Lonidamine is a dechlorinated derivative of indazole-3-carboxylic acid which preclinically synergizes with hyperthermia. Clinically, this non-myelosuppressive drug (given p.o. daily) is active as a single agent in a variety of malignancies. On this basis, a Phase I study which incorporates a drug escalation schema as well as an escalation in temperature, i.e., 41.0°C for 85 min to 41.8°C for 75 min, was executed. Induction therapy included seven whole-body hyperthermia treatments. Whole-body hyperthermia was delivered using a radiant heat system.

Twenty-four patients were entered on study. Of these, 20 were evaluable for response. Group A (60 mg/m2) had three patients with three no responses. Group B (180 mg/m2) consisted of three patients: one lymphoma, partial response; two gastrointestinal adenocarcinomas, one partial response and one improvement, i.e., less than a partial response. Group C (360 mg/m2) had 17 patients: two lung cancers, one complete response and one improvement; one melanoma, improvement; one ovarian, disease stabilization (>100 days); two adenocarcinomas of the gastrointestinal tract, two disease stabilizations; 11 patients, no responses; one patient entered at this level was ineligible for study and did not receive lonidamine. Therapy was well tolerated. Of 16 patients reporting myalgias, two required a lonidamine dose reduction; one patient required dose reduction for central nervous system toxicity. Results obtained encourage Phase II clinical trials.

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This study was supported by USPHS Grant RO1-35361-04 awarded by the National Cancer Institute, Department of Health and Human Services; NIH Grant RR 03186 from the Division of Research Resources to the University of Wisconsin; and by a grant from Angelini Pharmaceuticals, NJ.

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