1. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆
- Author
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S. Gallego Melcon, Francisco Bautista, Isabelle Aerts, Rajkumar Venkatramani, Alessandra Longhi, Cyril Lervat, Michela Casanova, Claudia Rossig, Cixin He, Marion Gambart, Nathalie Gaspar, Estelle Thebaud, Natacha Entz-Werle, Quentin Campbell-Hewson, Lea Dutta, Chinyere E. Okpara, Sandra J. Strauss, Franco Locatelli, A. Canete Nieto, Bruce Morland, Stefanie Hecker-Nolting, Perrine Marec-Berard, Institut Català de la Salut, [Gaspar N] Department of Childhood and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France. [Campbell-Hewson Q] The Great North Children's Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, UK. [Gallego Melcon S] Servei d'Oncologia i Hematologia Pediàtrica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Locatelli F] Department of Pediatric Hematology and Oncology, Ospedale Pediatrico Bambino Gesù, University of Rome, Rome, Italy. [Venkatramani R] Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, USA. [Hecker-Nolting S] Department of Pediatric Oncology, Hematology, Immunology, Klinikum Stuttgart - Olgahospital, Stuttgart, Germany, Vall d'Hebron Barcelona Hospital Campus, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Laboratoire de Bioimagerie et Pathologies (LBP), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
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Oncology ,Cancer Research ,medicine.medical_treatment ,lenvatinib ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,law.invention ,Iodine Radioisotopes ,chemistry.chemical_compound ,Randomized controlled trial ,law ,tyrosine kinase inhibitors ,Neoplasms::Neoplasms by Site::Bone Neoplasms [DISEASES] ,Clinical endpoint ,Child ,Original Research ,Osteosarcoma ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,neoplasias::neoplasias por localización::neoplasias óseas [ENFERMEDADES] ,solid tumors ,lenvatinib, osteosarcoma, pediatric, solid tumors, tyrosine kinase inhibitors ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,lenvatinib osteosarcoma pediatric solid tumors tyrosine kinase inhibitors ,Quinolines ,Lenvatinib ,medicine.drug ,medicine.medical_specialty ,Ossos - Càncer - Tractament ,Adolescent ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Antineoplastic Agents ,Bone Neoplasms ,Quimioteràpia combinada ,Young Adult ,Refractory ,Ossos - Malalties, en els infants ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Internal medicine ,medicine ,Humans ,Survival rate ,Chemotherapy ,Everolimus ,business.industry ,Phenylurea Compounds ,medicine.disease ,pediatric ,chemistry ,Neoplasm Recurrence, Local ,business - Abstract
Background We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). Patients and methods The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. Results In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan–Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. Conclusions The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755)., Highlights • The recommended phase II dose of lenvatinib in children with relapsed/refractory solid malignant tumors is 14 mg/m2. • This dose is equivalent to the recommended dose of 24 mg/day for single-agent lenvatinib in adults with DTC. • Single-agent lenvatinib showed activity of interest in children and young adults with osteosarcoma. • Based on this initial report, lenvatinib is currently being investigated in combination with chemotherapy in osteosarcoma.
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- 2021