Adding Base-Excision Repair Inhibitor TRC102 to Standard Pemetrexed–Platinum–Radiation in Patients with Advanced Nonsquamous Non–Small Cell Lung Cancer: Results of a Phase I Trial
| Autor: | Pingfu Fu, Monaliben Patel, John J. Pink, Tithi Biswas, Mitchell Machtay, Shufen Cao, Charles A Kunos, Debora S. Bruno, Stanton L. Gerson, David L. Bajor, Nancy L. Oleinick, Shakun Malik, Afshin Dowlati |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Guanine Lung Neoplasms DNA Repair medicine.medical_treatment Phases of clinical research Pemetrexed Article Glutamates Median follow-up Carcinoma Non-Small-Cell Lung Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Lung cancer Aged Platinum Cisplatin business.industry medicine.disease Radiation therapy Regimen Toxicity business medicine.drug |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-21-2025 |
| Popis: | Purpose: TRC102, a small-molecule base-excision repair inhibitor, potentiates the cytotoxicity of pemetrexed and reverses resistance by binding to chemotherapy-induced abasic sites in DNA. We conducted a phase I clinical trial combining pemetrexed and TRC102 with cisplatin–radiation in stage III nonsquamous non–small cell lung cancer (NS-NSCLC). Patients and Methods: Fifteen patients were enrolled from 2015 to 2019. The primary objective was to determine the dose-limiting toxicity and maximum tolerated dose of TRC102 in combination with pemetrexed, cisplatin, and radiotherapy. Secondary objectives were to assess toxicity, tumor response, and progression-free survival at 6 months. Based on our preclinical experiments, pemetrexed–TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated in the second cycle. After completion, two additional cycles of pemetrexed–cisplatin were given. Toxicities were assessed using NCI CTACAE versions 4/5. Results: The median age was 69 years (45–79) with the median follow-up of 25.7 months (range, 7.9–47.4). No dose-limiting toxicities and no grade 5 toxicity were seen. Hematologic and gastrointestinal toxicities were the most common side effects. No clinical radiation pneumonitis was seen. Of 15 evaluable patients, three had complete response (20%), and 12 had partial response (80%). The 6-month progression-free survival was 80%, and the 2-year overall survival was 83%. Conclusions: Pemetrexed–TRC102 combined with cisplatin/radiotherapy in NS-NSCLC is safe and well tolerated. The recommended phase II dose is 200 mg TRC102 along with cisplatin–pemetrexed. No additional safety signal was seen beyond the expected CRT risks. A phase II trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen, is warranted. |
| Databáze: | OpenAIRE |
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