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01.08.2008 | Original Article

A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors

verfasst von: Marwan G. Fakih, Lakshmi Pendyala, William Brady, Patrick F. Smith, Mary E. Ross, Patrick J. Creaven, Vladimir Badmaev, Joshua D. Prey, Youcef M. Rustum

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2008

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Abstract

Purpose

We conducted a phase I study to determine the recommended dose of selenomethionine (SLM) in combination with irinotecan that consistently results in a protective plasma selenium (Se) concentrations > 15 μM after 1 week of SLM loading.

Experimental Design

A 3-3 standard escalation design was followed. SLM was given orally twice daily (BID) for one week (loading) followed by continuous once daily (QD) dosing (maintenance). Seven dose levels of selenomethionine were investigated. Irinotecan was given intravenously at a fixed standard weekly dose, starting on the first day of maintenance SLM.

Results

Thirty-one patients were treated on study. Dose limiting diarrhea complicated by sepsis was noted in one of six patients at each of the dose-levels 1 and 7. Dose-levels ≥ 5 (4,800 mcg/dose loading maintenance) resulted in day 8 Se concentrations >15 μM while dose-level 7 (7,200 mcg/dose loading and maintenance) resulted in day 8 Se concentrations > 20 μM. No significant variations in SN-38 or biliary index were noted between weeks 1 and 4 of treatment. Despite achieving target Se concentrations, gastrointestinal and bone marrow toxicities were common and irinotecan dose modification was prevalent. Objective responses were seen in two patients and nine patients had disease control for 6 months or longer.

Conclusions

Selenomethionine can be escalated safely to 7,200 mcg BID × 1 week followed by 7,200 mcg QD in combination with a standard dose of irinotecan. No major protection against irinotecan toxicity was established; however, interesting clinical benefits were noted-supporting the investigation of this combination in future efficacy trials.

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Titel: A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors
verfasst von: Marwan G. Fakih
Lakshmi Pendyala
William Brady
Patrick F. Smith
Mary E. Ross
Patrick J. Creaven
Vladimir Badmaev
Joshua D. Prey
Youcef M. Rustum
Publikationsdatum: 01.08.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2008
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0631-4

Springer Medizin

A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors