Show simple item record

dc.contributor.authorKocher, HM
dc.contributor.authorBasu, B
dc.contributor.authorFroeling, FEM
dc.contributor.authorSarker, D
dc.contributor.authorSlater, S
dc.contributor.authorCarlin, D
dc.contributor.authordeSouza, NM
dc.contributor.authorDe Paepe, KN
dc.contributor.authorGoulart, MR
dc.contributor.authorHughes, C
dc.contributor.authorImrali, A
dc.contributor.authorRoberts, R
dc.contributor.authorPawula, M
dc.contributor.authorHoughton, R
dc.contributor.authorLawrence, C
dc.contributor.authorYogeswaran, Y
dc.contributor.authorMousa, K
dc.contributor.authorCoetzee, C
dc.contributor.authorSasieni, P
dc.contributor.authorPrendergast, A
dc.contributor.authorPropper, DJ
dc.date.accessioned2020-10-07T11:42:48Z
dc.date.issued2020-09-24
dc.identifier.citationNature communications, 2020, 11 (1), pp. 4841 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4128
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-020-18636-w
dc.description.abstractPre-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/m 2 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.formatElectronic
dc.format.extent4841 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectCarcinoma, Pancreatic Ductal
dc.subjectPancreatic Neoplasms
dc.subjectTretinoin
dc.subjectReceptors, Retinoic Acid
dc.subjectTreatment Outcome
dc.subjectMaximum Tolerated Dose
dc.subjectFatty Acid-Binding Proteins
dc.subjectBiomarkers, Tumor
dc.titlePhase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.
dc.typeJournal Article
dcterms.dateAccepted2020-09-02
rioxxterms.versionofrecord10.1038/s41467-020-18636-w
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-09-24
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
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/Magnetic Resonance
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/Magnetic Resonance
pubs.publication-statusPublished
pubs.volume11
pubs.embargo.termsNot known
icr.researchteamMagnetic Resonanceen_US
dc.contributor.icrauthordeSouza, Nanditaen


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0