A Phase 1/2 Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric and Young Adult Solid Tumors

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/m 2 (dose level [DL] 1, n = 18) or 8 mg/m 2 (DL −1, n = 5) combined with everolimus 3 mg/m 2 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. ClinicalTrials.gov number NCT03245151