On July 17, 2020, the manufacturer of enzastaurin announced that the FDA granted fast track designation for DB102 (enzastaurin), a protein kinase C (PKC) PKC beta inhibitor for the treatment of patients with newly diagnosed glioblastoma, the most common type of primary malignant brain cancer. The agent, DB102 (enzastaurin), is formulated as an oral investigational first-in-class, small-molecule, serine/threonine kinase inhibitor of the PKC beta, PI3K, and AKT pathways that has been studied in more than 3,000 patients across a variety of solid and hematological tumor types.

The manufacturer is also initiating a double-blind, placebo-controlled, phase III study evaluating enzastaurin in combination with temozolomide, both during and following radiation therapy, in patients with newly diagnosed glioblastoma. Additionally, information from Oncology Nursing News indicates that enzastaurin is being assessed in the phase III ENGINE trial. In this study, researchers attempted to enroll 235 patients with CD20-positive diffuse large B-cell lymphoma (DLBCL) and to  randomize the patients to obtain either enzastaurin added to the standard-of-care of rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) or R-CHOP alone for six cycles during the combination phase. 

The primary endpoint of the trial was overall survival (OS) in patients with DLBCL who test positive for DGM1, with a secondary endpoint of OS in patients without DGM1. The main objective of the trial is to ascertain whether the addition of the investigational agent to R-CHOP in the frontline could result in improved outcomes compared with R-CHOP alone, and whether the existence of DGM1 is related to a response to the agent in this setting. Moreover, in the phase III PRELUDE study, researchers compared the use of the PKC beta inhibitor with placebo in patients with high-risk DLBCL and found no statistically substantial variances in disease-free survival at 4 years (70% vs. 71%, respectively). 

Additionally, no variation was noted with regard to OS, either (81% vs. 82%, respectively). In another study, the phase II S028 trial assessed the use of this agent in the frontline setting in combination with R-CHOP compared with R-CHOP alone in patients with intermediate- or high-risk disease. These results also failed to demonstrate added advantage with enzastaurin. In spite of the negative data collected from PRELUDE and S028 studies, genomic research investigating DNA samples collected from study participants have led to the uncovering of the DGM1 polymorphism. Moreover, following retrospective genotyping of patient samples collected from the PRELUDE trial, researchers discovered that the biomarker could be predictive of response to the PKC beta inhibitor. 

Enzastaurin was found to considerably enhance OS in patients with DGM1-positive disease versus those without the polymorphism (HR, 0.27; P = .0002). This clinical data was upheld in a biomarker evaluation completed on patient DNA samples collected from the S028 study. This finding showed that enzastaurin was linked with a superior survival benefit in those with high-risk DLBCL who were also positive for DGM1 versus those without the polymorphism (HR, 0.28; P = .018). These endeavors validated the initiation of the ENGINE trial, which is being conducted to confirm these data.

In the press release, the manufacturer’s chief technical officer indicated, “This Fast Track designation in GBM is an important milestone in the development of DB102. We are pleased that the FDA has recognized our innovative biomarker approach to conquer GBM. It potentially accelerates our development of DB102 in GBM, a difficult-to-treat indication with a significant unmet need and adds value to our DB102 franchise.”

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