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Multiple resistance modulators combined with carboplatin for resistant malignancies: a pilot study
D J Stewart1, R Goel, M C Cripps
1Ontario Cancer Treatment and Research Foundation, University of Ottawa, Faculty of Medicine, Canada.
Investigational New Drugs
|January 1, 1997
Summary
Adding resistance modulators to carboplatin showed minimal toxicity at lower doses, with acceptable regimens for phase II studies in resistant cancers. Further research is needed to optimize combination therapy for improved patient outcomes.
Area of Science:
- Oncology
- Pharmacology
Background:
- Chemotherapy resistance in cancers is a complex issue.
- Investigated the feasibility of combining carboplatin with six resistance modulators in 53 patients with resistant cancers.
Purpose of the Study:
- To assess the safety and tolerability of adding multiple resistance modulators to carboplatin therapy.
- To determine acceptable doses for phase II studies of this combination regimen.
Main Methods:
- A dose-escalation study was conducted, adding resistance modulators sequentially to carboplatin.
- Modulators included pentoxifylline, dipyridamole, metronidazole, mannitol, saline, novobiocin, tamoxifen, and ketoconazole.
- Carboplatin doses were adjusted based on observed toxicity, ranging from 200 to 400 mg/m2.
Main Results:
- Excessive thrombocytopenia occurred at higher carboplatin doses (400 mg/m2).
- Toxicity was generally tolerable and reversible at carboplatin doses ≤300 mg/m2.
- Gastrointestinal and neurological toxicities increased with additional modulators; four minor responses were observed.
Conclusions:
- Recommended phase II doses include carboplatin 300 mg/m2 with specific doses and schedules for mannitol, saline, pentoxifylline, dipyridamole, metronidazole, novobiocin, tamoxifen, and ketoconazole.
- Supportive care with dexamethasone and ondansetron is advised.
- The combination shows potential for further investigation in resistant cancers.