MIAMI BEACH, Fla.—In separate announcements, and using markedly different therapeutics, Cortice Biosciences and Celldex Therapeutics, Inc. presented encouraging findings for the treatment of glioblastoma multiforme (GBM) to the 19th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology in Miami Beach.
Cortice unveiled initial results from CB-017, a Phase 1/2 clinical trial evaluating TPI 287 plus bevacizumab (Avastin®) for the treatment of GBM that has recurred following front-line treatment. TPI 287 is a novel microtubule stabilizing agent that readily penetrates the blood-brain barrier. Prior preclinical and clinical results support the potential of this agent for treatment of cancers of the brain, including GBM, a highly aggressive malignancy with few therapeutic options.
Cortice is running two multi-center clinical trials designed to determine the maximum tolerated dose and efficacy of TPI 287 in combination with standard-of-care bevacizumab for treatment of recurrent GBM that either has not been or has been previously treated with bevacizumab. The goal of both trials is to determine the maximum tolerated dose (MTD) of TPI 287 in these treatment settings as well as objective response, progression free survival, and overall survival.
"TPI 287 is a potent cytotoxic drug able to penetrate the brain at therapeutic concentrations. The results presented today support the safety and efficacy of this agent in glioblastoma," said Dr. Samuel Goldlust, medical director of the Brain and Spine Institute of the John Theurer Cancer Center and principal investigator of CB-017. "It is particularly promising to see frequent durable responses at doses of TPI 287 below the MTD. These results support the likelihood of bringing a much needed novel therapy to patients with few options at time of recurrence."
Results from the on-going dose-escalation stage of the CB-017 study, which is enrolling recurrent GBM patients who have not been previously treated with bevacizumab, were also presented. To date, the 15 patients enrolled have received one or more doses of TPI 287 at concentrations ranging from 140 to 180 mg/m2 administered intravenously every three weeks in combination with bevacizumab (10 mg/kg every two weeks). Responses were evaluated per RANO criteria by the site investigators. Six patients continue to be treated on study. At the time of the presentation, 13 patients were evaluable for efficacy at doses up to 170 mg/m2 of TPI 287.
Seven patients achieved objective responses, including 5 confirmed (1 complete response; 4 partial responses) and 2 unconfirmed (1 complete response; 1 partial response). The 5 confirmed responses were or have been durable (5.5 to 8.3 months); three remain on-going. Five patients achieved stable disease. Only one patient had progressive disease at first assessment for response. Safety data was available from 12 patients treated at doses up to 170 mg/m2 of TPI 287. With the exception of Grade 3 myelosuppression (2 patients), all adverse events regarded as possibly related to TPI 287 have been mild-to-moderate. No dose limiting toxicities have been observed to date.
Given that the MTD has not been reached, dose escalation with TPI 287 continues in the 180 mg/m2 treatment cohort. Cortice plans to provide further updates to CB-017, as well as preliminary results from CB-018, a Phase 2 trial evaluating TPI 287 in patients with prior bevacizumab treatment experience, at future medical meetings in 2015.
"The overall response rate of 54 percent achieved with the TPI 287 plus bevacizumab combination at this early stage of CB-017 is highly encouraging, especially in the context of the 24 percent response rate observed in the monotherapy cohorts of the Avastin registration studies for GBM," said George Farmer, Ph.D., CEO of Cortice. "Moreover, the results from CB-017 include two complete responses, outcomes rarely observed in this population. We look forward to additional follow up from this study and CB-018, which will help us understand the potential of TPI 287 in this devastating disease."
Celldex Therapeutics, Inc. announced an interim update from the Phase 2 ReACT study of rindopepimut in EGFRvIII-positive GBM. The ReACT results demonstrate clear signs of clinical activity in patients with recurrent glioblastoma, including groups both naive and refractory to bevacizumab. The data were presented in a platform presentation by David A. Reardon, M.D., clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Center and associate professor of medicine, Harvard Medical School, and the lead investigator of the ReACT study.
Rindopepimut (RINTEGA®) is an investigational immunotherapy that targets the tumor specific oncogene EGFRvIII. Patients with EGFRvIII-positive glioblastoma typically have a worse prognosis than the overall glioblastoma population, including poor long term survival.
Highlights of the interim data update included the primary endpoint of PFS-6 (percent alive without progression at 6 months)—rindopepimut 27 percent vs. control 11 percent; p=0.048; statistically significant overall survival benefit—hazard ratio of 0.47; p=0.0208; rindopepimut median 12.0 months vs. control median 8.8 months; and an increase in clinically meaningful tumor shrinkage. Rindopepimut plus bevacizumab was well tolerated with no serious adverse events attributed to rindopepimut. Early anti-EGFRvIII immune response correlated with survival benefit.
"The patients in this study have advanced and difficult to treat disease," said Dana-Faber’s Reardon. "While these are interim data, the ability to demonstrate a survival benefit in this patient population has been extremely rare. If final data are consistent with these results, it would be practice-changing for physicians treating glioblastoma and offer new hope to patients and their families."
"The interim data presented today are extremely encouraging and continue to add to an impressive and consistent data set for rindopepimut across multiple studies and stages of disease," said Thomas Davis, M.D., executive vice president and chief medical officer of Celldex. "We believe these interim data are clinically important to patients with recurrent glioblastoma and, if the final data remain consistent, we intend to discuss the significance of these findings with regulatory authorities."
