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

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. LairdKatherine V. Ferry-Galow, Robert J. Kinders, Ralph E. Parchment, James H. Doroshow, Alice P. Chen

Research output: Contribution to journalArticlepeer-review

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/m2 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.

Original languageEnglish (US)
Pages (from-to)3959-3971
Number of pages13
JournalOncotarget
Volume11
Issue number44
DOIs
StatePublished - Nov 3 2020
Externally publishedYes

Keywords

  • Base excision repair
  • DNA damage repair
  • MGMT
  • Molecular pharmacodynamics
  • Rational combination therapy

ASJC Scopus subject areas

  • Oncology

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