A phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients (pts) with recurrent high-grade glioma or uveal melanoma (UM).
Varun Monga, Tanner M. Johanns, Roger Stupp, Sunandana Chandra, Gerald S. Falchook, Pierre Giglio, Alexander Philipovskiy, Iyad Alnahhas, Naveen Babbar, William Sun, Meredith McKean
Abstract
3008 Background: PRMT5 catalyzes symmetric arginine dimethylation of protein substrates and is involved in histone modification, transcription, and spliceosome assembly. PRT811 is a potent, selective, brain-penetrant PRMT5 inhibitor being studied in a phase 1, multicenter, open-label, dose-escalation and -expansion study in pts with advanced solid tumors, central nervous system lymphoma, and recurrent high-grade glioma (NCT04089449). Results from the dose-escalation phase have been previously presented. We report on the safety and efficacy of PRT811 in the dose-expansion phase for pts with recurrent high-grade glioma or UM, who have limited treatment (tx) options. Methods: Eligible pts were aged ≥18 years, had an ECOG performance status (PS) of 0-1, adequate organ function, biopsy-confirmed recurrent high-grade glioma or UM, and were resistant, refractory, or ineligible to receive standard tx. Pts received 15-800 mg of PRT811 orally once daily (QD; 30 days = 1 cycle). The primary objectives were to evaluate the incidence of dose-limiting toxicities and determine the maximum tolerated/recommended phase 2 dose (RP2D) of PRT811. Key secondary objectives were to evaluate the safety, tolerability, and preliminary efficacy (per RECIST v1.1/RANO criteria) of PRT811. Results: As of January 13, 2023, 86 pts were enrolled; of the 61 pts with recurrent high-grade glioma (n=38) or metastatic UM (MUM; n=23). 57.4% were female, 24.6% were aged ≥65 years, 91.4% had an ECOG PS of 0-1, and 8.2% were systemic therapy naive. Most pts (n=42) received the predicted RP2D of 600 mg QD and 19 pts received between 15 to 800 mg PRT811 QD. Overall, 13% of pts remain on tx. Most pts discontinued tx primarily due to disease progression (83.0%), adverse events (AEs; 5.7%), or pt withdrawal (5.7%). The most common tx-related AEs (mainly grade 1/2) were nausea (49.2%), vomiting (39.3%), fatigue (27.9%), constipation (14.8%), and thrombocytopenia (14.8%). The most common grade 3 tx-related AEs were thrombocytopenia (9.8%; reversible on tx interruption), anemia, fatigue, and lymphopenia (all 3.3%). No tx-related grade 4/5 serious AEs (investigator assessed) were observed; 2 pt deaths were unrelated to tx. Among the 16 IDH1/2-mutated ( IDH+) pts with glioma, we observed 2 complete responses (CR; 1 ongoing, duration: 111+ weeks; 1 discontinued, duration: 33 weeks), 1 unconfirmed partial response (PR), and 8 pts with stable disease (SD). Among the 10 pts with MUM and a splicing gene mutation (SPLC+), 1 pt had a confirmed PR (duration: 43 weeks), 1 pt had an unconfirmed PR (ongoing), and 4 pts had SD. No CRs/PRs were observed in the 22 IDH– pts with glioma or 13 SPLC– pts with MUM. Additional follow-up data, including efficacy plots, will be presented. Conclusions: PRT811 demonstrated an acceptable safety profile and clinical activity in pts with glioma and MUM. Clinical trial information: NCT04089449 .