Niraparib and Temozolomide in Patients Glioblastoma

Summary

The study evaluates safety, tolerability, pharmacokinetics at recommended phase II dose (RP2D) and preliminary antitumor activity of Niraparib + dd-TMZ "one week on, one week off" in patients affected by recurrent GBM IDH wild-type and recurrent IDH mutant (WHO grade 2-4) gliomas. The treatment will be administered until progressive disease, unacceptable toxicity, consent withdrawal, lost to follow-up or death. The entire study is expected to last approximately 40 months.

Timeline

Start

2024-09

Primary completion

2026-12

Completion

2027-09

Publications

• Background Lamers LM, Stupp R, van den Bent MJ, Al MJ, Gorlia T, Wasserfallen JB, Mittmann N, Jin Seung S, Crott R, Uyl-de Groot CA; EORTC 26981/22981 NCI-C CE3 Intergroup Study. Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: a report from the EORTC 26981/22981 NCI-C CE3 Intergroup Study. Cancer. 2008 Mar 15;112(6):1337-44. doi: 10.1002/cncr.23297.
• Background Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M, Roth P, Ruda R, Short S, Smits M, Taphoorn MJB, von Deimling A, Westphal M, Soffietti R, Reifenberger G, Wick W. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. doi: 10.1038/s41571-020-00447-z. Epub 2020 Dec 8.
• Background Tan AC, Ashley DM, Lopez GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020 Jul;70(4):299-312. doi: 10.3322/caac.21613. Epub 2020 Jun 1.
• Background Mildenberger I, Bunse L, Ochs K, Platten M. The promises of immunotherapy in gliomas. Curr Opin Neurol. 2017 Dec;30(6):650-658. doi: 10.1097/WCO.0000000000000491.
• Background Nagane M. Dose-dense Temozolomide: Is It Still Promising? Neurol Med Chir (Tokyo). 2015;55 Suppl 1:38-49.
• Background Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, Hegi ME. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol. 2010 Jan;6(1):39-51. doi: 10.1038/nrneurol.2009.197. Epub 2009 Dec 8.
• Background Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond LA, Patnaik A, Goetz AD, Schwartz G, Edwards T, Reyderman L, Statkevich P, Cutler DL, Rowinsky EK. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer. 2003 Apr 7;88(7):1004-11. doi: 10.1038/sj.bjc.6600827.
• Background Lal S, Snape TJ. A therapeutic update on PARP inhibitors: implications in the treatment of glioma. Drug Discov Today. 2021 Feb;26(2):532-541. doi: 10.1016/j.drudis.2020.10.029. Epub 2020 Nov 4.
• Background van den Bent MJ, Mellinghoff IK, Bindra RS. Gray Areas in the Gray Matter: IDH1/2 Mutations in Glioma. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-8. doi: 10.1200/EDBK_280967.
• Background Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Gunel M, Glazer PM, Bindra RS. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 2017 Feb 1;9(375):eaal2463. doi: 10.1126/scitranslmed.aal2463.
• Background Wang P, Wu J, Ma S, Zhang L, Yao J, Hoadley KA, Wilkerson MD, Perou CM, Guan KL, Ye D, Xiong Y. Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep. 2015 Dec 22;13(11):2353-2361. doi: 10.1016/j.celrep.2015.11.029. Epub 2015 Dec 10.
• Background Wang Y, Wild AT, Turcan S, Wu WH, Sigel C, Klimstra DS, Ma X, Gong Y, Holland EC, Huse JT, Chan TA. Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas. Sci Adv. 2020 Apr 22;6(17):eaaz3221. doi: 10.1126/sciadv.aaz3221. eCollection 2020 Apr.
• Background Tateishi K, Higuchi F, Miller JJ, Koerner MVA, Lelic N, Shankar GM, Tanaka S, Fisher DE, Batchelor TT, Iafrate AJ, Wakimoto H, Chi AS, Cahill DP. The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1-Mutant Cancers and Potentiates NAD+ Depletion-Mediated Cytotoxicity. Cancer Res. 2017 Aug 1;77(15):4102-4115. doi: 10.1158/0008-5472.CAN-16-2263. Epub 2017 Jun 16.
• Background Lu Y, Kwintkiewicz J, Liu Y, Tech K, Frady LN, Su YT, Bautista W, Moon SI, MacDonald J, Ewend MG, Gilbert MR, Yang C, Wu J. Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair. Cancer Res. 2017 Apr 1;77(7):1709-1718. doi: 10.1158/0008-5472.CAN-16-2773. Epub 2017 Feb 15.
• Background Hanna C, Kurian KM, Williams K, Watts C, Jackson A, Carruthers R, Strathdee K, Cruickshank G, Dunn L, Erridge S, Godfrey L, Jefferies S, McBain C, Sleigh R, McCormick A, Pittman M, Halford S, Chalmers AJ. Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro Oncol. 2020 Dec 18;22(12):1840-1850. doi: 10.1093/neuonc/noaa104.
• Background Federico SM, Pappo AS, Sahr N, Sykes A, Campagne O, Stewart CF, Clay MR, Bahrami A, McCarville MB, Kaste SC, Santana VM, Helmig S, Gartrell J, Shelat A, Brennan RC, Hawkins D, Godwin K, Bishop MW, Furman WL, Stewart E. A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. Eur J Cancer. 2020 Sep;137:204-213. doi: 10.1016/j.ejca.2020.06.014. Epub 2020 Aug 11.
• Background Sun K, Mikule K, Wang Z, Poon G, Vaidyanathan A, Smith G, Zhang ZY, Hanke J, Ramaswamy S, Wang J. A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models. Oncotarget. 2018 Dec 14;9(98):37080-37096. doi: 10.18632/oncotarget.26354. eCollection 2018 Dec 14.
• Background Chugh R, Ballman KV, Helman LJ, Patel S, Whelan JS, Widemann B, Lu Y, Hawkins DS, Mascarenhas L, Glod JW, Ji J, Zhang Y, Reinke D, Strauss SJ. SARC025 arms 1 and 2: A phase 1 study of the poly(ADP-ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma. Cancer. 2021 Apr 15;127(8):1301-1310. doi: 10.1002/cncr.33349. Epub 2020 Dec 8.
• Background Chukwueke UN, Wen PY. Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical trials and clinical practice. CNS Oncol. 2019 Mar 1;8(1):CNS28. doi: 10.2217/cns-2018-0007. Epub 2019 Feb 26. No abstract available.
• Background 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 Jun;12(6):583-93. doi: 10.1016/S1470-2045(11)70057-2. Epub 2011 Apr 5.
• Background Rao VU, Reeves DJ, Chugh AR, O'Quinn R, Fradley MG, Raghavendra M, Dent S, Barac A, Lenihan D. Clinical Approach to Cardiovascular Toxicity of Oral Antineoplastic Agents: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021 Jun 1;77(21):2693-2716. doi: 10.1016/j.jacc.2021.04.009.
• Background van Andel L, Zhang Z, Lu S, Kansra V, Agarwal S, Hughes L, Tibben MM, Gebretensae A, Rosing H, Schellens JHM, Beijnen JH. Liquid chromatography-tandem mass spectrometry assay for the quantification of niraparib and its metabolite M1 in human plasma and urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jan 1;1040:14-21. doi: 10.1016/j.jchromb.2016.11.020. Epub 2016 Nov 19.
• Background Kim H, Likhari P, Parker D, Statkevich P, Marco A, Lin CC, Nomeir AA. High-performance liquid chromatographic analysis and stability of anti-tumor agent temozolomide in human plasma. J Pharm Biomed Anal. 2001 Jan;24(3):461-8. doi: 10.1016/s0731-7085(00)00466-0.

Drugs

Indications