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Coyne GO, Kummar S, Meehan RS, et al. Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas. Oncotarget. 2020;11(44):3959-3971doi: 10.18632/oncotarget.27784.
Coyne, G. O., Kummar, S., Meehan, R. S., Do, K., Collins, J. M., Anderson, L., Ishii, K., Takebe, N., Zlott, J., Juwara, L., Piekarz, R., Streicher, H., Sharon, E., Rubinstein, L., Voth, A. R., Lozier, J., Dull, A. B., Wilsker, D., Hinoue, T., Laird, P. W., Ferry-Galow, K. V., Kinders, R. J., Parchment, R. E., Doroshow, J. H., & Chen, A. P. (2020). Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas. Oncotarget, 11(44), 3959-3971. https://doi.org/10.18632/oncotarget.27784
Coyne, Geraldine O'Sullivan, et al. "Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas." Oncotarget vol. 11,44 (2020): 3959-3971. doi: https://doi.org/10.18632/oncotarget.27784
Coyne GO, Kummar S, Meehan RS, Do K, Collins JM, Anderson L, Ishii K, Takebe N, Zlott J, Juwara L, Piekarz R, Streicher H, Sharon E, Rubinstein L, Voth AR, Lozier J, Dull AB, Wilsker D, Hinoue T, Laird PW, Ferry-Galow KV, Kinders RJ, Parchment RE, Doroshow JH, Chen AP. Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas. Oncotarget. 2020 Nov 03;11(44):3959-3971. doi: 10.18632/oncotarget.27784. eCollection 2020 Nov 03. PMID: 33216844; PMCID: PMC7646836.
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Oncotarget. 2020 Nov 03;11(44):3959-3971. doi: 10.18632/oncotarget.27784. eCollection 2020 Nov 03.

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

Oncotarget

Geraldine O'Sullivan Coyne, Shivaani Kummar, Robert S Meehan, Khanh Do, Jerry M Collins, Larry Anderson, Kazusa Ishii, Naoko Takebe, Jennifer Zlott, Lamin Juwara, Richard Piekarz, Howard Streicher, Elad Sharon, Larry Rubinstein, Andrea Regier Voth, Jay Lozier, Angie B Dull, Deborah Wilsker, Toshinori Hinoue, Peter W Laird, Katherine V Ferry-Galow, Robert J Kinders, Ralph E Parchment, James H Doroshow, Alice P Chen

Affiliations

  1. Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  2. Current address: Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA.
  3. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, USA.
  4. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  5. Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  6. Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  7. Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
  8. Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  9. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  10. Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  11. Van Andel Institute, Center for Epigenetics, Grand Rapids, MI, USA.
  12. Division of Cancer Treatment and Diagnosis, and Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

PMID: 33216844 PMCID: PMC7646836 DOI: 10.18632/oncotarget.27784

Abstract

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

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.

Copyright: © 2020 Coyne et al.

Keywords: DNA damage repair; MGMT; base excision repair; molecular pharmacodynamics; rational combination therapy

Conflict of interest statement

CONFLICTS OF INTEREST Authors have no conflicts of interest to declare.

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