Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies.

Aflibercept 联合 S-1 治疗日本晚期实体恶性肿瘤患者的安全性、耐受性和药代动力学的 I 期剂量递增研究。

  • 影响因子:2.87
  • DOI:10.1007/s10637-019-00888-z
  • 作者列表:"Doi T","Boku N","Onozawa Y","Takahashi K","Kawaguchi O","Ohtsu A
  • 发表时间:2020-01-06

:Background Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3-6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.


背景: Aflibercept 是一种结合 VEGF-a 、 VEGF-B 和胎盘生长因子的重组融合蛋白,通过阻断血管生成抑制肿瘤生长。本 I 期剂量递增研究的目的是确定日本实体瘤患者中 aflibercept 联合 S-1 的推荐 II 期剂量 (RP2D)。患者和方法 3-6 例转移性或不可切除实体瘤患者的序贯队列,这些患者既往至少有一个标准治疗失败或不适合此类治疗, 每 2 周接受递增剂量的阿柏西普,从 2 mg/kg 开始,结合 40 mg/m2 的 S-1,每天两次(80 mg/m2/天; 4 周开/2 周休)。剂量递增是基于剂量限制性毒性 (DLT) 的发生率。采集血样进行药代动力学分析。结果在第一剂量水平 (aflibercept 2 mg/kg 加 S-1),6 例患者中有 1 例出现 DLT (4 级蛋白尿)。Aflibercept 剂量因此升级到 4 mg/kg; 在此剂量水平下治疗的 3 例患者中有 1 例 DLT (2 级胸腔积液), 另一名患者在 DLT 评估期后出现 3 级可逆性后部白质脑病综合征。因此,额外的患者被纳入第一剂量水平,以探索安全性和耐受性。该研究随后提前终止。日本患者未达到最大耐受剂量,RP2D 未确定。结论 aflibercept 2 mg/kg 联合 S-1 在日本晚期实体瘤患者中的耐受性和安全性得到证实。



作者列表:["Abrahamsson H","Jensen BV","Berven LL","Nielsen DL","Šaltytė Benth J","Johansen JS","Larsen FO","Johansen JS","Ree AH"]

METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.

翻译标题与摘要 下载文献
作者列表:["Suvina V","Kokulnathan T","Wang TJ","Balakrishna RG"]

METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.

翻译标题与摘要 下载文献
来源期刊:Cancer letters
作者列表:["Zhou Z","Zhou Q","Wu X","Xu S","Hu X","Tao X","Li B","Peng J","Li D","Shen L","Cao Y","Yang L"]

METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.

翻译标题与摘要 下载文献