Phase I, First‐in‐Human, Dose‐Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors

Lessons Learned Pharmacokinetic results underscore that the vorolanib (X‐82) study design was successful without the need for further dose escalation beyond 400 mg once daily (q.d.). Therefore, the recommended dose of X‐82 as a single agent in patients with advanced cancer is 400 mg q.d. Background Vorolanib (X‐82) is a novel, oral, multikinase vascular endothelial growth factor (VEGF) receptor/platelet‐derived growth factor (PDGF) receptor inhibitor that was developed on the same chemical scaffold as sunitinib, but designed to improve upon the safety profile while maintaining the efficacy of sunitinib. By targeting the VEGF and PDGF receptors, X‐82 was expected to disrupt tumor angiogenesis and be active in a broad spectrum of solid tumors. Therefore, we determined the maximum tolerated dose (MTD) and characterized the preliminary pharmacokinetics and clinical tumor response of X‐82 as a single agent in patients with advanced solid tumors. Methods Adult patients with advanced solid tumors received X‐82 as tablets or capsules (once daily [q.d.] or b.i.d.) every 4 weeks. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. Results Fifty‐two patients received study treatment in 17 cohorts. X‐82 capsule dosing was as follows: cohorts 1–6 (20–400 mg q.d.) and cohorts 7–8 (140–200 mg b.i.d.). Patients in cohorts 9–17 received 50–800 mg q.d. tablet dosing. The median time on treatment was 58 days. X‐82 blood pharmacokinetics appeared dose‐independent with a t1/2 of 5.13 hours and 6.48 hours for capsule and tablet formulations, respectively. No apparent accumulation was observed after 21 days of daily dosing. Conclusion X‐82 had a safety profile consistent with its mechanism of action. It has a short half‐life and was well tolerated by most patients. Study enrollment ended prior to the determination of the MTD because of the apparent saturation of absorption at 400–800 mg. The recommended dose of X‐82 as a single agent in patients with advanced cancer is 400 mg q.d. 经验获取 • 药代动力学结果强调，Vorolanib (X‐82) 研究设计成功，无需在400 mg每天一次 (q.d.) 用药之外进一步增加剂量。 • 因此，X‐82 作为单一药剂在晚期癌症患者中的建议剂量为400 mg每天一次用药。 摘要 背景。Vorolanib (X‐82) 是一种新型口服多重激酶血管内皮生长因子 (VEGF) 受体/血小板源性生长因子 (PDGF) 受体抑制剂，与舒尼替尼在相同的化学支架上研制，但是，它旨在保持舒尼替尼有效性的同时，改进安全特性。通过将 VEGF 和 PDGF 受体作为靶点，X‐82 预计能够破坏肿瘤血管生成，并在各种实体肿瘤中发挥活性作用。因此，我们确定了最大耐受剂量 (MTD) 并描述了 X‐82 作为单一药剂在晚期实体肿瘤患者中的临床前药动学和临床肿瘤反应的特性。 方法。患有晚期实体肿瘤的成年患者每 4 周接受片剂或胶囊形式的 X‐82 [每天一次用药 (q.d. )或每天两次用药(b.i.d.)]。患者