Phase I study of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine in patients with advanced malignancies.
| Autor: | Goldwasser, Francois, Faivre, Sandrine, Alexandre, Jerome, Coronado, Cinthya, Fernández-García, Eva, Kahatt, Carmen, Paramio, Pilar, Dios, Jorge, Miguel-Lillo, Bernardo, Raymond, Eric |
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| Předmět: |
ANTINEOPLASTIC agents
THERAPEUTIC use of antimetabolites CARBOPLATIN ACADEMIC medical centers BLOOD testing COMBINATION drug therapy CLINICAL trials DOSE-response relationship in biochemistry DRUG side effects MEDICAL cooperation MEDICAL protocols RESEARCH SAFETY TUMORS DATA analysis software DESCRIPTIVE statistics KAPLAN-Meier estimator PHARMACODYNAMICS INVESTIGATIONAL drugs THERAPEUTICS |
| Zdroj: | Investigational New Drugs; Jun2014, Vol. 32 Issue 3, p500-509, 10p |
| Abstrakt: | Objective To determine the maximum tolerated dose and the recommended dose (RD) for phase II trials of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine. Methods Open-label, dose-escalating, two-arm, uncontrolled, phase I study. Patients received carboplatin on Day (D) 1, followed by elisidepsin on D1 and D8, every 3 weeks, or gemcitabine on D1 and D15, followed by elisidepsin on D1 and D15, every 4 weeks. A pharmacokinetic analysis was done from blood samples collected during the first treatment infusion. Results Fifteen patients were treated with carboplatin/elisidepsin at doses from 4 AUC/1.0 mg flat dose (FD) to 5 AUC/2.5 mg FD. Two patients had dose-limiting toxicities (DLTs) at 5 AUC/2.0 mg, a dose delay >2 weeks due to grade-2 ALT increase and grade-3 thrombocytopenia, and a D8 infusion omission due to grade-3 ALT increase. The RD was established at 4 AUC/1.0 mg. Toxicity consisted mainly of mild-moderate anorexia, fatigue, and nausea. Twenty-two patients were treated with gemcitabine/elisidepsin at doses from 1,000 mg*m/1.0 mg FD to 1,250 mg*m/7.5 mg FD. Two patients had DLTs at 1,250 mg*m/7.5 mg, both a D15 dose omission due to grade-2 ALT increase. The RD was defined at 1,250 mg*m/5.0 mg. Toxicity consisted mainly of mild-moderate fatigue, pruritus, erythema, and myalgia. No objective response was observed. No relevant pharmacokinetic interaction was detected. Conclusion Infra-optimal doses of elisidepsin and carboplatin and a lack of antitumor activity despite using active drug concentrations in combination with gemcitabine do not warrant further clinical development for these two combinations. [ABSTRACT FROM AUTHOR] |
| Databáze: | Complementary Index |
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