Centre for Tumour Biology, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK.
Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK.
Nat Commun. 2020 Sep 24;11(1):4841. doi: 10.1038/s41467-020-18636-w.
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/m 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.
临床前模型表明，用全反式维甲酸（ATRA）靶向胰腺星状细胞可重编程胰腺基质，抑制胰腺导管腺癌（PDAC）生长。在此，在一项针对晚期不可切除 PDAC 患者（n=27）的 I 期、剂量递增和扩展试验中，ATRA 被重新用作基质靶向剂，与吉西他滨-纳布紫杉醇化疗联合使用，采用两步自适应连续再评估方法试验设计。最大耐受剂量（MTD）和推荐的 II 期剂量（RP2D，主要终点）是 FDA/EMA 批准的吉西他滨-纳布紫杉醇联合 ATRA 的剂量（45mg/m 口服，每天 1-15/周期）。剂量限制毒性（DLT）是 4 级血小板减少症（n=2）。次要终点显示 ATRA 药代动力学无损害。RP2D 治疗可评估人群的中位总生存期为 11.7 个月（95%CI 8.6-15.7m，n=15，局部晚期 2 例，转移性 13 例）。探索性药效学研究包括一个周期后扩散加权（DW）-MRI 测量的表观扩散系数的变化，以及各周期中循环特异性 pentraxin 3 水平的调节，表明基质调节。基线基质特异性视黄醇转运蛋白（FABP5、CRABP2）表达可能与反应有关。将 ATRA 重新用作吉西他滨-纳布紫杉醇的基质靶向剂是安全且可耐受的。这种联合治疗将在局部晚期 PDAC 的 II 期随机对照试验中进行评估。临床试验编号：EudraCT：2015-002662-23；NCT03307148。试验缩写：STARPAC。
