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dc.contributor.authorCrabb, SJ
dc.contributor.authorDanson, S
dc.contributor.authorCatto, JWF
dc.contributor.authorHussain, S
dc.contributor.authorChan, D
dc.contributor.authorDunkley, D
dc.contributor.authorDowns, N
dc.contributor.authorMarwood, E
dc.contributor.authorDay, L
dc.contributor.authorSaunders, G
dc.contributor.authorLight, M
dc.contributor.authorWhitehead, A
dc.contributor.authorEllis, D
dc.contributor.authorSarwar, N
dc.contributor.authorEnting, D
dc.contributor.authorBirtle, A
dc.contributor.authorJohnson, B
dc.contributor.authorHuddart, R
dc.contributor.authorGriffiths, G
dc.date.accessioned2021-03-02T11:33:18Z
dc.date.available2021-03-02T11:33:18Z
dc.date.issued2021-04-01
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2021
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4383
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-20-3946
dc.description.abstractPURPOSE: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers. PATIENT AND METHODS: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2-4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1-5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228. RESULTS: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1-5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred. CONCLUSIONS: The guadecitabine RP2D was 20 mg/m2, days 1-5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titlePhase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE).
dc.typeJournal Article
dcterms.dateAccepted2021-01-15
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/1078-0432.ccr-20-3946
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-01-20
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
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.embargo.termsNot known
icr.researchteamClinical Academic Radiotherapy (Huddart)
icr.researchteamClinical Academic Radiotherapy (Huddart)
dc.contributor.icrauthorHuddart, Robert


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