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.
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors: S A
authors: SA
authors: Laurie
authors: D G
authors: DG
authors: Pfister
authors: M G
authors: MG
authors: Kris
authors: W P
authors: WP
authors: Tong
authors: G
authors: G
authors: Chronowski
authors: K M
authors: KM
authors: Pisters
authors: R T
authors: RT
authors: Heelan
authors: F M
authors: FM
authors: Sirotnak
mesh_terms: D000328:Adult; D000368:Aged; D000630:Aminopterin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; C040210:edatrexate; D000630:Aminopterin; D002945:Cisplatin