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

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.

Conflict of interest statement

H.M.K. received research grant for conducting this trial (Celgene: institutional) and educational grant support for attending or organizing conferences (Celgene, Baxalta, Mylan, Medtronic, Oncosil: institutional) which are unrelated to this work. S.S. has consultancy with Eisai UK which have no direct relation to this work. B.B. has consulting role (Eisai Europe Limited, Roche, GenMab, Baxter Innovations, Celgene, Biocompatibles Ltd, Nordic Pharma SAS: all payments to institution), is on speaker’s bureau (Eisai Europe Limited), received research funding (Celgene: investigator initiated trial), and has educational grant support for attending conferences (Bayer, Celgene), all of which have no direct relation to this work. D.S. is on advisory boards for Eisai, Novartis, Ipsen, and Surface Oncology; speaker honoraria from Astra Zeneca, Eisai, M.S.D., and Bayer; travel sponsorship from Eisai, Ipsen, and MiNA Therapeutics, all of which have no direct relation to this work. The remaining authors declare no competing interests.

Figures

Fig. 1. CONSORT diagram for STARPAC clinical trial.

Number of patients at all dose levels (DL) in dose escalation, part 1 (using the STARPAC adaptive trial design) for maximum tolerated dose (MTD) estimation, showing dose-limiting toxicity (DLT) and dose expansion (part 2) of the trial for optimal biological dose (OBD) estimation leading to recommended phase 2 dose (RP2D).

Fig. 2. Primary and secondary endpoints for STARPAC clinical trial.

a Swimmer’s plot with color code for different dose levels (DL) and duration (months) on X-axis along with type of disease: locally advanced (LA) and metastatic (M), those who experienced DLT (*) and disease status (Death (D), progressive disease (PD)) censored at the pre-specified 12 months of starting on the trial. b Waterfall plot of best percentage change of sum of diameters in target lesion from baseline in RP2D treated patients based on an evaluable population. A positive change denotes an increase in the target lesion sum of diameters over time and, likewise, a negative change denotes a decrease in the target lesion sum of diameters over time. Reference lines added for response (−30% change in target lesion sum of diameters) and progression (20% change in target lesion sum of diameters). RECIST responses are marked with asterisk (*). There was progression for 6.7% (95% CI: 0.2–31.9%) and response in 46.7% (95% CI: 21.3–73.4%) of patients. c Post hoc (including data from beyond 12 months) estimated median overall survival in 15 patients receiving RP2D on evaluable population basis. Number of events = 13. Kaplan–Meier plot.

Fig. 3. ATRA pharmacokinetics, biochemical CA19-9 response and vitamin A levels.

a Serum ATRA levels for the first three cycles are summarized as mean (SEM) for the first 5 h after co-administration of ATRA at 45 mg/m2 with chemotherapy drugs. b Absolute CA19-9 levels on logarithmic Y-axis for patients on dose level 5 at start of each cycle. Summary statistics represented by box (median ± interquartile range) and whisker (range: LQR−(1.5 × IQR) and UQR + (1.5 × IQR)). Two-sided Skilling–Mack test, statistic 39.21, p < 0.001. c Normalized CA19-9 levels for each patient on dose level 5 with baseline being 100%. There were 14 biochemical responders (black) compared to 5 non-responders (unique colors). Responders are defined as those who show >30% reduction of CA19-9 from baseline with a sustained response (no greater than 20% rise from previous reading at any time). d Vitamin A on dose level 5 at start of each cycle. Summary statistics represented by box (median ± interquartile range) and whisker (range: LQR−(1.5 × IQR) and UQR + (1.5 × IQR)). Two-sided Skilling–Mack test, statistic 5.95, p = 0.31. e Individual values for vitamin A for patients with biochemical non-responders (CA19-9) highlighted in corresponding colors as in panel c. f Linear regression trend lines comparing biochemical responders (solid line) to non-responders (dashed line) demonstrate that a drop in serum vitamin A levels may indicate non-responders. N = X R: X is the number of responders at the stated cycle. N = X NR: X is the number of non-responders at the stated cycle.

Fig. 4. Biomarkers for STARPAC clinical trial.

a MRI sequences as indicated with primary pancreatic tumor (red arrow) and liver metastasis (white arrow) in T2-weighted images for localization, both lesions demonstrating change in the apparent diffusion coefficient (ADC) within these tumors, after just 1 month of treatment, indicative of an increased mobile water content due to reduction in dense cellularity with a rim of peripheral restricted tissue represents residual tumor. Summary statistics of changes in tumor volume (b), ADC values (c), and D values (d) between pre-treatment (baseline) and post-first-cycle (days 21–28) of treatment. Summary data as mean ± SEM. Data points represent values from individual patients. Two-tailed Wilcoxon matched-pairs sign-rank test. e Representative images of co-immuno-fluorescent images of pancreatic cancer biopsies prior to commencement of treatment, to assess prevalence of cellular retinoic acid-binding protein 2 (CRABP2) and fatty acid-binding protein 5 (FABP5), as indicated with co-staining with either cytokeratin (CK) or alpha-smooth muscle actin (αSMA) respectively, to demonstrate a 3+ stain for both CRABP2 and FABP5 in cancer cells and cancer-associated fibroblasts (CAF). Scale bar: 100 µm. f, g These quantifications (range 0 to 3+) were then assessed for all evaluable biopsies (n = 15) from single representative image using appropriate tissue controls and categorized according to disease control/progressive disease. Chi-square test. d.f. = 3. h Measurement of serum PTX3 by ELISA (GCLP standards, CV 0.17) in patients before (Base) and 5  h after (Post) taking ATRA in the first cycle (C1) on days 1, 8, and 15. i Measurement of serum PTX3 5 h after taking ATRA on the first day of each cycle (1–6). Each point represents an individual patient. h, i Box (median ± interquartile range) and whisker (full range). Individual measurements per patient represented as a dot derived from mean of two readings. Two-tailed Wilcoxon matched-pairs signed-rank test.