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  CHS-828

Description of CHS-828: CHS-828 is a synthetic guanidine-based small anticancer molecule. CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells.  In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors. Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity. CHS 828 was found to compare favorably with established chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped. CHS 828 is an effective new antitumor agent, with a potentially new mechanism of action. CHS-828 appeared to kill cancer cells by depleting NAD. CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer.

Current developer: Leo Pharmaceutical Products, Ballerup, Denmark.

Review of Phase I trials of CHS-828. Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials. Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low. (source: Cancer Chemother Pharmacol. 2010 May;65(6):1165-72).

Phase I study of CHS-828. CHS 828 was given orally once every 3 weeks. The starting dose was 50 mg, which was escalated to 500 mg. A total of 107 courses was administered to 37 patients. At the 500-mg dose level, two of three patients experienced dose-limiting toxicities (DLT) (grade 3 mucositis and grade 4 thrombocytopenia), establishing this as the MTD. One of seven patients treated at 420 mg dose experienced DLT (grade 4 leucopenia, grade 4 mucositis and grade 4 diarrhoea), and this was considered the recommended dose for phase II studies. Vomiting, haematuria, leucopenia and thrombocytopenia were other significant toxicities. The pharmacokinetics of CHS 828 showed large variations both between and within patients. No objective responses were seen. A dose of 420 mg of CHS 828 administered every 3 weeks is the recommended dose, while 500 mg is the MTD. (source: Eur J Cancer. 2005 Mar;41(5):702-7.).

1: von Heideman A, Berglund A, Larsson R, Nygren P. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother Pharmacol. 2010 May;65(6):1165-72. doi: 10.1007/s00280-009-1125-3. Epub 2009 Sep 30. PubMed PMID: 19789873.

2: Lövborg H, Burman R, Gullbo J. Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug. BMC Res Notes. 2009 Jun 29;2:114. doi: 10.1186/1756-0500-2-114. PubMed PMID: 19563661; PubMed Central PMCID: PMC2709656.

3: Olesen UH, Christensen MK, Björkling F, Jäättelä M, Jensen PB, Sehested M, Nielsen SJ. Anticancer agent CHS-828 inhibits cellular synthesis of NAD. Biochem Biophys Res Commun. 2008 Mar 21;367(4):799-804. doi: 10.1016/j.bbrc.2008.01.019. Epub 2008 Jan 15. PubMed PMID: 18201551.

4: Hassan SB, Lövborg H, Lindhagen E, Karlsson MO, Larsson R. CHS 828 kill tumour cells by inhibiting the nuclear factor-kappaB translocation but unlikely through down-regulation of proteasome. Anticancer Res. 2006 Nov-Dec;26(6B):4431-6. PubMed PMID: 17201165.

5: Johanson V, Arvidsson Y, Kölby L, Bernhardt P, Swärd C, Nilsson O, Ahlman H. Antitumoural effects of the pyridyl cyanoguanidine CHS 828 on three different types of neuroendocrine tumours xenografted to nude mice. Neuroendocrinology. 2005;82(3-4):171-6. Epub 2006 Feb 24. PubMed PMID: 16508338.

6: Friberg LE, Hassan SB, Lindhagen E, Larsson R, Karlsson MO. Pharmacokinetic-pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model. Eur J Pharm Sci. 2005 May;25(1):163-73. PubMed PMID: 15854812.

7: Ravaud A, Cerny T, Terret C, Wanders J, Bui BN, Hess D, Droz JP, Fumoleau P, Twelves C. Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3 weeks in solid tumours: an ECSG/EORTC study. Eur J Cancer. 2005 Mar;41(5):702-7. PubMed PMID: 15763645.

8: Olsen LS, Hjarnaa PJ, Latini S, Holm PK, Larsson R, Bramm E, Binderup L, Madsen MW. Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity. Int J Cancer. 2004 Aug 20;111(2):198-205. PubMed PMID: 15197771.

9: Lövborg H, Nygren P, Larsson R. Multiparametric evaluation of apoptosis: effects of standard cytotoxic agents and the cyanoguanidine CHS 828. Mol Cancer Ther. 2004 May;3(5):521-6. PubMed PMID: 15141009.