PHASE-I CLINICAL-TRIAL OF MELPHALAN AND 41.8-DEGREES-C WHOLE-BODY HYPERTHERMIA IN CANCER-PATIENTS

Purpose: To evaluate the biologic interactions and toxicities of melph alan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH ) for 60 minutes. Patients and Methods: Sixteen patients with refracto ry cancer were treated (May 1992 to May 1995) with WBH alone during we ek thereafter patients were randomized to receive either L-PAM alone a n week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patien ts who demonstrated clinical improvement received WBH plus L-PAM month ly. Dose levels of L-PAM were 10 mg/m(2) (n = 3), 15 mg/m(2) (n = 3), 17.5 mg/m(2) (n = 6), and 20 mg/m(2) (n = 4). L-PAM was administered a t target temperature; WBH was administered with on Aquatherm radiant-h eat device (patent pending; Cancer Research institute, New York, NY). Results: Comparisons of mean WBC count and platelet nadirs for L-PAM a lone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no insta nces of febrile neutropenia or bleeding, Toxicities allowed for escala tion of L-PAM to 20 mg/m(2); all four patients at this level experienc ed grade 4 myelosuppression. No significant myelosuppression was obser ved at 10 and 5 mg/m(2). Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m(2). Responses included complete remission (CR) of pancreatic cancer (10 mg/m(2)), partial remission (PR) of mal ignant melanoma in two patients (20 mg/m(2)), and transient clinical a nd/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is a lso discussed in detail. Conclusion: We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress. (C) 1997 by American Society af Clinical Onco logy.