This is an international, multicenter, double-blind clinical trial of rindopepimut in which up to 440 patients with newly diagnosed, resected, EGFRvIII positive glioblastoma will, after completion of standard chemoradiation, be randomized to receive either rindopepimut/GM-CSF or control (KLH), in combination with standard adjuvant temozolomide. Randomization will occur in a 1:1 ratio and will be stratified according to MGMT status (methylated/unmethylated/unknown), EORTC (adapted) RPA class (III or IV) (Mirimanoff, Gorlia et al. 2006) and geographical region (North America/Western Europe vs. Other).

After completion of screening assessments and determination of eligibility, enrolled patients will be randomized to receive two “priming” doses of either rindopepimut/GM-CSF vaccination or control vaccination (KLH) (hereafter referred to as “double-blind vaccine”) in a double-blind fashion. Approximately one week later, monthly cycles of TMZ will be given in combination with double-blind vaccine. TMZ will continue in accordance with local standards of care with a goal of six to twelve cycles, or until intolerance or disease progression. Greater than twelve cycles of temozolomide may be considered for individual patients on a case-by case basis after discussion with Celldex (or designee). Double-blind vaccine will continue every 28 days during and following TMZ, until intolerance or disease progression.

Screening assessments will include central review of tumor tissue including pathologic confirmation of glioblastoma, EGFRvIII expression status, and MGMT promoter methylation status. Brain MRIs from the post-operative period (ideally obtained with 72 hours of surgery) and post-chemoradiation period (within 1-14 days of completion of chemoradiation) will be obtained, and brain MRI will be conducted approximately every 12 weeks until disease progression, and whenever progression is suspected based on clinical symptoms. (Note: In certain circumstances where MRI is not possible for a particular patient, CT scans may be utilized. However, the same imaging modality must be used from the post-chemoradiation scan throughout the study.) For the purpose of treatment decisions, progression will be assessed by the treating investigator. For the analysis of the study endpoints (progression-free survival and tumor response), an external, independent review of radiologic imaging, blinded to treatment allocation and investigator assessments, will be performed. In all cases, progression-free survival and tumor response will be assessed using the RANO response criteria for high-grade gliomas (Wen, Macdonald et al. 2010), which considers radiologic imaging, neurological status, and steroid dosing. Additionally, health-related quality of life will be assessed in a subset of patients (those who speak a language in which the questionnaire(s) are validated) via the EORTC core Quality of Life Questionnaire (QLQ-C30) and Brain Cancer Module (BN20), while the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) will be utilized to capture patient self reports of symptom severity and interference with daily activities throughout the treatment period. Humoral immunologic response will be measured at baseline and at selected times following vaccination and at the time of disease progression. HLA typing will also be performed at baseline. Safety will be evaluated throughout the trial by the incidence of adverse events, physical examination findings, vital signs and clinical laboratory test results. Adverse events will be graded for severity using NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0, and collection of adverse events will continue until 28 days after the last dose of trial treatment or until the initiation of subsequent anticancer treatment, whichever occurs first. Any serious adverse event occurring any time after the reporting period must be promptly reported if a causal relationship to study treatment (double-blind vaccine) is suspected. If a tumor biopsy or resection is performed upon progression, all attempts should be made to send tissue to the sponsor-designated centralized laboratory for repeat analysis of EGFRvIII expression and possibly other tumor or immune markers. Following documentation of disease progression, all patients will be followed every 12 weeks for survival status until study closure.

An independent data monitoring committee (DMC) will be convened for this study and will act in an advisory capacity to the sponsor with respect to safeguarding the interests of study patients, assessing interim safety and efficacy data, and for monitoring the overall conduct of the study.