Children’s Oncology Group study to assess targeted therapy for low-grade glioma
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The most common type of pediatric central nervous system tumor, low-grade glioma, typically grows slowly and follows a relatively indolent course.
However, children with these tumors can experience substantial functional impairment, including vision deficits, motor dysfunction and hormone irregularities, that can greatly impact their quality of life.
Classic chemotherapy remains the standard of care for children with low-grade glioma. Yet, this type of cytotoxic therapy destroys healthy cells along with cancerous cells, leading to severe adverse effects.
To minimize these effects and improve functional outcomes, Children’s Oncology Group (COG) has initiated a multicenter clinical trial (COG ACNS1831) to evaluate targeted therapy for children with neurofibromatosis type 1 (NF1)-associated low-grade glioma.
“With low-grade gliomas, we’ve learned that most of the time, children will not succumb to the disease; however, many children will be fighting the disease on and off throughout their childhood,” Jason Fangusaro, MD, director of developmental therapeutics for Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta and principal investigator of the COG study, told Healio. “So, what we’ve really focused on in the last several years is maximizing their functional outcomes and their quality of life. If we’re using a treatment that gives children severe side effects and decreases their quality of life, we’re not serving our patients well.”
Fangusaro spoke with Healio about the trial, its objectives and the potential of targeted therapy for treatment of pediatric brain tumors.
Question: What risks are associated with the current standard treatment for low-grade glioma?
Answer: Resection of these tumors is the gold standard, but in some cases, you can’t remove all of the tumor safely and, in these situations, other therapies are often necessary. The most commonly accepted standard chemotherapy for low-grade glioma consists of carboplatin and vincristine given via IV once a week for over a year. This requires an IV poke or some type of central line and a weekly visit to the clinic, all of which can affect quality of life for these children. In terms of the more direct adverse effects of chemotherapy, patients can experience peripheral neuropathy from vincristine, as well as constipation and sodium dysregulation. With carboplatin, there is a 20% to 30% risk for developing an anaphylactic reaction and it can also cause decreases in blood counts that may require blood and platelet transfusions in addition to weakening the patient’s immune system. So, we’ve focused on trying to find treatments that are not only helping the tumor to shrink or stay stable but also are minimizing the side effects and maximizing the patient’s quality of life.
Q: How does selumetinib act against low-grade glioma?
A: Selumetinib (Koselugo, AstraZeneca) is an MEK 1 inhibitor, and we’ve found that most tumors in patients with pediatric low-grade glioma have abnormalities in the MAP kinase pathway where MEK resides. This drug blocks the flow of that pathway and blocks tumor propagation. We recently published a phase 2 study, conducted by the Pediatric Brain Tumor Consortium (PBTC) and sponsored by the NCI, that looked at selumetinib among patients with recurrent low-grade glioma. Between 30% and 40% of patients had at least a partial response, and most had stable disease, even though they were progressing when they entered the trial. The current trial being led by COG and sponsored by NCI, and of which I am the principal investigator, includes patients with newly diagnosed low-grade glioma who have a genetic disorder called NF1, which puts them at increased risk for developing low-grade gliomas. A separate COG trial with almost the exact same design includes patients with low-grade glioma who do not have NF1. I am vice chair on this second trial, and my colleague, Peter de Blank, MD, MSCE, of Cincinnati Children’s Hospital Medical Center, is the principal investigator. Both trials will be looking at responses and PFS in addition to functional outcome of patients randomly assigned to the classic chemotherapy regimen of carboplatin and vincristine or selumetinib, an oral medication taken twice a day that requires a lot fewer visits to the clinic. Patients can come once a month, usually, for evaluation. They don’t need a central line, and most would argue that the adverse effect profile is less than that of the chemotherapy.
Q: Where does the trial stand?
A: We opened the trial in October 2019 and are in the process of opening at multiple COG institutions in the United States. There are about 220 COG hospitals in the nation, and we have enrolled about nine patients nationally who have already started therapy.
Q: Do you hope that selumetinib will replace chemotherapy as standard of care for children with low-grade glioma?
A: Yes. Our primary objective for the trial is to compare the response rates and PFS of patients, but other objectives include looking at their functional outcome. For example, a lot of these children will have tumors in their optic pathway, which leads to vision deterioration. One objective is to determine whether kids treated with selumetinib vs. carboplatin and vincristine have a better visual outcome. We also are looking at some secondary objectives, such as motor outcomes, neurocognitive outcomes and patient-reported quality of life. Once the study is completed, we may find that the response rate and PFS was about the same between the two arms, but if quality of life, functional outcomes and visual outcomes are better in the selumetinib arm, we would still consider that a success. If it is a success, as we hypothesize, we hope that this would become the new standard of care for these patients.
Q. Do you think targeted therapy will ultimately be the treatment of the future for most pediatric brain tumors?
A: Yes, it’s looking that way. Tumors like low-grade glioma that seem to be driven by one pathway will benefit the most from these molecular targeted agents. Other types of tumors with multiple pathways and multiple abnormalities often are more aggressive. Sometimes, even if we target one pathway in these tumors, it’s not enough. So, I think the future is going to be twofold: some tumors will respond well to molecular targeted agents, and others will require combination therapies. These combinations might include molecular targeted agents, immunotherapy and maybe even classic chemotherapy with or without radiation therapy.
For more information:
Jason Fangusaro, MD, can be reached at Egleston Hospital, 1405 Clifton Road NE, Atlanta, GA 30322; email: jfangus@emory.edu.
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