A phase I/II study of lenvatinib (LEN) plus everolimus (EVE) in recurrent and refractory pediatric solid tumors, including CNS tumors.

Abstract

10527 Background: Proangiogenic signaling pathways cooperate with mTOR-mediated regulation of cell growth and maintenance to drive development of many pediatric cancers. We report results of the phase 1 dose escalation for LEN + EVE in pediatric patients (pts) with recurrent solid and CNS tumors conducted by Children’s Oncology Group. Methods: Dose escalation was conducted using a rolling-6 design. Pts received LEN + EVE orally once daily in continuous 28-day cycles. Dose determination was based on toxicity (CTCAE v4.03) during cycle 1. Pharmacokinetics (PK) of plasma LEN and EVE were monitored. Results: 17 pts were enrolled (9 male; 8 female). Median (range) age was 10 (3–21) years; 8 pts had CNS tumors. 17 were evaluable for dose-limiting toxicity (DLT). Enrollment started at dose level 1 (DL 1; LEN 11 mg/m2 + EVE 3 mg/m2) and, after treatment of 3 pts, was initially de-escalated to DL –1 (LEN 8 mg/m2 + EVE 3 mg/m2) due to DLT of proteinuria in 1 pt and self-resolving headache in another who, on review, did not meet the definition of DLT. No pts enrolled at DL –1 (n = 5) experienced DLT. Overall, DLTs were observed in 2 of the first 6 patients enrolled at DL 1: the initial pt with proteinuria and 1 more pt with hypertriglyceridemia and hypercholesteremia. Because 2 pts had reversible DLT of different categories not related to Cmax or AUC, the DL 1 cohort was expanded to enroll an additional 6 pts, none of whom had DLT. Thus, 2/12 pts experienced DLT at DL 1. Overall, most common treatment-emergent adverse events (TEAEs; ≥ 50% of pts) were diarrhea, hypertension, hypertriglyceridemia, vomiting, abdominal pain, headache, and hypothyroidism. 47% of pts had ≥ 1 treatment-related TEAE grade ≥ 3; the most frequent was proteinuria (n = 2). On cycle 1 day 15, mean (SD) Cmax (ng/mL) for LEN at DL –1 and DL 1, respectively, was 314 (150) and 359 (270), and mean (SD) AUC0-8h (hr•ng/mL) for LEN was 1570 (935) and 1780 (1100). Taking all toxicities and PK into account, no further dose escalation was recommended. Best overall response in pts with measurable disease was 2/11 stable disease, 7/11 progressive disease, and 2/11 not evaluable. Conclusions: The recommended phase 2 dose of LEN + EVE in children with solid and CNS tumors was LEN 11 mg/m2 + EVE 3 mg/m2, with maximum daily doses capped at 18 mg and 5 mg, respectively. The toxicity profile was no more than additive to single-agent therapy. PK exposure was comparable with children on single-agent LEN and to adults receiving LEN + EVE. Enrollment to the phase 2 portion (Ewing sarcoma, high-grade glioma, and rhabdomyosarcoma strata) is ongoing. Clinical trial information: NCT03245151.