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

Abstract

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 ...

Managing local‐regional failure in children with high‐risk neuroblastoma: A single institution experience

“…’ Most patients in our series were managed with ICE at relapse, although some were treated with IT. The use of IT in combination with dinutuximab, an anti‐GD2 monoclonal antibody, is now a favored regimen given the recent (March 2015) FDA approval for primary therapy . Only one patient in our series was managed with anti‐GD2 monoclonal antibody at relapse and is alive at present with stable disease.…”

“…More recently, 5‐day IT has been shown to have favorable response rates, minimal organ toxicity, and limited immunosuppression, and as a result has become the backbone for addition of other agents . ’ Most patients in our series were managed with ICE at relapse, although some were treated with IT. The use of IT in combination with dinutuximab, an anti‐GD2 monoclonal antibody, is now a favored regimen given the recent (March 2015) FDA approval for primary therapy .…”

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

“…Furthermore, the data also revealed idasanutlin mediated downregulation of MTORC1 signalling which has previously been linked to chemoresistance and could therefore sensitise cells to temozolomide. However, a recent Phase II trial of irinotecan‐temozolomide with temsirolimus in children with refractory/relapsed neuroblastoma did not observe outcomes meriting further study . A recent study has reported potent preclinical efficacy combining the MTORC1 inhibitor temsirolimus with idasanutlin in neuroblastoma preclinical models .…”

Anti-GD2 immunotherapy for neuroblastoma

“…[82] Preliminary results from a randomized phase II study conducted by the COG (NCT01767194) indicate a significantly higher response rate to a combination of dinutuximab, irinotecan, temozolomide and GMCSF compared to the combination of dinutuximab and temsirolimus (52.9% versus 5.5%), though the former group also had a higher complication rate including respiratory and renal toxicities. [83] A more definitive study of the chemoimmunotherapy arm is under way to further evaluate response and toxicity. A further chemoimmunotherapy strategy using hu3F8, though with different timing of therapeutic components is also being tested at MSKCC.…”

“…[83] Although these findings need to be confirmed in a larger population of patients, and the mechanism of synergy elucidated, the possible role of chemoimmunotherapy as part of first-line chemotherapy for HR-NB is being considered for investigation. MoAb-based radioimmunotherapy has thus far been hampered by collateral BM damage due to off-target effects.…”