Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.
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Embargo End Date
ICR Authors
Authors
Kocher, HM
Basu, B
Froeling, FEM
Sarker, D
Slater, S
Carlin, D
deSouza, NM
De Paepe, KN
Goulart, MR
Hughes, C
Imrali, A
Roberts, R
Pawula, M
Houghton, R
Lawrence, C
Yogeswaran, Y
Mousa, K
Coetzee, C
Sasieni, P
Prendergast, A
Propper, DJ
Basu, B
Froeling, FEM
Sarker, D
Slater, S
Carlin, D
deSouza, NM
De Paepe, KN
Goulart, MR
Hughes, C
Imrali, A
Roberts, R
Pawula, M
Houghton, R
Lawrence, C
Yogeswaran, Y
Mousa, K
Coetzee, C
Sasieni, P
Prendergast, A
Propper, DJ
Document Type
Journal Article
Date
2020-09-24
Date Accepted
2020-09-02
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.
Citation
Nature communications, 2020, 11 (1), pp. 4841 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Magnetic Resonance