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A phase II study of the IkB kinase inhibitor CHS 828 in patients with chronic lymphocytic leukemia
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-93820OAI: oai:DiVA.org:uu-93820DiVA: diva2:167420
Available from: 2005-11-24 Created: 2005-11-24Bibliographically approved
In thesis
1. Preclinical and Clinical Development of the Novel Cyanoguanidine CHS 828 for Cancer Treatment
Open this publication in new window or tab >>Preclinical and Clinical Development of the Novel Cyanoguanidine CHS 828 for Cancer Treatment
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

CHS 828 is a cyanoguanidine with anti-tumour properties which has shown promising effects in several preclinical models. This thesis describes both preclinical and clinical studies aiming to investigate disease specific activity, clinical tolerability and efficacy of CHS 828.

In paper I we investigated CHS 828 activity in a cell line panel with human myeloma cells, three of these cell-lines were also tested in vivo using a hollow fibre rat-model. In paper II we investigated CHS 828 activity in primary human tumour samples from patients. CHS 828 showed an effect on all tumour cell types tested both the primary human tumour samples and the myeloma cell lines. Notably, CHS 828 showed a high relative in vitro activity against tumour cells from chronic lymphocytic leukaemia and high-grade lymphoma.

In a phase I trial we determined the maximum tolerated dose (MTD) of CHS 828. Haematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Non-haematological toxicity was mostly of gastrointestinal origin. The recommended phase two dose (RPTD) of CHS 828 was estimated to be 20 mg once daily for five days in cycles of 28 days duration.

In a phase II trial we investigated the effect of CHS 828 on patients diagnosed with B-CLL. In total 12 patients were enrolled. CHS 828 was found to be well tolerated and the most common haematological toxicity was thrombocytopenia. Non-haematological toxicities were generally mild. Transient decreases in lymphocyte counts could be discerned coinciding with drug dosing, but no sustained clinical responses could be achieved.

In conclusion, CHS 828 demonstrated marked effects in the preclinical investigations suggesting haematological malignancies as the main target. The clinical phase I study established a safe dose and the subsequent phase II trial in B-CLL patients showed biological effect but with no clinical disease response.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 39 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 91
Clinical drug development, CHS 828, Cyanoguanidines, Oncology, Clinical Drug Development, Klinisk läkemedelsutveckling
National Category
Medicinal Chemistry
urn:nbn:se:uu:diva-6178 (URN)91-554-6414-9 (ISBN)
Public defence
2005-12-16, Rubecksalen, Rudbecklaboratoriet, Uppsala, 09:15
Available from: 2005-11-24 Created: 2005-11-24Bibliographically approved

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