Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas.

Autor:	Coyne GO; Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Kummar S; Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.; Current address: Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA., Meehan RS; Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Do K; Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Collins JM; Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, USA., Anderson L; Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, USA., Ishii K; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Takebe N; Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Zlott J; Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Juwara L; Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Piekarz R; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Streicher H; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Sharon E; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Rubinstein L; Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA., Voth AR; Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Lozier J; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Dull AB; Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Wilsker D; Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Hinoue T; Van Andel Institute, Center for Epigenetics, Grand Rapids, MI, USA., Laird PW; Van Andel Institute, Center for Epigenetics, Grand Rapids, MI, USA., Ferry-Galow KV; Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Kinders RJ; Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Parchment RE; Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Doroshow JH; Division of Cancer Treatment and Diagnosis, and Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Chen AP; Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2020 Nov 03; Vol. 11 (44), pp. 3959-3971. Date of Electronic Publication: 2020 Nov 03 (Print Publication: 2020).
DOI:	10.18632/oncotarget.27784
Abstrakt:	Background: TRC102 inhibits base excision repair by binding abasic sites and preventing AP endonuclease processing; it potentiates the activity of alkylating agents, including temozolomide, in murine models. In published xenograft studies, TRC102 enhanced the antitumor effect of temozolomide regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA methyltransferase (MGMT), mismatch repair (MMR), or p53 status. Materials and Methods: We conducted a phase 1 trial of TRC102 with temozolomide given orally on days 1-5 of 28-day cycles in adult patients with refractory solid tumors that had progressed on standard therapy. Tumor induction of nuclear biomarkers of DNA damage response (DDR) γH2AX, pNBs1, and Rad51 was assessed in the context of MGMT and MMR protein expression for expansion cohort patients. Results: Fifty-two patients were enrolled (37 escalation, 15 expansion) with 51 evaluable for response. The recommended phase 2 dose was 125 mg TRC102, 150 mg/m 2 temozolomide QDx5. Common adverse events (grade 3/4) included anemia (19%), lymphopenia (12%), and neutropenia (10%). Four patients achieved partial responses (1 non-small cell lung cancer, 2 granulosa cell ovarian cancer, and 1 colon cancer) and 13 patients had a best response of stable disease. Retrospective analysis of 15 expansion cohort patients did not demonstrate a correlation between low tumor MGMT expression and patient response, but treatment induced nuclear Rad51 responses in 6 of 12 patients. Conclusions: The combination of TRC 102 with temozolomide is active, with 4 of 51 patients experiencing a partial response and 13 of 51 experiencing stable disease, and the side effect profile is manageable. Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare. (Copyright: © 2020 Coyne et al.)
Databáze:	MEDLINE
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