PRT543, a protein arginine methyltransferase 5 inhibitor, in patients with advanced adenoid cystic carcinoma: An open-label, phase I dose-expansion study

  • Oral Oncol. 2024 Feb:149:106634. doi: 10.1016/j.oraloncology.2023.106634.
Renata Ferrarotto  1 ,  Paul L Swiecicki  2 ,  Dan P Zandberg  3 ,  Robert A Baiocchi  4 ,  Robert Wesolowski  5 ,  Cristina P Rodriguez  6 ,  Meredith McKean  7 ,  Hyunseok Kang  8 ,  Varun Monga  9 ,  Rajneesh Nath  10 ,  Neil Palmisiano  11 ,  Naveen Babbar  12 ,  William Sun  12 ,  Glenn J Hanna  13
Affiliations
  • 1. Department of Thoracic/Head and Neck Medical, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].
  • 2. Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
  • 3. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 4. Department of Medicine, Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • 5. Department of Medicine, Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • 6. Department of Medicine, University of Washington, Seattle, WA, USA.
  • 7. Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA.
  • 8. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • 9. Department of Medicine, Division of Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
  • 10. Banner MD Anderson Cancer Center, Gilbert, AZ, USA.
  • 11. Department of Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
  • 12. Prelude Therapeutics, Research and Development, Wilmington, DE, USA.
  • 13. Center for Head and Neck Oncology, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
PMID: 38118249 DOI: 10.1016/j.oraloncology.2023.106634
Abstract

Objectives: Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC.

Materials and methods: This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy.

Results: Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease.

Conclusion: In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.

Keywords
Adenoid Cystic; Carcinoma; Protein-Arginine N-Methyltransferases.
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