Safety and activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrent glioblastoma (GBM).

Abstract

2027 Background: Hypoxia inducible factor 2-alpha (HIF2a) mediates cellular responses to hypoxia and is overexpressed in GBM. PT2385 is an oral HIF2a inhibitor with in vivo activity against GBM. Methods: A two-stage single-arm open-label phase II study of adults with first recurrent GBM following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (CR+PR); secondary outcomes were safety and survival. Exploratory objectives included PK (day 15 Cmin), PD, and pH-weighted amine-CEST MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤1 response. Results: Of the 24 patients, mean age was 61±11 years, median KPS 80, MGMT promoter methylated in 46%. PT2385 was well tolerated. Grade ≥3 drug-related AEs were hypoxia (n = 2), anemia (1), hyperglycemia (1), hyponatremia (2) and lymphopenia (2). No objective radiographic responses were observed; median PFS was 1.8 months (95%CI 1.6-3.1). Drug exposure varied widely (Table) and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, 0.009). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. Baseline acidity correlated significantly with treatment duration (R2= 0.49, p = 0.017). Conclusions: Drug exposure to PT2385 was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic (e.g. hypoxic) lesions on baseline imaging. A second-generation HIF2a inhibitor is being studied. Clinical trial information: NCT03216499. [Table: see text]