Phase I trial of lonidamine with whole body hyperthermia in advanced cancer.

Lonidamine is a dechlorinated derivative of indazole-3-carboxylic acid which preclinically synergizes with hyperthermia. Clinically, this nonmyelosuppressive 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 degrees C for 85 min to 41.8 degrees 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 (greater than 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.

A pilot study of whole body hyperthermia and local irradiation for advanced non-small cell lung cancer confined to the thorax.

Six patients with Stage III non-small cell lung cancer completed therapy which consisted of 4 whole body hyperthermia (WBH) treatments during the first 2 weeks of a 6 week course of radiotherapy (60 Gy). A radiant heat system was used to deliver the 41.8 degree C WBH. To reduce the danger of transverse myelitis, the spinal cord (and therefore part of the mediastinum and contralateral hilar region) was not irradiated during the first 2 weeks of radiotherapy and concurrent WBH. Subsequent treatments (weeks 3-6) included conventional irradiation to the primary tumor, mediastinal lymph nodes and spinal cord. Areas of gross disease responded to therapy in 5/6 patients. No radiation pneumonitis was observed. In 2/6 patients, relapse (after 10 months and 6 months, respectively) occurred with malignant pericardial effusions. The mediastinum in these patients was not an area of bulky disease involvement initially. To eliminate such WBH-radiation sanctuary zones, the protocol was modified to include greater combined WBH-radiation treatment. This is accomplished by having one WBH treatment "sandwiched" between 2 radiation fractions. The preclinical basis for the revised protocol is presented.