UCSF

Abstract

BACKGROUND

Hypoxia inducible factor 2-alpha (HIF2a) is a stress response transcription factor that mediates the cellular response to hypoxia. HIF2a is an underexplored target in glioma. PT2385 is a first-in-class oral HIF2a inhibitor with favorable blood-brain barrier penetrating properties and in vivo single-agent activity against glioblastoma (GBM).

METHODS

A single-arm open-label phase II study of adults with bevacizumab-naïve first recurrence of GBM following chemoradiation with measurable disease was conducted within the Adult Brain Tumor Consortium. PT2385 was administered at the recommended phase II dose (800 mg b.i.d.). The primary study outcome is objective radiographic response (CR+PR). Secondary objectives are safety, overall survival, and progression-free survival. Patients at selected study sites underwent pH-weighted amine-CEST MRI imaging to quantify tumor acidity at baseline and explore associations with drug response. Results of planned interim analysis are presented.

RESULTS

24 patients were enrolled; mean age 61 ± 11 years, 63% male, 92% white, median KPS 80. MGMT promoter was methylated in 46%, unmethylated in 50%, and indeterminate in 1 patient. Prior surgery included biopsy (8%), subtotal (38%) and gross total resection (54%). To date, 21 patients have progressed at a median of 7.7 weeks (95%CI 4.66–12.3 weeks). No objective radiographic responses have been observed. Three patients continue on treatment at a median of 19 weeks (95%CI 12–19.1). The drug was well tolerated with expected side effect profile. Common Grade 1–2 drug-related adverse events were anemia, dyspnea, and thrombocytopenia. Grade 3–4 drug-related adverse events included hypoxia (n=2, 8%), anemia (n=1, 4%), and hypophosphatemia (n=1, 4%). At baseline, pH-weighted MRI showed high levels of acidity and intratumoral heterogeneity. PK and PD data are forthcoming.

CONCLUSIONS

Results of this planned interim analysis suggest that single-agent PT2385 has acceptable safety but minimal activity in glioblastoma patients after first recurrence. Ongoing analysis will explore patterns of progression and correlate these with tumor acidity measurements.