A PHASE I II STUDY OF QUINIDINE, A POTENTIAL MULTIDRUG-RESISTANCE REVERSING AGENT, IN COMBINATION WITH PIRARUBICIN IN PATIENTS WITH ADVANCED REFRACTORY BREAST-CANCER/

Background: Because MDR1 RNA is frequently encountered in advanced bre ast cancer, we have initiated a phase I/II study with pirarubicin in c ombination with the multidrug resistance modifier quinidine. Patients and Methods: Fourteen patients with metastatic breast cancer refractor y to conventional anticancer chemotherapy with anthracyclines and/or v inca alkaloids were entered into this trial. All patients were given 2 50 mg quinidinebisulfate twice daily for a total of 5 days, and the an thracycline derivative pirarubicin was administered on the 4th day of the cycle. The pirarubicin starting dose was 50 mg/m(2) body surface a nd was escalated during the study in cohorts of 3 patients each. Cycle s were repeated every 3-4 weeks. Results: Ah patients were evaluable f or toxicity and response assessment. The maximum tolerated dose of pir arubicin was 70 mg/m(2). Overall treatment-associated toxicity was mil d and comparable with conventional pirarubicin monotherapy. The median leukocyte nadir was 2000/mm(3), partial alopecia (70%) and nausea/eme sis (20%) were the most frequently encountered nonhematologic side eff ects. Quinidine-associated side effects were not reported. There was n o objective response. Six patients had stable disease, while the tumor progressed in eight. Conclusions: Quinidine in combination with pirar ubicin is not active in advanced refractory breast cancer.