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Phase I Clinical and Pharmacological Study of 4'-(9-Acridinylamino)-methanesulfon-m-anisidide Using an Intermittent Biweekly Schedule

Clinical Oncology Branch, Baltimore Cancer Research Program, Division of Cancer Treatment, National Cancer Institute, Baltimore, Maryland 21201 [D. A. V. E., M. S., P. H. W.]; Chemotherapy Evaluation Program [D. F. C.] and Laboratory of Chemical Pharmacology [P. E. G.], Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205; and Clinical Cancer Program, Sinai Hospital, Baltimore, Maryland 21215 [J. L. L.]

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA, NSC 249992), an acridine derivative, was given to 28 patients with solid tumors and one patient with Hodgkin's disease in a Phase I clinical trial. The dose schedule used was a single dose given every 14 days for three doses. The amount given ranged from 10 to 120 mg/sq m/dose. Dose-limiting toxicity was moderate to severe leukopenia which occurred at and above 70 mg/sq m. Thrombocytopenia was infrequent and did not require transfusion. Nonhematological side effects were mild and included nausea, vomiting, local irritation, and fever. Antineoplastic activity was noted in liposarcoma, adenocarcinoma of unknown primary origin, and squamous carcinoma of unknown primary origin (one patient each). Pharmacokinetics studies were done in 19 patients. Total m-AMSA and free m-AMSA concentrations showed a biphasic distribution with an initial rapid phase of t_1/2 = 10 to 15 min for both, and a second slow phase of t_1/2 = 8 to 9 hr for total m-AMSA and 3 hr for free m-AMSA. Phase II studies with m-AMSA, in hematological cancers are warranted, since its most consistent effect is on leukocytes. The recommended dosages for solid-tumor Phase II studies are 70 mg/sq m for good-risk patients and 50 mg/sq m for poor-risk patients, given as a single dose every other week, or 120 mg/sq m for good-risk patients and 90 mg/sq m for poor-risk patients for the single-dose every-3-week schedule.

¹ To whom requests for reprints should be addressed, at Clinical Oncology Branch, Baltimore Cancer Research Program, Division of Cancer Treatment, National Cancer Institute, University of Maryland Hospital, 22 South Greene Street, Baltimore, Md. 21201.

Received 1/18/79. Accepted 6/21/79.