Phase I clinical study of N-[(4-chlorophenyl)amino]carbonyl-2,3-dihydro-1H-indene-5-sulfonamide (LY186641)

• Published in: Cancer research (Chicago, Ill.) Vol. 49; no. 18; pp. 5217 - 5220
• Main Authors: HAINSWORTH, J. D, HANDE, K. R, SATTERLEE, W. G, KUTTESCH, J, JOHNSON, D. H, GRINDEY, G, JACKSON, L. E, GRECO, F. A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-1989
• Subjects: Antineoplastic agents; Antineoplastic Agents - adverse effects; Biological and medical sciences; Chemotherapy; Drug Evaluation; Female; Humans; Male; Medical sciences; Methemoglobinemia - chemically induced; Middle Aged; Neoplasms - drug therapy; Pharmacology. Drug treatments; Sulfonylurea Compounds - adverse effects; Sulfonylurea Compounds - pharmacokinetics; Sulfonylurea Compounds - therapeutic use; Time Factors; Antineoplastic agent; Human; Phase I trial; Chemotherapy; Treatment
• ISSN: 0008-5472; 1538-7445

Between February 1987 and July 1988, 45 patients with advanced refractory cancer were treated with LY186641, a diarylsulfonylurea that has shown a broad spectrum of activity in preclinical testing. Patients received a weekly p.o. dose of LY186641 for 6 consecutive weeks; responding and stable patients continued weekly therapy until progression occurred. Using a standard phase I study design, the first three patients received LY186641 at 30 mg/m2 week; the dose was escalated in subsequent patients until dose-limiting toxicity occurred. Methemoglobinemia was the major toxicity observed and was dose related. Methemoglobin levels peaked approximately 24 h after LY186641 was administered and fell to low levels after 48 h. Six patients developed fatigue, cyanosis, and dyspnea associated with serum methemoglobinemia levels of greater than 20%; four of these patients were subsequently removed from the study. Hemolytic anemia was also observed but was clinically significant in only 10 patients. Other side effects were mild and infrequent. The maximum tolerated dose of LY186641, when given at this schedule, was 2550 mg/m2/week. No objective tumor responses were observed.