Journal of Clinical Oncology, Vol 6, 308-314, Copyright © 1988 by American Society of Clinical Oncology
Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development
ME Horowitz, E Etcubanas, ML Christensen, JA Houghton, SL George, AA Green and PJ Houghton
Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN.
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.
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