Center for Cancer and Blood Disorders, Children's National Hospital, Washington, District of Columbia.
The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
Pediatr Blood Cancer. 2021 Nov;68(11):e29282. doi: 10.1002/pbc.29282. Epub 2021 Aug 12.
Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints.
Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2.
Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles.
The recommended dose for pediatric patients was sorafenib 150 mg/m /dose twice daily with irinotecan 70 mg/m /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.
索拉非尼是一种口服生物利用度的多靶点酪氨酸激酶抑制剂，伊立替康是一种拓扑异构酶 I 抑制剂，已在儿科和成人恶性肿瘤中显示出活性。我们评估了索拉非尼联合伊立替康在复发或难治性实体瘤儿童中的毒性、药代动力学（PK）和药物基因组学（PGX）特征，并评估了将患者报告的结果（PRO）作为传统终点的辅助手段的可行性。
索拉非尼，连续口服，每日两次，与伊立替康联合应用，每日一次，第 1-5 天，每 21 天重复（NCT01518413）。根据耐受性，计划先增加索拉非尼的剂量，然后再增加伊立替康的剂量。每个剂量水平最初招募 3 名患者。在第 1 周期中进行了索拉非尼和伊立替康的 PK 分析。在第 1 和第 2 周期中收集了 PRO 测量结果。
15 名患者可评估。2 名患者在剂量水平 2 时发生剂量限制毒性（DLT），为 3 级腹泻和 3 级低钠血症。因此，剂量水平 1 扩大到 12 名患者，2 名患者发生 DLT，为 4 级血小板减少症，3 级升高的脂肪酶。15 名患者中有 9 名（60%）有最佳的疾病稳定反应，其中 4 名患者接受了≥6 个周期的治疗。
推荐儿科患者的剂量为索拉非尼 150mg/m 2 /剂量，每日两次，伊立替康 70mg/m 2 /剂量，每日一次，连用 5 天，每 21 天重复。这种口服门诊方案耐受性良好，可延长疾病稳定期。两种药物联合使用时，其 PK 特征无明显改变。患者愿意并能够报告他们对该方案的主观体验。
