Phase Iia (Proof Of Concept) Trial Of Valproic Acid With Chemotherapy And Radiotherapy For Patients With Diffuse Intrinsic Pontine Glioma In Childhood And Adolescence - Valquiria
Creators: name: Felix, Francisco
Publisher: name: Zenodo
Year: 2016
Subjects: diffuse intrinsic pontine glioma, clinical trial, valproic acid, chemotherapy, radiotherapy

description: The treatment of pediatric patients with diffuse intrinsic pontine gliomas (DIPG) is still associated with unsatisfactory results. Virtually no patients with this disease have prolonged survival. Valproic acid (sodium valproate - VPA) is used for the treatment of seizures in patients with brain tumors. We compared the survival of patients treated with valproate with a historical untreated control. Comparing the overall and event-free survival in patients with DIPG, we found a statistically significant difference in favor of those who did seizure prophylaxis with VPA. This reassuring result led us to plan a prospective clinical trial evaluating survival in patients with DIPG treated with VPA associated with radiation and chemotherapy, compared with a historical control group treated with chemoradiation alone. The main objective is to evaluate the overall survive at 12 and 24 months in patients with diffuse intrinsic pontine glioma treated with a combination of chemoradiation and valproic acid. The secondary objectives are to compare the 12 and 24-months overall survival with those reported by GPOH in the trial HIT- GBM-C for pontine tumors; compare overall survival and progression-free survival of patients with survival curves of patients in the historical group of our service, treated with radiotherapy and a different combination treatment and to compare the overall survival and progression-free survival of patients with survival curves of the patients described in a clinical trial with Brazilian children with DIPG. In addition, evaluations of radiological response, toxicity and quality of life will be performed. The research will be hosted in Hospital Infantil Albert Sabin and its Pediatric Cancer Center unit, including patients aged 0-18 years, diagnosed with DIPG. Using the prior information available, the required minimum number of patients for the experimental group (1:2 design) is 16 patients. It is expected that 2 years will be required to recruit this sample.
description: Project proposal that was submitted to the Institutional Review Board of Hospital Infantil Albert Sabin and approved in 01/16/2016. Number of approval CAAE 30166714.8.0000.5042
description: {"references": ["1. Jenkin RD, Boesel C, Ertel I, et al. Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Children\u2019s Cancer Study Group. J Neurosurg 1987:66(2):227-233.", "2. Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 2006;7:241-248.", "3. Wells EM, Gaillard WD, Packer RJ. Pediatric Brain Tumors and Epilepsy. Semin Pediatr Neurol 2012; 19(1):3-8.", "4. Tremont-Lukats I, Ratilal B, Armstrong T, et al. Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev 2008(2):CD004424.", "5. Felix FH, Trompieri NM, de Araujo OL, da Trindade KM, Fontenele JB. Potential role for valproate in the treatment of high-risk brain tumors of childhood-results from a retrospective observational cohort study. Pediatr Hematol Oncol. 2011;28:556-570.", "6. Felix FH, de Araujo OL, da Trindade KM, Trompieri NM, Fontenele JB. Retrospective evaluation of the outcomes of children with diffuse intrinsic pontine glioma treated with radiochemotherapy and valproic acid in a single center. J Neurooncol. 2013 doi:10.1007/ s11060-013-1280-6", "7. Chassot A, Canale S, Varlet P, et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol. 2012;106(2): 399-407.", "8. Oberndorfer S, Piribauer M, Marosi C, et al. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neuro-Oncol 2005;72:255-260.", "9. Masoudi A, Elopre M, Amini E, et al. Influence of valproic acid on outcome of high-grade gliomas in children. Anticancer Res 2008:28(4C):2437-2442.", "10. Wolff J, Kramm C, Kortmann R, et al. Valproic acid was well tolerated in heavily pretreated pediatric patients with high-grade glioma. J Neurooncol 2008:90(3):309-314.", "11. Santini V, Gozzini A, Ferrari G. Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application. Curr Drug Metab 2007:8(4):383-393.", "12. Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77:1156-1164.", "13. Guthrie GD, Eljamel S. Impact of particular antiepileptic drugs on the survival of patients with glioblastoma multiforme. J Neurosurg 2012; doi: 10.3171/2012.10.JNS12169", "14. Felix FH, de Araujo OL, da Trindade KM, et al. Survival of children with malignant brain tumors receiving valproate: a retrospective study. Childs Nerv Syst. 2013;29(2):195-7.", "15. Kleinbaum, D.G. Klein, M. Survival Analysis: A Self-Learning Text. Statistics for Biology and Health, 2005, Springer.", "16. Weller M, Stupp R, Wick W. Epilepsy meets cancer: when, why, and what to do about it? Lancet Oncol 2012; 13(9):e375-82.", "17. Brandes AA, Franceschi E, Gorlia T, et al; European Organisation for Research and Treatment of Cancer Brain Tumour Group. Appropriate end-points for right results in the age of antiangiogenic agents: future options for phase II trials in patients with recurrent glioblastoma. Eur J Cancer. 2012;48(6):896-903.", "18. Hargrave D, Chuang N, Bouffet E. Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol. 2008;86(3):313-9.", "19. Su JM, Li XN, Thompson P, et al. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report. Clin Cancer Res 2011;17(3): 589-597.", "20. Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, Lazarus KH, Packer RJ, Prados M, Sposto R, Vezina G, Wisoff JH, Pollack IF. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(21):2641-7.", "21. Cohen KJ, Heideman RL, Zhou T, Holmes EJ, Lavey RS, Bouffet E, Pollack IF. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol. 2011;13(4):410-6.", "22. Wolff JE, Driever PH, Erdlenbruch B, Kortmann RD, Rutkowski S, Pietsch T, Parker C, Metz MW, Gnekow A, Kramm CM. Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol. Cancer. 2010;116(3):705-12.", "23. Wolff JE, Kortmann RD, Wolff B, Pietsch T, Peters O, Schmid HJ, Rutkowski S, Warmuth-Metz M, Kramm C. High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D pilot study. J Neurooncol. 2011;102(3):433-42.", "24. Broniscer A, Leite CC, Lanchote VL, Machado TM, Crist\u00f3fani LM. Radiation therapy and highdose tamoxifen in the treatment of patients with diffuse brainstem gliomas: results of a Brazilian cooperative study. Brainstem Glioma Cooperative Group. J Clin Oncol. 2000;18(6):1246-53.", "25. Saad, Everardo D., et al. \"Crit\u00e9rios comuns de toxicidade do Instituto Nacional de C\u00e2ncer dos Estados Unidos.\" Rev Bras Cancerol 2002;48(10): 63-96.", "26. Gil, AC. M\u00e9todos e t\u00e9cnicas de pesquisa social. 6\u00aa Edi\u00e7\u00e3o, Editora Atlas, 2008. p. 104.", "27. Palmer SN, Meeske KA, Katz ER, Burwinkle TM, Varni JW. The PedsQL Brain Tumor Module: initial reliability and validity. Pediatr Blood Cancer. 2007;49(3):287-93.", "28. Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement ofperformance in childhood cancer patients. Cancer. 1987;60(7):1651-6", "29. Nassar Junior AP, Pires Neto RC, de Figueiredo WB, Park M. Validity, reliability and applicability of Portuguese versions of sedation-agitation scales among critically ill patients. Sao Paulo Med J. 2008;126(4):215-9.", "30. Wolff JE, Mohiuddin K, Jorch N, Graf N, Wagner S, Vats T, Gnekow A. Measuring performance status in pediatric patients with brain tumors--experience of the HIT-GBM-C protocol. Pediatr Blood Cancer. 2010;55(3):520-4.", "31. Wolff, JE. HIT-GBM-D Protocol: Treatment of Children and Adolescents with Diffuse Intrinsic Pontine Glioma and High Grade Glioma (English), 2nd edition, Wolff Publishing, 2010.", "32. Brown SR, Brown J, Buyse M, Twelves C, Parmar M, Seymour M and Gregory W. Choosing your phase II trial design: a practical guide for cancer studies, University of Leeds, 2010.", "33. van den Bent MJ, Wefel JS, Schiff D, Taphoorn MJ, Jaeckle K, Junck L, Armstrong T, Choucair A, Waldman AD, Gorlia T, Chamberlain M, Baumert BG, Vogelbaum MA, Macdonald DR, Reardon DA, Wen PY, Chang SM, Jacobs AH. Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol. 2011;12(6):583-93.", "34. Brannath W., Bauer P, Posch M. On the efficiency of adaptive designs for flexible interim decisions in clinical trials. J Statistical Planning Inference 2006; 136: 1956-61"]}