Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for Patients with Recurrent Glioblastoma in the Phase 2 Adult Brain Tumor Consortium Trial BERT
Recommended Citation
Ahluwalia MS, Ozair A, Drappatz J, Ye X, Peng S, Lee M, Rath S, Dhruv H, Hao Y, Berens ME, Walbert T, Holdhoff M, Lesser GJ, Cloughesy TF, Sloan AE, Takebe N, Couce M, Peereboom DM, Nabors B, Wen PY, Grossman SA, and Rogers LR. Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for patients with Recurrent Glioblastoma in the Phase 2 Adult Brain Tumor Consortium Trial BERT. Clin Cancer Res 2024.
Document Type
Article
Publication Date
8-1-2024
Publication Title
Clinical cancer research
Abstract
PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM).
PATIENTS AND METHODS: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity.
RESULTS: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors."
CONCLUSIONS: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.
Medical Subject Headings
Aged; Female; Humans; Male; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Excision Repair; Glioblastoma; Hydroxylamines; Neoplasm Recurrence, Local; Prognosis; Temozolomide
PubMed ID
38836759
ePublication
ePub ahead of print
Volume
30
Issue
15
First Page
3167
Last Page
3178
