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/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.

Gov number: NCT03245151.

Keywords: Ewing sarcoma; everolimus; high‐grade glioma; lenvatinib; pediatric solid tumors; rhabdomyosarcoma.