PHASE-1 CLINICAL INVESTIGATION OF 9,10-ANTHRACENEDICARBOXALDEHYDE BIS[(4,5-DIHYDRO-H-1-IMIDAZOL-2-YL)HYDRAZONE] DIHYDROCHLORIDE WITH CORRELATIVE INVITRO HUMAN TUMOR CLONOGENIC-ASSAY

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (3) , 1170-1175
Abstract
9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride (bisantrene) is a new anthracene bishydrazone derivative which was entered into a phase I clinical trial (1 dose/wk for 3 wk). When possible, patients were entered into the phase I study if, their tumors showed in vitro sensitivity to bisantrene and resistance to standard agents, using a human tumor stem cell assay. Thirty-one patients were treated with bisantrene over a 10- mo. period, starting at a dose of 70 mg/m2 per wk. The appearance of leukopenia determined the dose-limiting toxicity of bisantrene. The maximally tolerated dose appeared to be 200 mg/m2 in that 3 of 5 patients tolerated these weekly-for-3-wk doses while experiencing only mild or moderate leukopenia. The 220-mg/m2 dose caused moderate to life-threatening leukopenia after just 2 weekly doses in 4 of 5 patients. Local bisantrene toxicity included mild to severe arm swelling, phlebitis, pain, urticaria and erythema in 68% of the patients. In general, these toxicities were well tolerated and rapidly reversible but 2 patients had severe local swelling for up to 6 mo. In this phase I trial, bisantrene showed clinical antitumor activity against both hematological cancer (i.e., lymphoma and myeloma) and solid tumors (i.e., bladder, lung, and renal cancer and melanoma). Of importance, 4 of the 6 responses occurred in patients whose therapy was selected on the basis of in vitro sensitivity to bisantrene using the human tumor stem cell assay. One patient with disseminated melanoma had complete disappearance of an axillary node metastasis (for more than 6 mo.) while developing a brain metastasis, suggesting that bisantrene does not concentrate in the CNS.