We describe events that led to successful testing of
melphalan, one of the
nitrogen mustard compounds, in children with newly diagnosed, poor-risk
rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by
melphalan compared with other agents commonly used to treat this
tumor. However, in a conventional phase II trial,
melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent
tumors. Subsequent comparison of the
drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in
drug disposition. Therefore, we elected to retest
melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the
drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II
drug trials in previously treated patients and suggest a useful paradigm for the development of
antineoplastic drugs.