The immunotherapy will continue to be offered in the phase 3 trial and compassionate use programs.
Treatment with Rintega (rindopepimut) plus temozolomide failed to improve overall survival (OS) compared with temozolomide and a control for patients with newly diagnosed EGFRvIII-positive glioblastoma multiforme (GBM). These topline findings from the phase 3 ACT IV study were released by the developer of the immunotherapy, Celldex Therapeutics.
In the study, the median OS with Rintega was 20.4 months compared with 21.1 months in the control arm. Based on this assessment, which was conducted by an independent data safety and monitoring board, the study was discontinued, according to Celldex; however, the immunotherapy will continue to be offered in the phase 3 trial and compassionate use programs.
“We are extremely disappointed for patients that the ACT IV study was not successful,” Anthony Marucci, co-founder, president, and chief executive officer of Celldex Therapeutics, said in a statement. “While this is certainly not the desired outcome, we remain steadfast believers in the power of immunotherapy to transform the future of cancer treatment.”
Rintega consists of an EGFRvIII peptide conjugated to keyhole limpet hemocyanin (KLH). The vaccine works by generating a specific immune response against tumors that express EGFRvIII, which is a tumor-specific oncogene expressed in approximately 30 percent of GBMs.
In the phase 3 study, 700 patients were randomized in a one-to-one ratio to receive temozolomide plus either Rintega with GM-CSF or intradermal injections of the control KLH. In both arms, temozolomide was administered at 150 to 200 mg/m2 for five days for up to a maximum of 12 cycles or until intolerance or progression. All patients had documented EGFRvIII-positive GBM and had undergone surgical resection followed by conventional chemoradiation.
According to Celldex, the Rintega combination showed OS data similar to expectations in the phase 3 study while patients in the control arm significantly outperformed. The level of activity expected for Rintega in the phase 3 study had been established in a prior phase 2 trial named ReACT. This trial demonstrated a significant improvement in OS, which culminated in a breakthrough therapy designation from the FDA for Rintega in February 2015.
In the phase 2 study, 73 Avastin (bevacizumab)-naïve patients in their first or second relapse with EGFRvIII-expressing GBM were randomized in a one-to-one ratio to Avastin plus either Rintega (36 patients) or KLH (37 patients). A majority of patients in the Rintega arm had experienced one relapse (92 percent). In the control arm, 76 percent of patients were in their first relapse and 24 percent had experienced two prior relapses.
In updated findings for OS presented at the 2015 Society for Neuro-Oncology Annual Meeting, 25 percent of patients treated with Rintega plus bevacizumab remained alive at two years compared with none in the control arm. The median OS with Rintega was 11.3 versus 9.3 months in the control arm.
In earlier assessments of data from the phase 2 trial, the 12-month OS rate was 44 percent with Rintega versus 32 percent in the control arm. At 18 months, the OS rate was 32 percent and 13 percent, for Rintega and the control, respectively. Five patients in the Rintega arm continue to receive treatment. The six-month progression-free survival rate with Rintega was 28 percent versus 16 percent with the control, which met the primary endpoint for the study.
By expert review, the objective response rate with Rintega was 30 percent compared with 18 percent in the control arm. The duration of response was 7.8 months with Rintega compared with 5.6 months in the control arm.
The most frequently reported all-grade adverse events (AEs) experienced by patients in the Rintega arm versus the control were arthralgia (23 percent vs 5 percent, respectively), nausea (23 percent vs 11 percent), back pain (17 percent vs 8 percent), vomiting (17 percent vs 5 percent), diarrhea (17 percent vs 5 percent) and falls (17 percent vs 5 percent). In some incidences, AEs were lower in the Rintega arm versus the control, specifically for hemiparesis (6 percent vs 16 percent, respectively), hyperglycemia (9 percent vs 11 percent) and headaches (23 percent vs 24 percent).
The most frequently reported AEs of at least grade 3 in the Rintega arm were convulsion (11 percent) and back pain (6 percent). For the control arm, AEs of at least grade 3 consisted of hyperglycemia (8 percent), hypertension (8 percent), hemiparesis (5 percent), headache (5 percent) and fatigue (5 percent).
Reardon DA, Desjardins A, Schuster J, et al. ReACT: Long-term survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Presented at: 2015 Annual Meeting of the Society for Neuro-Oncology; November 19-22, 2015; San Antonio, TX. Abstract IMCT-08.