443TiP - A multicenter, open-label, randomized phase II study to compare the efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma (OLIE; ITCC-082)

Background

Osteosarcoma is a bone malignancy that occurs primarily in adolescents and young adults. Approximately 30% of patients (pts) with localized disease and 80% of pts with metastatic disease at diagnosis will relapse. Lenvatinib (LEN) is a multikinase inhibitor that directly inhibits tumor growth, and may increase the uptake of chemotherapy into tumor tissue by inhibiting angiogenesis. In a phase I/II study (E7080-G000-207; ITCC-050), LEN (14 mg/m² dose) + ifosfamide (I) + etoposide (E) demonstrated a PFS rate at 4 months (PFS-4m) of 80% (95% CI: 61–91), with a manageable safety profile in pts with relapsed/refractory osteosarcoma (Gaspar ESMO 2019). This study aims to confirm the activity of LEN + I and E that was observed in the completed phase I/II study.

Trial design

This study will evaluate LEN in combination with I and E in pts (proposed N=72, with randomization of at least 32 pts < 18 yrs old) aged 2 to 25 yrs with confirmed diagnosis of osteosarcoma that is refractory or relapsed following 1-2 prior systemic treatments. Pts previously treated with I and E are eligible, except those with a history of I-related grade ≥ 3 nephrotoxicity or encephalopathy. Randomization will be stratified by time to first relapse/refractory disease (< 18 or ≥ 18 mos) and by age (< 18 or ≥ 18 yrs). Pts in arm A will receive daily oral LEN 14 mg/m² + I 3000 mg/m²/day (IV, Days 1-3 of each cycle for ≤5 cycles) and E 100 mg/m²/day (IV, Days 1-3 of each cycle for ≤5 cycles). Pts in arm B will receive I 3000 mg/m²/day (IV, Days 1-3 of each cycle for ≤5 cycles) and E 100 mg/m²/day (IV, Days 1-3 of each cycle for ≤5 cycles). Treatment will occur in 21-day cycles. The primary objective is PFS-4m by independent imaging review (IIR) using RECIST 1.1 (% of pts alive without progressive disease at week 18). Secondary objectives include PFS, OS, ORR, safety and tolerability, LEN pharmacokinetics characterization in pts in arm A, and quality of life. Tumor assessments will be performed by the investigator every 6 wks. Disease progression must be confirmed by IIR. All AEs will be recorded.

Clinical trial identification

NCT04154189.

Legal entity responsible for the study

Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

N. Gaspar: Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy: Ipsen. Q. Campbell-Hewson: Travel/Accommodation/Expenses: Eisai. S.S. Bielack: Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Lilly; Advisory/Consultancy: Sensorion; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Roche; Advisory/Consultancy: Boehringer Ingelheim; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Loxo. F. Bautista: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Travel/Accommodation/Expenses: Jazz Pharmaceuticals; Advisory/Consultancy: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: EUSA Pharma; Travel/Accommodation/Expenses: Takeda. C. Meazza: Speaker Bureau/Expert testimony: Takeda. K. Janeway: Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Research grant/Funding (institution): Amgen. D.A. Morgenstern: Advisory/Consultancy: Boehringer-Ingelheim; Advisory/Consultancy: Roche; Advisory/Consultancy: Bayer; Research grant/Funding (institution): Bristol-Myers Squibb; Travel/Accommodation/Expenses: EUSA Pharma. L. Dutta, J. McKenzie, K. O'Hara, J. Huang, C.E. Okpara: Full/Part-time employment: Eisai. B. Bidadi: Full/Part-time employment: Merck & Co. Inc.; Shareholder/Stockholder/Stock options: Merck. All other authors have declared no conflicts of interest.