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

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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Hemant Kocher
Feb 26, 2020 All clinical data were collected on an in-house built Electronic Case Report Form (eCRF) designed using ORACLE v11.2.0. Sample size calculations were performed using the software package PASS version 12.0. Diffusion-weighted images were analyzed by a board-certified radiologist in OsiriX version 9.0 In the laboratory images were visualized using Zeiss Zen 2.3 software All clinical efficacy endpoints were analyzed using STATA version 13.1. Laboratory data were analyzed using PRISM (GraphPad Inc) version 8. Statistical tests are described as used.
'The data supporting this Article are available within the Article, Supplementary Information or available from the authors upon request.

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All coefficient of variation are produced for DW-MRI, pharmacokinetic and biomarker assays. All data were reproducible with low coefficient of variation. These are reported in respective sections. Briefly two board certified radiologist assessed DW-MRI images. Two laboratory scientists assessed immunoflourescene images with inter-day reproducibility using standards. PTX3 assays were replicated in duplicate with overalpping standard curves across assays conducted on different days.
Not applicable, as it was a phase I clinical trial. In this dose finding and expansion study, randomisation was not required but allocation to a dose level was done by a two-step adaptive Bayesian continual reassessment method .
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For staining of tissue sections: Organotypic sections, as previously described (Carapuca E et al, J Pathol 2016), were used for positive and negative staining controls. Controls were uniformly negative with appropriate isotype-specific immunoglobulin at matching dilutions. Antibody and staining scoring validation is described in Hughes et al Ann Diagno Pathol 2020.
For ELISA: Validated protocol is described in Latini, Circulation 2004.