CTNI-44 - Neoadjuvant treatment with ST101, C/EBPβ antagonist, triggers necrosis as a pathological response in newly diagnosed GBM patients. Tissue-based analysis from a surgical window of opportunity trial.

Friday, November 17, 2023

7:30 PM - 9:30 PM PT

Location: Exhibit Hall A/B

Poster Presenter(s)

FI

Fabio M. Iwamoto

Division of Neuro-Oncology, New York-Presbyterian/Columbia University Medical Center
New York, New York, United States

Author(s)

AV

Abi Vainstein-Haras

Sapience Therapeutics
NY, New York, United States
Jim Rotolo

Sapience Therapeutics
NY, New York, United States
CL

Clara Levrero

Columbia University
NY, New York, United States
RM

Robert Michel

Bexon Clinical Consultants
The Woodlands, Texas, United States
NK

Nicolas Kostelecky

Northwestern Medicine - CDH Cancer Center
Warrenville, Illinois, United States
AP

Anastasia Papaioannou

Northwestern Medicine - CDH Cancer Center
Warrenville, Illinois, United States
RB

Robin Buerki

Northwestern Medicine - CDH Cancer Center
Warrenville, Illinois, United States

Background: CCAAT/enhancer-binding protein β (C/EBPβ) is a master regulator of mesenchymal transformation in GBM (Carro, 2010) and is required for maintenance of immunosuppressive tumor-associated macrophage (TAM) populations. ST101 is a first-in-class C/EBPβ antagonist, that promotes selective tumor cell death without impacting normal cell viability (Darvishi, 2022). In an ongoing phase 1/2 clinical study in rGBM (NCT04478279), ST101 administration resulted in 1 durable PR and 5 SD (range 18 to 53+ weeks). We designed a window of opportunity study to assess the effect of ST101 on clinical outcomes and pharmacodynamic biomarkers in the neoadjuvant setting in newly diagnosed GBM (ndGBM).

Methods: The study will enroll 12 ndGBM patients to be treated with 2-4 500 mg ST101 IV QW) before surgical resection. After surgery, patients will continue ST101 QW + standard chemoradiation with temozolomide.

Results: As of June 9th, 2023, 6 patients with ndGBM received 2-3 doses of ST101. MRI performed before and after neoadjuvant ST101 indicated stable disease in all patients. At surgery, however, histopathology of tumor samples showed that 4/6 patients had geographic necrosis, indicative of treatment effect after ST101 monotherapy. Evaluation of immunostaining for ST101 and molecular changes in the post-treatment tissue by bulk and single nucleus RNAseq will be conducted.

Conclusions: ndGBM treated with neoadjuvant ST101 monotherapy shows extensive treatment effects on the tumors that have never been treated with chemoradiation. Stability of enhancing lesions after ST101 monotherapy may not reflect the extent of treatment effect as revealed by treatment-related necrosis in the resected tissue. Analyses of the pharmacodynamics effects of ST101 on GBM cells and tumor microenvironment will be completed and presented. In addition, this study demonstrates the feasibility of a multi-institutional window of opportunity clinical trial in ndGBM patients, a decisive opportunity for determining the penetration and on-target activity of novel agents in neuro-oncology.