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Title: | Phase i trial of CYT997, a novel cytotoxic and vascular-disrupting agent. | Authors: | Burge M.;Vasey P.A.;Coulthard A.;Smith G.;Griffin M.;Rose S.;Lickliter J.D.;Francesconi A.B.;Milne R.;McCarron J.;Yeadon T.;Wilks A.;Cubitt A.;Wyld D.K. | Institution: | (Lickliter, Francesconi, Burge, Cubitt, Wyld, Vasey) Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston 4029, QLD, Australia (Lickliter, McCarron, Yeadon) Leukaemia Foundation Laboratory, Queensland Institute of Medical Research, Herston 4029, QLD, Australia (Lickliter) Phase i Cancer Trials Program, Monash Medical Centre, Monash Institute of Medical Research, 27-31 Wright Street, Clayton 3168, VIC, Australia (Smith, Wilks) Cytopia Research Pty Ltd., Richmond 3121, VIC, Australia (Coulthard, Rose, Griffin) Centre for Magnetic Resonance, University of Queensland, St Lucia 4072, QLD, Australia (Milne) Sansom Institute, University of South Australia, Adelaide 5000, SA, Australia | Issue Date: | 12-Oct-2012 | Copyright year: | 2010 | Publisher: | Nature Publishing Group (Houndmills, Basingstoke, Hampshire RG21 6XS, United Kingdom) | Place of publication: | United Kingdom | Publication information: | British Journal of Cancer. 103 (5) (pp 597-606), 2010. Date of Publication: August 2010. | Abstract: | Background: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. Method(s): This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours. Result(s): Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m-2). Doses up to 202 mg m-2 were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m 2, consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour Ktrans values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of 65 mg m-2. Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for 2 cycles. Conclusion(s): CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours. © 2010 Cancer Research UK All rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1038/sj.bjc.6605841 | PubMed URL: | 20733579 [http://www.ncbi.nlm.nih.gov/pubmed/?term=20733579] | ISSN: | 0007-0920 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/31040 | Type: | Article | Subjects: | multiple cycle treatment nausea/si [Side Effect] neutropenia/si [Side Effect] phase 1 clinical trial priority journal proteinuria/si [Side Effect] QT prolongation/si [Side Effect] randomized controlled trial side effect/si [Side Effect] solid tumor/dt [Drug Therapy] *solid tumor/dt [Drug Therapy] thrombocytopenia/si [Side Effect] treatment response visual impairment/si [Side Effect] *antineoplastic agent/ct [Clinical Trial] *antineoplastic agent/dt [Drug Therapy] *antineoplastic agent/pk [Pharmacokinetics] *antineoplastic agent/pd [Pharmacology] caspase cytokeratin 18/ec [Endogenous Compound] unclassified drug von Willebrand factor/ec [Endogenous Compound] *cyt997/ae [Adverse Drug Reaction] *cyt997/ct [Clinical Trial] *cyt997/do [Drug Dose] *cyt997/dt [Drug Therapy] *cyt997/iv [Intravenous Drug Administration] *cyt997/pk [Pharmacokinetics] *cyt997/pd [Pharmacology] male abdominal pain/si [Side Effect] adult *advanced cancer aged anemia/si [Side Effect] area under the curve article clinical article clinical trial controlled clinical trial controlled study creatinine blood level cytotoxicity drug dose escalation drug half life drug mechanism drug metabolism drug safety drug tolerability dyspnea/si [Side Effect] female headache/si [Side Effect] human hypertension/si [Side Effect] hypoxia/si [Side Effect] lymphocytopenia/si [Side Effect] controlled study creatinine blood level cytotoxicity drug dose escalation drug half life drug mechanism drug metabolism drug safety drug tolerability dyspnea / side effect female headache / side effect human hypertension / side effect hypoxia / side effect lymphocytopenia / side effect male multiple cycle treatment nausea / side effect neutropenia / side effect phase 1 clinical trial priority journal proteinuria / side effect QT prolongation / side effect adult side effect / side effect solid tumor / drug therapy *solid tumor / *drug therapy thrombocytopenia / side effect treatment response visual impairment / side effect abdominal pain / side effect randomized controlled trial *advanced cancer aged anemia / side effect area under the curve article clinical article clinical trial controlled clinical trial |
Type of Clinical Study or Trial: | Randomised controlled trial |
Appears in Collections: | Articles |
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