Elsevier

The Lancet Oncology

Volume 18, Issue 7, July 2017, Pages 946-957
The Lancet Oncology

Articles
Irinotecan–temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30355-8Get rights and content

Summary

Background

Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its acceptable toxicity profile makes it an excellent backbone for study of new agents. We aimed to test the addition of temsirolimus or dinutuximab to irinotecan–temozolomide in patients with relapsed or refractory neuroblastoma.

Methods

For this open-label, randomised, phase 2 selection design trial of the Children's Oncology Group (COG; ANBL1221), patients had to have histological verification of neuroblastoma or ganglioneuroblastoma at diagnosis or have tumour cells in bone marrow with increased urinary catecholamine concentrations at diagnosis. Patients of any age were eligible at first designation of relapse or progression, or first designation of refractory disease, provided organ function requirements were met. Patients previously treated for refractory or relapsed disease were ineligible. Computer-based randomisation with sequence generation defined by permuted block randomisation (block size two) was used to randomly assign patients (1:1) to irinotecan and temozolomide plus either temsirolimus or dinutuximab, stratified by disease category, previous exposure to anti-GD2 antibody therapy, and tumour MYCN amplification status. Patients in both groups received oral temozolomide (100 mg/m2 per dose) and intravenous irinotecan (50 mg/m2 per dose) on days 1–5 of 21-day cycles. Patients in the temsirolimus group also received intravenous temsirolimus (35 mg/m2 per dose) on days 1 and 8, whereas those in the dinutuximab group received intravenous dinutuximab (17·5 mg/m2 per day or 25 mg/m2 per day) on days 2–5 plus granulocyte macrophage colony-stimulating factor (250 μg/m2 per dose) subcutaneously on days 6–12. Patients were given up to a maximum of 17 cycles of treatment. The primary endpoint was the proportion of patients achieving an objective (complete or partial) response by central review after six cycles of treatment, analysed by intention to treat. Patients, families, and those administering treatment were aware of group assignment. This study is registered with ClinicalTrials.gov, number NCT01767194, and follow-up of the initial cohort is ongoing.

Findings

Between Feb 22, 2013, and March 23, 2015, 36 patients from 27 COG member institutions were enrolled on this groupwide study. One patient was ineligible (alanine aminotransferase concentration was above the required range). Of the remaining 35 patients, 18 were randomly assigned to irinotecan–temozolomide–temsirolimus and 17 to irinotecan–temozolomide–dinutuximab. Median follow-up was 1·26 years (IQR 0·68–1·61) among all eligible participants. Of the 18 patients assigned to irinotecan–temozolomide–temsirolimus, one patient (6%; 95% CI 0·0–16·1) achieved a partial response. Of the 17 patients assigned to irinotecan–temozolomide–dinutuximab, nine (53%; 95% CI 29·2–76·7) had objective responses, including four partial responses and five complete responses. The most common grade 3 or worse adverse events in the temsirolimus group were neutropenia (eight [44%] of 18 patients), anaemia (six [33%]), thrombocytopenia (five [28%]), increased alanine aminotransferase (five [28%]), and hypokalaemia (four [22%]). One of the 17 patients assigned to the dinutuximab group refused treatment after randomisation; the most common grade 3 or worse adverse events in the remaining 16 patients evaluable for safety were pain (seven [44%] of 16), hypokalaemia (six [38%]), neutropenia (four [25%]), thrombocytopenia (four [25%]), anaemia (four [25%]), fever and infection (four [25%]), and hypoxia (four [25%]); one patient had grade 4 hypoxia related to therapy that met protocol-defined criteria for unacceptable toxicity. No deaths attributed to protocol therapy occurred.

Interpretation

Irinotecan–temozolomide–dinutuximab met protocol-defined criteria for selection as the combination meriting further study whereas irinotecan–temozolomide–temsirolimus did not. Irinotecan–temozolomide–dinutuximab shows notable anti-tumour activity in patients with relapsed or refractory neuroblastoma. Further evaluation of biomarkers in a larger cohort of patients might identify those most likely to respond to this chemoimmunotherapeutic regimen.

Funding

National Cancer Institute.

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

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