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Lancet Oncol. 2017 Oct;18(10):1373-1385. doi: 10.1016/S1470-2045(17)30517-X. Epub 2017 Aug 23.

Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial.

Collaborators (168)

Butowski N, Campian J, Recht L, Lim M, Ashby L, Drappatz J, Hirte H, Iwamoto F, Mechtler L, Goldlust S, Becker K, Barnett G, Nicholas G, Desjardins A, Benkers T, Wagle N, Groves M, Kesari S, Horvath Z, Merrell R, Curry R, O'Rourke J, Schuster D, Wong M, Mrugala M, Jensen R, Trusheim J, Lesser G, Belanger K, Sloan A, Purow B, Fink K, Raizer J, Schulder M, Nair S, Peak S, Perry J, Brandes A, Weller M, Mohile N, Landolfi J, Olson J, Finocchiaro G, Jennens R, DeSouza P, Robinson B, Crittenden M, Shih K, Flowers A, Ong S, Connelly J, Hadjipanayis C, Giglio P, Mott F, Mathieu D, Lessard N, Sepulveda SJ, Lövey J, Wheeler H, Inglis PL, Hardie C, Bota D, Lesniak M, Portnow J, Frankel B, Junck L, Thompson R, Berk L, McGhie J, Macdonald D, Saran F, Soffietti R, Blumenthal D, André de SBCM, Nowak A, Singhal N, Hottinger A, Schmid A, Srkalovic G, Baskin D, Fadul C, Nabors L, LaRocca R, Villano J, Paleologos N, Kavan P, Pitz M, Thiessen B, Idbaih A, Frenel JS, Domont J, Grauer O, Hau P, Marosi C, Sroubek J, Hovey E, Sridhar PS, Cher L, Dunbar E, Coyle T, Raymond J, Barton K, Guarino M, Raval S, Stea B, Dietrich J, Hopkins K, Erridge S, Steinbach JP, Pineda LE, Balana QC, Sonia Del BB, Wenczl M, Molnár K, Hideghéty K, Lossos A, Myra van L, Levy A, Harrup R, Patterson W, Lwin Z, Sathornsumetee S, Lee EJ, Ho JT, Emmons S, Duic JP, Shao S, Ashamalla H, Weaver M, Lutzky J, Avgeropoulos N, Hanna W, Nadipuram M, Cecchi G, O'Donnell R, Pannullo S, Carney J, Hamilton M, MacNeil M, Beaney R, Fabbro M, Schnell O, Fietkau R, Stockhammer G, Malinova B, Odrazka K, Sames M, Miguel Gil G, Razis E, Lavrenkov K, Castro G, Ramirez F, Baldotto C, Viola F, Malheiros S, Lickliter J, Gauden S, Dechaphunkul A, Thaipisuttikul I, Thotathil Z, Ma HI, Cheng WY, Chang CH, Salas F, Dietrich PY, Mamot C, Nayak L, Nag S.

Author information

1
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. Electronic address: michael.weller@usz.ch.
2
Department of Neurological Surgery, University of California, San Francisco, CA, USA.
3
Washington University, St Louis, MO, USA.
4
Stanford University Medical Center, Palo Alto, CA, USA.
5
The Johns Hopkins Hospital, Baltimore, MD, USA.
6
Juravinski Cancer Centre, Hamilton, ON, Canada.
7
Barrow Neurological Institute, Phoenix, AZ, USA.
8
DENT Neurologic Institute, Buffalo, NY, USA.
9
John Theurer Cancer Center, Hackensack, NJ, USA.
10
Columbia University Medical Center, New York, NY, USA.
11
University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
12
Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
13
Westmead Hospital, Westmead, NSW, Australia.
14
University of Calgary, Department of Clinical Neurosciences, Division of Neurosurgery, Foothills Hospital, Calgary, AB, Canada.
15
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
16
Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
17
The University of Heidelberg and German Cancer Research Center, Heidelberg, Germany.
18
Celldex Therapeutics, Inc, Hampton, NJ, USA.
19
Department of Oncology, University Hospital and University of Zurich, Zurich, Switzerland.
20
The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

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.

PMID:
28844499
DOI:
10.1016/S1470-2045(17)30517-X
[Indexed for MEDLINE]
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