Elsevier

The Lancet Oncology

Volume 14, Issue 6, May 2013, Pages 472-480
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(13)70095-0Get rights and content

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 harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted.

Funding

Pfizer and National Cancer Institute grant to the Children's Oncology Group.

Introduction

The ALK oncogene is a promising therapeutic target in a subset of human malignancies. ALK, an orphan receptor tyrosine kinase (RTK) usually expressed in the developing nervous system,1 was originally cloned from a cytogenetically recognisable translocation between chromosomes 2 and 5 that fused the kinase domain of ALK to the protein dimerisation domain of NPM.2 Over a dozen ALK fusion partners have since been identified including RANBP2 in inflammatory myofibroblastic tumour,3, 4 EML4 in 3–7% of non-small-cell lung cancers (NSCLCs),5 and TPM3 in renal cancer.6 The discovery of activating mutations in the tyrosine kinase domain of the ALK oncogene as the most common cause of hereditary neuroblastoma, and the finding that these mutations are also somatically acquired in 7–10% of sporadic cases, provides a tractable molecular target.7, 8, 9, 10 Others have suggested an oncogenic role for overexpressed but non-mutated ALK in lung cancer,11 thyroid cancer (rare mutations identified),12 glioblastoma multiforme,13 and rhabdomyosarcoma.14

Crizotinib, a small molecule competitive inhibitor of ALK and MET kinase activity, has transformed the therapeutic landscape of NSCLC harbouring ALK translocations, yielding high response rates in chemotherapy-refractory patients.15, 16 Crizotinib has also shown efficacy, such as high cytoreductive antitumour activity, in preclinical models of neuroblastoma17 and anaplastic large-cell lymphoma18 that express activated translocated, mutated, or amplified ALK. These combined data have provided the rationale for ALK inhibition as a useful therapeutic strategy in neuroblastoma, anaplastic large-cell lymphoma, and potentially other paediatric tumours.

We aimed to study the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma.

Section snippets

Study design and participants

Children's Oncology Group (COG) study ADVL0912 had three primary aims: (1) to estimate the maximum tolerated dose and recommended phase 2 dose of crizotinib given orally twice daily to children with relapsed or refractory solid tumours and anaplastic large-cell lymphoma; (2) to define and describe the toxic effects of crizotinib given on this schedule; and (3) to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Secondary endpoints included examining best

Results

79 patients with a median age of 10·1 years (range 1·1–21·4) were enrolled in the study from Oct 2, 2009, to May 31, 2012 (table 1); all were eligible for enrolment and began therapy, and 65 were fully evaluable for DLT. 14 patients were not fully evaluable for toxic effects, mainly because of disease progression before completion of the first cycle (12 from the dose escalation group, and one each in the other two groups in the study). Eight of the patients in the neuroblastoma group were not

Discussion

Our results show that crizotinib, a targeted inhibitor of ALK, was well tolerated in children with recurrent or refractory cancer; that the recommended phase 2 dose of 280 mg/m2 twice daily was about twice the recommended adult dose; and most notably, that single-agent crizotinib therapy resulted in objective antitumour activity against recurrent or refractory paediatric malignancies harbouring ALK translocations or oncogenic mutations, particularly anaplastic large-cell lymphoma. The design of

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