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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

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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, Vol. 25, No. 7, 07.2024, p. 922-932.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Corbacioglu, S, Lode, H, Ellinger, S, Zeman, F, Suttorp, M, Escherich, G, Bochennek, K, Gruhn, B, Lang, P, Rohde, M, Debatin, KM, Steinbach, D, Beilken, A, Ladenstein, R, Spachtholz, R, Heiss, P, Hellwig, D, Tröger, A, Koller, M, Menhart, K, Riemenschneider, MJ, Zoubaa, S, Kietz, S, Jakob, M, Sommer, G, Heise, T, Hundsdörfer, P, Kühnle, I, Dilloo, D, Schönberger, S, Schwabe, G, von Luettichau, I, Graf, N, Schlegel, P-G, Frühwald, M, Jorch, N, Paulussen, M, Schneider, DT, Metzler, M, Leipold, A, Nathrath, M, Imschweiler, T, Christiansen, H, Schmid, I, Crazzolara, R, Niktoreh, N, Cario, G, Faber, J, Demmert, M, Babor, F, Fröhlich, B, Bielack, S, Bernig, T, Greil, J, Eggert, A, Simon, T & Foell, J 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 ONCOL, vol. 25, no. 7, pp. 922-932. https://doi.org/10.1016/S1470-2045(24)00202-X

APA

Corbacioglu, S., Lode, H., Ellinger, S., Zeman, F., Suttorp, M., Escherich, G., Bochennek, K., Gruhn, B., Lang, P., Rohde, M., Debatin, K. M., Steinbach, D., Beilken, A., Ladenstein, R., Spachtholz, R., Heiss, P., Hellwig, D., Tröger, A., Koller, M., ... Foell, J. (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 ONCOL, 25(7), 922-932. https://doi.org/10.1016/S1470-2045(24)00202-X

Vancouver

Corbacioglu S, Lode H, Ellinger S, Zeman F, Suttorp M, Escherich G et al. 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 ONCOL. 2024 Jul;25(7):922-932. https://doi.org/10.1016/S1470-2045(24)00202-X

Bibtex

@article{5ec3c77bd59440c5919f249c91e961ad,
title = "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",
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/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.",
keywords = "Humans, Temozolomide/administration & dosage, Irinotecan/administration & dosage, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Male, Female, Neuroblastoma/drug therapy, Child, Preschool, Child, Dasatinib/administration & dosage, Adolescent, Neoplasm Recurrence, Local/drug therapy, Infant, Adult, Sirolimus/administration & dosage, Young Adult, Germany, Drug Resistance, Neoplasm, Progression-Free Survival",
author = "Selim Corbacioglu and Holger Lode and Susanne Ellinger and Florian Zeman and Meinolf Suttorp and Gabriele Escherich and Konrad Bochennek and Bernd Gruhn and Peter Lang and Marius Rohde and Debatin, {Klaus Michael} and Daniel Steinbach and Andreas Beilken and Ruth Ladenstein and Rainer Spachtholz and Peter Heiss and Dirk Hellwig and Anja Tr{\"o}ger and Michael Koller and Karin Menhart and Riemenschneider, {Markus J} and Saida Zoubaa and Silke Kietz and Marcus Jakob and Gunhild Sommer and Tilman Heise and Patrick Hundsd{\"o}rfer and Ingrid K{\"u}hnle and Dagmar Dilloo and Stefan Sch{\"o}nberger and Georg Schwabe and {von Luettichau}, Irene and Norbert Graf and Paul-Gerhardt Schlegel and Michael Fr{\"u}hwald and Norbert Jorch and Michael Paulussen and Schneider, {Dominik T} and Markus Metzler and Alfred Leipold and Michaela Nathrath and Thomas Imschweiler and Holger Christiansen and Irene Schmid and Roman Crazzolara and Naghmeh Niktoreh and Gunnar Cario and Joerg Faber and Martin Demmert and Florian Babor and Birgit Fr{\"o}hlich and Stefan Bielack and Toralf Bernig and Johann Greil and Angelika Eggert and Thorsten Simon and Juergen Foell",
note = "Copyright {\textcopyright} 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.",
year = "2024",
month = jul,
doi = "10.1016/S1470-2045(24)00202-X",
language = "English",
volume = "25",
pages = "922--932",
journal = "LANCET ONCOL",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "7",

}

RIS

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 -