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dc.contributor.authorKocher, Hemant M.
dc.contributor.authorBasu, Bristi
dc.contributor.authorFroeling, Fieke E. M.
dc.contributor.authorSarker, Debashis
dc.contributor.authorSlater, Sarah
dc.contributor.authorCarlin, Dominic
dc.contributor.authordeSouza, Nandita M.
dc.contributor.authorDe Paepe, Katja N.
dc.contributor.authorGoulart, Michelle R.
dc.contributor.authorHughes, Christine
dc.contributor.authorImrali, Ahmet
dc.contributor.authorRoberts, Rhiannon
dc.contributor.authorPawula, Maria
dc.contributor.authorHoughton, Richard
dc.contributor.authorLawrence, Cheryl
dc.contributor.authorYogeswaran, Yathushan
dc.contributor.authorMousa, Kelly
dc.contributor.authorCoetzee, Carike
dc.contributor.authorSasieni, Peter
dc.contributor.authorPrendergast, Aaron
dc.contributor.authorPropper, David J.
dc.date.accessioned2021-09-24T15:32:24Z
dc.date.available2021-09-24T15:32:24Z
dc.date.issued2020-09-24
dc.date.submitted2020-07-06
dc.identifier.others41467-020-18636-w
dc.identifier.other18636
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/328485
dc.description.abstractAbstract: Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1–15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6–15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.
dc.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/692/4020/1503/1712/1713
dc.subject/692/308/2779/109/1940
dc.subject/692/4028/67/1504/1713
dc.subjectarticle
dc.titlePhase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer
dc.typeArticle
dc.date.updated2021-09-24T15:32:24Z
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.volume11
dc.identifier.doi10.17863/CAM.75933
dcterms.dateAccepted2020-09-02
rioxxterms.versionofrecord10.1038/s41467-020-18636-w
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidKocher, Hemant M. [0000-0001-6771-1905]
dc.contributor.orcidBasu, Bristi [0000-0002-3562-2868]
dc.contributor.orcidCarlin, Dominic [0000-0002-1783-412X]
dc.contributor.orcidGoulart, Michelle R. [0000-0001-8333-3908]
dc.contributor.orcidImrali, Ahmet [0000-0003-3661-9932]
dc.contributor.orcidYogeswaran, Yathushan [0000-0002-5220-9135]
dc.contributor.orcidCoetzee, Carike [0000-0002-4933-1279]
dc.contributor.orcidSasieni, Peter [0000-0003-1509-8744]
dc.contributor.orcidPrendergast, Aaron [0000-0002-9668-6689]
dc.contributor.orcidPropper, David J. [0000-0002-4274-5460]
dc.identifier.eissn2041-1723


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