FDA Grants Fast Track Status to Enzastaurin for Newly Diagnosed Glioblastoma

The FDA has granted a fast track designation for the PKCβ inhibitor enzastaurin (DB102) for the treatment of patients with newly diagnosed glioblastoma (GBM), according to an announcement from Denovo Biopharma LLC.¹

“This fast track designation in GBM is an important milestone in the development of [enzastaurin],” Xiao-Xiong Lu, PhD, chief technical officer at Denovo stated in a recent press release. “We are pleased that the FDA has recognized our innovative biomarker approach to conquer GBM. It potentially accelerates our development of [enzastaurin] in GBM, a difficult-to-treat indication with a significant unmet need and adds value to our DB102 franchise.”

Denovo plans to launch a pivotal phase 3 trial evaluating enzastaurin in combination with temozolomide, both during and following radiation therapy, in patients with newly diagnosed glioblastoma.

The agent is also being evaluated in the phase 3 ENGINE trial (NCT03263026).² In this trial, investigators set out to enroll 235 patients with CD20-positive diffuse large B-cell lymphoma (DLBCL) and randomize them to receive either enzastaurin added to the standard-of-care of rituximab (Rituxan) plus cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) or R-CHOP alone for 6 cycles during the combination phase.

The primary end point of the trial was overall survival (OS) in patients with DLBCL who test positive for DGM1, with a secondary end point of OS in patients without DGM1. The key objective of the trial is to determine whether the addition of the investigational agent to R-CHOP in the frontline could lead to better outcomes compared with R-CHOP alone, and whether the presence of DGM1 correlates with response to the agent in this setting.

Additionally, in the phase 3 PRELUDE study (NCT00332202), investigators compared the PKCβ inhibitor with placebo in patients with high-risk DLBCL and found no statistically significant difference in disease-free survival at 4 years, at 70% versus 71%, respectively.³ No difference was observed with regard to OS, either (81% vs 82%, respectively). Another effort, the phase 2 S028 trial (NCT00451178), examined the novel agent in the frontline setting, in combination with R-CHOP compared with R-CHOP alone, in patients with intermediate- or high-risk disease. Again, results failed to show added benefit with enzastaurin.

Despite the negative data from PRELUDE and S028, genomic research examining DNA samples collected from study participants have been fruitful in that they led to the discovery of the DGM1 polymorphism. Specifically, following retrospective genotyping of patient samples collected from the PRELUDE trial, investigators found that the biomarker could be predictive of response to the PKCβ inhibitor. Enzastaurin was found to significantly improve OS in patients with DGM1-positive disease versus those without the polymorphism (HR, 0.27; P = .0002).

These data were upheld in a biomarker analysis performed on patient DNA samples collected from the S028 study. Here, 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 efforts supported the initiation of the ENGINE trial, which is being conducted to validate these data.

References

1. FDA grants fast track designation for DB102 in patients with newly diagnosed glioblastoma (GBM). News release. Denovo Biopharma LLC. July 17, 2020. Accessed July 22, 2020. https://bit.ly/39kp6Tv.
2. Smith S, Zhu J, O’Connor OA, et al. ENGINE: phase III randomized study of enzastaurin/R-CHOP versus placebo/R-CHOP in frontline high-risk diffuse large B-cell lymphoma patients with novel genetic biomarker DGM1. J Clin Oncol. 2019;37(suppl 15; abstr TPS7569). doi:10.1200/JCO.2019.37.15_suppl.TPS7569
3. Luo W, Sun H, Zhu J, Smith SD, Han I, Shazer R. Improved survival with enzastaurin treatment in diffuse large B-cell lymphoma patients with the novel genetic biomarker, DGM1. Blood. s2018;132 (suppl 1):4207. doi:10.1182/blood-2018-99-115807