title: A phase I trial of amifostine (WR-2721) and melphalan in children with refractory cancer.
abstract: Melphalan has a steep dose-response curve, but the use of high doses results in unacceptable myelosuppression. Strategies to circumvent this dose-limiting myelosuppression would allow for the administration of higher, more effective doses of melphalan. Amifostine (WR-2721) has been shown in preclinical studies to protect the bone marrow from the myelotoxicity of melphalan, and in clinical trials, to protect from the myelotoxicity of other alkylating agents. A Phase I trial of the combination of amifostine and melphalan was performed in children with refractory cancers to: (a) define the acute toxicities of amifostine and its maximum tolerated dose (MTD); and (b) to determine whether the dose of melphalan could be safely escalated when administered in combination with amifostine. Amifostine was administered i.v. as a 15-min infusion 30 min before melphalan. The starting dose of amifostine was 750 mg/m2, with planned dose escalations in 30% increments. Melphalan was administered as a 5-min infusion using the previously defined MTD in heavily pretreated patients, 35 mg/m2, as the starting dose. The dose of melphalan was escalated by 30% increments. Nineteen patients, ranging in age from 3 to 24 years (median, 15 years), were entered on trial. The dose of amifostine was escalated to 2700 mg/m2, which is approximately 3-fold higher than the adult recommended dose, without reaching a MTD. Fifteen patients experienced nondose-limiting (< 25%), transient decreases in blood pressure after the amifostine infusion. Other nondose-limiting toxicities of amifostine included mild nausea and vomiting, flushing, anxiety, diarrhea, and urinary retention. Six patients, three each at the 2100 and 2700 mg/m2 amifostine dose levels were treated with an escalated dose of melphalan (45 mg/m2). All of these patients experienced grade 4 neutropenia (< 500/mm3), and five of six patients had grade 4 thrombocytopenia. The duration of this dose-limiting myelosuppression exceeded 7 days in four of six patients. Although no dose-limiting (grade 3 or 4) toxicity was attributed to amifostine, significant anxiety and reversible urinary retention occurred at the two highest amifostine dose levels. A dose of 1650 mg/m2 for pediatric Phase II trials is recommended. High doses of amifostine, however, do not appear to allow for escalation of melphalan beyond its single agent MTD of 35 mg/m2.
authors.affiliation: Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: J E
authors.initials: JE
authors.lastname: Belasco
authors.forename: B
authors.initials: B
authors.lastname: Lange
authors.forename: S L
authors.initials: SL
authors.lastname: Berg
authors.forename: S M
authors.initials: SM
authors.lastname: Blaney
authors.forename: C
authors.initials: C
authors.lastname: Craig
authors.forename: D G
authors.initials: DG
authors.lastname: Poplack
mesh_terms: D000293:Adolescent; D000328:Adult; D004999:Amifostine / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D004999:Amifostine; D008558:Melphalan