Objective: A Phase I clinical trial was initiated using Doxil® following fever-range whole body hyperthermia (FR-WBH) in patients with advanced incurable malignancies This study was based on changes in functional tumor microvessel density and uptake of Doxil® in murine tumor models following FR-WBH. Previously we performed a Phase I study of FR-WBH alone.

Methods: The trial design evaluated dose limiting toxicity (DLT) in patients undergoing 6 hours of FR-WBH (39.3 -39.8^oC) followed by Doxil®. Cycle # 1 was given as above, with FR-WBH, but in cycle #2, Doxil® was given without FR-WBH. Doxil® was administered at either 30 or 40 mgm/m² according to the dose escalation algorithm. Patients continue Doxil® and WBH as long as disease is stable or they are responding to therapy. Blood measurements include pharmacokinetics of doxorubicin, cytokine expression, lymphocyte phenotype and evaluation of heat shock protein (HSP 70 and HSP 110). Tumor response is assessed by radiologic means and when appropriate by follow-up of tumor markers.

Results: Thus far, nine patients (5 female, 4 male) entered the trial with ECOG performance status < 1 at a median age of 52. Three patients were treated at dose level 30 mgm/m² with no responses. Three patients who did not start chemotherapy were replaced. One treatment related death occurred in a patient who never received Doxil®. Of three patients treated with Doxil® at 40 mgm/m² there was one stabilization and a partial response (PR). Additional patients are being added to this cohort. The pharmacokinetic analysis and relationship of response to cytokine expression and lymphocyte phenotype are ongoing and interim data will be presented.

Conclusion: With careful patient selection and appropriate care, WBH between 39.3^oC and 39.8 ^oC can be given safely. DLT is still being assessed. This Phase I study shows the feasibility and tolerability of FR-WBH and Doxil®.