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Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug
M E Horowitz1, E Etcubanas, M L Christensen
1Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN.
Abstract:
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.
Insights
Melphalan showed significant antitumor activity in children with newly diagnosed rhabdomyosarcoma (RMS). Retesting in untreated patients confirmed efficacy, highlighting limitations of trials in previously treated populations for developing new cancer drugs.
Area of Science:
- Pediatric Oncology
- Medical Oncology
- Pharmacology
Background:
- Rhabdomyosarcoma (RMS) is a pediatric cancer.
- Melphalan, a nitrogen mustard compound, showed preclinical promise against RMS xenografts.
- Previous Phase II trials in recurrent RMS patients yielded poor results.
Purpose of the Study:
- To evaluate the efficacy of melphalan in newly diagnosed, poor-risk pediatric rhabdomyosarcoma.
- To investigate the reasons for melphalan's failure in previously treated patients.
- To establish a paradigm for antineoplastic drug development.
Main Methods:
- Preclinical testing using human RMS xenografts in immune-deprived mice.
- Phase II clinical trial of melphalan in heavily pretreated, recurrent RMS patients.
- Pharmacokinetic analysis comparing mice and patients.
- Phase II trial of melphalan in newly diagnosed, poor-risk RMS patients.
Main Results:
- Melphalan demonstrated superior oncolytic activity in RMS xenografts compared to other agents.
- The drug failed to produce responses in 13 heavily pretreated patients.
- Pharmacokinetics did not explain the poor clinical performance in recurrent disease.
- Ten of 13 newly diagnosed children achieved partial responses after 6 weeks of melphalan treatment.
Conclusions:
- Melphalan exhibits significant antitumor activity in newly diagnosed, poor-risk rhabdomyosarcoma.
- Phase II trials in previously treated patients may not accurately reflect a drug's potential.
- This study suggests a valuable approach for developing novel antineoplastic agents.