Phase III Study for Rindopepimut in GBM Discontinued After OS Endpoint was Missed

The topline findings from the phase III ACT IV study show the median OS with rindopepimut was 20.4 months, as compared with 21.1 months in the control arm (HR, 0.99). This assessment, conducted by an independent data safety and monitoring board, was the foundation for the study being discontinued, according to Celldex; however, the immunotherapy will continue to be offered in the phase III 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.”

Rindopepimut 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% of GBMs.

In the phase III study, 700 patients were randomized in a 1:1 ratio to receive temozolomide plus either rindopepimut with GM-CSF or intradermal injections of the control KLH. In both arms, temozolomide was administered at 150 to 200 mg/m2 for 5 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 rindopepimut combination showed OS data similar to expectations in the phase III study while patients in the control arm significantly outperformed. The level of activity expected for rindopepimut in the phase III study had been established in a prior phase II trial named ReACT. This trial demonstrated a significant improvement in OS, which culminated in a breakthrough therapy designation from the FDA for rindopepimut in February 2015.

In the phase II study, 73 bevacizumab-naïve patients in their first or second relapse with EGFRvIII-expressing GBM were randomized in a 1:1 ratio to bevacizumab plus either rindopepimut (n = 36) or KLH (n = 37). A majority of patients in the rindopepimut arm had experienced one relapse (92%). In the control arm, 76% of patients were in their first relapse and 24% had experienced two prior relapses.

In updated findings for OS presented at the 2015 Society for Neuro-Oncology Annual Meeting, 25% of patients treated with rindopepimut plus bevacizumab remained alive at 2-years compared with none in the control arm. The median OS with rindopepimut was 11.3 versus 9.3 months in the control arm (HR, 0.53; CI, 0.32-0.88; P = .0137).

In earlier assessments of data from the phase II trial, the 12-month OS rate was 44% with rindopepimut versus 32% in the control arm. At 18 months, the OS rate was 32% and 13%, for rindopepimut and the control, respectively. Five patients in the rindopepimut arm continue to receive treatment. The 6-month progression-free survival rate with rindopepimut was 28% versus 16% with the control (one sided P = .1163), which met the primary endpoint for the study.

By expert review, the objective response rate with rindopepimut was 30% compared with 18% in the control arm. The duration of response was 7.8 months with rindopepimut compared with 5.6 months in the control arm.

The most frequently reported all-grade adverse events (AEs) experienced by patients in the rindopepimut arm versus the control were arthralgia (23% vs 5%, respectively), nausea (23% vs 11%), back pain (17% vs 8%), vomiting (17% vs 5%), diarrhea (17% vs 5%), and falls (17% vs 5%). In some incidences, AEs were lower in the rindopepimut arm versus the control, specifically for hemiparesis (6% vs 16%, respectively), hyperglycemia (9% vs 11%), and headaches (23% vs 24%).

The most frequently reported grade ≥3 AEs in the rindopepimut arm were convulsion (11%) and back pain (6%). For the control arm, grade ≥3 AEs consisted of hyperglycemia (8%), hypertension (8%), hemiparesis (5%), headache (5%), and fatigue (5%).

References

1. 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.