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

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Froeling, Fieke EM 
Sarker, Debashis 
Slater, Sarah 

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.

Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Fatty Acid-Binding Proteins, Humans, Maximum Tolerated Dose, Pancreatic Neoplasms, Receptors, Retinoic Acid, Treatment Outcome, Tretinoin
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Nat Commun
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Springer Science and Business Media LLC
RCUK | Medical Research Council (MRC) - MR/M015610/1 [Kocher] Celgene (Celgene Corporation) - AX-CL-Panc-PI-003922 [Kocher] Pancreatic Cancer Research Fund (PCRF) - Tissue Bank award [Kocher]