Background: PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591).
Patients And Methods: In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed.
Results: PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease.
Conclusions: Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.
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http://dx.doi.org/10.1016/j.esmoop.2024.103653 | DOI Listing |
Expert Opin Drug Saf
December 2024
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
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J Orofac Orthop
December 2024
Paediatric Dentistry, Preclinical Dentistry Department, European University of Madrid, Madrid, Spain.
Aim: To determine whether unilateral preferent chewing (UPC) affects the position and angulation of the permanent maxillary canine germ on the preferred side.
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Chem Biodivers
December 2024
North-West University - Mafikeng Campus, Indigenous Knowledge Systems Centre, G10, 2735, Mmabatho, SOUTH AFRICA.
The genus Grewia are known for their medicinal properties. We isolated and characterized five endophytic fungi from Grewialasiocarpa for in vitro antibacterial and antioxidant activities. Five [Aspergillus fumigatus (MK243397.
View Article and Find Full Text PDFAdv Healthc Mater
December 2024
Dept of Biomedical Sciences. Institute of Clinical Sciences, University of Birmingham, Birmingham, UK.
Intra-articular glucocorticoid injections are effective in controlling inflammation and pain in arthritides but restricted by short duration of action and risk of joint degeneration. Controlled drug release using biocompatible hydrogels offers a unique solution, but limitations of in situ gelation restrict their application. Gellan sheared hydrogels (GSHs) retain the advantages of hydrogels, however their unique microstructures lend themselves to intra-articular application - capable of shear thinning under force but restructuring at rest to enhance residence.
View Article and Find Full Text PDFACS Omega
December 2024
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
Radiometal chelator conjugation is a cornerstone of radioimmunotherapy (RIT). Continued interest in selective placement of chelators remains an active topic of discussion in the field. With several simple site-specific methods being recently reported, it was of interest to investigate the benefits and potential drawbacks of the site-specific method with a full comparison to a more typical random conjugation method that is currently utilized in clinical applications.
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