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\xa0≤\xa025 years with r/r osteosarcoma and Results In the phase Ib dose-finding cohort (n\xa0=\xa022), pts received LEN 11\xa0mg/m2 (n\xa0=\xa07) and 14\xa0mg/m2 (n\xa0=\xa015) + chemo. Dose-limiting toxicities were: Grade (G) 4 thrombocytopenia (n\xa0=\xa01; LEN 11\xa0mg/m2), G4 thrombocytopenia and G3 epistaxis (n\xa0=\xa01; LEN 14\xa0mg/m2), G2 oral dysesthesia, G3 muscle spasm, and G2 back pain (n\xa0=\xa01; LEN 14\xa0mg/m2). RPh2D was LEN 14\xa0mg/m2 + chemo. In the expansion cohort (n\xa0=\xa020), 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\xa0≥\xa03 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\xa0=\xa06) and expansion cohort (n\xa0=\xa01); 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 (14\xa0mg/m2) + 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.