Phase-I dose finding and pharmacokinetic study of the novel hydrophilic camptothecin ST-1968 (namitecan) in patients with solid tumors

M. Joerger, D. Hess, A. Delmonte, E. Gallerani, P. Barbieri, S. Pace, C. Sessa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. Methods: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3∈+∈3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non-hematological toxicity. Results: Thirty-four patients were included into the D1-D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8-Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. Conclusions: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen.

Original languageEnglish
Pages (from-to)472-479
Number of pages8
JournalInvestigational New Drugs
Volume33
Issue number2
DOIs
Publication statusPublished - Apr 1 2015

Fingerprint

Camptothecin
Pharmacokinetics
Neoplasms
Neutropenia
Febrile Neutropenia
Maximum Tolerated Dose
Cholangiocarcinoma
Endometrial Neoplasms
Thrombocytopenia
namitecan
Safety

Keywords

  • Antineoplastic agens
  • Camptothecan
  • Maximum tolerated dose
  • Namitecan
  • Neutropenia
  • Phase 1 clinical trial

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology
  • Medicine(all)

Cite this

Phase-I dose finding and pharmacokinetic study of the novel hydrophilic camptothecin ST-1968 (namitecan) in patients with solid tumors. / Joerger, M.; Hess, D.; Delmonte, A.; Gallerani, E.; Barbieri, P.; Pace, S.; Sessa, C.

In: Investigational New Drugs, Vol. 33, No. 2, 01.04.2015, p. 472-479.

Research output: Contribution to journalArticle

Joerger, M. ; Hess, D. ; Delmonte, A. ; Gallerani, E. ; Barbieri, P. ; Pace, S. ; Sessa, C. / Phase-I dose finding and pharmacokinetic study of the novel hydrophilic camptothecin ST-1968 (namitecan) in patients with solid tumors. In: Investigational New Drugs. 2015 ; Vol. 33, No. 2. pp. 472-479.
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AU - Hess, D.

AU - Delmonte, A.

AU - Gallerani, E.

AU - Barbieri, P.

AU - Pace, S.

AU - Sessa, C.

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AB - Purpose: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. Methods: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3∈+∈3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non-hematological toxicity. Results: Thirty-four patients were included into the D1-D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8-Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. Conclusions: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen.

KW - Antineoplastic agens

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KW - Namitecan

KW - Neutropenia

KW - Phase 1 clinical trial

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