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
{"title":"A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric and Young Adult Solid Tumors.","authors":"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","doi":"10.1002/pbc.31692","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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).</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. 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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov number: </strong>NCT03245151.</p>","PeriodicalId":19822,"journal":{"name":"Pediatric Blood & Cancer","volume":" ","pages":"e31692"},"PeriodicalIF":2.4000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pediatric Blood & Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/pbc.31692","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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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