Varun Monga, MD, clinical associate professor, internal medicine, hematology, oncology, and blood and marrow transplantation, University of Iowa, discusses the background for investigating the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in a phase 1 study (NCT04089449) in patients with recurrent high-grade glioma or uveal melanoma, as well as the agent’s mechanism of action. 

In this first-in-human, open-label, multi-center study, investigators aimed to expand on previous data shared regarding the use of PRT811 in high-grade glioma or uveal melanoma. In a previously reported portion of the study, the PRMT5 brain-penetrant inhibitor exhibited beneficial responses in patients who received the agent at 600 mg daily. In an updated readout of the safety and efficacy data that was given at the 2023 ASCO Annual Meeting, investigators shared that treatment with PRT811 exhibited clinical activity in patients with 

-positive glioma or uveal melanoma with limited treatment options. The agent alsocontinued to show an acceptable safety profile consistent with previous findings. Notably, PRT811 elicited an overall response rate (ORR) of 12.5% in patients with 

-positive glioma and an ORR of 10% in patients with splicing mutation (SPLC)–positive uveal melanoma.

PRT811 is a novel compound that targets PRMT5, which is highly expressed in patients with glioblastoma and hybrid glioma tumors, as well as in patients whose tumors are SPLC-positive, Monga begins. The activity of PRT811 was previously defined in the phase 1 trial, Monga explains.

Although this phase of the trial included patients with all solid tumor subtypes, the data shared at the 2023 ASCO Annual Meeting highlighted the evaluation of this agent in patients with 

-positive glioma, as well as in patients with or without SPLC-positive uveal melanoma, he says. Notably, PRT811 targets PRMT5, which regulates arginine and dimethylates the protein substrates, controlling key cellular processes via epigenetic and spliceosome inhibition mechanisms, he concludes.

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Varun Monga, MD, discusses the background for investigating the protein arginine methyltransferase 5 brain-penetrant inhibitor PRT811 in a phase 1 study in patients with recurrent high-grade glioma or uveal melanoma, as well as the agent’s mechanism of action.

Dr Monga on the Background of Investigating PRT811 in Glioma and Melanoma

Varun Monga, MD, clinical associate professor, Internal Medicine, Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa, discusses the investigation of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients with recurrent high-grade glioma or uveal melanoma.

A phase 1 trial (NCT04089449) investigated PRT811 monotherapy in patients with advanced solid tumors, central nervous system lymphoma, or glioma. Data from cohorts of patients with high-grade glioma (n = 38) and uveal melanoma (n = 23) who enrolled in the expansion phase of the trial and received the recommended phase 2 dose of 600 mg of oral PRT811 per day, Monga says. Safety findings were consistent with previous data from the dose-escalation portion of the study, he says. The majority of treatment-emergent adverse effects were grade 1 or 2, and they included gastrointestinal toxicities, fatigue, fall, and myelosuppression.

 mutation status within the glioma cohort by splicing mutation status in the uveal melanoma cohort, Monga explains.

The overall response (ORR) rate in patients with 

-positive glioma (n = 16) was 12.5%, with both responders experiencing a complete response. However, no patients responded in the 

-negative group (n = 22). Those with uveal melanoma group with splicing mutations (n = 10) had an ORR of 10%, with 1 patient achieving a partial response. No patients responded in the group of patients without splicing mutations (n = 13). he expands.

The clinical benefit rate (CBR) was 31.3% for the 

-mutated glioma population, and it was 4.5% for the IDH-unmutated population. In patients with uveal melanoma, the CBR was 30.0% and 7.7% for the splicing mutation–positive and –negative populations, respectively.

Varun Monga, MD, discusses the investigation of the protein arginine methyltransferase 5 brain-penetrant inhibitor PRT811 in patients with recurrent high-grade glioma or uveal melanoma.

Varun Monga, MD

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