Stemmer Salomon M, Benjaminov Ofer, Silverman Michael H, Sandler Uziel, Purim Ofer, Sender Naomi, Meir Chen, Oren-Apoteker Pnina, Ohana Joel, Devary Yoram
Davidoff Center, Rabin Medical Center, Institute of Oncology, Petah Tikva 49414, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Mol Clin Oncol. 2018 Jan;8(1):22-29. doi: 10.3892/mco.2017.1505. Epub 2017 Nov 15.
The aim of the present phase I first-in-human study was to investigate the safety/efficacy of dTCApFs (a novel hormone peptide that enters cells through the T1/ST2 receptor), in advanced/metastatic solid tumors. The primary objective of this open-label dose-escalation study was to determine the safety profile of dTCApFs. The study enrolled patients (aged ≥18 years) with pathologically confirmed locally advanced/metastatic solid malignancies, who experienced treatment failure or were unable to tolerate previous standard therapy. The study included 17 patients (64% male; median age, 65 years; 47% colorectal cancer, 29% pancreatic cancer). The patients received 1-3 cycles of escalating dTCApFs doses (6-96 mg/m). The mean number ± standard deviation of treatment cycles/patient was 3.2±1.4; no dose-limiting toxicities were observed up to a dose of 96 mg/m, and the maximum tolerated dose was not reached. Half-life, maximal plasma concentration, and dTCApFs exposure were found to be linearly correlated with dose. Five patients were treated for ≥3 months (12, 24, 48 mg/m) and experienced stable disease throughout the treatment period, and 1 experienced pathological complete response. Analysis of serum biomarkers revealed decreased levels of angiogenic factors at dTCApFs concentrations of 12-48 mg/m, increased levels of anticancer cytokines, and induction of the endoplasmic reticulum (ER) stress biomarker GRP78/BiP. Efficacy and biomarker data suggest that patients whose tumors were T1/ST2-positive exhibited a better response to dTCApFs. In conclusion, dTCApFs was found to be safe/well-tolerated, and potentially efficacious, with linear pharmacokinetics. Consistent with preclinical studies, the mechanism through which dTCApFs exerts anticancer effects appears to involve induction of ER stress, suppression of angiogenesis, and activation of the innate immune response. However, further studies are warranted.
本I期首次人体研究的目的是调查新型激素肽dTCApFs（一种通过T1/ST2受体进入细胞的激素肽）在晚期/转移性实体瘤中的安全性/有效性。这项开放标签剂量递增研究的主要目的是确定dTCApFs的安全性。该研究纳入了年龄≥18岁、经病理证实为局部晚期/转移性实体恶性肿瘤、经历过治疗失败或无法耐受先前标准治疗的患者。该研究包括17名患者（64%为男性；中位年龄65岁；47%为结直肠癌，29%为胰腺癌）。患者接受了1 - 3个周期递增剂量的dTCApFs（6 - 96 mg/m²）治疗。每位患者治疗周期的平均数±标准差为3.2±1.4；在剂量达到96 mg/m²之前未观察到剂量限制性毒性，且未达到最大耐受剂量。发现半衰期、最大血浆浓度和dTCApFs暴露量与剂量呈线性相关。5名患者接受了≥3个月（12、24、48 mg/m²）的治疗，在整个治疗期间病情稳定，1名患者出现病理完全缓解。血清生物标志物分析显示，在dTCApFs浓度为12 - 48 mg/m²时，血管生成因子水平降低，抗癌细胞因子水平升高，并且诱导了内质网（ER）应激生物标志物GRP78/BiP。疗效和生物标志物数据表明，肿瘤为T1/ST2阳性的患者对dTCApFs表现出更好的反应。总之，发现dTCApFs安全/耐受性良好，且可能有效，具有线性药代动力学。与临床前研究一致，dTCApFs发挥抗癌作用的机制似乎涉及诱导ER应激抑制血管生成和激活先天免疫反应。然而，仍需要进一步研究。
