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
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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. / Corbacioglu, Selim; Lode, Holger; Ellinger, Susanne; Zeman, Florian; Suttorp, Meinolf; Escherich, Gabriele; Bochennek, Konrad; Gruhn, Bernd; Lang, Peter; Rohde, Marius; Debatin, Klaus Michael; Steinbach, Daniel; Beilken, Andreas; Ladenstein, Ruth; Spachtholz, Rainer; Heiss, Peter; Hellwig, Dirk; Tröger, Anja; Koller, Michael; Menhart, Karin; Riemenschneider, Markus J; Zoubaa, Saida; Kietz, Silke; Jakob, Marcus; Sommer, Gunhild; Heise, Tilman; Hundsdörfer, Patrick; Kühnle, Ingrid; Dilloo, Dagmar; Schönberger, Stefan; Schwabe, Georg; von Luettichau, Irene; Graf, Norbert; Schlegel, Paul-Gerhardt; Frühwald, Michael; Jorch, Norbert; Paulussen, Michael; Schneider, Dominik T; Metzler, Markus; Leipold, Alfred; Nathrath, Michaela; Imschweiler, Thomas; Christiansen, Holger; Schmid, Irene; Crazzolara, Roman; Niktoreh, Naghmeh; Cario, Gunnar; Faber, Joerg; Demmert, Martin; Babor, Florian; Fröhlich, Birgit; Bielack, Stefan; Bernig, Toralf; Greil, Johann; Eggert, Angelika; Simon, Thorsten; Foell, Juergen.
in: LANCET ONCOL, Jahrgang 25, Nr. 7, 07.2024, S. 922-932.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - 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
AU - Corbacioglu, Selim
AU - Lode, Holger
AU - Ellinger, Susanne
AU - Zeman, Florian
AU - Suttorp, Meinolf
AU - Escherich, Gabriele
AU - Bochennek, Konrad
AU - Gruhn, Bernd
AU - Lang, Peter
AU - Rohde, Marius
AU - Debatin, Klaus Michael
AU - Steinbach, Daniel
AU - Beilken, Andreas
AU - Ladenstein, Ruth
AU - Spachtholz, Rainer
AU - Heiss, Peter
AU - Hellwig, Dirk
AU - Tröger, Anja
AU - Koller, Michael
AU - Menhart, Karin
AU - Riemenschneider, Markus J
AU - Zoubaa, Saida
AU - Kietz, Silke
AU - Jakob, Marcus
AU - Sommer, Gunhild
AU - Heise, Tilman
AU - Hundsdörfer, Patrick
AU - Kühnle, Ingrid
AU - Dilloo, Dagmar
AU - Schönberger, Stefan
AU - Schwabe, Georg
AU - von Luettichau, Irene
AU - Graf, Norbert
AU - Schlegel, Paul-Gerhardt
AU - Frühwald, Michael
AU - Jorch, Norbert
AU - Paulussen, Michael
AU - Schneider, Dominik T
AU - Metzler, Markus
AU - Leipold, Alfred
AU - Nathrath, Michaela
AU - Imschweiler, Thomas
AU - Christiansen, Holger
AU - Schmid, Irene
AU - Crazzolara, Roman
AU - Niktoreh, Naghmeh
AU - Cario, Gunnar
AU - Faber, Joerg
AU - Demmert, Martin
AU - Babor, Florian
AU - Fröhlich, Birgit
AU - Bielack, Stefan
AU - Bernig, Toralf
AU - Greil, Johann
AU - Eggert, Angelika
AU - Simon, Thorsten
AU - Foell, Juergen
N1 - Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
PY - 2024/7
Y1 - 2024/7
N2 - 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.FUNDING: Deutsche Krebshilfe.
AB - 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.FUNDING: Deutsche Krebshilfe.
KW - Humans
KW - Temozolomide/administration & dosage
KW - Irinotecan/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Male
KW - Female
KW - Neuroblastoma/drug therapy
KW - Child, Preschool
KW - Child
KW - Dasatinib/administration & dosage
KW - Adolescent
KW - Neoplasm Recurrence, Local/drug therapy
KW - Infant
KW - Adult
KW - Sirolimus/administration & dosage
KW - Young Adult
KW - Germany
KW - Drug Resistance, Neoplasm
KW - Progression-Free Survival
U2 - 10.1016/S1470-2045(24)00202-X
DO - 10.1016/S1470-2045(24)00202-X
M3 - SCORING: Journal article
C2 - 38936379
VL - 25
SP - 922
EP - 932
JO - LANCET ONCOL
JF - LANCET ONCOL
SN - 1470-2045
IS - 7
ER -