Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial - PubMed (original) (raw)
Clinical Trial
. 2017 Oct;18(10):1373-1385.
doi: 10.1016/S1470-2045(17)30517-X. Epub 2017 Aug 23.
Nicholas Butowski 2, David D Tran 3, Lawrence D Recht 4, Michael Lim 5, Hal Hirte 6, Lynn Ashby 7, Laszlo Mechtler 8, Samuel A Goldlust 9, Fabio Iwamoto 10, Jan Drappatz 11, Donald M O'Rourke 12, Mark Wong 13, Mark G Hamilton 14, Gaetano Finocchiaro 15, James Perry 16, Wolfgang Wick 17, Jennifer Green 18, Yi He 18, Christopher D Turner 18, Michael J Yellin 18, Tibor Keler 18, Thomas A Davis 18, Roger Stupp 19, John H Sampson 20; ACT IV trial investigators
Collaborators, Affiliations
- PMID: 28844499
- DOI: 10.1016/S1470-2045(17)30517-X
Free article
Clinical Trial
Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial
Michael Weller et al. Lancet Oncol. 2017 Oct.
Free article
Abstract
Background: Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.
Methods: In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.
Findings: Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5-22·1) in the rindopepimut group versus 20·0 months (18·1-21·9) in the control group (HR 1·01, 95% CI 0·79-1·30; p=0·93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut.
Interpretation: Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.
Funding: Celldex Therapeutics, Inc.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Comment in
- ACT IV: the final act for rindopepimut?
Gerstner ER. Gerstner ER. Lancet Oncol. 2017 Oct;18(10):1294-1296. doi: 10.1016/S1470-2045(17)30619-8. Epub 2017 Aug 23. Lancet Oncol. 2017. PMID: 28844498 No abstract available. - EGFRvIII vaccine in glioblastoma-InACT-IVe or not ReACTive enough?
Platten M. Platten M. Neuro Oncol. 2017 Oct 19;19(11):1425-1426. doi: 10.1093/neuonc/nox167. Neuro Oncol. 2017. PMID: 29059447 Free PMC article. No abstract available. - Go, no-go decision making for phase 3 clinical trials: ACT IV revisited.
Nguyen HTN, Grogan P, Robins HI. Nguyen HTN, et al. Lancet Oncol. 2017 Dec;18(12):e708. doi: 10.1016/S1470-2045(17)30857-4. Lancet Oncol. 2017. PMID: 29208432 No abstract available. - Go, no-go decision making for phase 3 clinical trials: ACT IV revisited - Authors' reply.
Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F, Drappatz J, O'Rourke DM, Wong M, Hamilton MG, Finocchiaro G, Perry J, Wick W, Green J, He Y, Turner CD, Yellin MJ, Keler T, Davis TA, Stupp R, Sampson JH. Weller M, et al. Lancet Oncol. 2017 Dec;18(12):e709-e710. doi: 10.1016/S1470-2045(17)30856-2. Lancet Oncol. 2017. PMID: 29208433 No abstract available.
Similar articles
- Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.
Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent MJ, Hicking C, Markivskyy A, Picard M, Weller M; European Organisation for Research and Treatment of Cancer (EORTC); Canadian Brain Tumor Consortium; CENTRIC study team. Stupp R, et al. Lancet Oncol. 2014 Sep;15(10):1100-8. doi: 10.1016/S1470-2045(14)70379-1. Epub 2014 Aug 19. Lancet Oncol. 2014. PMID: 25163906 Clinical Trial. - A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study.
Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD, Mrugala MM, Jensen R, Baehring JM, Sloan A, Archer GE, Bigner DD, Cruickshank S, Green JA, Keler T, Davis TA, Heimberger AB, Sampson JH. Schuster J, et al. Neuro Oncol. 2015 Jun;17(6):854-61. doi: 10.1093/neuonc/nou348. Epub 2015 Jan 13. Neuro Oncol. 2015. PMID: 25586468 Free PMC article. Clinical Trial. - Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial.
Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (NCBTSG). Malmström A, et al. Lancet Oncol. 2012 Sep;13(9):916-26. doi: 10.1016/S1470-2045(12)70265-6. Epub 2012 Aug 8. Lancet Oncol. 2012. PMID: 22877848 Clinical Trial. - The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients.
Paff M, Alexandru-Abrams D, Hsu FP, Bota DA. Paff M, et al. Hum Vaccin Immunother. 2014;10(11):3322-31. doi: 10.4161/21645515.2014.983002. Hum Vaccin Immunother. 2014. PMID: 25625931 Free PMC article. Review. - Rindopepimut: a promising immunotherapeutic for the treatment of glioblastoma multiforme.
Swartz AM, Li QJ, Sampson JH. Swartz AM, et al. Immunotherapy. 2014;6(6):679-90. doi: 10.2217/imt.14.21. Immunotherapy. 2014. PMID: 25186601 Free PMC article. Review.
Cited by
- Molecular targets and strategies in the development of nucleic acid cancer vaccines: from shared to personalized antigens.
Chi WY, Hu Y, Huang HC, Kuo HH, Lin SH, Kuo CJ, Tao J, Fan D, Huang YM, Wu AA, Hung CF, Wu TC. Chi WY, et al. J Biomed Sci. 2024 Oct 9;31(1):94. doi: 10.1186/s12929-024-01082-x. J Biomed Sci. 2024. PMID: 39379923 Review. - EGFRVIII and EGFR targeted chimeric antigen receptor T cell therapy in glioblastoma.
Sterner RC, Sterner RM. Sterner RC, et al. Front Oncol. 2024 Sep 19;14:1434495. doi: 10.3389/fonc.2024.1434495. eCollection 2024. Front Oncol. 2024. PMID: 39364321 Free PMC article. Review. - Molecular Testing in Gliomas: What is Necessary in Routine Clinical Practice?
Alnahhas I. Alnahhas I. Curr Oncol Rep. 2024 Oct 3. doi: 10.1007/s11912-024-01602-w. Online ahead of print. Curr Oncol Rep. 2024. PMID: 39361075 Review. - Transcriptomic and proteomic spatial profiling of pediatric and adult diffuse midline glioma H3 K27-Altered.
Damodharan S, Shireman JM, Xie E, Distler E, Kendziorski C, Dey M. Damodharan S, et al. Sci Rep. 2024 Sep 30;14(1):22668. doi: 10.1038/s41598-024-73199-w. Sci Rep. 2024. PMID: 39349581 Free PMC article. - The prognostic significance of androgen receptor expression in gliomas.
Zhang C, Zhao N, Khan R, Hung MY, Zhang C, Wang S, Wang TJC, Lin C. Zhang C, et al. Sci Rep. 2024 Sep 27;14(1):22122. doi: 10.1038/s41598-024-72284-4. Sci Rep. 2024. PMID: 39333688 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous