Show simple item record

dc.contributor.authorHochhauser, D.*
dc.contributor.authorMeyer, T.*
dc.contributor.authorSpanswick, V.J.*
dc.contributor.authorWu, J.*
dc.contributor.authorClingen, P.H.*
dc.contributor.authorLoadman, Paul M.*
dc.contributor.authorCobb, M.*
dc.contributor.authorGumbrell, L.*
dc.contributor.authorBegent, R.H.*
dc.contributor.authorHartley, J.A.*
dc.contributor.authorJodrell, D.*
dc.date.accessioned2014-04-28T10:46:34Z
dc.date.available2014-04-28T10:46:34Z
dc.date.issued2009
dc.identifier.citationHochhauser, D., Meyer, T., Spanswick, V. J., Wu, J., Clingen, P. H., Loadman, P., Cobb, M., Gumbrell, L., Begent, R. H., Hartley, J. A., Jodrell, D. (2009) Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. Clinical Cancer Research, 15(6), 2140-2147.
dc.identifier.urihttp://hdl.handle.net/10454/6020
dc.description.abstractPURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.
dc.relation.isreferencedbyhttp://dx.doi.org/10.1158/1078-0432.CCR-08-1315
dc.subjectAdult;
dc.subjectAged;
dc.subjectAntineoplastic agents: Therapeutic use;
dc.subjectBenzodiazepinones; Adverse effects; Pharmacokinetics;
dc.subjectDNA; Metabolism;
dc.subjectHistones; Analysis;
dc.subjectHumans;
dc.subjectMaximum tolerated dose;
dc.subjectMiddle aged; Minor groove DNA binding agent;
dc.subjectNeoplasms; Drug therapy;
dc.subjectPhase I; Pyrroles; SJG 136;
dc.subjectREF 2014
dc.titlePhase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors
dc.typeArticle


This item appears in the following Collection(s)

Show simple item record