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Ruxolitinib Safety and Feasibility in NHGGs: Final Toxicity Report

The results of the CRUX study, which focused on the safety and feasibility of the JAK stat inhibitor Ruxolitinib in newly diagnosed high-grade glioma patients, discussed by Dr. Manmeet Ahluwalia, were presented at ASCO 2023. High-grade gliomas, particularly those with unmethylated MGMT, have poor outcomes despite advancements in surgery, radiation, and chemotherapy. The effectiveness of Temozolomide, an oral chemotherapy, is limited in these patients, providing only a 21-day advantage in glioblastoma cases. Moreover, combining new therapies with Temozolomide often leads to increased toxicity.

 

The CRUX trial took a two-pronged approach. In the first arm, Ruxolitinib was combined with radiation in patients with unmethylated high-grade gliomas. The second arm used Ruxolitinib along with Temozolomide, radiation, and the standard dose of Temozolomide in patients with methylated MGMT high-grade gliomas. This was a phase one study that enrolled a total of 60 patients.

 

The study found that Ruxolitinib, at all dose levels, was safe without any dose-limiting toxicities, even at the highest dose of 20 milligrams BID (twice a day) along with radiation in arm one and with radiation and Temozolomide in arm two. Additionally, preliminary efficacy data showed promising results in the subset of patients with unmethylated MGMT glioblastoma tumors (from arm one), with an overall survival of around 18 months. This is a significant improvement compared to the average survival of 12 to 13 months for these patients.

 

Although the survival data for arm two (MGMT methylated patients) is not yet matured, the results so far indicate that it may exceed the traditional benchmarks of 18 to 20 months. Based on these promising findings, a phase two trial is being planned, where Ruxolitinib at a dose of 20 milligrams BID, along with Temozolomide and radiation, will be further evaluated in both methylated and unmethylated glioblastoma patients.

 

The notable surprise in the CRUX trial was the high tolerance of the combination therapy. It was initially expected that there would be myelosuppression at the highest doses of Ruxolitinib, especially when combined with Temozolomide. However, no dose-limiting toxicities were observed even with the highest dose of Ruxolitinib, making it a promising candidate for phase two trials in combination with standard Temozolomide doses. This approach offers hope for improving outcomes in patients with high-grade gliomas, who are in urgent need of novel therapeutic options.

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