Falchook Gerald S, Wheler Jennifer J, Naing Aung, Jackson Edward F, Janku Filip, Hong David, Ng Chaan S, Tannir Nizar M, Lawhorn Kristie N, Huang Mei, Angelo Laura S, Vishwamitra Deeksha, Hess Kenneth, Howard Adrienne N, Parkhurst Kristin L, Amin Hesham M, Kurzrock Razelle
Sarah Cannon Research Institute, Denver, CO 80218.
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Oncotarget. 2014 Nov 15;5(21):10280-92. doi: 10.18632/oncotarget.2163.
We hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.
Patients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.
Ninety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m(2). Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥ 6 months (Total SD ≥ 6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in K(trans) although analysis was limited by small sample size (N=12).
Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved.
我们假设硼替佐米（一种抑制HIF-1α转录活性的药物）与贝伐单抗联合使用时，将消除HIF-1α耐药途径。该I期试验的目的是评估这种联合用药的安全性和生物学活性。
晚期难治性恶性肿瘤患者符合条件。患者接受贝伐单抗和硼替佐米治疗（3周周期），如果观察到反应并用于评估相关性，则允许剂量增加。药效学评估包括血浆VEGF、VEGFR2、20S蛋白酶体抑制、动态对比增强磁共振成像（DCE-MRI）和HIF-1α肿瘤表达。
91例患者接受了治疗（中位数=6次先前治疗）。两种药物均安全达到FDA批准的剂量，推荐的2期剂量（RP2D）为贝伐单抗15mg/kg联合硼替佐米1.3mg/m²。4例患者获得部分缓解（PR），7例患者疾病稳定（SD）≥6个月（总SD≥6个月/PR=11例（12%））。最常见的药物相关毒性包括血小板减少（23%）和疲劳（19%）。DCE-MRI分析显示K(trans)没有剂量依赖性降低，尽管分析受小样本量（N=12）限制。
贝伐单抗和硼替佐米联合用药耐受性良好，在先前治疗的晚期恶性肿瘤患者中已显示出临床活性。药效学评估表明已实现血管生成活性的抑制。
