Single-agent dose-finding cohort of a phase 1/2 study of lenvatinib (LEN) in children and adolescents with refractory or relapsed solid tumors.

Abstract

10544 Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced renal cell carcinoma. We show results from the single-agent LEN dose-finding part of a phase 1/2 study in children and adolescents with solid tumors. Methods: Pts had any relapsed or refractory solid tumor, evaluable or measurable disease, were aged 2 to ≤18 years, had < 2 prior VEGF-targeted therapies, and adequate organ function. A starting dose of LEN 11 mg/m2was escalated with a time-to-event continual reassessment method. The primary endpoint was to determine the LEN recommended dose (RD). Secondary objectives included best overall response (BOR), objective response rate, safety, and pharmacokinetics (PK). Results: 23 pts enrolled (11 mg/m2: n = 5, 14 mg/m2: n = 11, 17 mg/m2: n = 7). The most common tumors were rhabdomyosarcoma (n = 5), Ewing sarcoma (n = 4), and neuroblastoma (n = 3). 3 Dose-limiting toxicities occurred in cycle 1 at 14 mg/m2 (increased alanine aminotransferase: 1; hypertension: 2). All pts had any-grade treatment-emergent adverse events (TEAEs; grade 3/4: 65%). Most common any-grade TEAEs were vomiting (52%), abdominal pain (48%), decreased appetite (48%), diarrhea (44%), and hypothyroidism (44%). 1 Pt discontinued LEN due to a LEN-related TEAE (hypertension). BOR was stable disease (n = 10). Effect of age on oral clearance and central volume of distribution was not significant. Exposure was similar to that in adults. LEN 14 mg/m2/day was therefore identified as the RD. Updated cohort 1 data will be shown. Conclusions: The LEN RD in children and adolescents was similar to the adult dose and showed a reasonable safety profile. PK in these pts did not differ significantly from that in adults. The phase 1b dose-finding study of LEN in combination with chemotherapy in osteosarcoma (OS) and phase 2 LEN monotherapy (RD 14 mg/m2) parts in DTC and OS are ongoing. Clinical trial information: NCT02432274.