March 21, 2017
This article was first published in the March 2017 edition of the Dana-Farber Cancer Institute's Inside the Institute.
Dana-Farber scientists have launched a new type of clinical trial designed to more rapidly evaluate experimental drugs and genomic biomarkers for treating brain tumors.
Unlike most conventional trials, the new study, called INSIGhT, is simultaneously testing three different investigational drugs for glioblastoma, the deadliest form of brain cancer.
As the study progresses, a flexible feature of the trial will assign more patients to the arm or arms of the trial in which subjects are showing better results.
"This will help us get answers faster as to whether the drugs are helping people and in what biomarker-defined populations,” says Brian Alexander, MD, MPH, in the Dana-Farber Center for Neuro-Oncology. He is the principal investigator of the INSIGhT trial. The phase 2 study is sponsored by Dana-Farber, and supported by three drug companies and a foundation, Accelerate Brain Cancer Cure.
The researchers will also be looking for biological signals, or biomarkers, in patients that correlate with their response to the experimental drugs.
The researchers plan to recruit 280 patients who have had surgery to remove as much as possible of their glioblastoma. All participants will receive radiation treatment for 42 days. One arm, the comparison group, will get temozolomide (Temodar), an approved glioblastoma drug, along with radiation and following radiation.
Another arm of the study will receive radiation plus temozolomide during radiation but replace temozolomide after radiation with abemaciclib, a targeted drug that blocks the CDK4/6 pathway.
Patients in another arm will undergo radiation and receive temozolomide during radiation but replace temozolomide after radiation with neratinib, which targets the EGFR growth-promoting pathway in cancer cells.
The fourth arm will test an investigational drug, CC-115, which acts to make cells more sensitive to radiation treatment in addition to its anti-tumor effects. Patients will receive CC-115, which is also an mTOR inhibitor, plus radiation, followed by CC-115 but will not receive temozolomide.
The arms will function almost as separate studies running in parallel. The objective measurement of effectiveness will be the same for all arms: overall survival, the time from randomization until death.
Alexander explains that at the beginning of the trial, patients will be randomly assigned to the four arms of the study since there is no prior information to guide which arm is best. A predetermined statistical algorithm will be watching the outcomes of patients in the different arms; if one or more drugs appear to be having more benefit than others, “the algorithm will increase the odds that the next patient, given their biomarker profile, will be assigned to that arm,” says Alexander. In that way, the study adapts to the performance of the drugs while it’s in progress, rather than waiting until the trials have completed to compare results.
Bayesian outcome adaptively randomized platform trials are a recent innovation aimed at shortening the often lengthy period of study needed to show whether an investigational drug is safe and effective. Alexander says the Dana-Farber group is the first to use this kind of design in a clinical trial of treatment for brain tumors.
“It is exciting to see this approach, the first of its kind to bring treatment options to newly diagnosed patients rather than when they have a recurrence,” says David Sandak, vice president of research at Accelerate Brain Cancer Cure. “By using robust genomic profiling and innovative clinical trial design, we are hopeful INSIGhT will better match patients to drugs from which they will benefit and speed the overall development process.”