Irinotecan and temozolomide combined with dasatinib and rapamycin for patients with relapsed or refractory neuroblastoma: Results of the prospective randomized RIST trial.

person Selim Corbacioglu University Hospital of Regensburg, Regensburg, Germany info_outline Selim Corbacioglu, Holger N. Lode, Marcus Jakob, Meinolf Suttorp, Gabriele Escherich, Bernd Gruhn, Susanne Ellinger, Thorsten Simon, Peter Lang, Marius Rohde, Florian Zeman, Klaus-Michael Debatin, Andreas Beilken, Peter Heiss, Dirk Hellwig, Markus Riemenschneider, Ruth Lydia Ladenstein, Konrad Bochennek, Angelika Eggert, Juergen Foell

Authors person Selim Corbacioglu University Hospital of Regensburg, Regensburg, Germany info_outline Selim Corbacioglu, Holger N. Lode, Marcus Jakob, Meinolf Suttorp, Gabriele Escherich, Bernd Gruhn, Susanne Ellinger, Thorsten Simon, Peter Lang, Marius Rohde, Florian Zeman, Klaus-Michael Debatin, Andreas Beilken, Peter Heiss, Dirk Hellwig, Markus Riemenschneider, Ruth Lydia Ladenstein, Konrad Bochennek, Angelika Eggert, Juergen Foell Organizations University Hospital of Regensburg, Regensburg, Germany, University Medicine Greifswald, Pediatric Hematology and Oncology, Greifswald, Germany, University Medical Center Regensburg; Department of Pediatric Hematology, Oncologa and Stem Cell Transplantation, Regenaburg, Germany, University Medical Center Dresden, Dresden, Germany, University Medical Center Eppendorf Hamburg, Hamburg, Germany, University of Jena, Jena, Germany, University Medical Center Regensburg; Department of Pediatric Hematology, Oncologa and Stem Cell Transplantation, Regensburg, Germany, University Medical Center Cologne; Department of Pediatric Hematology and Oncology, Köln, Germany, University Children's Hospital, Tubingen, Germany, University Medical Center Giessen; Department of Pediatric Hematology and Oncology, Giessen, Germany, University Medical Center Regensburg; Center for Clinical Trials, Regensburg, Germany, University Medical Center Ulm, Germany; Department of Pediatric Hematology and Oncology, Ulm, Germany, Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany, University Medical Center Regensburg, Germany; Department for Radiology, Regensburg, Germany, University Medical Center Regensburg, Germany; Department of Nuclear Medicine, Regensburg, Germany, University of Regensburg, Regensburg, Germany, St. Anna Children's Hospital and St. Anna Kinderkrebsforschung, Department of Paediatrics, Medical University Vienna, Vienna, Austria, University Medical Center Frankfurt/Main; Department of Pediatric Hematology and Oncology, Frankfurt/Main, Germany, Charité, University Medical Center, Berlin, Germany, University Medical Center Regensburg, Germany; Department of Pediatric Hematology, Oncologa and Stem Cell Transplantation, Regensburg, Germany Abstract Disclosures Research Funding Other Deutsche Krebshilfe Background: Relapsed or refractory neuroblastoma (r/rNB) are associated with a dismal outcome. RIST is the acronym for irinotecan and temozolomide (I/T) as backbone in combination with dasatinib (S) and rapamycin (R) aligned in a molecular targeted, metronomic design. Methods: RIST-rNB-2011, an open label randomised Phase II trial (NCT01467986), compared RIST (experimental arm) with I/T (control arm; CA). Patients with high-risk r/rNB (stage 4 and all MYCN amplified stages; MYCN+) were randomized with a block-wise (block length of 6) randomization stratified by MYCN. RIST treatment consists of courses of R/S (4 days/week) followed by I/T (5 days/week). Phase 1 is defined by 4 cycles with one R/S and one I/T course (8 weeks). In phase 2 each of the 4 cycles comprise 2 R/S and 1 I/T course (12 weeks). CA consisted of I/T courses only.The primary endpoint was progression-free survival (PFS), analysed by a Cox proportional hazards model adjusted for MYCN- to test the null hypothesis of a hazard ratio of 1 assuming proportional hazard rates at a two-sided 5% significance level. A point estimate and a two-sided 95% confidence interval was provided. A sample size of N = 114 patients was calculated. Primary analysis was based on the intention-to-treat principle (ITT). Toxicity was assessed in all participants who received at least one dose of protocol therapy. Results: Subjects (N = 124) eligible for follow-up were enrolled from 08/2012 – 09/2020. Median age was 5.37 years (y) (range 1.1 – 24.6 y). Disease characteristics were relapse in 80% ( < 18 months (m) after diagnosis: 40%) and refractory disease in 20%, MYCN+ was present in 39%. Median overall follow-up was 72 m. In the ITT population median PFS was 11 m in RIST vs 5 m in CA (HR: 0.62 (95%-CI: 0.42, 0.92), p = 0.019), and 16 m in RIST vs 4 m in the CA (HR: 0.53 (95%-CI: 0.31, 0.90), p = 0.018) in the per protocol (PP) population. Subgroup analyses showed a selective effect in the MYCN+ (HR: 0.45 (95%-CI: 0.24, 0.84), p = 0.012) compared to MYCN- patients (HR: 0.84 (95%-CI: 0.51, 1.38), p = 0.492). PFS at 2 y in MYCN+ was 38% vs 8% in CA (ITT) and 50% vs 6% (PP), respectively. In MYCN+ patients with a relapse < 18 m from initial diagnosis (N = 33) PFS remained significantly better (p = 0.048). Median overall survival (OS) for RIST vs CA was 20 m vs 16 m in ITT (HR: 0.68 (95%-CI: 0.45, 1.04), p = 0.073) and 26 m vs 16 m in PP (HR: 0.55 (95%-CI: 0.32, 0.98), p = 0.041). OS was significantly better in MYCN+ patients: 11 m vs 6.5 m in ITT (HR: 0.51 (95%-CI: 0.27, 0.96), p = 0.037) and 17 m vs 5 m in PP (HR: 0.34 (95%-CI: 0.14, 0.83), p = 0.018). In MYCN- no differences were observed neither in PFS nor in OS. R/S did not add additional toxicity to I/T. Conclusions: RIST was well tolerated and led to a significantly improved PFS and OS in MYCN+ patients, allowing a targeted approach for this high-risk population. Clinical trial information: NCT01467986.