Phase I and preliminary phase II evaluation of adriamycin (NSC 123127).

Summary Adriamycin is a new antibiotic isolated from cultures of Streptomyces peucetius caesius with antitumor activity in man. Its structural formula is very similar to that of daunorubicin. Preclinical studies in experimental animal tumors have shown that adriamycin has a higher therapeutic index (1.25) than daunorubicin (0.67). Of 155 patients (34 children and 121 adults) with different forms of leukemia and solid tumors studied for Phase I and II evaluation, 146 were evaluable. Adriamycin has been administered in 147 cases through rapid single i.v. injections with three different dosages (0.4, 0.65, and 0.8 mg/kg) and with three different schedules (loading, alternate, and intermittent). In 5 patients, the drug was given through an intraarterial infusion and in 3 cases it was given intrapleurally. Children tolerated higher doses than adults, while patients pretreated with other anticancer agents were usually rapidly intoxicated after few doses. Toxicity consisted primarily of stomatitis, bone marrow depression, and alopecia. Irreversible marrow aplasia was observed in 11 cases. Nausea, vomiting, diarrhea, and fever were of minor importance. No conclusive evidence of cardiac toxicity was found, although some EKG changes were seen after drug administration in 48 patients. No significant abnormalities in liver chemistries and renal function tests were observed. Adriamycin produced consistent regressions in ten histologically different types of neoplastic disease, but mostly in acute lymphoblastic and chronic (myeloid and lymphocytic) leukemias, as well as in all types of malignant lymphomas, neuroblastoma, Ewing sarcoma, soft-tissue sarcomas, and chorioepithelioma of the uterus. The drug appears to be a potent growth-inhibiting compound and seems more useful in inducing tumor regression rather than as maintenance therapy. In comparison to daunorubicin, adriamycin seems to be therapeutically active at lower doses and on a larger variety of neoplastic diseases.