Phase I and pharmacokinetic study of the novel oral cell-cycle inhibitor Ro 31-7453 in patients with advanced solid tumors

被引:12
|
作者
Dupont, J
Bienvenu, B
Aghajanian, C
Pezzulli, S
Sabbatini, P
Vongphrachanh, P
Chang, C
Perkell, C
Ng, K
Passe, S
Breimer, L
Zhi, LG
DeMario, M
Spriggs, D
Soignet, SL
机构
[1] Mem Sloan Kettering Canc Ctr, Dev Chemotherapy Serv, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, Dept Med, New York, NY 10021 USA
[3] Cornell Univ, Weill Med Coll, New York, NY 10021 USA
[4] Hoffmann La Roche Inc, Nutley, NJ 07110 USA
关键词
D O I
10.1200/JCO.2004.12.007
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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/m(2)/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 3). 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/m(2)/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.
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收藏
页码:3366 / 3374
页数:9
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