Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study
Mené dans 10 pays sur 83 enfants ou adolescents (âge
Background : Several paediatric malignancies, including anaplastic large cell lymphoma (ALCL),inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbouractivation of anaplastic lymphoma kinase (ALK) through different mechanisms. Here,we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies.
Methods : This multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to <18 years) diagnosed with locally advanced or metastatic ALK-positive malignancies that had progressed despite standard therapy,or for which no effective standard therapy were available, were eligible. ALK-positivemalignancies were defined as those with ALK rearrangement, amplification, point mutation, or in the case of rhabdomyosarcoma,expression in the absence of any genetic alteration. Eligible patients had evaluableor measurable disease as defined by either Response Evaluation Criteria in Solid Tumours,version 1.1 for patients with non-haematological malignancies, International NeuroblastomaResponse Criteria scan for patients with neuroblastoma, or International Working Groupcriteria for patients with lymphoma. Other eligibility criteria were Karnofsky performancestatus score of at least 60% for patients older than 12 years or Lansky score of atleast 50% for patients aged 12 years or younger. This study included a dose-escalationpart, followed by a dose-expansion part, in which all patients received treatmentat the recommended dose for expansion (RDE) established in the dose-escalation part.Both parts of the study were done in fasted and fed states. In the dose-escalationpart, patients were treated with once-daily ceritinib orally, with dose adjusted forbody-surface area, rounded to the nearest multiple of the 50 mg dose strength. Thestarting dose in the fasted state was 300 mg/m2 daily and for the fed state was 320 mg/m2 daily. The primary objective of this study was to establish the maximum tolerateddose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was establishedon the basis of the incidence of dose-limiting toxicities in patients who completeda minimum of 21 days of treatment with safety assessments and at least 75% drug exposure,or who discontinued treatment earlier because of dose-limiting toxicity. Overall responserate (defined as the proportion of patients with a best overall response of completeresponse or partial response) was a secondary endpoint. Activity and safety analyseswere done in all patients who received at least one dose of ceritinib. This trialis registered with ClinicalTrials.gov (NCT01742286) and is completed.
Findings : Between Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion(n=43) groups. The RDE of ceritinib was established as 510 mg/m2 (fasted) and 500 mg/m2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and sevenwith other tumour types) were treated with ceritinib at the RDE (13 patients at 510mg/m2 fasted and 42 patients at 500 mg/m2 fed). The median follow-up was 33·3 months (IQR 24·8–39·3) for patients with neuroblastoma,33·2 months (27·9–35·9) for those with IMT, 34·0 months (21·9–46·4) for those withALCL, and 27·5 months (22·4–36·9) for patients with other tumour types. An overallresponse was recorded in six (20%; 95% CI 8–39) of 30 patients with neuroblastoma,seven (70%; 33–93) of ten patients with IMT, six (75%; 35–97) of eight patients withALCL, and one (14%; <1–58) of seven patients with other tumours. The safety profileof ceritinib was consistent with that observed in adult patients. All patients hadat least one adverse event. Grade 3 or 4 adverse events occurred in 67 (81%) of 83patients and were mostly increases in aminotransferases (alanine aminotransferaseincrease in 38 [46%] patients and aspartate aminotransferase increase in 27 [33%]patients). At least one serious adverse event was reported in 40 (48%) of 83 patientsand 31 (37%) of 83 patients had at least one grade 3 or 4 serious adverse event. 14(17%) deaths occurred during the study, of which 12 were on-treatment deaths and twowere after 30 days of the last dose. Of the 12 on-treatment deaths, ten were due todisease progression (neuroblastoma), one due to sepsis, and one due to intractablehypotension.
Interpretation : Ceritinib 500 mg/m2 once daily with food is the recommended dose for paediatric patients with ALK-positivemalignancies. Ceritinib showed promising preliminary antitumour activity in patientswith ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsedor refractory neuroblastoma, with a manageable safety profile. Our data support thenotion that ALK inhibitors should be considered in therapeutic strategies for paediatricpatients with malignancies with genetic ALK alterations.
The Lancet Oncology , résumé, 2020