Phase I combination dose-finding/phase II expansion cohorts of lenvatinib + etoposide + ifosfamide in patients (pts) aged 2 to ≤ 25 years with relapsed/refractory (r/r) osteosarcoma

Abstract

Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR1-3 and other targets. We report data from phase Ib dose-finding and phase II expansion cohorts of LEN +etoposide + ifosfamide in pts with r/r osteosarcoma. Methods: Pts were aged 2 to≤25 years with r/r osteosarcoma and<2 prior VEGF-targeted therapies. The phase Ib starting dose was LEN 11 mg/m2/day+ ifosfamide 3000 mg/ m2+ etoposide 100 mg/ m2 daily/3 days. On determination of the recommended phase II dose (RPh2D) of LEN +chemo, pts were enrolled into the phase II expansion cohort. Primary end points: phase Ib, RPh2D; phase II, 4months' progression-free survival (PFS-4). Results: In the phase Ib dose-finding cohort (n=22), pts received LEN 11 mg/ m2 (n=7) and 14 mg/ m2 (n=15)+ chemo. Dose-limiting toxicities were: Grade (G) 4 thrombocytopenia (n=1; LEN 11 mg/ m2), G4 thrombocytopenia and G3 epistaxis (n=1; LEN 14 mg/ m2), G2 oral dysesthesia, G3 muscle spasm, and G2 back pain (n=1; LEN 14 mg/ m2). RPh2D was LEN 14 mg/ m2+ chemo. In the expansion cohort (n=20), the median number of LEN cycles received was 4 (range: 1-7). As reported in the database, the most frequent treatment-emergent adverse events (TEAEs) were platelet count decreased/thrombocytopenia (50%/30%), neutropenia/neutrophil count decreased (45%/25%), anemia (45%), nausea (40%), ALT increased, diarrhea, and white blood cell count decreased (30% each). Most frequent G≥3 TEAEs were neutropenia/ neutrophil count decreased (45%/25%), platelet count decreased/thrombocytopenia (40%/20%), white blood cell count decreased (30%), and anemia (25%). Pneumothorax was observed in the dose-finding cohort (n=6) and expansion cohort (n=1); 2 (dose-finding cohort) were ≥G3; and 1 was post-thoracotomy. 4 Pts (dosefinding cohort) discontinued treatment due to TEAEs. There were no treatment-related fatal serious AEs. In the dose-finding combination cohort, 12/18 evaluable pts (66.7%) achieved PFS-4. In the phase II expansion cohort, 5/8 evaluable pts (62.5%) achieved PFS-4. Conclusions: The combination of RPh2D LEN (14 mg/ m2)+chemo had a manageable safety profile with promising preliminary evidence of efficacy.