Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors
Publication date
2009Author
Hochhauser, D.Meyer, T.
Spanswick, V.J.
Wu, J.
Clingen, P.H.
Loadman, Paul

Cobb, M.
Gumbrell, L.
Begent, R.H.
Hartley, J.A.
Jodrell, D.
Keyword
AdultAged
Antineoplastic agents: Therapeutic use
Benzodiazepinones
Adverse effects
Pharmacokinetics
DNA
Metabolism
Histones
Analysis
Humans
Maximum tolerated dose
Middle aged
Minor groove DNA binding agent
Neoplasms
Drug therapy
Phase I
Pyrroles
SJG 136
REF 2014
Open Access status
closedAccess
Metadata
Show full item recordAbstract
PURPOSE: 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.Version
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Hochhauser, 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.Link to Version of Record
https://doi.org/10.1158/1078-0432.CCR-08-1315Type
Articleae974a485f413a2113503eed53cd6c53
https://doi.org/10.1158/1078-0432.CCR-08-1315