ACT IV of Rindopepimut in Glioblastoma Continues, Recommends DSMB

David Reardon, MD

David Reardon, MD

An independent data safety and monitoring board (DSMB) has recommended continuation of the phase III ACT IV clinical trial of rindopepimut (Rintega) in patients with newly diagnosed glioblastoma multiforme (GBM), according to a news release from the drug’s developer, Celldex Therapeutics, Inc.¹

The announcement is encouraging, but by no means definitive, according to David Reardon, MD, clinical director, Center for Neuro-Oncology at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston, in an interview withTargeted Oncology.More details are expected with the second interim analysis in late 2015/early 2016.

The ACT IV clinical trial¹is a randomized, double-blind, placebo controlled study of rindopepimut plus GM-CSF added to standard of care temozolomide in patients with newly diagnosed, surgically resected, epidermal growth factor receptor variant III (EGFRvIII)-positive GBM.

ACT IV enrolled 745 patients to reach the required 374 patients with minimal residual disease (assessed by central review) needed for analysis of the primary overall survival (OS) endpoint. All patients, including those with disease that exceed this threshold, will be included in a secondary analysis of OS, as well as analyses of progression-free survival (PFS), safety and tolerability, and quality of life. The timing of the OS primary endpoint data is event-driven. Interim analyses assessing safety, futility, and efficacy conducted by an independent DSMB were prespecified at 50% and 75% of events.¹

At the 2015 ASCO Annual Meeting, Reardon updated efficacy data from the randomized placebo-controlled phase II ReACT study. This study was designed to determine if adding rindopepimut to the standard of care for recurrent glioblastoma, bevacizumab, improved outcomes for patients with recurrent EGFRvIII-positive glioblastoma.

“The efficacy of Rintega among recurrent Glioblastoma patients treated on the ReACT study ishistoricdata. These are the first data derived from a placebo-controlled study evaluating the entire intent-to-treat population in the history of GBM therapy to demonstrate that an immunotherapy can improve survival for this indication,” Reardon said. “In addition to improving survival, patients treated with Rintega on ReACT had a longer PFS, a higher rate of durable radiographic response, as well as a lower need for steroids. Thus multiple efficacy parameters were all positive.”

In February 2015, the US Food and Drug Administration (FDA) granted rindopepimut a breakthrough therapy designation for the treatment of adult patients with GBM that tests positive for EGFRvIII. EGFRvIII is expressed in up to 30% of glioblastomas and is associated with poor outcomes.^2-5The breakthrough therapy designation was based on data from the phase II ReACT study in recurrent GBM, the phase II ACT III study in newly diagnosed GBM, and additional phase II studies. ACTIVATE, ACT II, and ACT III have been completed in newly diagnosed EGFRvIII-positive GBM and have shown efficacy in both OS and median PFS.¹

The most common adverse events shown with rindopepimut include injection-site reactions, fatigue, rash, nausea, and pruritus.

“The vaccine is very safe and elicited remarkable immune responses as measured by anti-EGFRvIII antibody titers,” Reardon said. “The only drawback is that the vaccine’s target, EGFRvIII is only present in about 30% of GBM patients. Nonetheless, these positive, proof-of-concept results, pave the way to further explore immunotherapy strategies for this desperate unmet oncology need population.”

Rindopepimut, an investigational therapeutic vaccine, targets EGFRvIII. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long-term survival in clinical studies of patients with GBM, according to the Celldex news release. In addition, EGFRvIII-positive cells are believed to stimulate proliferation of non-EGFRvIII cells through IL-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells, transferring tumor-promoting activity. EGFRvIII expression may also be associated with tumor stem cells that have been identified in GBM. These stem cells contribute to resistance to cytotoxic therapy and tumor recurrence.¹

References

1. Celldex Therapeutics news release.Independent Data Safety and Monitoring Board Recommends Continuation of Celldex's Phase 3 Study of RINTEGA(R) (rindopepimut) in Newly Diagnosed Glioblastoma.http://ir.celldex.com/releasedetail.cfm?ReleaseID=919779. Accessed June 29, 2015.
2. Schuster J, Lai RK, Recht LD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study [published online ahead of print January 13, 2015].Neuro Oncol. pii: nou348.
3. Pelloski CE, Ballman KV, Furth AF, et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma.J Clin Oncol. 2007;25(16):2288-2294.
4. Shinojima N, Tada K, Shiraishi S, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme.Cancer Res. 2003;63(20):6962-6970.
5. Heimberger AB, Hlatky R, Suki D, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients.Clin Cancer Res. 2005;11(4):1462-1466.