A PHASE-I TRIAL OF AMIFOSTINE (WR-2721) AND MELPHALAN IN CHILDREN WITH REFRACTORY CANCER

Melphalan has a steep dose-response curve, but the use of high doses r esults 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 be en shown in preclinical studies to protect the bone marrow from the my elotoxicity of melphalan, and in clinical trials, to protect from the myelotoxicity of other alkylating agents. A Phase I trial of the combi nation of amifostine and melphalan was performed in children with refr actory cancers to: (a) define the acute toxicities of amifostine and i ts maximum tolerated dose (MTD); and (b) to determine whether the dose of melphalan could be safely escalated when administered in combinati on with amifostine. Amifostine was administered i.v, as a 15-min infus ion 30 min before melphalan, The starting dose of amifostine was 750 m g/m(2), 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/m(2), as the starting dose. The dos e of melphalan was escalated by 30% increments. Nineteen patients, ran ging in age from 3 to 24 years (median, 15 years), were entered on tri al. The dose of amifostine was escalated to 2700 mg/m(2), which is app roximately 3-fold higher than the adult recommended dose, without reac hing a MTD. Fifteen patients experienced nondose-limiting (<25%), tran sient decreases in blood pressure after the amifostine infusion. Other nondose-limiting toxicities of amifostine included mild nausea and vo miting, flushing, anxiety, diarrhea, and urinary retention. Six patien ts, three each at the 2100 and 2700 mg/m(2) amifostine dose levels wer e treated with an escalated dose of melphalan (45 mg/m(2)). All of the se patients experienced grade 4 neutropenia (<500/mm(3)), and five of six patients had grade 4 thrombocytopenia. The duration of this dose-l imiting myelosuppression exceeded 7 days in four of six patients. Alth ough no dose-limiting (grade 3 or 4) toxicity was attributed to amifos tine, significant anxiety and reversible urinary retention occurred at the two highest amifostine dose levels. A dose of 1650 mg/m(2) for pe diatric Phase II trials is recommended. High doses of amifostine, howe ver, do not appear to allow for escalation of melphalan beyond its sin gle agent MTD of 35 mg/m(2).