With a median overall survival of a little more than a year and five-year survival rates just barely in the single digits, glioblastoma multiforme (GBM) is among one of the deadliest forms of cancer. Unfortunately, there are still, as yet, very few effective treatment options for GBM patients. Developing new therapies has, unfortunately, proved challenging, as a new report published this month by the Pharmaceutical Research and Manufacturers of America (PhRMA) identifies. PhRMA's research looked at three difficult-to-treat cancers, including those occurring in the brain, and found that during the past 15 years there have only been three new drug approvals for brain cancer, while another 75 medicines have failed in the development process.

One of those was integrin inhibitor cilengitide from EMD Serono, a subsidiary of Merck KGaA, of Darmstadt, Germany, which reported that it failed to significantly improve overall survival (OS), the primary endpoint, in the phase III CENTRIC trial investigating the agent when added to standard chemoradiotherapy (temozolomide and radiotherapy). The study included more than 500 patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter status. The trial was designed and conducted in partnership with the European Organization for Research and Treatment of Cancer. (See BioWorld Today, Feb. 26, 2013.)

The PhRMA report, "Researching Cancer Medicines: Setbacks and Stepping Stones," details the tremendous challenges that cancer drug developers face by focusing on three cancers that are particularly difficult to treat: melanoma, lung cancer and brain cancer.

Among the key findings are that, from 1998 to the present, 96 potential treatments for melanoma failed to progress through clinical trials, and seven new therapies were approved; the attrition for therapies targeting lung cancer has reached 167, with just 10 successfully making it through to regulatory approval during their reporting period.

Despite that poor run rate, companies continue to build on the knowledge gained from those previous unsuccessful trials, noted PhRMA president and CEO John J. Castellani.

The pace of innovation in the cancer field is reflected by the 50 candidate therapies that are in development in the U.S. targeting melanoma and 98 that are targeting lung cancer. The data were drawn from another recently released PhRMA report that documents there are 771 cancer therapies and vaccines, being developed by America's biopharmaceutical research companies, either in clinical trials or awaiting review by the FDA.

BRAIN CANCER

Approximately 6 percent of the compounds highlighted in the report are indicated for brain cancer.

Among the products in development that are furthest along is Celldex Therapeutics Inc.'s experimental therapy. At the end of last year the company raised net proceeds of about $162.7 million from a public offering to support an ongoing phase III program with rindopepimut, often known as "rindo. The immunotherapeutic vaccine is designed to target EGFRvIII and is being tested in GBM patients whose brain tumors overexpress the oncogene, which means a significantly worse prognosis. (See BioWorld Today, Dec. 6, 2013.)

The ACT IV study is a randomized, double-blind, controlled study of rindopepimut plus GM-CSF added to standard of care temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. Patients are randomized into a treatment or control arm after the completion of surgery and standard chemoradiation. The primary objective of the study is to determine whether rindopepimut plus GM-CSF improves the overall survival of patients with newly diagnosed EGFRvIII-positive glioblastoma after gross total resection (GTR) when compared to treatment with the current standard of care. Approximately 700 patients are being enrolled at more than 200 centers worldwide, with plans to recruit 374 patients with GTR for inclusion in the primary analysis.

Northwest Biotherapeutics Inc., of Bethesda, Md., also has a lead program with DCVax-L, a dendritic cell-based vaccine, in a 348-patient phase III trial in both the U.S. and Europe in newly diagnosed GBM patients.

BLOCKADE

Blockade of the immune checkpoint is an advancing therapeutic approach in the field, where it is being employed against a number of cancers, including GBM. Research is leading to an understanding that cancer cells may exploit regulatory pathways such as checkpoint pathways to cloak themselves from the immune system in order to avoid attack and destruction. Anti-PD-1 inhibitors are thought to play a role in uncloaking the presence of cancer cells. Bristol-Myers Squibb Co., of Princeton, N.J., is investigating its PD-1 immune checkpoint inhibitor Opdivo (nivolumab) in combination with Yervoy (ipilimumab) in adult subjects with recurrent GBM. The study will be a randomized phase III open-label study of nivolumab vs. Avastin (bevacizumab, Roche AG) and a safety study of nivolumab or nivolumab plus ipilimumab. According to Clinicaltrials.gov, 372 patients have been enrolled and the completion date for the study is expected in early 2018.

Recently, BMS reported positive results from CheckMate-037, a phase III randomized, controlled open-label study of Opdivo vs. investigator's choice chemotherapy in patients with advanced melanoma who were previously treated with Yervoy, so it will certainly be interesting to see if the company has similar success in GBM.

In November, Cytrx Corp., of Los Angeles, started a phase II trial with its aldoxorubicin for the treatment of unresectable GBM. The open-label study is designed to investigate the preliminary efficacy and safety of aldoxorubicin in patients whose tumors have progressed following prior treatment with surgery, radiation and temozolomide.

The trial is expected to enroll up to 28 subjects and tumor response will be monitored every six weeks by MRI until disease progression occurs. The primary objective of the clinical trial is to determine progression-free survival (PFS) and OS.

Cytrx president and CEO Steven Kriegsman said his firm "is encouraged by aldoxorubicin's apparent ability to cross the blood-brain barrier, potentially creating a new approach to attacking brain tumors."

Aldoxorubicin combines doxorubicin with a single-molecule linker that binds directly and specifically to circulating albumin.

North Chicago-based Abbvie Inc. has in its pipeline investigational compound ABT-414, an anti-epidermal growth factor receptor antibody-drug conjugate, which is being evaluated for safety and efficacy in patients with GBM. In August, the company received orphan drug designation for the compound from the EMA and the FDA. ABT-414 has progressed to phase II testing.

COMMON COLD

Even elements of the common cold are being exploited against GBM with Dnatrix Inc., of Houston, using an oncolytic viral approach. The company's lead compound, DNX-2401, is an adenovirus made potent and safe by engineering two stable genetic changes in the DNA genome that cause it to replicate selectively in retinoblastoma (Rb)-pathway-deficient cells and zero in more efficiently on cells that express certain of the often-targeted RGD-binding integrins. Because tumor cells are defective in Rb function, DNX-2401 replicates in and kills those tumor cells selectively, efficiently and far better than wild-type adenovirus, the company explained.

Dnatrix said the first patient was treated with DNX-2401 in an open-label phase Ib study in recurrent glioblastoma. Patients in the TARGET 1 (Therapeutic Adenovirus for Recurrent Glioblastoma EffecT) trial will be randomized to receive sequential therapy of DNX-2401 plus or minus interferon gamma, an immunomodulatory cytokine that plays a role in antitumor immunity. (See BioWorld Today, Sept.22, 2014.)

The company recently raised $20 million from a series B financing round, which will fuel further development of its clinical program.

Editor's note: Part 2 of this feature will look at other emerging therapeutic strategies that target GBM as well as review therapies targeting other difficult to treat cancers.