacokinetic studies suggested a possible effect of cisplatin on the day 8 clearance of edatrexate. Studies on patients on schedule B did not show a clear effect of cisplatin on the day 15 edatrexate clearance. On schedule A, 5 of 9 evaluable patients had major responses (1 complete); whereas on schedule B, 8 of 25 patients had major responses (1 complete). Responses were seen in both head and neck and non-small cell lung cancer patients. For Phase II studies, use of cisplatin 60 mg/m2 and edatrexate 80 mg/m2, both given biweekly, is recommended.
Keywords: adult; clinical article; controlled study; treatment outcome; aged; middle aged; clinical trial; fatigue; cisplatin; area under the curve; cancer combination chemotherapy; drug potentiation; antineoplastic agents; controlled clinical trial; leukopenia; lung non small cell cancer; mucosa inflammation; nausea; randomized controlled trial; thrombocytopenia; antineoplastic combined chemotherapy protocols; carcinoma, non-small-cell lung; lung neoplasms; kidney failure; dose-response relationship, drug; time factors; head and neck cancer; head and neck neoplasms; drug response; drug clearance; area under curve; maximum tolerated dose; phase 1 clinical trial; folic acid antagonist; folic acid antagonists; aminopterin; edatrexate; humans; human; male; female; priority journal; article
Journal Title: Clinical Cancer Research
Volume: 7
Issue: 3
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2001-03-01
Start Page: 501
End Page: 509
Language: English
PUBMED: 11297240
PROVIDER: scopus
Notes: Export Date: 21 May 2015 -- Source: Scopus