Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial
Creators: name: Corbacioglu, Selim
name: Lode, Holger
name: Ellinger, Susanne
name: Zeman, Florian
name: Suttorp, Meinolf
name: Escherich, Gabriele
name: Bochennek, Konrad
name: Gruhn, Bernd
name: Lang, Peter
name: Rohde, Marius
name: Debatin, Klaus Michael
name: Steinbach, Daniel
name: Beilken, Andreas
name: Ladenstein, Ruth
name: Spachtholz, Rainer
name: Heiss, Peter
name: Hellwig, Dirk
name: Tröger, Anja
name: Koller, Michael
name: Menhart, Karin
name: Riemenschneider, Markus J.
name: Zoubaa, Saida
name: Kietz, Silke
name: Jakob, Marcus
name: Sommer, Gunhild
name: Heise, Tilman
name: Hundsdörfer, Patrick
name: Kühnle, Ingrid
name: Dilloo, Dagmar
name: Schönberger, Stefan
name: Schwabe, Georg
name: von Luettichau, Irene
name: Graf, Norbert
name: Schlegel, Paul-Gerhardt
name: Frühwald, Michael
name: Jorch, Norbert
name: Paulussen, Michael
name: Schneider, Dominik T.
name: Metzler, Markus
name: Leipold, Alfred
name: Nathrath, Michaela
name: Imschweiler, Thomas
name: Christiansen, Holger
name: Schmid, Irene
name: Crazzolara, Roman
name: Niktoreh, Naghmeh
name: Cario, Gunnar
name: Faber, Joerg
name: Demmert, Martin
name: Babor, Florian
name: Fröhlich, Birgit
name: Bielack, Stefan
name: Bernig, Toralf
name: Greil, Johann
name: Eggert, Angelika
name: Simon, Thorsten
name: Foell, Juergen
Publisher: name: Universität Regensburg
Year: 2024
Subjects: subject: 610 Medizin

description: Background
Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan–temozolomide and dasatinib–rapamycin (RIST) in patients with relapsed or refractory neuroblastoma.
Methods
The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1–25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan–temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2–4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin–dasatinib and irinotecan–temozolomide for four cycles over 8 weeks, then two courses of rapamycin–dasatinib followed by one course of irinotecan–temozolomide for 12 weeks) with irinotecan–temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual.
Findings
Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7–8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31–88), the median progression-free survival was 11 months (95% CI 7–17) in the RIST group and 5 months (2–8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4–24) in the RIST group versus 2 months (2–5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9–7) in the RIST group versus 8 months (4–15) in the control group (HR 0·84 [95% CI 0·51–1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure).
Interpretation
RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting.