Brian M. Alexander, MD
In an ongoing phase II trial, researchers are investigating several targeted agents for use in the treatment of patients with glioblastoma (GBM).
The study, known as the INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT; NCT02977780), will randomize patients to 1 of 4 arms—either the control arm of standard-of-care agent temozolomide (Temodar), or 1 of 3 experimental arms. The experimental arms are abemaciclib in combination with temozolomide, neratinib (Nerlynx) with temozolomide, and CC-115 alone. All 4 arms include daily radiation for a maximum of 49 days.
Temozolomide is FDA approved for the treatment of patients with GBM, while abemaciclib, neratinib, and CC-115 are all currently experimental in this landscape.
Primary outcomes of the study, which is currently accruing patients, are overall survival in the experimental arms compared with standard temozolomide, and secondary endpoints among the experimental arms include incidence of treatment-emergent adverse events, and progression-free survival.
Eligible patients must have evidence that their tumor MGMT
promoter is unmethylated and must be immunohistochemically negative for IDH1
In an interview with OncLive
, principal investigator Brian M. Alexander, MD, disease center leader, Radiation Oncology, Center for Neuro-Oncology, senior physician, associate professor of radiation oncology, Harvard Medical School, Dana-Farber Cancer Institute, discusses the significance of the INSIGhT trial in GBM.
OncLive: Please describe the INSIGhT trial.
The INSIGhT trial is a disease-specific platform trial, which means we have come up with a clinical trial design that fits patients with GBM who have newly diagnosed tumors and specific kinds of molecular abnormalities. It is a platform trial, in that it is testing multiple different kinds of therapies at the same time. Instead of running 3 separate clinical trials, we run 1 platform trial that tests all the drugs at the same time against a common control arm.
The lingo is confusing. "Basket trial" has been thrown around a lot. Sometimes, a basket trial means that patients are eligible for a specific drug or a specific set of drugs if they have a specific biomarker, no matter what kind of tumor they have. INSIGhT is more like the I-SPY 2 trial (for breast cancer)—testing multiple therapies for a specific disease indication with experimental arms that can be added or dropped during the trial.
This trial is currently open at the Dana-Farber Cancer Institute with additional sites going through the approval process now. One benefit for patients is that they have a higher chance of being randomized to an experimental arm than if we did these trial separately. Also, patients often ask which trial is best for then. That is normally hard to answer because we can't compare across trials. In INSIGhT, while we still can’t say which arm is best, we have an adaptive randomization algorithm that, if one arm is performing better during the course of the trial it is more likely to put future patients on that arm, considering their biomarker profile.
We can say that this answers patients’ questions in that way by saying that we don’t explicitly know which arm is the best. However, in this construct, we have designed it in a way that you are more likely to put patients on the arm that looks best for them.
We have a maximum of 70 patients for each arm. If the drug looks like it’s working, we will continue enrolling patients until we reach 70 so that there will be robust information on how to design a phase III trial, including biomarkers.
Could you expand on the separate arms of this trial?
We started off with 4 arms but the trial is designed so that it can accept new arms if the opportunity arises. Instead of opening a new, separate phase II trial with similar characteristics, we would rather just add an arm to this trial. There are 3 experimental arms and 1 control arm, which is radiation therapy and temozolomide. From a patient enrolling on the trial perspective, you have a greater chance to be randomized to an experimental therapy. But we also are persevering the opportunity to compare that with a control arm, which is important for us to make any decisions about the therapy that will impact future patients.
One of the arms is neratinib. In the trial, neratinib is substituted for temozolomide after radiation plus temozolomide. In that arm, patients get radiation and temozolomide at the same time, same as the standard of care. But then, instead of getting temozolomide afterwards, they would get neratinib.