Corbacioglu, Selim and Lode, Holger and Ellinger, Susanne and Zeman, Florian and Suttorp, Meinolf and Escherich, Gabriele and Bochennek, Konrad and Gruhn, Bernd and Lang, Peter and Rohde, Marius and Debatin, Klaus Michael and Steinbach, Daniel and Beilken, Andreas and Ladenstein, Ruth and Spachtholz, Rainer and Heiss, Peter and Hellwig, Dirk and Troeger, Anja and Koller, Michael and Menhart, Karin and Riemenschneider, Markus J. and Zoubaa, Saida and Kietz, Silke and Jakob, Marcus and Sommer, Gunhild and Heise, Tilman and Hundsdoerfer, Patrick and Kuehnle, Ingrid and Dilloo, Dagmar and Schoenberger, Stefan and Schwabe, Georg and von Luettichau, Irene and Graf, Norbert and Schlegel, Paul-Gerhardt and Fruehwald, Michael and Jorch, Norbert and Paulussen, Michael and Schneider, Dominik T. and Metzler, Markus and Leipold, Alfred and Nathrath, Michaela and Imschweiler, Thomas and Christiansen, Holger and Schmid, Irene and Crazzolara, Roman and Niktoreh, Naghmeh and Cario, Gunnar and Faber, Joerg and Demmert, Martin and Babor, Florian and Froehlich, Birgit and Bielack, Stefan and Bernig, Toralf and Greil, Johann and Eggert, Angelika and Simon, Thorsten and Foell, Juergen (2024) 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. LANCET ONCOLOGY, 25 (7). pp. 922-932. ISSN 1470-2045, 1474-5488
Full text not available from this repository. (Request a copy)Abstract
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/m(2) on day 1, maintenance 1 mg/m(2) 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/m(2) per day] and oral temozolomide [150 mg/m(2) 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<middle dot>4 years (IQR 3<middle dot>7-8<middle dot>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<middle dot>62, one-sided 90% CI 0<middle dot>81; p=0<middle dot>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<middle dot>45 [95% CI 0<middle dot>24-0<middle dot>84], p=0<middle dot>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<middle dot>84 [95% CI 0<middle dot>51-1<middle dot>38], p=0<middle dot>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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HIGH-RISK NEUROBLASTOMA; GROWTH IN-VITRO; CHILDREN; INHIBITORS; CELLS; CHEMOTHERAPY; TEMSIROLIMUS; PROGRESSION; EXPRESSION; SURVIVAL |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation Medicine > Abteilung für Neuropathologie Medicine > Lehrstuhl für Röntgendiagnostik Medicine > Abteilung für Nuklearmedizin Medicine > Zentren des Universitätsklinikums Regensburg > Zentrum für Klinische Studien |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Jan 2026 08:57 |
| Last Modified: | 27 Jan 2026 08:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65069 |
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