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

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.

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

“…Alkylating agents and platinum-based compounds used to treat a wide range of solid tumors directly attacking the DNA bases forming covalent DNA adducts that interfere with the progression of DNA polymerases. Expression of O-6-methylguanine-DNA methyltransferase (MGMT) is a commonly used biomarker for the alkylating agent temozolomide in glioma and glioblastoma patients [ 25 ], and temozolomide has recently shown to be effective in combination with the base excision repair inhibitor TRC102 (methoxamine) in patients with relapsed solid tumors and lymphomas [ 53 ] ( Table 1 ). The sensitivity of platinum compounds including cisplatin and carboplatin is increased in triple-negative breast and serous ovarian cancers with overexpression of the Bloom (BLM) helicase [ 54 ].…”

DNA damage response inhibition‐based combination therapies in cancer treatment: Recent advances and future directions

“…Another phase I clinical trial (ClinicalTrials.gov Identifier: NCT01658319) focusing on advanced hematologic malignancies showed that, among 20 patients diagnosed with advanced hematologic malignancies excluding acute myeloid leukemia, and administered with methoxyamine in combination with fludarabine, four patients achieved a partial remission, and eight achieved SD 53 . In patients with relapsed solid tumors and lymphomas, TRC102 with temozolomide showed active results, with 4 of 51 patients experiencing a partial response (PR) and 13 having a best response of SD 55 …”

“…53 In patients with relapsed solid tumors and lymphomas, TRC102 with temozolomide showed active results, with 4 of 51 patients experiencing a partial response (PR) and 13 having a best response of SD. 55 APE1 activity is also associated with response to radiotherapy. Bobola et al 56 demonstrated that APE1 activity is predictive of outcome following radiotherapy in pediatric ependymoma.…”

Selective Antitumor Activity and Photocytotoxicity of Glutathione-Activated Abasic Site Trapping Agents

“…20,21 Several alkoxyamines work with alkylating agents to efficiently kill cells and exhibit encouraging outcomes in Phase I trials as combination chemotherapy agents. 20,22,23 However, no attention has been paid to reducing the side effects on normal cells from unselective AP capture, challenging their future development. 22 The selective release of alkoxyamines by an abundant biomolecule in cancer cells offers a solution for this challenge.…”

“…20,22,23 However, no attention has been paid to reducing the side effects on normal cells from unselective AP capture, challenging their future development. 22 The selective release of alkoxyamines by an abundant biomolecule in cancer cells offers a solution for this challenge. We describe the use of glutathione (GSH) for this purpose.…”