dc.contributor.author | Kocher, HM | |
dc.contributor.author | Basu, B | |
dc.contributor.author | Froeling, FEM | |
dc.contributor.author | Sarker, D | |
dc.contributor.author | Slater, S | |
dc.contributor.author | Carlin, D | |
dc.contributor.author | deSouza, NM | |
dc.contributor.author | De Paepe, KN | |
dc.contributor.author | Goulart, MR | |
dc.contributor.author | Hughes, C | |
dc.contributor.author | Imrali, A | |
dc.contributor.author | Roberts, R | |
dc.contributor.author | Pawula, M | |
dc.contributor.author | Houghton, R | |
dc.contributor.author | Lawrence, C | |
dc.contributor.author | Yogeswaran, Y | |
dc.contributor.author | Mousa, K | |
dc.contributor.author | Coetzee, C | |
dc.contributor.author | Sasieni, P | |
dc.contributor.author | Prendergast, A | |
dc.contributor.author | Propper, DJ | |
dc.date.accessioned | 2020-10-07T11:42:48Z | |
dc.date.issued | 2020-09-24 | |
dc.identifier.citation | Nature communications, 2020, 11 (1), pp. 4841 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4128 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-020-18636-w | |
dc.description.abstract | 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.format | Electronic | |
dc.format.extent | 4841 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Carcinoma, Pancreatic Ductal | |
dc.subject | Pancreatic Neoplasms | |
dc.subject | Tretinoin | |
dc.subject | Receptors, Retinoic Acid | |
dc.subject | Treatment Outcome | |
dc.subject | Maximum Tolerated Dose | |
dc.subject | Fatty Acid-Binding Proteins | |
dc.subject | Biomarkers, Tumor | |
dc.title | Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-09-02 | |
rioxxterms.versionofrecord | 10.1038/s41467-020-18636-w | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-09-24 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature communications | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 11 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Magnetic Resonance | |
dc.contributor.icrauthor | deSouza, Nandita | |