Abstract
Abstract P044: A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas
Molecular cancer therapeutics, Vol.20(12_Supplement), pp.P044-P044
12/01/2021
DOI: 10.1158/1535-7163.TARG-21-P044
Abstract
Abstract
Background: PRMT5 catalyzes symmetric arginine dimethylation of protein substrates with important roles in cancer cell growth/survival, including glioblastoma (GBM) cells. PRT811 is a brain penetrant, potent, selective, oral PRMT5 inhibitor with preclinical efficacy in a GBM orthotopic model (Zhang AACR 2020). An open-label Phase I study of PRT811 in patients (pts) with advanced solid tumors and recurrent high-grade glioma (NCT04089449) is ongoing. Dose escalation results are presented herein. Materials and Methods: This study assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity (RECIST v1.1, Lugano, & RANO) of PRT811 administered at varying doses/schedules (15-600 mg daily [QD]; 300 mg twice daily [BID]). Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively. Results: As of 18 June 2021, 38 unselected pts with recurrent or refractory disease had enrolled (22 solid tumor, 16 GBM). Median number of prior lines of systemic therapies was 2. No dose-limiting toxicities have been identified. Most frequent treatment-related adverse events (TRAEs), any grade, were nausea (n=10, 26%), vomiting (n=7, 18%), diarrhea (n=4, 11%), fatigue (n=4, 11%), constipation (n=3, 8%), and pruritis (n=3, 8%). Decreased lymphocyte count (n=1, 3%) and vomiting (n=1, 3%) were the only Grade ≥3 TRAEs. 28 pts discontinued treatment, mainly due to disease progression. No pts discontinued due to treatment-emergent AEs (TEAEs). PRT811 exhibited linear PK characteristics. At the highest evaluated dose (600 mg QD), Cmax,of 3777 nM, AUC of 12,487 nM.hr, and T½ of 5.8 hrs were observed. Comparison of PK parameters of 300 mg administered either QD or BID demonstrated similar PK with no accumulation with the BID schedule. Serum sDMA levels decreased by 80% with 600 mg QD. PRMT5-mediated mRNA splicing fidelity in peripheral blood mononuclear cells showed increased intron retention in specific transcripts at the higher PRT811 doses, indicating PRMT5 functional activity was decreased. A partial response was observed in 1 pt with GBM (>9 months duration) who remains on study. In addition, a pt with uveal melanoma (spliceosome SF3B1 mutation) achieved a 25% decrease in tumor burden per RECIST v1.1. An additional 3 pts with solid tumors had stable disease ≥6 mo. Conclusions: PRT811 was well tolerated with a favorable safety profile when administered at either QD or BID schedules. Target engagement and inhibition of PRMT5 functional activity were observed across multiple dose levels. Preliminary evidence of antitumor activity was observed in GBM and uveal melanoma. The expansion phase of the study will be initiated in select tumor types upon establishing the recommended expansion dose.
Citation Format: Gerald S. Falchook, Jon Glass, Varun Monga, Pierre Giglio, David Mauro, John Viscusi, Peggy Scherle, Neha Bhagwat, William Sun, Rachel Chiaverelli, Eric Mintah, Lydia Clements, Tanner M. Johanns, Meredith McKean. A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P044.
Details
- Title: Subtitle
- Abstract P044: A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas
- Creators
- Gerald S. Falchook - Sarah Cannon Research InstituteJon Glass - Thomas Jefferson UniversityVarun Monga - University of IowaPierre Giglio - The Ohio State University Wexner Medical CenterDavid Mauro - Prelude Therapeutics, Research & Development, Wilmington, DE,John Viscusi - Prelude Therapeutics, Research & Development, Wilmington, DE,Peggy Scherle - Prelude Therapeutics, Research & Development, Wilmington, DE,Neha Bhagwat - Prelude Therapeutics, Research & Development, Wilmington, DE,William Sun - Prelude Therapeutics, Research & Development, Wilmington, DE,Rachel Chiaverelli - Prelude Therapeutics, Research & Development, Wilmington, DE,Eric Mintah - Prelude Therapeutics, Research & Development, Wilmington, DE,Lydia Clements - Christiana Care Health SystemTanner M. Johanns - Washington University in St. LouisMeredith McKean - Sarah Cannon Research Institute
- Resource Type
- Abstract
- Publication Details
- Molecular cancer therapeutics, Vol.20(12_Supplement), pp.P044-P044
- DOI
- 10.1158/1535-7163.TARG-21-P044
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Language
- English
- Date published
- 12/01/2021
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984363289802771
Metrics
1 Record Views