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Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors
Noboru Yamamoto1, Tomohide Tamura, Yoshikazu Kamiya
1Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
Background:
KRN5500, a novel spicamycin derivative, shows an inhibitory effect on protein synthesis. This phase I study was aimed at investigating the toxicity, maximum tolerated dose (MTD) and pharmacokinetics of this compound.
Patients And Methods:
Patients with solid tumors not amenable to standard forms of treatment were eligible. KRN5500 was administered as a 2 h intravenous infusion every 4 weeks at doses of 3, 6, 10, 15 and 21 mg/m(2). Pharmacokinetic evaluation was performed at the first cycle.
Results:
Eighteen patients with advanced solid tumors were enrolled. A total of 26 cycles of KRN5500 were administered. The major toxicities were nausea, vomiting, diarrhea, fatigue and a mild reversible prolongation of prothrombin time. Grade 4 pulmonary toxicity (interstitial pneumonitis) was observed in one patient at a dose level of 15 mg/m(2). Severe fatigue was observed in one patient at a dose level of 21 mg/m(2) and the duration of fatigue tended to increase with the dose of KRN5500. Nausea and vomiting were frequently observed and became prolonged with increasing dose of KRN5500. These toxicity profiles were identified as unacceptable and further dose escalation above 21 mg/m(2) was withheld. The MTD was therefore determined as 21 mg/m(2). The peak plasma concentration and the area under the concentration-time curve of KRN5500 increased proportionally to the dose, suggesting linear pharmacokinetics. No objective antitumor response was observed.
Conclusion:
KRN5500, a structurally novel protein synthesis inhibitor, warrants further investigation to overcome these toxicity profiles and improve its efficacy.
Insights
KRN5500, a novel protein synthesis inhibitor, showed dose-limiting toxicities including pulmonary toxicity and severe fatigue in a phase I trial. The maximum tolerated dose (MTD) was determined as 21 mg/m(2).
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- KRN5500, a novel spicamycin derivative, exhibits protein synthesis inhibitory effects.
- This phase I study aimed to evaluate the safety and pharmacokinetics of KRN5500.
Purpose of the Study:
- Determine the toxicity profile of KRN5500.
- Establish the maximum tolerated dose (MTD) of KRN5500.
- Characterize the pharmacokinetic properties of KRN5500.
Main Methods:
- Patients with advanced solid tumors received KRN5500 intravenously every 4 weeks.
- Dose escalation ranged from 3 to 21 mg/m(2).
- Pharmacokinetic assessments were conducted during the first cycle.
Main Results:
- Eighteen patients were enrolled, receiving a total of 26 cycles.
- Major toxicities included nausea, vomiting, diarrhea, fatigue, and mild prothrombin time prolongation.
- Grade 4 pulmonary toxicity and severe fatigue were observed, leading to the MTD determination of 21 mg/m(2).
- Linear pharmacokinetics were observed, but no objective antitumor response was noted.
Conclusions:
- KRN5500 demonstrates a novel mechanism as a protein synthesis inhibitor.
- Further investigation is needed to address toxicity and enhance the efficacy of KRN5500.