Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.
Клиническое исследование I фазыСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Goldsmith Kelly C, Park Julie R, Kayser Kimberly, Malvar Jemily, Chi Yueh-Yun, Groshen Susan G, Villablanca Judith G, Krytska Kateryna, Lai Lillian M, Acharya Patricia T, Goodarzian Fariba, Pawel Bruce, Shimada Hiroyuki, Ghazarian Susan, States Lisa, Marshall Lynley, Chesler Louis, Granger Meaghan, Desai Ami V, Mody Rajen, Morgenstern Daniel A, Shusterman Suzanne, Macy Margaret E, Pinto Navin, Schleiermacher Gudrun, Vo Kieuhoa, Thurm Holger C, Chen Joseph, Liyanage Marlon, Peltz Gerson, Matthay Katherine K, Berko Esther R, Maris John M, Marachelian Araz, Mossé Yael P
Аннотация
Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .