ArticlesSafety 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
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.
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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
References (30)
- et al.
Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK
Neoplasia
(2009) - et al.
Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis
Lancet Oncol
(2011) - et al.
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study
Lancet Oncol
(2012) - et al.
Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma
Blood
(2007) - et al.
A new 123I-MIBG whole body scan scoring method—application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma
Eur J Cancer
(1995) - et al.
Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90
Blood
(2001) - et al.
Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma
Oncogene
(2012) - et al.
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma
Science
(1994) - et al.
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK
Proc Natl Acad Sci USA
(2011) - et al.
Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors
Cancer Res
(1999)
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer
Nature
Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method
Cancer
Oncogenic mutations of ALK kinase in neuroblastoma
Nature
Activating mutations in ALK provide a therapeutic target in neuroblastoma
Nature
Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma
Nature
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