The Brain Tumor Awareness Month (BTAM) that runs in May is designed to raise awareness about the serious condition that afflicts approximately 35,000 people each year in the U.S., according to the National Cancer Institute. Glioblastoma multiforme (GBM) is one of the most common and aggressive forms of the disease that progresses rapidly, resulting in poor prognosis for those patients. It represents a significant unmet need and a number of biopharmaceutical companies are developing therapies in that area.

However, as Charles Theuer, president and CEO of Tracon Pharmaceuticals Inc., pointed out, "glioblastoma is a very challenging indication for drug development."

He was commenting on the company's lead candidate, TRC-105 (carotuximab), which did not meet its primary endpoint of median progression-free survival (PFS) in a phase II trial in combination with Avastin (bevacizumab, Roche Holding AG) to treat patients with recurrent glioblastoma. (See BioWorld Today, Feb. 13, 2017.)z

The top-line results were from a randomized study of 101 patients who received Avastin or Avastin plus TRC-105.

Curtain closes

Last year, Celldex Therapeutics Inc. also drew the curtain on its phase III glioblastoma trial with Rintega (rindopepimut). The company's data safety monitoring board recommended stopping the study in patients with newly diagnosed, epidermal growth factor variant III-positive disease, since it would not hit statistical significance on the primary endpoint: overall survival (OS) in those with minimal residual disease. (See BioWorld Today, March 8, 2016.)

Despite those setbacks, the clinical pipeline for investigational therapies focused on GBM is deep, with well over 300 studies in progress or currently recruiting patients; about 20 of the therapies have reached late-stage testing. (See Drugs in Development for Glioblastoma, below.)

For example, Tel Aviv, Israel-based VBL Therapeutics Inc. reported late last month that the independent data safety monitoring committee unanimously recommended that the firm's phase III GLOBE study investigating ofranergene obadenovec (VB-111) in recurrent glioblastoma (rGBM) continue as planned.

The study is comparing VB-111 in combination with Avastin to Avastin alone and has recruited 256 patients in the U.S., Canada and Israel, and top-line results are expected to read out early next year.

In a phase II trial with 24 rGBM patients treated with VB-111 monotherapy, a median OS of 59 weeks was achieved, compared to 32 weeks for historical patients treated with Avastin alone.

According to H. C. Wainwright analyst Swayampakula Ramakanth, from the phase II reported results, he said he believes "that the GLOBE study has a high likelihood of success and VB-111 could become the new standard of care for this difficult to treat indication." He projected "risk-adjusted VB-111 GBM revenues to grow from $12 million in 2019 to $293 million in 2026."

In February, Northwest Biotherapeutics Inc. said the partial clinical hold on its phase III trial of Dcvax-L for GBM had been lifted by the FDA, and that it had accumulated a sufficient number of events toward the PFS endpoint, but not yet for the OS endpoint.

There are 331 patients enrolled and endpoints involve thresholds of 248 "events" for PFS and 233 "events" for OS, which the company estimates it is still several months away from achieving.

In its first-quarter financials and business update, Boston-based Ziopharm Oncology Inc. CEO Laurence Cooper said his firm is making progress on finalizing a registration path for Ad-RTS-hIL-12 plus orally administered veledimex for rGBM. Back in March, Ziopharm received positive guidance from an FDA end-of-phase II meeting on the gene therapy product candidate.

San Diego-based Tocagen Inc., which has just raised $97.8 million from an IPO, has completed patient enrollment in the phase II segment of Toca 5, a randomized, international phase II/III trial of a combination of gene therapy treatment Toca-511 and the prodrug 5-fluorocytosine for the treatment of patients with rGBM.

The study, whose primary endpoint is overall survival, is designed to serve as a potential registrational trial, and top-line results from the phase II segment are anticipated in the first half of next year.

Immunocellular Therapeutics Ltd., of Los Angeles, is developing lead product ICT-107, a dendritic cell-based immunotherapy targeting six tumor-associated antigens on glioblastoma stem cells. It is currently being tested in a phase III registration trial in patients with newly diagnosed GBM. The company reported in March that it submitted an amendment of the trial protocol to the FDA. The key change will enable patients to be randomized 30 days after commencing screening procedures, accelerating the time to randomization by approximately two months.

Midstage trials

According to data from Cortellis Clinical Trials Intelligence, there are more than 130 trials with GBM therapies at phase II testing. Among those is Vancouver, British Columbia-based Delmar Pharmaceuticals Inc.'s lead drug candidate, VAL-083. Following a successful closing of a $9 million registered public offering, the company is gearing up for late-stage testing of VAL-083 (dianhydrogalactitol) being developed for the treatment of GBM.

In February, patient dosing was initiated in a phase II study of VAL-083 for methylguanine methyltransferase (MGMT)-unmethylated Avastin-naïve recurrent glioblastoma. The trial will test safety, tolerability and clinical efficacy of VAL-083 in 48 adult subjects with MGMT-unmethylated GBM whose tumors have recurred following surgery and standard chemoradiation with temozolomide. Patients will receive 40 mg/m2 VAL-083 (I.V.) on days one, two and three of a 21-day treatment-cycle, for up to 12 21-day treatment cycles, to determine if treatment with VAL-083 improves OS compared to historical controls.

The company said documented studies have reported that expression of MGMT is an important factor in predicting the outcome of GBM patients treated with alkylating agents such as temozolomide, carmustine and lomustine.

Patients whose tumors exhibit a high expression of MGMT appear to have a poor prognosis and significantly shorter PFS and OS in comparison to patients with a methylated MGMT promoter and low MGMT expression.

Delmar has also entered a three-year collaboration with Duke University to evaluate VAL-083 as a front-line treatment for newly diagnosed patients with GBM. The company said it will fund a series of preclinical studies to be conducted by Duke University's Glioblastoma Drug Discovery Group to evaluate VAL-083, either alone or in combination with other agents, for activity against a range of glioblastoma subtypes with the goal to identify molecular characteristics of GBM tumors that are more likely to respond to VAL-083, and not the standard of care, temozolomide, as a front-line treatment or through combination therapies.

GW Pharmaceuticals plc, of London, is testing the potential role that cannabinoids can play in oncology. It reported an exploratory phase II placebo-controlled study with 21 patients, testing its combination of tetrahydrocannabinol and cannabidiol (THC:CBD), which showed patients with documented rGBM treated with THC:CBD had an 83 percent one-year survival rate compared with 53 percent for patients in the placebo cohort (p=0.042). Median survival for the THC:CBD group was greater than 550 days compared with 369 days in the placebo group.

Phil Nadeau, analyst with Cowen & Co., commented that those results were "intriguing" and "establish proof of concept for CBD:THC in GBM."

Weston, Fla.-based Cantex Pharmaceuticals Inc. has initiated dosing this month in its phase II trial for CX-02, a combination of disulfiram plus copper, in rGBM. The study will evaluate the efficacy, safety and tolerability of CX-02 in approximately 20 patients.

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