Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours

JJEM (Jos) Kitzen, Maja de Jonge, Cor Lamers, Ferry Eskens, AJ (Diane) van der Biessen, L van Doorn, Judith Steeg, M Brandely, C Puozzo, Jaap Verweij

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Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappa B. Therefore, compounds that inhibit NF-kappa B stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide. (C) 2009 Elsevier Ltd. All fights reserved.
Original languageUndefined/Unknown
Pages (from-to)1764-1772
Number of pages9
JournalEuropean Journal of Cancer
Issue number10
Publication statusPublished - 2009

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