Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study

Abstract

Summary Background Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. Methods In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2 per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials. gov, NCT00939770. Findings 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10·1 years (range 1·1–21·4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1–6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). Interpretation The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbou...

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2immunotherapy and isotretinoin: a prospective Phase II study

“…Tumor burden might be significantly reduced by surgery and high-dose salvage conventional chemotherapy regimens, 33,36 supplemented by local radiotherapy and relatively non-toxic systemic therapies that are noncross-resistant with prior treatments and have anti-NB activity. Examples include investigative agents 1 (e.g., fenretinide 37 and crizotinib 38 ), and targeted radiotherapy using 131 I-MIBG or radiolabeled mAbs. 39,40 Immunotherapy with anti-G D2 mAbs might eradicate remaining MRD, as has been documented in patients in first CR/VGPR 23 and as shown now in the current report on second or later CR/VGPR.…”

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK+ T‐cell lymphoma

“…Using TrkAi as a monotherapy or combined with low concentrations of CHOP hindered the growth of the lymphoma tumors in vivo and improved mice survival. Although selective ALK inhibitors represent an emerging strategy to treat ALK + neoplasms including NPM‐ALK + T‐cell lymphoma (Mosse et al ., 2013), several resistance mechanisms to these inhibitors have been already identified and characterized, which represents an important limitation (Dong et al ., 2016; Isozaki et al ., 2016; Katayama et al ., 2016; Zdzalik et al ., 2014). Our findings suggest that TrkA inhibition could represent an alternative therapeutic approach to tackle this aggressive neoplasm.…”

Targeted immunotherapy for pediatric solid tumors

“…38,39 A COG phase I study was completed in refractory solid tumors and anaplastic large cell lymphoma (NCT00939770), it was well tolerated and antitumor activity was appreciated in tumors with ALK translocations. 40 Crizotinib continues to be tested in the phase II setting in relapsed/refractory solid tumors with ALK mutations (NCT00939770 and NCT02034981). A second generation ALK inhibitor, Ceritnib (LDK-378) was developed after resistance ensued in patients with primary ALK mutated lung tumors with Crizotinib.…”