Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer

Hemant M. Kocher (), Bristi Basu, Fieke E. M. Froeling, Debashis Sarker, Sarah Slater, Dominic Carlin, Nandita M. deSouza, Katja N. De Paepe, Michelle R. Goulart, Christine Hughes, Ahmet Imrali, Rhiannon Roberts, Maria Pawula, Richard Houghton, Cheryl Lawrence, Yathushan Yogeswaran, Kelly Mousa, Carike Coetzee, Peter Sasieni, Aaron Prendergast and David J. Propper
Additional contact information
Hemant M. Kocher: Queen Mary University London
Bristi Basu: University of Cambridge and Cambridge University Hospitals NHS Foundation Trust—Addenbrooke’s Hospital
Fieke E. M. Froeling: Imperial College London—Hammersmith Hospital
Debashis Sarker: Guy’s Hospital Campus
Sarah Slater: Barts Health NHS Trust
Dominic Carlin: The Institute of Cancer Research
Nandita M. deSouza: The Institute of Cancer Research
Katja N. De Paepe: The Institute of Cancer Research
Michelle R. Goulart: Queen Mary University London
Christine Hughes: Queen Mary University London
Ahmet Imrali: Queen Mary University London
Rhiannon Roberts: Queen Mary University London
Maria Pawula: Robinson Way
Richard Houghton: Robinson Way
Cheryl Lawrence: Queen Mary University of London
Yathushan Yogeswaran: Queen Mary University of London
Kelly Mousa: Queen Mary University of London
Carike Coetzee: Queen Mary University of London
Peter Sasieni: Queen Mary University of London
Aaron Prendergast: Queen Mary University of London
David J. Propper: Queen Mary University of London

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18636-w

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