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Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for Patients with Recurrent Glioblastoma in the
Manmeet S Ahluwalia1,2,3, Ahmad Ozair2,4, Jan Drappatz5
1Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
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.
Insights
The combination of TRC102 (methoxyamine) and temozolomide (TMZ) demonstrated safety in recurrent glioblastoma (GBM) patients. Further trials should explore this combination in GBM patients with specific DNA damage response (DDR) pathways.
Area of Science:
- Neuro-oncology
- Clinical Pharmacology
- Genomics
Background:
- Glioblastoma (GBM) carries a poor prognosis, with resistance to standard chemotherapy temozolomide (TMZ) being a significant challenge.
- TRC102 (methoxyamine), a base excision repair inhibitor, has shown potential in preclinical models to overcome TMZ resistance.
- Recurrent GBM (rGBM) necessitates novel therapeutic strategies to improve patient outcomes.
Purpose of the Study:
- To investigate the efficacy and safety of oral TRC102 combined with TMZ in patients with recurrent glioblastoma (rGBM).
- To assess response rates, overall survival (OS), progression-free survival (PFS), and toxicity of the TRC102+TMZ combination therapy.
Main Methods:
- A phase 2 clinical trial (BERT, NCT02395692) was conducted with patients receiving recurrent GBM.
- The primary endpoint was response rate, with secondary endpoints including OS, PFS, PFS at 6 months (PFS6), and toxicity.
- Tumor tissue from "extended survivors" was analyzed using RNA sequencing to identify potential biomarkers.
Main Results:
- The combination therapy was found to be safe and feasible in the studied rGBM population.
- No objective responses were observed, and the combination did not proceed to a second arm for bevacizumab-refractory patients.
- Median OS was 11.1 months and median PFS was 1.9 months. Two patients identified as "extended survivors" showed enriched signatures of DNA damage response (DDR), chromosomal instability (CIN), and cellular proliferation (PCNA) pathways.
Conclusions:
- The TRC102+TMZ combination is safe and feasible for rGBM treatment.
- Further investigation in biomarker-selected patient populations, particularly those with hyperactivated DDR pathways, is warranted.
- Identifying biomarkers like DDR, CIN, and PCNA signatures may guide future therapeutic strategies for GBM.
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