| Title: |
Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. |
| Authors: |
Kocher, Hemant M; Basu, Bristi; Froeling, Fieke EM; Sarker, Debashis; Slater, Sarah; Carlin, Dominic; deSouza, Nandita M; De Paepe, Katja N; Goulart, Michelle R; Hughes, Christine; Imrali, Ahmet; Roberts, Rhiannon; Pawula, Maria; Houghton, Richard; Lawrence, Cheryl; Yogeswaran, Yathushan; Mousa, Kelly; Coetzee, Carike; Sasieni, Peter; Prendergast, Aaron; Propper, David J |
| Publisher Information: |
Springer Nature; //doi.org/10.1038/s41467-020-18636-w |
| Publication Year: |
2020 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Biomarkers; Tumor; Carcinoma; Pancreatic Ductal; Fatty Acid-Binding Proteins; Humans; Maximum Tolerated Dose; Pancreatic Neoplasms; Receptors; Retinoic Acid; Treatment Outcome; Tretinoin |
| Description: |
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. ; 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] |
| Document Type: |
article in journal/newspaper |
| File Description: |
Electronic; application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/310754 |
| DOI: |
10.17863/CAM.57843 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/310754; https://doi.org/10.17863/CAM.57843 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.990CB600 |
| Database: |
BASE |