Filemon S Dela Cruz, Elizabeth Fox, Steven G DuBois, Gregory K Friedman, James M Croop, AeRang Kim, Daniel A Morgenstern, Frank M Balis, Margaret E Macy, Joseph G Pressey, Tanya Watt, Julie I Krystal, Kieuhoa T Vo, Rajen Mody, Theodore W Laetsch, Brenda J Weigel, Karen O'Hara, Cixin S He, Jagadeesh Aluri, Chinyere E Okpara, Julia L Glade Bender
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Phase 2 was limited to patients with Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), or high-grade glioma (HGG), and ≤2 prior VEGF/VEGFR-targeted therapies. Primary endpoints included the determination of maximum tolerated dose (MTD), RP2D, safety/toxicity (Phase 1), and objective response rate (ORR) per RECIST version 1.1 (RANO for HGG) at Week 16 (Phase 2).</p><p><strong>Results: </strong>In Phase 1, 23 patients received lenvatinib 11 mg/m<sup>2</sup> (dose level [DL] 1, n = 18) or 8 mg/m<sup>2</sup> (DL -1, n = 5) combined with everolimus 3 mg/m<sup>2</sup> orally once daily. DL1 was declared the MTD/RP2D given dose-limiting toxicities (proteinuria [n = 1]; hypertriglyceridemia and hypercholesterolemia [n = 1]) observed in two of 12 patients treated at DL1. In Phase 2, 41 patients (EWS, n = 10; RMS, n = 20; HGG, n = 11) were treated with the RP2D. Two patients with RMS experienced partial response by Week 16. No other objective responses were observed. 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引用次数: 0
摘要
开发具有可控毒性的靶向治疗仍然是儿科癌症的重中之重。我们试图确定lenvatinib+依维莫司的推荐2期剂量（RP2D），并评估lenvatinib+依维莫司在患有复发/难治性实体瘤的儿童/年轻人中的抗肿瘤活性。方法：选取年龄2 ~ 21岁的患者。第一阶段采用滚六设计。2期研究仅限于Ewing肉瘤（EWS）、横纹肌肉瘤（RMS）或高级别胶质瘤（HGG）患者，且既往接受过≤2次VEGF/ vegfr靶向治疗。主要终点包括16周（2期）时最大耐受剂量（MTD）、RP2D、安全性/毒性（1期）和客观缓解率（ORR） （HGG的RANO）。结果：在一期试验中，23例患者接受lenvatinib 11 mg/m2（剂量水平[DL] 1， n = 18）或8 mg/m2（剂量水平[DL] 1， n = 5）联合依维莫司3 mg/m2口服，每日1次。由于剂量限制性毒性，DL1被宣布为MTD/RP2D(蛋白尿[n = 1]；在12例DL1治疗的患者中，有2例出现了高甘油三酯血症和高胆固醇血症[n = 1])。在第二阶段，41例患者(EWS, n = 10；RMS, n = 20；HGG, n = 11)用RP2D治疗。两名RMS患者在第16周出现部分缓解。未观察到其他客观反应。2例EWS患者病情控制时间延长（≥23周）。没有发现新的安全信号。安全性与接受治疗的成人肾细胞癌相似。结论：Lenvatinib+依维莫司在该儿科人群中具有可控的安全性。尽管未达到疗效终点，但在RMS和EWS中观察到的抗肿瘤活性可能值得在选定的儿童实体瘤中进一步研究。临床试验：政府编号：NCT03245151。
A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric and Young Adult Solid Tumors.
Introduction: Developing targeted therapies with manageable toxicities remains a high priority for pediatric cancer. We sought to determine the recommended Phase 2 dose (RP2D) and evaluate the antitumor activity of lenvatinib+everolimus in children/young adults with select recurrent/refractory solid tumors.
Methods: Patients 2-21 years old were eligible. Phase 1 used a rolling-six design. Phase 2 was limited to patients with Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), or high-grade glioma (HGG), and ≤2 prior VEGF/VEGFR-targeted therapies. Primary endpoints included the determination of maximum tolerated dose (MTD), RP2D, safety/toxicity (Phase 1), and objective response rate (ORR) per RECIST version 1.1 (RANO for HGG) at Week 16 (Phase 2).
Results: In Phase 1, 23 patients received lenvatinib 11 mg/m2 (dose level [DL] 1, n = 18) or 8 mg/m2 (DL -1, n = 5) combined with everolimus 3 mg/m2 orally once daily. DL1 was declared the MTD/RP2D given dose-limiting toxicities (proteinuria [n = 1]; hypertriglyceridemia and hypercholesterolemia [n = 1]) observed in two of 12 patients treated at DL1. In Phase 2, 41 patients (EWS, n = 10; RMS, n = 20; HGG, n = 11) were treated with the RP2D. Two patients with RMS experienced partial response by Week 16. No other objective responses were observed. Two patients with EWS experienced prolonged disease control (≥23 weeks). No new safety signals were identified. The safety profile was similar to those of treated adults with renal cell carcinoma.
Conclusion: Lenvatinib+everolimus has a manageable safety profile in this pediatric population. Despite unmet efficacy endpoints, the antitumor activity observed in RMS and EWS may warrant further study in select pediatric solid tumors.
期刊介绍：
Pediatric Blood & Cancer publishes the highest quality manuscripts describing basic and clinical investigations of blood disorders and malignant diseases of childhood including diagnosis, treatment, epidemiology, etiology, biology, and molecular and clinical genetics of these diseases as they affect children, adolescents, and young adults. Pediatric Blood & Cancer will also include studies on such treatment options as hematopoietic stem cell transplantation, immunology, and gene therapy.
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