Department of Medicine, Division of Hematology/Oncology.
Developmental Therapeutics Program, Division of Hematology/Oncology, Feinberg School of Medicine, Chicago, IL.
Am J Clin Oncol. 2019 May;42(5):413-420. doi: 10.1097/COC.0000000000000543.
Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib.
This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis.
A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response.
The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).
帕唑帕尼是一种多激酶血管生成抑制剂。阿利斯替尼是一种高度选择性的有丝分裂 Aurora A 激酶抑制剂。有临床前证据表明，有丝分裂靶向药物具有抗血管生成作用。因此，这两种药物的联合使用可能对肿瘤血管具有协同作用。本研究的主要目的是确定阿利斯替尼和帕唑帕尼的最大耐受剂量（OTD）。
这项 1b 期研究评估了阿利斯替尼每天两次（第 1 至 7 天）与帕唑帕尼联合使用，每天一次，连续 21 天为一个周期，均为口服。每 2 个周期使用实体瘤反应评价标准 1.1 评估疾病反应。扩大 OTD 队列以确保安全性并进行药代动力学分析。
共 27 例患者接受了治疗。77%的患者至少接受了 3 种先前的化疗方案。剂量限制毒性发生在剂量水平（DL）2+（血小板减少症 4 级和黏膜炎 3 级）和 DL 3（肝转氨酶升高 3 级和腹痛 3 级）。确定 OTD 为 DL 2：阿利斯替尼每天 2 次，每次 20mg；帕唑帕尼每天 600mg。药代动力学分析显示，与无帕唑帕尼存在时相比，帕唑帕尼存在时阿利斯替尼的清除率降低了约 40%。14 例患者病情稳定，2 例患者部分缓解。
阿利斯替尼与帕唑帕尼联合使用具有可管理的安全性，并在晚期恶性肿瘤患者中显示出早期抗肿瘤活性的临床证据（NCT01639911）。
