Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer
Authors
Froeling, Fieke E. M.
Sarker, Debashis
Slater, Sarah
deSouza, Nandita M.
De Paepe, Katja N.
Hughes, Christine
Roberts, Rhiannon
Pawula, Maria
Houghton, Richard
Lawrence, Cheryl
Mousa, Kelly
Publication Date
2020-09-24Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
11
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
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Kocher, H. M., Basu, B., Froeling, F. E. M., Sarker, D., Slater, S., Carlin, D., deSouza, N. M., et al. (2020). Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. Nature Communications, 11 (1) https://doi.org/10.1038/s41467-020-18636-w
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.
Keywords
Article, /692/4020/1503/1712/1713, /692/308/2779/109/1940, /692/4028/67/1504/1713, article
Identifiers
s41467-020-18636-w, 18636
External DOI: https://doi.org/10.1038/s41467-020-18636-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/328485
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Licence:
http://creativecommons.org/licenses/by/4.0/
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