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Phase I and Pharmacokinetic Study of the Novel Oral Cell-Cycle Inhibitor Ro 31-7453 in Patients With Advanced Solid Tumors

From the Developmental Chemotherapy Service and the Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and the Joan and Sanford I. Weill Medical College of Cornell University, New York, NY; Hoffmann-La Roche Inc, Nutley, NJ

Address reprint requests to Jakob Dupont, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: dupontj{at}mskcc.org

PURPOSE: To determine maximum tolerated dose, pharmacokinetics (PK), and safety of Ro 31-7453, a novel, oral cell-cycle inhibitor.

PATIENTS AND METHODS: Using an accelerated dose-escalation schedule, 48 patients with advanced solid tumors were treated with doses of Ro 31-7453 ranging from 25 to 800 mg/m²/d given for 4 consecutive days, every 3 weeks. The total daily dose was taken as a single dose (schedule A) or divided into two equal doses taken 12 hours apart (schedule B). PK samples of blood and urine were collected on the first and last days of dosing in cycles 1 and 2.

RESULTS: Forty-five patients completed at least one cycle of therapy. Myelosuppression and stomatitis were dose-limiting toxicities, occurring at the 800 mg/m²/d dose level for both schedules. Toxicity was independent of body-surface area, leading to the recommended phase II flat dose of 1,000 mg daily for 4 days for both schedules. Common adverse events included diarrhea, nausea, vomiting, fatigue, alopecia, and elevated liver-function tests. One death, related to neutropenic sepsis, occurred on study. The PK of the parent compound and major metabolites were apparently linear, with a half-life of approximately 9 hours and a maximum concentration of approximately 4 hours. Minor antitumor activity was observed against carcinoma of the lung, breast, pancreas, and ovary.

CONCLUSION: Ro 31-7453 was well tolerated, with manageable adverse effects. Significant PK variability (absorption, metabolism, and excretion) was observed, and a substantial number of additional patients are needed to confirm the recommended phase II dose. Additional pharmacology and phase II studies are under way to explore the dose-toxicity relationship.

Supported in part by funds granted by the Charles H. Revson Foundation, the American Society of Clinical Oncology Young Investigator and Career Development Awards, and by funds from the Lymphoma Foundation.

Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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