A phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-06939999 (PRMT5 inhibitor) in patients with selected advanced or metastatic tumors with high incidence of splicing factor gene mutations.
| Autor: | Rodon J; Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston. Electronic address: JRodon@mdanderson.org., Rodriguez E; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami., Maitland ML; Inova Schar Cancer Institute and University of Virginia Comprehensive Cancer Center, Fairfax., Tsai FY; Hematology/Oncology, HonorHealth, Scottsdale., Socinski MA; AdventHealth Cancer Institute, Orlando., Berlin JD; Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville., Thomas JS; Division of Medical Oncology - Head and Neck, University of Southern California Norris Comprehensive Cancer Center, Los Angeles., Al Baghdadi T; Hematology Oncology, IHA Medical Group, Ypsilanti., Wang IM; Pfizer Inc, New York., Guo C; Pfizer Inc, San Diego., Golmakani M; Pfizer Inc, New York., Clark LN; Pfizer Inc, New York., Gazdoiu M; Pfizer Inc, New York., Li M; Pfizer Inc, New York., Tolcher AW; NEXT Oncology, San Antonio, USA. |
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| Jazyk: | angličtina |
| Zdroj: | ESMO open [ESMO Open] 2024 Apr; Vol. 9 (4), pp. 102961. Date of Electronic Publication: 2024 Apr 18. |
| DOI: | 10.1016/j.esmoop.2024.102961 |
| Abstrakt: | Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates dysregulated in cancer, including spliceosome machinery components. PF-06939999 is a selective small-molecule PRMT5 inhibitor. Patients and Methods: This phase I dose-escalation and -expansion trial (NCT03854227) enrolled patients with selected solid tumors. PF-06939999 was administered orally once or twice a day (q.d./b.i.d.) in 28-day cycles. The objectives were to evaluate PF-06939999 safety and tolerability to identify maximum tolerated dose (MTD) and recommended part 2 dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics [changes in plasma symmetric dimethylarginine (SDMA) levels], and antitumor activities. Results: In part 1 dose escalation, 28 patients received PF-06939999 (0.5 mg q.d. to 6 mg b.i.d.). Four of 24 (17%) patients reported dose-limiting toxicities: thrombocytopenia (n = 2, 6 mg b.i.d.), anemia (n = 1, 8 mg q.d.), and neutropenia (n = 1, 6 mg q.d.). PF-06939999 exposure increased with dose. Steady-state PK was achieved by day 15. Plasma SDMA was reduced at steady state (58%-88%). Modulation of plasma SDMA was dose dependent. No MTD was determined. In part 2 dose expansion, 26 patients received PF-06939999 6 mg q.d. (RP2D). Overall (part 1 + part 2), the most common grade ≥3 treatment-related adverse events included anemia (28%), thrombocytopenia/platelet count decreased (22%), fatigue (6%), and neutropenia (4%). Three patients (6.8%) had confirmed partial response (head and neck squamous cell carcinoma, n = 1; non-small-cell lung cancer, n = 2), and 19 (43.2%) had stable disease. No predictive biomarkers were identified. Conclusions: PF-06939999 demonstrated a tolerable safety profile and objective clinical responses in a subset of patients, suggesting that PRMT5 is an interesting cancer target with clinical validation. However, no predictive biomarker was identified. The role of PRMT5 in cancer biology is complex and requires further preclinical, mechanistic investigation to identify predictive biomarkers for patient selection. (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.) |
| Databáze: | MEDLINE |
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