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PF-06952229, a selective TGF-β-R1 inhibitor: preclinical development and a first-in-human, phase I, dose-escalation
T A Yap1, A D Choudhury2, E Hamilton3
1Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston.
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.
Insights
PF-06952229, a TGF-β receptor 1 inhibitor, demonstrated antitumor activity in preclinical models. The phase I study showed manageable toxicity and durable responses in some patients with advanced solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- PF-06952229 is a selective small-molecule inhibitor targeting the transforming growth factor-β (TGF-β) receptor 1.
- Preclinical studies evaluated its antitumor potential, leading to a phase I clinical trial (NCT03685591) assessing safety, pharmacokinetics, and pharmacodynamics.
Purpose of the Study:
- To evaluate the antitumor activity of PF-06952229 in preclinical models.
- To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06952229 in a phase I clinical study.
Main Methods:
- In vitro and in vivo preclinical studies were conducted.
- A phase I study enrolled 49 patients with advanced/metastatic solid tumors or metastatic castration-resistant prostate cancer (mCRPC), receiving PF-06952229 monotherapy or combination therapy with enzalutamide.
- Primary endpoints included dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities, with efficacy and biomarker modulation also assessed.
Main Results:
- PF-06952229 exhibited antitumor activity in preclinical models, including pSMAD2 modulation.
- The study reported DLTs in 8.6% of patients at 375 mg, with the most frequent grade 3 treatment-related AEs being elevated alanine aminotransferase and anemia (9.5% each). No grade 4-5 TRAEs were observed.
- One patient with prostate cancer achieved a partial response lasting 31 months, and 8 patients achieved stable disease.
Conclusions:
- PF-06952229 demonstrated antitumor activity in preclinical settings.
- The drug was generally well-tolerated with manageable toxicity in the phase I study.
- A subset of patients experienced durable responses or disease stabilization, indicating therapeutic potential.
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