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A Phase I Trial of Amifostine (WR-2721) and Melphalan in Children with Refractory Cancer

Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892 [P. C. A., F. M. B., C. G., S. L. B., S. M. B., D. G. P.], and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 [J. E. B., B. L.]

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.

¹ To whom requests for reprints should be addressed, at Pediatric Branch, National Cancer Institute, Building 10, Room 13N240, 9000 Rockville Pike, Bethesda, MD 20892.

² Present address: Texas Children's Hospital, Houston, TX 77030.

Received 4/26/95. Accepted 7/19/95.

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