Kessler Elizabeth R, Eckhardt S Gail, Pitts Todd M, Bradshaw-Pierce Erica L, O'byrant Cindy L, Messersmith Wells A, Nallapreddy Sujatha, Weekes Colin, Spratlin Jennifer, Lieu Christopher H, Kane Madeleine A, Eppers Sarah, Freas Elizabeth, Leong Stephen
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.
University of Colorado Cancer Center, Aurora, Colorado, USA.
Invest New Drugs. 2016 Apr;34(2):176-83. doi: 10.1007/s10637-015-0316-5. Epub 2015 Dec 30.
Vandetanib is a multitargeted tyrosine kinase inhibitor that affects vascular endothelial growth factor receptor (VEGF), epidermal growth factor (EGF), and rearranged during transfection (RET) mediated receptors which are important for growth and invasion of biliary and pancreatic cancers. This phase I study evaluated the safety profile of vandetanib in combination with standard doses of gemcitabine and capecitabine in order to determine the maximum tolerated dose (MTD).
In this single center phase I trial, patients received gemcitabine intravenously (i.v.) at 1000 mg/m2 days 1, 8, 15 in a 28 day cycle, capecitabine orally at 850 mg/m2 twice daily on days 1-21, and escalating doses of vandetanib (200 or 300 mg orally daily). Once the MTD was defined, an expansion cohort of patients with advanced biliary cancers and locally advanced or metastatic pancreatic cancer was enrolled. Blood samples were also collected at predetermined time points for biomarker analysis.
Twenty-three patients were enrolled: 9 in the dose escalation and 14 in the dose expansion cohort. One dose limiting toxicity (DLT), of grade 4 neutropenia, occurred in the 200 mg vandetanib cohort. The most common adverse effects were diarrhea (39 %), nausea and vomiting (34%), and rash (33%). There were 3 partial responses and stable disease of >2 months (range 2-45, median 5) was observed in 15/23 patients. There was no association between changes in biomarker analytes and disease response.
The combination of gemcitabine, capecitabine and vandetanib is well tolerated at the recommended phase II dose of gemcitabine 1000 mg/m2 weekly for three consecutive weeks, capecitabine 850 mg/m2 BID days 1-21, and vandetanib 300 mg daily, every 28 days. This combination demonstrated promising activity in pancreaticobiliary cancers and further evaluation is warranted in these diseases. NCT00551096.
凡德他尼是一种多靶点酪氨酸激酶抑制剂，可影响血管内皮生长因子受体（VEGF）、表皮生长因子（EGF）以及转染重排（RET）介导的受体，这些受体对胆管癌和胰腺癌的生长及侵袭至关重要。这项I期研究评估了凡德他尼与标准剂量吉西他滨和卡培他滨联合使用时的安全性，以确定最大耐受剂量（MTD）。
在这项单中心I期试验中，患者在28天周期的第1、8、15天静脉注射（i.v.）1000 mg/m²吉西他滨，在第1 - 21天每天口服两次850 mg/m²卡培他滨，并递增凡德他尼剂量（每日口服200或300 mg）。一旦确定了MTD，就纳入晚期胆管癌以及局部晚期或转移性胰腺癌患者的扩大队列。还在预定时间点采集血样进行生物标志物分析。
共纳入23例患者：9例在剂量递增组，14例在剂量扩大组。在200 mg凡德他尼组出现1例4级中性粒细胞减少的剂量限制毒性（DLT）。最常见的不良反应为腹泻（39%）、恶心和呕吐（34%）以及皮疹（33%）。23例患者中有3例部分缓解，15例患者观察到疾病稳定>2个月（范围2 - 45，中位数5）。生物标志物分析物的变化与疾病反应之间无关联。
吉西他滨、卡培他滨和凡德他尼联合使用时，在推荐的II期剂量下耐受性良好，即吉西他滨1000 mg/m²每周连续使用三周，卡培他滨850 mg/m²每日两次，第1 - 21天，凡德他尼每日300 mg，每28天一次。这种联合方案在胰胆管癌中显示出有前景的活性，有必要对这些疾病进行进一步评估。NCT00551096。
