ReACT: A Phase 2 Study of Rindopepimut (CDX-110) plus Bevacizumab in Relapsed Glioblastoma

ReACT: A Phase 2 Study of Rindopepimut (CDX-110) plus Bevacizumab in Relapsed Glioblastoma

Case Report: A 65 year old otherwise healthy female presented with seizure in May of 2011 and was found to have a large left frontal mass (Figure 1A). It was gross totally resected at an outside hospital and the pathology revealed glioblastoma (GBM). She underwent concurrent radiation and chemotherapy including Bevacizumab and Temozolomide at an outside institution. Her platelet counts initially dropped so Bevacizumab was discontinued but they recovered enough so that she did receive adjuvant monthly Temozolomide after her chemoradiation. The patient suffered two breakthrough seizures in March of 2012 and an MRI revealed recurrent disease at the site of the initial resection cavity (Figure 1B). She underwent a re-resection with gross total resection at Stanford University (Figure 1C). Pathology revealed radiation necrosis and recurrent glioblastoma (MGMT positive). EGFRvIII testing was performed and the tumor was positive for the EGFRvIII mutation.

What are EGFRvIII and Rindopepimut (CDX-110): EGFRvIII is the most common variant of the epidermal growth factor (EGF) receptor and is present in many different cancer types, but not on normal tissue. This mutation was first identified in human glioblastoma where it is present in 24-67% of GBMs and is linked to poor survival. EGFRvIII results from an in-frame deletion corresponding to exons 2-7 of the EGF receptor gene resulting in the fusion of exon 1 to exon 8 while generating a novel glycine at the junction. While it does not bind ligand, EGFRvIII is constitutively active and can lead directly to cancer phenotypes due to its constant oncogenic properties. EGFRvIII is an attractive target for cancer because it is not expressed in normal neural tissue and because cells producing EGFRvIII have an enhanced capacity for unregulated growth, survival, invasion, and angiogenesis. It is an especially valuable target for immunotherapeutic approaches because the juxtaposition of ordinarily distant amino acids plus the unique glycine at the junction produces a highly immunogenic epitope. A peptide vaccine targeting this unique EGFRvIII epitope has been created and chemically conjugated to keyhole limpet hemocyanin (KLH) and has been named Rindopepimut (CDX-110).

Prior Rindopepimut (CDX-110) Trials: After a number of successful preclinical trials, three phase 2 trials conducted from 2004 to present have tested the combination of the EGFRvIII vaccine given in conjunction with GM-CSF for the treatment of newly diagnosed resected EGFRvIII positive glioblastoma after chemoradiation without progression. There were very few treatment related serious adverse events. EGFRvIII was eliminated in recurrent tumors after vaccination in 81% of the patients while 15 non-protocol comparator patients who recurred all still expressed EGFRv III. EGFRvIII specific immune response was detected in most patients. Progression free and overall survival was significantly elevated when compared to historical controls. There is currently a multi center, international, phase 3 randomized trial (ACT 4) testing this vaccine strategy against newly diagnosed EGFRvIII positive glioblastoma. Stanford is one of the sites.

Clinical Trial: Because of the success of the vaccine against newly diagnosed glioblastoma, Celldex Therapeutics has sponsored a new phase 2 multicenter trial testing Rindopepimut plus Bevacizumab in patients with EGFRvIII relapsed glioblastoma. The patient from the case study is currently enrolled in this study at the Stanford University site. There are currently 17 centers across the country recruiting EGFRvIII positive relapsed glioblastoma patients for this trial with a goal recruitment of 95 patients at up to 25 centers by 2013. There are two groups to the study: 1.) patients who are Bevacizumab naïve and 2.) patients who have recurrent glioblastoma despite Bevacizumab. Group 1 patients will be randomized to KLH as a control plus Bevacizumab or Rindopepimut plus Bevacizumab. Group 2 patients will receive Rindopepimut plus Bevacizumab on an open label fashion. Patients who are in their 1st or 2nd relapse of EGFRvIII expressing glioblastoma who have been treated prior by conventional radiation and Temozolomide and are taking less than 4mg per day of Dexamethasone are included for the trial.

For more information regarding sites, inclusion and exclusion criteria, and the treatment, visit: http://clinicaltrials.gov/ct2/show/NCT01498328

Contact Information for the Stanford Site:
Contact: Bhagyashree Yadav, CCRA 650-723-6456 or
Contact: Cathy Recht, RN 650-723-6095
Principal Investigator: Gordon Li, MD

References:

  1. Li G and Wong A. EGF Receptor Variant III as a Target Antigen for Tumor Immunotherapy. Expert Review of Vaccines. 2008 Sept 7(7): 977-985
  2. Reardon D, Vredenburgh J, Desjardins A, Steis R, Dunbar E, Chandramouli N, Rixe O, Green J, Davis T, and Sampson J. REACT: A Phase II Study of Rindopepimut (CDX-110) plus Bevacizumab in Relapsed Glioblastoma. Presented at the 2012 ASCO annual Meeting.