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, David J Propper, 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, David J Propper
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.
Conflict of interest statement
H.M.K. received research grant for conducting this trial (Celgene: institutional) and educational grant support for attending or organizing conferences (Celgene, Baxalta, Mylan, Medtronic, Oncosil: institutional) which are unrelated to this work. S.S. has consultancy with Eisai UK which have no direct relation to this work. B.B. has consulting role (Eisai Europe Limited, Roche, GenMab, Baxter Innovations, Celgene, Biocompatibles Ltd, Nordic Pharma SAS: all payments to institution), is on speaker’s bureau (Eisai Europe Limited), received research funding (Celgene: investigator initiated trial), and has educational grant support for attending conferences (Bayer, Celgene), all of which have no direct relation to this work. D.S. is on advisory boards for Eisai, Novartis, Ipsen, and Surface Oncology; speaker honoraria from Astra Zeneca, Eisai, M.S.D., and Bayer; travel sponsorship from Eisai, Ipsen, and MiNA Therapeutics, all of which have no direct relation to this work. The remaining authors declare no competing interests.
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