Phase 1 study of ceritinib in pediatric patients with malignancies harboring activated anaplastic lymphoma kinase (ALK): Safety, pharmacokinetics and efficacy results from the fed population

• Published in: European journal of cancer (1990) Vol. 69; pp. S49 - S50
• Main Authors: Fischer, M, Wulff, B, Baruchel, S, Berlanga, P, Trahair, T, Mechinaud, F, Schulte, J, Modak, S, Merks, J.H, Zwaan, C.M, Marshall, L.V, Casanova, M, Branle, F, Malet, I, Emeremni, A.C, Geoerger, B
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science Ltd 01.12.2016
• Subjects: ALK protein; Anaplastic large-cell lymphoma; Anticancer properties; Antitumor activity; Cancer therapies; Children; Effectiveness; Expansion; Food; Hematology, Oncology and Palliative Medicine; Immunohistochemistry; Inflammation; Inhibitor drugs; Intestine; Kinases; Lung cancer; Lymphoma; Mutation; Neuroblastoma; Non-small cell lung carcinoma; Patients; Pharmacokinetics; Pharmacology; Protein-tyrosine kinase; Proteins; Rhabdomyosarcoma; Safety; Toxicity; Tumors; Xenografts; Xenotransplantation
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32732-0

Background: Ceritinib, a second generation ALK inhibitor, had shown 20-fold more potency than crizotinib with demonstrated durable activity in xenografts expressing crizotinib-resistant ALK mutations. Efficacy was observed in adult patients with ALK-mutated non-small cell lung cancer exposed to prior crizotinib treatment or not and in non-lung tumors. In this phase 1 study (NCT01742286) of ceritinib in pediatric malignancies, the recommended dose for expansion (RDE) was established as 510 mg/rn2 once daily in a fasted regimen (cohorts 1 to 6). Preliminary results from this part of the study demonstrated antitumor activity in patients with ALK- mutated inflammatory myofibroblastic tumor (IMT) and anaplastic large cell lymphoma (ALCL), with objective response rates of 63% (5/8 [95% CI: 35, 97]) and 100% (4/4 [95% Cl: 40, 100]), respectively (Geoerger B et al, ASCO 2015 Abstract #10005). The fed escalation part of this study (cohorts 7 to 9) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce gastro-intestinal toxicity, white maintaining PK exposure at lower doses. Methods: The trial enrolled pediatric patients ~1 to <18 years. ALK gene aberration was required, except in ALCL and in rhabdomyosarcoma, where ALK protein expression by immunohistochemistry was sufficient. In this fed, dose-escalation phase, patients received ceritinib at 320-500 mg/rn2 once daily to determine the RDE. Patients were assessed for safety, PK, and efficacy. Results: Fifteen patients were enrolled in 7 centers in 6 countries over 12 months into 3 cohorts: cohort 7 (320mg/rn2), cohort 8 (400 mg/m2), and cohort 9 (500 mg/m2). Diagnoses included: 2 ALCL, 1 IMT, 10 neuroblastoma, and 2 rhabdomyosarcoma. Completion of the fed escalation phase established a RDE of 500 mg/m2/day. One patient had a dose limiting grade 3 hepatic toxicity at 400 mg/rn2. As of 8 June 2016, 6 patients at 500 mg/m2 are ongoing in the fed-regimen (3 in fed escalation cohort 9 and 3 in the fed expansion phase). More mature results on safety, pharmacokinetics and early efficacy including neuroblastoma patients for the fed cohorts as well as those who entered the expansion phase will be reported during the congress. Conclusion: The RDE in children is 500 mg/m2/day with food. The study is currently enrolling in the expansion phase at this recommended dose.