Preliminary clinical evaluation of piperazinedione (P), a new crystalline antibiotic

P, a Streptomyces fermentation product, is a new crystalline antibiotic which has shown impressive activity in animal tumor system including the L1210 and AKR leukemias and Lewis lung carcinoma, with only moderate preclinical toxicity affecting mainly the gastroenteric and hematopoietic systems. Accordingly, a Phase I study was begun with P using doses of 1.5-36 mg/M² IV repeated every 3 to 4 weeks. Of 45 evaluable pts (41 with extensive prior chemotherapy), there were 4 partial responses (>50%) (PR) & 8 improvements (25-50%) (IMP) including 2PR/16 melanoma (4&2mos); 2PR/2 chronic myelogenous leukemia in blast crisis (3+&2mos); 6IMP/6 myelogenous leukemia (AML); 1IMP/1 prostate cancer (ca) & 1IMP/1 renal ca. No responses were seen in 5 colon ca; 5 squamous cell ca; or in 9 other solid tumors. Despite extensive prior therapy, disappearance of blastemia was noted in all AML's treated, with M₂ marrows achieved in 2. Hematopoietic toxicity was dose limiting, affecting both granulocytes and platelets maximally 2 1/2 weeks after P with recovery in 7 to 12 days, with rare prolonged marrow aplasia. Vomiting, anemia and mild prothrombin time prolongations were the only other toxic effects seen. Starting doses of 15 mg/M² for solid tumor pts (12₂ mg/M² for impaired marrow reserve) and 24 mg/M² for leukemia pts repeated every 3 to 4 weeks are now being used for Phase II trials.