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

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 11mg/m 2 /day + ifosfamide 3000mg/m 2 + etoposide 100mg/m 2 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, 4 months' progression-free survival (PFS-4). Results In the phase Ib dose-finding cohort (n=22), pts received LEN 11mg/m 2 (n=7) and 14mg/m 2 (n=15) + chemo. Dose-limiting toxicities were: Grade (G) 4 thrombocytopenia (n=1; LEN 11mg/m 2), G4 thrombocytopenia and G3 epistaxis (n=1; LEN 14mg/m 2), G2 oral dysesthesia, G3 muscle spasm, and G2 back pain (n=1; LEN 14mg/m 2). RPh2D was LEN 14mg/m 2 + 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 (dose-finding 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 (14mg/m 2) + chemo had a manageable safety profile with promising preliminary evidence of efficacy. Clinical trial identification NCT02432274. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. Disclosure A. Longhi: Non-remunerated activity/ies, non-financial support: PharmaMar, Takeda; Research grant / Funding (institution): Takeda. M. Casanova: Advisory / Consultancy, advisory role: Bayer; Advisory / Consultancy, advisory role: Lilly; Advisory / Consultancy, advisory role: Roche; Advisory / Consultancy, advisory role: Tesaro. S.S. Bielack: Travel / Accommodation / Expenses, site fees for study preparation: Eisai; Travel / Accommodation / Expenses, personal fees from Clinigen: Clinigen; Travel / Accommodation / Expenses, personal fees from Lilly: Lilly; Travel / Accommodation / Expenses, personal fees from Novartis: Novartis; Travel / Accommodation / Expenses, personal fees from Bayer: Bayer; Travel / Accommodation / Expenses, personal fees from Pfizer: Pfizer; Travel / Accommodation / Expenses, personal fees from Isofol: Isofol; Travel / Accommodation / Expenses, personal fees from Sensorion: Sensorion; Travel / Accommodation / Expenses, personal fees from Ipsen: Ipsen; Advisory / Consultancy, Institution negotiating consultancy agreement with Eisai: Eisai. S. Gallego Melcon: Travel / Accommodation / Expenses: Loxo Oncology; Advisory / Consultancy: Bayer, Eusa. All other authors have declared no conflicts of interest.