A phase I clinical and pharmacokinetic study of Ro 31-7453 given as a 7- or 14-day oral twice daily schedule every 4 weeks in patients with solid tumors.
OBJECTIVE
This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models.


METHODS
Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively.


RESULTS
Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40-77 years), and median Karnofsky performance status was 80 (range, 60-100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m(2) twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m(2) bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1-7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m(2) bid and 125 mg/m(2) bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t(1/2) of approximately 9 h and a t(max) of approximately 4 h. One patient with pretreated lung cancer had a partial response.


CONCLUSIONS
Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m(2) bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.
Salazar
Ramon
R
Cancer Research UK, Department of Medical Oncology, Beatson Laboratories, University of Glasgow, United Kingdom.
Bissett
Donald
D
Twelves
Chris
C
Breimer
Lars
L
DeMario
Mark
M
Campbell
Sophia
S
Zhi
Jay
J
Ritland
Steve
S
Cassidy
Jim
J
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002277:Carcinoma / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors
D000970:Antineoplastic Agents; D007211:Indoles; D004492:Edetic Acid; C488881:1H-pyrrole-2,5-dione, 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-