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Glioblastoma Platform Trial Investigating Multiple Drugs in Parallel

Angelica Welch
Published: Wednesday, Sep 06, 2017

Another experimental arm is similar in setup; however, it uses abemaciclib, which is a CDK 4/6 inhibitor. Patients would get radiation and temozolomide like they would in standard of care, but then instead of getting temozolomide afterwards, they would get abemaciclib.

The final experimental arm uses CC-115, which may improve radiation when given concurrently. In that arm, temozolomide is substituted completely out, and patients get radiation and CC-115 at the same time followed by CC-115 alone.

CC-115 inhibits DNA protein kinase (DNA-PK), which is a protein that is involved in repair of damage from radiation due to double-strand breaks caused by radiation. By inhibiting DNA-PK, the hypothesis is that it will help the radiation further damage the tumor cells.

What are the biomarkers for this trial?

The definition of GBM has undergone a lot of change recently, especially as we find out more molecular information about the tumors. We find that tumors with certain molecular characteristics behave like other tumors with those molecular characteristics, rather than only judging by what you sometimes see under a microscope.

One example is the IDH mutation. IDH1 and IDH2 are 2 genes that can be mutated in GBM. The most common mutation is called the IDH1 R132H mutation, but there can be other IDH mutations. Any of these mutations are associated with many different things. Patients have a much better prognosis if they have an IDH mutated tumor. For that reason, the new molecular classification of GBM includes IDH in determining what kind of tumor it is. GBM with IDH wild-type is considered separate from a GBM with an IDH mutation.

Newly diagnosed GBM with an unmethylated MGMT promoter is the molecular abnormality that we are looking at specifically. To be eligible for trial enrollment, you must be IDH wild-type and have an unmethylated MGMT promotor. 

Do biomarkers vary among the different arms?

Regarding how the biomarkers relate to the therapies, a lot of biomarker-driven trials will say that you need a biomarker positive tumor to be eligible for a certain arm. The upside of that type of strategy is that if we know a lot about that kind of biomarker, then we know that only patients with biomarker-positive tumors are going to respond. We know that from other clinical studies or strong preclinical research. Then, we are limiting the number of patients who are not going to respond by not letting them on the study.

Conversely, if we do not know a lot about the biomarker, we are just making an educated guess based on the biology and there is not much clinical information, we may be making a mistake. Especially by saying that only the biomarker-positive patients would respond to a given drug but we don't know that for sure.

For GBM, the biomarkers that we are looking at are based on genetic profiling. We don’t have strong evidence to suggest that the biomarker is going to be sufficient or necessary for response to any one of these drugs. We do have hypotheses though, because all of these drugs interact with molecular pathways that are abnormal in GBM.

What we are going to do in this trial is take an initially agnostic approach. In the treatment arm, there is a hypothesized biomarker but both biomarker-positive and biomarker-negative patients are eligible to get the therapy. If, during the trial, we find out that it is only the biomarker-positive patients who are deriving benefit, the adaptive randomization procedure will stop putting patients with biomarker-negative tumors on that arm. However, since we don't know how good our information is at the beginning of the trial, any patient is eligible to be randomized to any arm of the trial.

You mentioned unmethylated MGMT promoters. Could you expand on that?

There are two major molecular prognostic biomarkers for GBM—the IDH mutation but also MGMT promotor methylation. MGMT is a gene that repairs damage caused by temozolomide and methylation of this gene turns it off, so it is less able to repair that damage.

We know from randomized trials that patients with methylated MGMT promotors have both better responses to temozolomide and have overall better prognosis. Even by taking temozolomide out of it, their tumors are less aggressive and patients have longer life expectancy. However, the MGMT absolute and likely relative benefit that you get from temozolomide is larger if you have a methylated MGMT promotor. Giving temozolomide for patients with MGMT promotors is standard of care, and all of the clinical trials that we do for patients with methylated MGMT promotors add an experimental therapy to that standard of care.

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Provider and Caregiver Connection™: Addressing Patient Concerns While Managing GlioblastomaSep 29, 20182.0
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