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Phase I Clinical Investigation of 9,10-Anthracenedicarboxaldehyde Bis[(4,5-dihydro-1 H-imidazol-2-yl)hydrazone] dihydrochloride (CL216,942)¹

Department of Medicine, Division of Oncology [D. D. V. H., J. W. M., G. C., C. A. C.] and School of Pharmacy [J. K.], University of Texas Health Science Center at San Antonio, and Audie Murphy VA Hospital, San Antonio, Texas 78284, and The Austin Diagnostic Clinic [J. S.], Austin, Texas 78765, and Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965 [R. P.]

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride (CL216,942) is a new anthracene bishydrazone derivative that was evaluated in a Phase I clinical trial. The schedule of administration consisted of a single i.v. injection repeated at 4-week intervals. Twenty-eight patients received a total of 61 courses of the drug in a dose range of 20 to 280 mg/sq m. Leukopenia was the dose-limiting toxicity. It was of short duration and reversible. A drug-induced hypotension was noted at higher doses in three patients. The hypotension was not dose limiting, it was reversible, and it could largely be avoided by prolonging the drug infusion time to 1 hr. One patient with unsuspected severe coronary artery disease died of complications of myocardial infarction subsequent to a hypotensive episode. Significant phlebitis was also noted at higher doses of drug. This degree of phlebitis could be lessened by diluting the drug in larger volumes of fluid. Three patients experienced diaphoresis, nausea, palpitations, and chest discomfort at the conclusion of the infusions. None of the patients had electrocardiographic changes. Mild fever, alopecia, and nausea and vomiting were noted occasionally. One patient with a hypernephroma and one patient with hepatocellular carcinoma experienced partial responses of their tumors secondary to the drug. Phase II studies of CL216,942 are planned at a starting dose of 260 mg/sq m as a single dose repeated at 21- to 28-day intervals.

¹ Supported by a Grant from the Medical Research Division, American Cyanamid Company.

² To whom requests for reprints should be addressed, at Department of Medicine, Division of Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284.

Received 11/13/80. Accepted 5/11/81.