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

Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial
Survival for children with high risk neuroblastoma remains approximately 50%. Neuroblastoma cells are sensitive to mTOR inhibitors (such as temsirolimus) in vitro and in vivo. Dinutuximab is a chimeric antibody targeting GD2, which is expressed on neuroblastoma cells. This trial was designed to determine whether dinituximab or temsirolimus should be used in the next front-line trial in combination with chemotherapy.
This open-label, randomized, phase 2 "pick-the-winner" COG trial (ANBL 1221) included patients of any age with neuroblastoma or ganglioneuroblastoma at first designation of relapse, progression, or refractory disease. Patients were excluded if bone marrow was the only site of disease or if they were previously treated for refractory or relapsed disease (including if they previously received irinotecan-temozolomide). Patients all received irinotecan and temozolamide with the randomized addition of either temsirolimus or dinutuximab (plus GM-CSF) in 21-day cycles up to a maximum of 17 cycles. The primary endpoint was the proportion of patients achieving an objective response (complete or partial) after 6 cycles.
Between February 2013 and March 2015, 18 patients received irinotecan-temozolomide-temsirolimus and 17 patients received irinotecan-temozolomide-dinutuximab. Only 1 patient on the temsirolimus arm achieved a partial response while 9 patients on the dinutuximab arm had objective responses. In 7 of the 9 patients who responded to dinutuximab, the best response was seen after only 2 cycles. The toxicity profile of irinotecan-temozolomide-dinutuximab was manageable. Adverse events known to accompany dinutuximab (pain, fever, electrolyte abnormalities) were seen although hematological toxicity was relatively modest.
Small sample size is a limitation. As well, only patients with first episode of relapsed or refractory disease were included, so the role of this therapy in other settings remains unclear. Overall survival may be impacted by other factors such as other therapy following the study treatment. It is unclear how many cycles therapy should be given for.
Irinotecan-temozolomide-dinutuximab showed notable anti-tumor activity in patients with relapsed or refractory neuroblastoma and met criteria for selection as the combination meriting further study. ANBL1221 is an ongoing study now with a single arm but responses in the relapsed population are encouraging as an initial strategy for patients with relapsed/refractory neuroblastoma who have not previously received dinutuximab and can tolerate toxicities of therapy.

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