ArticlesIrinotecan–temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial
Introduction
Despite the use of maximally intensive treatment, survival for children with newly diagnosed high-risk neuroblastoma remains about 50%.1 Molecularly targeted therapies are being studied, and the combination of targeted agents with chemotherapy could be advantageous. Irinotecan and temozolomide can be safely administered to patients with relapsed or refractory neuroblastoma, providing a backbone onto which targeted agents can be integrated.2, 3
Temsirolimus inhibits mTOR, which has a role in regulation of protein synthesis and cell proliferation.4 Neuroblastoma cells are sensitive to mTOR inhibitors in vitro and in vivo.5, 6 Although single-agent activity was modest in some preclinical studies,7, 8 data suggest that mTOR inhibitors might be effective in subsets of neuroblastoma tumours.9 Additionally, mTOR inhibitors have synergistic or additive effects when combined with chemotherapeutics.10, 11 Previous studies12, 13 provided information about temsirolimus dosing, and a Children's Oncology Group (COG) trial14 showed that irinotecan–temozolomide–temsirolimus could be delivered safely to children with relapsed or refractory solid tumours. In 15 evaluable patients with neuroblastoma, two had objective responses, supporting further study of this combination.14
Dinutuximab, a chimeric antibody targeting the disialoganglioside GD2, was also combined with irinotecan–temozolomide during our trial. GD2 is expressed on neuroblastoma cells, but expression in healthy tissues is restricted to cerebellar neurons, skin melanocytes, and peripheral pain fibres.15, 16, 17 Because of this expression pattern, anti-GD2 antibodies have been studied as targeted immunotherapy for neuroblastoma.18 Dinutuximab became a standard component of high-risk therapy after a randomised COG trial showed an improvement in event-free survival for patients assigned to receive dinutuximab with granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 2 following myeloablative therapy.19 GM-CSF was selected for use in this study rather than interleukin 2 because interleukin 2 has been associated with more substantial capillary leak syndrome and more frequent renal dysfunction when given in combination with dinutuximab.19 Because monoclonal antibodies in combination with chemotherapy were shown to be effective beyond the setting of minimal residual disease in adults,20, 21, 22, 23, 24, 25, 26, 27 the combination of irinotecan–temozolomide–dinutuximab with GM-CSF merits evaluation.
This COG trial (ANBL1221) was designed to study responses to irinotecan–temozolomide with either temsirolimus or dinutuximab. The primary objective was to determine whether temsirolimus or dinutuximab merits testing in a front-line trial for children with high-risk neuroblastoma.
Section snippets
Study design and participants
COG ANBL1221 was an open-label, randomised, phase 2 trial with a so-called pick-the-winner selection design,28, 29, 30 open to all member institutions in the COG, which includes more than 200 hospitals, universities, and cancer centres across North America, Australia, New Zealand, Europe, and in Saudi Arabia (appendix p 6). Within each treatment regimen, a Simon's two-stage activity design was used to ascertain whether a given regimen did not meet the minimum required clinical activity and
Results
Between Feb 22, 2013, and March 23, 2015, 36 patients were enrolled (figure 1). One patient's alanine aminotransferase concentration was above the required range for eligibility and was therefore ineligible. Of the remaining 35 patients, 18 were randomly assigned to irinotecan–temozolomide–temsirolimus and 17 to irinotecan–temozolomide–dinutuximab. One patient randomly assigned to the dinutuximab group withdrew before receiving any treatment; this patient was included in the intention-to-treat
Discussion
The results of our study show that the chemo-immunotherapy combination irinotecan–temozolomide–dinutuximab has substantial activity in patients with relapsed or refractory neuroblastoma, with a manageable toxicity profile. Nine of 17 patients randomly assigned to irinotecan–temozolomide–dinutuximab had objective responses whereas only one of 18 patients assigned to irinotecan–temozolomide–temsirolimus had an objective response. Therefore, the a-priori benchmark for activity (≥four of 17
References (62)
- et al.
Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma
J Hepatol
(2008) - et al.
Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma
Eur J Cancer
(2012) - et al.
Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord
Biochim Biophys Acta
(1994) - et al.
GD2-targeted immunotherapy and radioimmunotherapy
Semin Oncol
(2014) - et al.
The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group
Blood
(2004) - et al.
Immunogenic anti-cancer chemotherapy as an emerging concept
Curr Opin Immunol
(2008) - et al.
Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group
Blood
(2005) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009) - et al.
Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry
Eur J Cancer
(2009) - et al.
Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial
Lancet Oncol
(2013)
More than the genes, the tumor microenvironment in neuroblastoma
Cancer Lett
Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene
Blood
Advances in risk classification and treatment strategies for neuroblastoma
J Clin Oncol
Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study
J Clin Oncol
Irinotecan plus temozolomide for relapsed or refractory neuroblastoma
J Clin Oncol
Targeting PI3K/Akt/mTOR signaling in cancer
Front Oncol
Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo
Oncogene
Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program
Pediatr Blood Cancer
Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program
Pediatr Blood Cancer
Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program
Pediatr Blood Cancer
Targeting the mTOR complex by everolimus in NRAS mutant neuroblastoma
PLoS One
Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells
Clin Cancer Res
Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors
J Clin Oncol
Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group study
Pediatr Blood Cancer
Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients
Cancer Res
Monoclonal antibodies to a glycolipid antigen on human neuroblastoma cells
Cancer Res
Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma
N Engl J Med
CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma
N Engl J Med
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
N Engl J Med
Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors
Cancer Res
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
N Engl J Med
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