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

// Geraldine O'Sullivan Coyne 1 , Shivaani Kummar 1 , 11 , Robert S. Meehan 1 , Khanh Do 1 , Jerry M. Collins 2 , Larry Anderson 2 , Kazusa Ishii 3 , Naoko Takebe 1 , Jennifer Zlott 1 , Lamin Juwara 4 , Richard Piekarz 5 , Howard Streicher 5 , Elad Sharon 5 , Larry Rubinstein 6 , Andrea Regier Voth 7 , Jay Lozier 8 , Angie B. Dull 9 , Deborah Wilsker 9 , Toshinori Hinoue 10 , Peter W. Laird 10 , Katherine V. Ferry-Galow 9 , Robert J. Kinders 9 , Ralph E. Parchment 9 , James H. Doroshow 12 and Alice P. Chen 1 1 Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 2 Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, USA 3 Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA 4 Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA 5 Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 6 Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA 7 Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA 8 Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 9 Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA 10 Van Andel Institute, Center for Epigenetics, Grand Rapids, MI, USA 11 Current address: Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA 12 Division of Cancer Treatment and Diagnosis, and Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Correspondence to: Alice P. Chen, email: chenali@mail.nih.gov Keywords: DNA damage repair; base excision repair; MGMT; rational combination therapy; molecular pharmacodynamics Received: July 13, 2020     Accepted: September 29, 2020     Published: November 03, 2020 Copyright: © 2020 Coyne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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 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.