Background
Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide (I/T) has activity in these patients, and the toxicity profile of I/T makes it an excellent backbone for study of new agents. Temsirolimus (TEM) and dinutuximab (DIN) were selected for testing with I/T in subjects with relapsed or refractory neuroblastoma.
Methods
Children’s Oncology Group (COG) ANBL1221, a randomised Phase II selection design trial, compared response and toxicity in subjects treated with I/T and either temsirolimus (I/T/TEM) or dinutuximab with granulocyte-macrophage colony stimulating factor (I/T/DIN). Patients were eligible at first relapse/progression or first designation of refractory disease, provided organ function requirements were met. Patients had to have histologic verification of neuroblastoma and/or demonstration of tumour cells in bone marrow with increased urinary catecholamines at diagnosis. Patients were eligible at first designation of relapse (defined as recurrence after response to treatment), or first designation of refractory disease (defined as inadequate response to treatment that included at least 4 cycles of ≥2 chemotherapeutic agents, including an alkylator and a platinum-containing compound. Patients previously treated for refractory or relapsed disease were ineligible. Computer-based randomisation with sequence generation defined by permuted block randomisation, with blocks of size 2, was used to assign patients 1:1 to I/T/TEM or I/T/DIN. Randomisation was stratified to ensure equal distribution of disease category (measurable vs. evaluable), prior exposure to anti-GD2 antibody therapy, and tumour MYCN amplification status. Patients on both regimens received oral temozolomide (100 mg/m2/dose) and intravenous (IV) irinotecan (50 mg/m2/dose) on days 1–5 of 21-day cycles. TEM (35 mg/m2/dose IV) was given on days 1 and 8. DIN (17·5 or 25 mg/m2/day IV) was administered on days 2–5. The primary endpoint was objective (complete or partial) response; responses were centrally reviewed by an independent panel of radiologists. Response was analysed on an intent-to-treat basis. Toxicity was assessed in all participants who received at least one dose of protocol therapy. Follow up of the initial cohort is ongoing. This study is registered at ClinicalTrials.gov (NCT01767194).
Findings
Thirty-five eligible subjects were enrolled from February 22, 2013-March 23, 2015. Median age was 5.7 years (range 2·1–16·2 years; interquartile range (IQR) 4·5–9·1 years). Among 18 subjects randomised to I/T/TEM, 1 PR was observed (5·6%, 95% confidence interval (CI): [0·0%, 16·1%]). Among 17 patients randomised to I/T/DIN, 9 (53%, 95% CI: [29·2%, 76·7%]) had objective responses (4 PR, 5 CR), including responses in 5/10 patients with relapsed/progressive disease and 4/7 with refractory disease. I/T/DIN met protocol-defined criteria for selection as the combination meriting further study.
The most common ≥Grade 3 toxicities among I/T/TEM patients were neutropenia ...