AIDS CLINICAL-TRIALS GROUP-STUDY-094 - A PHASE I II TRIAL OF ABV CHEMOTHERAPY WITH ZIDOVUDINE AND RECOMBINANT HUMAN GM-CSF IN AIDS-RELATED KAPOSIS-SARCOMA/

PURPOSE To define the maximum tolerated dose of doxorubicin when combi ned with fixed doses of bleomycin, vincristine, zidovudine, and recomb inant human granulocyte macrophage colony-stimulating factor (rhGM-CSF ) in patients with advanced AIDS-related Kaposi's sarcoma. PATIENTS AN D METHODS Twenty male patients were treated with zidovudine at doses o f either 100 or 200 mg by mouth every 4 hours, and cytotoxic chemother apy with bleomycin 10 U/m(2) and vincristine 1.4 mg/m(2) by vein every 2 weeks. Four successive cohorts received fixed doses of doxorubicin given intravenously every 2 weeks: two cohorts each received 10 mg/m(2 ) (levels 1, 2) or 20 mg/m(2) (levels 3, 4). The first cohere received rhGM-CSF at a dose of 10 mu g/kg, given subcutaneously on days 2 thro ugh 11 (level 1). Due to toxicity, the dose of rhGM-CSF was reduced to 5 mu g/kg (levels 2, 3) and then to 2.5 mu g/kg (level 4). RESULTS Th e dose-limiting toxicity was severe neutropenia, occurring in 10 patie nts, Severe neutropenic episodes occurred after a median of three cycl es of chemotherapy, with the nadir occurring after 14 days (median). M oderate neutropenia occurred in 14% of all cycles administered, Consti tutional toxicities of moderate or greater severity occurred in four p atients, Five of 10 patients at a doxorubicin dose of 20 mg/m(2) (leve ls 3 and 4) experienced severe neutropenia. Thus, doxorubicin at 10 mg /m(2), with BV (bleomycin, vincristine chemotherapy), zidovudine (100 mg five times daily), and rhGM-CSF (5 mu g/kg/day), was defined as the maximum tolerated dose. CONCLUSIONS The maximum tolerated dose of dox orubicin is 10 mg/ m(2) every 2 weeks when given in combination with B V chemotherapy, zidovudine, and rhGM-CSF. While the addition of rhGM-C SF at doses of 2.5 to 5 mu g/kg decreased the duration of neutropenia, it did not prevent die occurrence of severe neutropenia from combined myelotoxic therapy.