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Clinical Trial
. 2018 Jul 1;7(3):CNS22.
doi: 10.2217/cns-2018-0009. Epub 2018 Aug 29.

Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: interim results and correlations with CD4+ T-lymphocyte counts

Daniela A Bota  1   2   3 , Jinah Chung  3 , Manisha Dandekar  3 , Jose A Carrillo  1   2   3 , Xiao-Tang Kong  1   2   3 , Beverly D Fu  1   3 , Frank Pk Hsu  2   3 , Axel H Schönthal  4 , Florence M Hofman  5 , Thomas C Chen  6 , Raphael Zidovetzki  7 , Chrystel Pretto  8 , Ankie Strik  6   8 , Virgil Ejc Schijns  8   9 , Apostolos Stathopoulos  8   9   10
Affiliations
Clinical Trial

Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: interim results and correlations with CD4+ T-lymphocyte counts

Daniela A Bota et al. CNS Oncol. .

Abstract

Aim: ERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors.

Methods: In this double-blinded, randomized, Phase II study bevacizumab-naive patients with recurrent GBM were randomized to receive either ERC1671 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine® or sargramostim) and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. Interim results: Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4+ T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group.

Conclusion: The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.

Keywords: CD4+ T lymphocyte; ERC1671; GBM; GBM vaccine; allogeneic; autologous; bevacizumab; glioma surgery; immunotherapy.

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Conflict of interest statement

Financial & competing interests disclosure

This study was supported by funding from Epithopoietic Research Corporation. The study is an investigator-initiated study (DA Bota) funded by Epitopoietic Research Corporation (ERC). DA Bota has designed the study in collaboration with the study sponsor and the other investigators and managed the clinical trial database, and performed statistical analysis (with R Zidovetzki support). The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The following authors are on the ERC advisory board, board of directors, employed by ERC or own ERC shares: TC Chen, C Pretto, V EJC Schijns and A Stathopoulos. Grant number: UCI Cancer Center Award [P30CA062203] from the National Cancer Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Study schema.
Each treatment cycle is 28 days long. The first day of the first cycle is scheduled 29 days from surgery, which satisfies the US FDA mandated waiting time of 4 weeks between surgery and first use of bevacizumab, and allows for sufficient time to process the patient's tumor tissue for vaccine production. The timeline for days 1 through 5 (bevacizumab, followed by cyclophosphamide) is implemented strictly, whereas subsequent administration of each individual dose of vaccine (in combination with GM-CSF) is flexible by ±1 day. ERC-D is the autologous component, whereas ERC-A, -B and -C are allogeneic components from three different GBM patient donors. Both groups, active treatment group and placebo group, receive bevacizumab on day 1 and 15 (±1) of each cycle. This course of treatment is repeated every 28 days until disease progression or intolerance, at which time assignment of the respective patient will be unblinded. GBM: Glioblastoma; GM-CSF: Granulocyte-macrophage colony-stimulating factor.
<b>Figure 2.</b>
Figure 2.. MRI of the brain for a patient randomized to the ERC1671/bevacizumab arm.
Showing the tumor size before starting in the ERC1671/bevacizumab treatment and end of cycle 7. The MRI shows significant decrease in contrast enhancement over time and stable fluid-attenuated inversion recovery signal.
<b>Figure 3.</b>
Figure 3.. Overall survival and comparisons with previous studies.
(A) Median OS was 363 days in the active treatment group (4 patients), compared with 229 days in the placebo group (4 patients). (B) A total of 12 months OS in the ERC1671/bevacizumab arm of the study is superior to previously published single-arm bevacizumab studies. OS: Overall survival.
<b>Figure 4.</b>
Figure 4.. CD3+/CD4+ lymphocyte counts highly correlate with overall survival in the ERC1671/bevacizumab treatment arm.
The maximal values, as well as end-of-treatment values, of CD3+/CD4+ mature helper/inducer T lymphocytes were determined in all patients from the ERC1671/bevacizumab group (A) and the placebo/bevacizumab group (B). Cell numbers were plotted over overall survival time.
See this image and copyright information in PMC

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