'Groundbreaking' Global Brain Cancer Trial Planned

Donald A. Berry, PhD

An international coalition of experts is planning an innovative clinical trial aimed at speeding up the development of new treatments for patients with glioblastoma multiforme (GBM), putting into motion a biomarker-driven approach that has been employed in other malignancies.

GBM AGILE would utilize an adaptive clinical trial design with a master protocol in which patients would be screened for preselected molecular biomarkers and then channeled into randomized studies of novel agents with matching signatures, one of the architects of the trial explained in a presentation at the 2015 Society for Neuro-Oncology Annual Meeting.

“It’s a brave new world,” said Donald A. Berry, PhD, a professor of Biostatistics at The University of Texas MD Anderson Cancer Center who is co-principal investigator on the trial. “We’re experimenting ... and we’re experimenting with clinical trials.”

Berry said investigators would be able to conduct multiple phase II trials simultaneously as patients would be randomized within their subtype versus standard-of-care treatments, with approximately 150 patients in each arm and overall survival as an endpoint. He said the design would allow for testing combination and sequential therapies.

By analyzing patient outcomes data, researchers would calculate the probability that an experimental therapy might offer an improvement over the standard. Based on the results, promising agents would then “graduate” to phase III trials, Berry said. Studies into agents that reach a futility mark would be halted, while new novel agents could be continuously cycled into the protocol.

Hopes are high for GBM AGILE as the complex planning process for the trial gets into full swing. “As a neuro-oncologist taking care of GBM patients every day, GBM AGILE is groundbreaking in so many ways,” said Timothy Cloughesy, MD, the trial’s principal investigator.

“The adaptive design will allow us to modify the trial as it proceeds based on the data collected—and to test many drugs and combinations versus single agents—and to do it faster,” said Cloughesy, who is director of the Neuro-Oncology Program at UCLA. “It's an opportunity for patients to benefit from precision medicine, and a real source of hope for patients and their families.”

“Crowdsourcing” Effort

GBM AGILE is in the planning and design phase. The organizers hope to begin enrolling patients by mid-2016. No specific drug candidates for inclusion in the trial have been disclosed, and the group is still seeking to raise funds for the study.Through the trial, researchers hope to leverage recent advances in the understanding of the molecular drivers of GBM and the cooperation of scientists throughout the world. The trial will be conducted in the United States, China, Europe, and Australia, organizers said in announcing plans for the initiative in mid-November.

GBM AGILE grew out of a “scientific crowdsourcing” effort that has brought together more than 100 neurosurgeons, neuro-oncologists, pathologists, imagers, neuroscientists, and patient advocates to plan the study. Leading the effort is the National Biomarker Development Alliance (NBDA), a nonprofit organization created as part of the Research Collaboratory at Arizona State University.

The research initiative was announced with a sense or urgency in light of the aggressive nature of GBM, the most common adult brain tumor. Organizers said 50% of patients with GBM survive for 1 year or less and that the 5-year survival rate is less than 2%.

Moreover, despite hundreds of clinical trials, the most notable therapeutic advance in GBM occurred more than 10 years ago when the combination of temozolomide and radiation therapy demonstrated the ability to extend survival by about 2 months, according to the NBDA.

Modeled on I-SPY 2

"We have to do something more—something different—something that brings the best science and innovative clinical trials together to identify therapies that work," Mitchel S. Berger, MD, a GBM AGILE co-investigator who chairs the Department of Neurological Surgery at the University of California, San Francisco, said in a statement. "GBM AGILE is the best path to achieve those goals that I have seen for decades."Berry, who is the founding head of the Division of Quantitative Services at MD Anderson, is a leader in the development of innovative statistical methodology for the improvement of clinical trial design and analysis, especially the Bayesian methods used in the I-SPY breast cancer clinical trials. The GBM AGILE trial also would use the Bayesian methodology.

During his presentation, Berry said the FDA recognized a decade ago that adaptive trial design and Bayesian methods could help improve upon the high costs and low success rate of phase III clinical trials. He also said the FDA has acknowledged that the clinical trial paradigm must be changed in order to speed the progress of personalized drugs to market.

Berry described GBM AGILE as a platform trial that would be modeled after I-SPY 2, which was launched in 2010. In the breast cancer trial, 8 pharmaceutical companies have “put aside their differences” to participate in the phase II trials, in which more than 900 patients have been randomized to studies evaluating 10 experimental therapies, Berry indicated.

Thus far, 3 drugs that were tested in combination regimens have met the standards for graduation from I-SPY 2, according to ClinicalTrials.gov website records, which were last updated in mid-July (NCT01042379). Those drugs are veliparib, neratinib, and MK-2206.

Berry said I-SPY 2 has inspired researchers in other areas of medicine to pursue similar trials. Europe’s Innovative Medicines Initiative collaborative efforts include biomarker-driven studies into Alzheimer disease and a wide-ranging Ebola research program.

In oncology, master protocol trials also have been utilized in melanoma with the MICAT trials and in lung cancer with the BATTLE and ongoing Lung-MAP studies.

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