New Clinical Trial Tests a Kind of Precision Medicine Treatment for IDH-Mutant Brain Tumors

February 12, 2024, by Rebecca Zacuto, Neuro-Oncology Branch Communications Fellow

Gliomas are a common type of primary brain tumor. They account for about 30 percent of all brain tumors and 80 percent are cancerous. And for cancerous gliomas, especially ones that come back or recur after standard treatments, there are few treatment options to help people live longer. 

Neuro-Oncologist Jing Wu, M.D., Ph.D., was among the first to study zotiraciclib—an oral drug and potential new treatment—for gliomas. As the head of the NCI Center for Cancer Research Neuro-Oncology Branch (NOB) Translational Research Program, Dr. Wu specializes in designing clinical trials for brain and spine cancers based on findings from her laboratory. Her team’s preclinical research on zotiraciclib laid the foundation for her new phase 1/2 clinical trial, which examines whether zotiraciclib is effective in people with recurrent gliomas containing mutations in the IDH1 or IDH2 genes. 

Laying the Groundwork for a Clinical Trial 

The IDH1 and IDH2 genes carry the instructions to build two enzymes: isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2, respectively. Over 80 percent of lower-grade gliomas contain IDH mutations. These enzymes are involved in regulating metabolism, but mutations can alter their normal function and drive cells to become cancerous.

Yet, according to Dr. Wu’s preclinical laboratory research, these mutations also make IDH-mutant gliomas uniquely vulnerable to zotiraciclib. “Zotiraciclib is a kind of precision medicine for IDH-mutant gliomas,” Dr. Wu explains. Her previous phase 1 trial also showed that it was safe to treat brain tumor patients with this drug. Because of the unique tumor biology and the way in which the drug acts, zotiraciclib kills IDH-mutant glioma cells at a lower dose than it needs to kill cells without the IDH mutation. 

“If we can lower the dose of a drug while achieving the same efficacy, then that is wonderful,” Dr. Wu says. “It means that a patient may have an effective tumor treatment with less toxicity, and therefore a better quality of life.” 

Thanks to Dr. Wu’s work, the U.S. Food and Drug Administration (FDA) granted zotiraciclib orphan drug status for use in glioma patients in 2019. This designation is given to therapies that treat, prevent, or diagnose rare diseases, such as IDH-mutant gliomas. It incentivizes drug developers to research and develop these designated therapies. 

Helping Patients with Recurrent Gliomas

Dr. Wu’s new clinical trial is a combined phase 1/2 trial based on her extensive zotiraciclib research. It aims to determine if the drug is effective in people with recurrent IDH-mutant gliomas. This means participants must have had prior radiation treatment and/or conventional therapies to participate, and despite those, their tumor returned. 

Unlike Dr. Wu’s previous phase 1/2 clinical trial that looked at zotiraciclib in combination with temozolomide—a common chemotherapy used to treat brain and spine cancers—this study seeks to understand zotiraciclib as a single agent in a particular subset of malignant gliomas. 

The objective of the phase 1 portion is to determine the optimal dose of zotiraciclib in patients with recurrent malignant gliomas with IDH mutations. For the phase 2 portion, the goal is to determine if zotiraciclib leads to 12 months of progression-free survival (prevent tumor growth) in people with high-grade IDH-mutant gliomas. Progression-free survival is defined as the time after a patient has started treatment until their cancer grows or spreads. If a patient can maintain a relatively normal daily life while they receive the treatment, that is also a great success.

Participants who enroll in the clinical trial will take zotiraciclib orally at home on specified days throughout a 28-day cycle. They will have a medication diary to track their doses. Additionally, patients will visit the Neuro-Oncology Clinic at the NIH’s Bethesda, Maryland campus about once a month for checkups and will undergo magnetic resonance imaging (MRI) scans every eight weeks. This process will repeat for up to one-and-a-half years. 

Implementing a Novel Clinical Trial Design

Dr. Wu has designed this clinical trial with several novel features. First, all participants enrolled in the trial will receive zotiraciclib. The clinical team will record the patients’ prognostic features—characteristics of the tumor and the patient that help estimate the outcome of disease, such as tumor size and grade and patient age. These are matched to an individual with similar features who is not part of the trial. Those matched individuals become the control group—a point of comparison to see if the drug is working for the people who received it.

“This means I don’t have to tell our participants that they have a 50-50 chance of receiving a placebo,” Dr. Wu says. “Instead, everyone will receive the treatment.” This approach also saves time and resources. 

Second, this clinical trial also will treat patients who require surgery to remove their tumor. They will be given a dose of zotiraciclib prior to surgery. Then the surgeon will take tumor samples, which will allow Dr. Wu’s team to analyze the biological effects of the drug on the tissue. This will provide molecular and biochemical evidence, in addition to clinical observation, to show whether zotiraciclib is doing what it is expected to do. 

Third, this trial seeks to find the optimal dose of zotiraciclib—that is, the lowest dose that is effective for patients. Traditionally, clinical trials seek to find the maximum tolerated dose of a drug, which is the highest dose that a patient can take before experiencing serious side effects. Dr. Wu prefers the optimal dose approach. “Providing what is needed to control the tumor and limiting unnecessary toxicities are what we are aiming for” she says.

As a cancer researcher, Dr. Wu says it is her mission to improve the lives of brain and spine tumor patients. “The message I would like to get out is that targeting tumor vulnerabilities may provide a better chance to treat IDH-mutant gliomas and this is what this clinical trial is aiming at,” she adds. 

For questions or to enroll in this study, the patient's treating physician can contact the Neuro-Oncology Clinic.