Abstract
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)
Journal of clinical oncology, Vol.41(16_suppl), pp.3008-3008
06/01/2023
DOI: 10.1200/JCO.2023.41.16_suppl.3008
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 .
Details
- Title: Subtitle
- 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)
- Creators
- Varun Monga - University of IowaTanner Michael Johanns - Washington University in St. LouisRoger Stupp - Northwestern UniversitySunandana Chandra - Northwestern UniversityGerald Steven Falchook - Sarah CannonPierre Giglio - The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteAlexander Philipovskiy - Sarah CannonIyad Alnahhas - Thomas Jefferson UniversityNaveen Babbar - Prelude Therapeutics, Inc., Wilmington, DEWilliam Sun - Prelude Therapeutics Incorporated, Wilmington, DEMeredith McKean - Sarah Cannon
- Resource Type
- Abstract
- Publication Details
- Journal of clinical oncology, Vol.41(16_suppl), pp.3008-3008
- DOI
- 10.1200/JCO.2023.41.16_suppl.3008
- ISSN
- 0732-183X
- eISSN
- 1527-7755
- Grant note
- name: Prelude Therapeutics Incorporated
- Language
- English
- Date published
- 06/01/2023
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984442222802771
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