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dc.contributor.authorCrabb, S
dc.contributor.authorDanson, SJ
dc.contributor.authorCatto, JWF
dc.contributor.authorMcDowell, C
dc.contributor.authorLowder, JN
dc.contributor.authorCaddy, J
dc.contributor.authorDunkley, D
dc.contributor.authorRajaram, J
dc.contributor.authorEllis, D
dc.contributor.authorHill, S
dc.contributor.authorHathorn, D
dc.contributor.authorWhitehead, A
dc.contributor.authorKalevras, M
dc.contributor.authorHuddart, R
dc.contributor.authorGriffiths, G
dc.date.accessioned2018-05-04T15:05:41Z
dc.date.issued2018-04-03
dc.identifier.citationTrials, 2018, 19 (1), pp. 216 - ?
dc.identifier.issn1745-6215
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1667
dc.identifier.eissn1745-6215
dc.identifier.doi10.1186/s13063-018-2586-7
dc.description.abstractBACKGROUND:Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer , Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. METHODS:The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1-5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. DISCUSSION:SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC. TRIAL REGISTRATION:EudraCT Number: 2015-004062-29 (entered Dec 7, 2015) ISRCTN registry number: 16332228 (registered on Feb 3, 2016).
dc.formatElectronic
dc.format.extent216 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectCisplatin
dc.subjectAzacitidine
dc.subjectDeoxycytidine
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectTreatment Outcome
dc.subjectChemotherapy, Adjuvant
dc.subjectNeoadjuvant Therapy
dc.subjectCystectomy
dc.subjectDrug Resistance, Neoplasm
dc.subjectTime Factors
dc.subjectUrinary Bladder Neoplasms
dc.subjectMulticenter Studies as Topic
dc.subjectRandomized Controlled Trials as Topic
dc.subjectClinical Trials, Phase I as Topic
dc.subjectClinical Trials, Phase II as Topic
dc.subjectUnited Kingdom
dc.titleSPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial.
dc.typeJournal Article
dcterms.dateAccepted2018-03-08
rioxxterms.versionofrecord10.1186/s13063-018-2586-7
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-04-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfTrials
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Clinical Academic Radiotherapy (Huddart)
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Clinical Academic Radiotherapy (Huddart)
pubs.publication-statusPublished
pubs.volume19
pubs.embargo.termsNot known
icr.researchteamClinical Academic Radiotherapy (Huddart)en_US
dc.contributor.icrauthorHuddart, Roberten


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