Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors

Noboru Yamamoto, Tomohide Tamura, Yoshikazu Kamiya, Hiroyuki Ono, Hitoshi Kondoh, Kuniaki Shirao, Yasuhiro Matsumura, Yusuke Tanigawara, Yasuhiro Shimada

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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/m2. 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/m2. Severe fatigue was observed in one patient at a dose level of 21 mg/m2 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/m2 was withheld. The MTD was therefore determined as 21 mg/m2. 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.

Original languageEnglish
Pages (from-to)302-308
Number of pages7
JournalJapanese Journal of Clinical Oncology
Volume33
Issue number6
DOIs
Publication statusPublished - 2003 Jun 1

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Pharmacokinetics
Neoplasms
Fatigue
Maximum Tolerated Dose
Nausea
Vomiting
Protein Synthesis Inhibitors
Prothrombin Time
Interstitial Lung Diseases
septacidin
KRN 5500
Intravenous Infusions
Diarrhea
Lung
Proteins

Keywords

  • Fatigue
  • KRN5500
  • Phase I study
  • Protein synthesis inhibitor
  • Pulmonary toxicity

ASJC Scopus subject areas

  • Oncology

Cite this

Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors. / Yamamoto, Noboru; Tamura, Tomohide; Kamiya, Yoshikazu; Ono, Hiroyuki; Kondoh, Hitoshi; Shirao, Kuniaki; Matsumura, Yasuhiro; Tanigawara, Yusuke; Shimada, Yasuhiro.

In: Japanese Journal of Clinical Oncology, Vol. 33, No. 6, 01.06.2003, p. 302-308.

Research output: Contribution to journalArticle

Yamamoto, N, Tamura, T, Kamiya, Y, Ono, H, Kondoh, H, Shirao, K, Matsumura, Y, Tanigawara, Y & Shimada, Y 2003, 'Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors', Japanese Journal of Clinical Oncology, vol. 33, no. 6, pp. 302-308. https://doi.org/10.1093/jjco/hyg051
Yamamoto, Noboru ; Tamura, Tomohide ; Kamiya, Yoshikazu ; Ono, Hiroyuki ; Kondoh, Hitoshi ; Shirao, Kuniaki ; Matsumura, Yasuhiro ; Tanigawara, Yusuke ; Shimada, Yasuhiro. / Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors. In: Japanese Journal of Clinical Oncology. 2003 ; Vol. 33, No. 6. pp. 302-308.
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AU - Yamamoto, Noboru

AU - Tamura, Tomohide

AU - Kamiya, Yoshikazu

AU - Ono, Hiroyuki

AU - Kondoh, Hitoshi

AU - Shirao, Kuniaki

AU - Matsumura, Yasuhiro

AU - Tanigawara, Yusuke

AU - Shimada, Yasuhiro

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N2 - 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/m2. 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/m2. Severe fatigue was observed in one patient at a dose level of 21 mg/m2 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/m2 was withheld. The MTD was therefore determined as 21 mg/m2. 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.

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