Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.
Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.
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DOI：
10.1038/s41467-020-18636-w
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发表时间：
2020-09-24
影响因子：
16.6
通讯作者：
Propper DJ
中科院分区：
文献类型：
--
作者：
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
临床前模型已经显示，用全反式维甲酸（ATRA）靶向胰腺星状细胞重新编程胰腺基质以抑制胰腺导管腺癌（PDAC）生长。在此，在一项针对晚期不可切除PDAC患者（n = 27）的Ib期、剂量递增和扩展试验中，使用两步适应性连续再评估方法试验设计，将ATRA重新用作与吉西他滨-nab-紫杉醇化疗组合的基质靶向剂。最大耐受剂量（MTD）和推荐的2期剂量（RP 2D，主要结局）是FDA/EMEA批准的吉西他滨-nab-紫杉醇联合ATRA的剂量（45 mg/m2口服，第1-15天/周期）。剂量限制性毒性（DLT）为4级血小板减少症（n = 2）。次要结局显示对ATRA药代动力学无损害。RP 2D治疗的可评价人群的中位总生存期为11.7个月（95%CI 8.6-15.7 m，n = 15，局部晚期（2）和转移性（13））。探索性药效学研究，包括一个周期后弥散加权（DW）-MRI测量的表观弥散系数的变化，以及不同周期内周期特异性血清正五聚蛋白3水平的调节表明基质调节。基线基质特异性类维生素A转运蛋白（FABP 5，CRABP 2）表达可能是反应的预测。将ATRA重新用作吉西他滨-nab-紫杉醇的基质靶向药物是安全和可耐受的。将在一项针对局部晚期PDAC的II期随机对照试验中评价该联合用药。临床试验编号：EudraCT：2015-002662-23; NCT 03307148。试验缩写：STARPAC。已知全反式维甲酸（ATRA）可重新调节小鼠胰腺癌间质。在这里，作者在胰腺癌患者中进行了一项Ib期试验，表明ATRA联合化疗是晚期胰腺癌患者的一种安全的潜在治疗方法，并证明了基质调节作用。
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. All-trans retinoic acid - ATRA- is known to remodulate the stroma of pancreatic cancer in mice. Here, the authors carried out a Phase Ib trial in pancreatic patients and show that ATRA in combination with chemotherapy is a safe potential treatment for patients with advanced pancreatic cancer, and demonstrate a stromal modulatory effect.
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影响因子：
29.4
作者：
Froeling, Fieke E. M.;Feig, Christine;Kocher, Hemant M.
通讯作者：
Kocher, Hemant M.
影响因子：
4.6
作者：
Huang X;Gao Y;Zhi X;Ta N;Jiang H;Zheng J
通讯作者：
Zheng J
DOI：
10.1016/j.pan.2016.05.393
发表时间：
2016-11
期刊：
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
影响因子：
--
作者：
Di Maggio F;Arumugam P;Delvecchio FR;Batista S;Lechertier T;Hodivala-Dilke K;Kocher HM
通讯作者：
Kocher HM
DOI：
10.1158/1078-0432.ccr-11-2165
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gupta S;Pramanik D;Mukherjee R;Campbell NR;Elumalai S;de Wilde RF;Hong SM;Goggins MG;De Jesus-Acosta A;Laheru D;Maitra A
通讯作者：
Maitra A
影响因子：
2
作者：
Hughes, Christine S.;Chinaleong, Jo-Anne;Kocher, Hemant M.
通讯作者：
Kocher, Hemant M.