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Chronic oral administration of CI-994: a phase 1 study
S Prakash1, B J Foster, M Meyer
1Karmanos Cancer Institute at Wayne State University School of Medicine, Department of Internal Medicine, USA.
Investigational New Drugs
|April 9, 2001
Summary
The maximum tolerated daily oral dose for CI-994 (N-acetyl dinaline) in solid tumor patients is 8 mg/m2/day for 8 weeks. This dose, with a 2-week break, is recommended for Phase 2 studies.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- CI-994 (N-acetyl dinaline) is an oral agent showing activity against various murine and human tumor xenografts.
- Its mechanism involves histone deacetylation inhibition and cytostatic effects on cell proliferation.
- This study aimed to establish the maximum tolerated dose (MTD) for chronic oral administration of CI-994.
Purpose of the Study:
- Determine the maximum tolerated daily oral dose (MTD) of CI-994 for chronic administration in patients with solid tumors.
- Establish a safe and effective dosing schedule for further clinical investigation.
Main Methods:
- A Phase 1 dose-escalation study was conducted in 53 patients with solid tumors.
- Two phases assessed MTD: a 2-week acute dosing phase and an 8-week chronic dosing phase.
- Pharmacokinetic studies evaluated the effect of food on drug absorption.
Main Results:
- Thrombocytopenia was the dose-limiting toxicity, establishing the MTD at 8 mg/m2/day for 8 weeks.
- Common toxicities included fatigue and gastrointestinal issues (nausea, vomiting, diarrhea, constipation, mucositis).
- One partial response (adenocarcinoma of the lung) and three instances of stable disease were observed.
Conclusions:
- The recommended Phase 2 starting dose for CI-994 is 8 mg/m2/day, administered for 8 weeks, followed by a 2-week drug-free interval.
- This dosing regimen is supported by toxicity and preliminary efficacy data.
- CI-994 demonstrates a manageable toxicity profile and potential clinical activity in solid tumors.