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


Authors: Dupont, J.; Bienvenu, B.; Aghajanian, C.; Pezzulli, S.; Sabbatini, P.; Vongphrachanh, P.; Chang, C.; Perkell, C.; Ng, K.; Passe, S.; Breimer, L.; Zhi, J.; DeMario, M.; Spriggs, D.; Soignet, S. L.
Article Title: Phase I and pharmacokinetic study of the novel oral cell-cycle inhibitor Ro 31-7453 in patients with advanced solid tumors
Abstract: 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 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. © 2004 by American Society of Clinical Oncology.
Keywords: adult; cancer chemotherapy; clinical article; aged; aged, 80 and over; middle aged; unclassified drug; clinical trial; drug tolerability; fatigue; neutropenia; advanced cancer; diarrhea; drug safety; solid tumor; antineoplastic agents; antineoplastic agent; neoplasm; neoplasms; cell cycle; bone marrow suppression; nausea; stomatitis; thrombocytopenia; vomiting; cancer mortality; pancreas carcinoma; drug fatality; blood sampling; chemically induced disorder; breast carcinoma; ovary carcinoma; single drug dose; sepsis; lung carcinoma; drug metabolism; drug absorption; liver function test; maximum tolerated dose; phase 1 clinical trial; drug half life; urinalysis; drug metabolite; indoles; drug dose regimen; administration, oral; drug determination; alopecia; indole derivative; drug excretion; oral drug administration; observation; linear system; humans; human; male; female; priority journal; article; ro 317453; ro 31 7453; ro 31-7453
Journal Title: Journal of Clinical Oncology
Volume: 22
Issue: 16
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2004-08-15
Start Page: 3366
End Page: 3374
Language: English
DOI: 10.1200/jco.2004.12.007
PROVIDER: scopus
PUBMED: 15310782
DOI/URL:
Notes: J. Clin. Oncol. -- Cited By (since 1996):15 -- Export Date: 16 June 2014 -- CODEN: JCOND -- Source: Scopus
Altmetric Score
MSK Authors
  1. Kenneth K Ng
    36 Ng
  2. Steven L Soignet
    52 Soignet
  3. Jakob Dupont
    64 Dupont
  4. Paul J Sabbatini
    199 Sabbatini
  5. David R Spriggs
    309 Spriggs