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

Published on Sep 24, 2020in Nature Communications12.121
· DOI :10.1038/S41467-020-18636-W
Hemant M. Kocher41
Estimated H-index: 41
(QMUL: Queen Mary University of London),
Bristi Basu19
Estimated H-index: 19
(Cambridge University Hospitals NHS Foundation Trust)
+ 18 AuthorsDavid Propper27
Estimated H-index: 27
(QMUL: Queen Mary University of London)
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.
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Last. Hemant M. Kocher (QMUL: Queen Mary University of London)H-Index: 41
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Abstract Recently, stromal targeting, by agents such as All trans retinoic acid (ATRA), has been regarded as a promising avenue for the treatment of pancreatic ductal adenocarcinoma (PDAC). The intra-cellular transportation of ATRA to the nuclear receptors is performed by either: fatty acid binding protein 5 (FABP5) or cellular retinoic acid binding protein 2 (CRABP2), dictating the transcription of downstream genes and, thus, eventual cell phenotype. Here, we explored the levels of each protein...
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A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed...
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This is the peer reviewed version of the following article: Neuzillet, C., et al. (2019). "Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma." The Journal of Pathology 248(1): 51-65., which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
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All-trans retinoic acid (atRA) is a front-line treatment of acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atR...
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This work was supported by project grants from the Knowledge Transfer Network (Engineering and Physical Sciences Research Committee) and Pancreatic Cancer Research Fund (UK) to HMK. CF was supported by an EMBO long term fellowship and by a Marie Curie Intra8European Fellowship within the 7th European Community Framework Programme. TB and FR were supported by Cancer Research UK (grant C14303/A17197). Other grant funding includes project grants from Pancreatic Cancer Research Fund, Cancer Research...
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INTRODUCTION All-trans retinoic acid (ATRA, tretinoin) is the main drug used in the treatment of acute promyelocytic leukemia (APL). Despite its impressive activity against APL, the same could not be clinically observed in other types of cancer. Nanotechnology can be a tool to enhance ATRA anticancer efficacy and resolve its drawbacks in APL as well as in other malignancies. AREAS COVERED This review covers ATRA use in APL and non-APL cancers, the problems that were found in ATRA therapy and how...