A data safety and monitoring board (DSMB) has determined that continuation of a phase 3 study of rindopepimut (Rintega, Celldex Therapeutics) in patients with newly diagnosed epidermal growth factor receptor vIII (EGFRvIII)-positive glioblastoma will not reach statistical significance for overall survival in patients with minimal residual disease––the study’s primary endpoint––as both the rindopepimut arm and the control arm were performing on par with each other. The median overall survival for rindopepimut was 20.4 months compared with 21.1 months for the control.
Based on the DSMB’s recommendation, Celldex is discontinuing the study.
The ACT IV trial was a randomized, double-blind, controlled study of rindopepimut plus granulocyte-macrophage colony-stimulating factor (GM-CSF) added to standard-of-care temozolomide (Temodar, Merck) in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. A total of 374 patients with minimal residual disease were included in the primary analysis. The patients were randomly assigned to a treatment or control arm after the completion of surgery and standard chemoradiation.
The treatment-arm regimen included a vaccine priming phase after radiation, followed by a maintenance therapy phase with adjuvant temozolomide and rindopepimut. Patients were treated until disease progression. The control-arm regimen included standard-of-care temozolomide plus injections of keyhole limpet hemocyanin (KLH). KLH is a component of Rintega and was selected because of its ability to generate an injection-site reaction similar to that observed with rindopepimut, which improved the blinding of the study.
The trial’s primary objective was to determine whether rindopepimut plus GM-CSF improves the overall survival of patients with newly diagnosed EGFRvIII-positive glioblastoma after gross total resection compared with patients treated with the current standard of care, temozolomide. Secondary endpoints included progression-free survival; the safety and tolerability of rindopepimut and GM-CSF in combination with temozolomide; neurologic status; and quality of life.
Rindopepimut is an investigational immunotherapy that targets the tumor-specific oncogene EGFRvIII (also known as EGFRv3), a functional and permanently activated mutation of EGFR, a protein that has been validated as a target for cancer therapy. The expression of EGFRvIII correlated with increased tumorigenicity in mouse models and poor long-term survival in clinical studies of glioblastoma patients, according to Celldex. In addition, EGFRvIII-positive cells are believed to stimulate proliferation of non-EGFRvIII cells through interleukin-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells, transferring tumor-promoting activity. EGFRvIII is expressed in tumors in approximately 30% of glioblastoma patients.
Rindopepimut is administered via intradermal injection and consists of the EGFRvIII-specific peptide sequence conjugated to keyhole limpet hemocyanin (KLH), a carrier protein. Rindopepimut stimulates the patient’s immune system, inducing pronounced EGFRvIII-specific humoral and cellular responses. Eighty-five percent of patients in clinical trials evaluating rindopepimut developed significant anti-EGFRvIII antibody titers.
Three phase 2 trials of rindopepimut (ACTIVATE, ACT II, and ACT III) have been completed in newly diagnosed patients with EGFRvIII-positive glioblastoma, and the patients continue to be followed for survival. Across all three studies, the most common adverse events for rindopepimut included injection-site reactions, fatigue, rash, nausea, and pruritus.
Source: Celldex Therapeutics; March 7, 2016.