Triphase Accelerator, a private drug development company dedicated to advancing novel compounds through clinical phase II proof-of-concept, has announced positive full enrollment results from its multicenter, open label, phase I study evaluating marizomib (MRZ) in combination with bevacizumab (BEV) in patients with WHO grade IV malignant glioma. Triphase separately announced on November 17, 2016 that Celgene acquired the assets relating to MRZ.
“These results continue to demonstrate the potential benefit of both the combination therapy of MRZ and BEV, as well as MRZ monotherapy, for recurrent glioma," said Daniela Bota, M.D., medical director of Neuro-Oncology and associate professor of neurology at the University of California, Irvine, and lead investigator of the study. “As we reported for our interim results, adding the expansion cohort of monotherapy with MRZ was extremely helpful in achieving robust results, and we think we may have established an optimal dosing regimen.”
The phase I open-label dose-escalation study included three dose escalation cohorts plus an expansion cohort, for a total of 36 recurrent glioma patients receiving MRZ on days one, eight and 15, with standard dose of bevacizumab (BEV at 10mg/kg) on days one and 15, of a 28-day cycle. The MRZ+BEV combination was well tolerated with no dose limiting toxicity at 0.8 mg/m2, which was the highest dose of MRZ evaluated in this study.
The Response Rate (by Response Assessment in Neuro-Oncology (RANO) criteria) was 42% (14/33) in efficacy evaluable patients, with 34% of patients achieving six months progression-free survival (PFS) and 55% achieving nine months overall survival (OS). The six and nine months PFS in patients with unmethylated MGMT—a marker of poor prognosis and resistance to standard-of-care in glioblastoma—were 34% and 23%, respectively. These data are comparable to PFS in all patients (34% PFS 6 months, 22% PFS nine months), suggesting a potentially unique clinical benefit of MRZ+BEV in this difficult to treat segment of glioblastomas. To date, the nine months OS in unmethylated MGMT patients is 44%, with data collection continuing for most patients.
In an ongoing phase II (MRZ monotherapy) portion of the study, a total of 15 recurrent glioma patients have been enrolled to date, receiving 0.8 mg/m2 MRZ on days one, eight and 15 of a 28-day cycle. MRZ monotherapy in these patients has resulted in a partial remission in one patient, and stable disease in two additional patients, demonstrating activity of MRZ as a single agent. Based on these data, the study will continue enrollment up to 30 total patients. MRZ is generally well tolerated in combination with BEV and as monotherapy. The most common study treatment-related adverse events across both phases of the study include fatigue, headache, nausea, diarrhea, dysphonia, hypertension, vomiting, hallucination and weakness.
“These clinical proof of concept results further support the value of MRZ as a potential treatment for recurrent glioma,” said Mohit Trikha, Ph.D., chief scientific officer and head of Triphase Accelerator Research and Development. “Equally as important for Triphase Accelerator, these results were instrumental to Celgene’s decision to acquire the compound.”