Limited Clinical Benefit for the Combination of TRC102 and Temozolomide in Refractory Colorectal Cancer

The following article features coverage from the American Association for Cancer Research (AACR) 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

The objective response rate (ORR) of patients with relapsed colorectal cancer enrolled in a phase 2 study of the combination of TRC102, a small-molecule inhibitor of the DNA base excisional repair (BER) pathway, and temozolomide, a DNA alkylating agent, was only 6%. The findings from this study were presented at the American Association for Cancer Research (AACR) Annual Meeting 2019.

Because the BER pathway is involved in the development of resistance to alkylating agents, the combination of temozolomide with the BER inhibitor, TRC102, was thought to represent a logical treatment approach.

A phase 1/2 trial of this combination therapy was conducted in patients with refractory solid tumors and lymphomas (ClinicalTrials.gov Identifier: NCT01851369). In the phase 1 portion of the trial, the major dose-limiting toxicity was anemia, and the recommended phase 2 dose for most patients was 125 mg oral TRC102 plus 150 mg/m² oral temozolomide once daily on days 1 through 5 of a 28-day cycle.

Following the observation of a single prolonged partial response (PR) — defined as 21 cycles of treatment and no disease progression at 17 months following treatment — in a patient with KRAS-mutant colorectal cancer enrolled in the phase 1 portion of the trial, 16 patients with refractory colorectal cancer were enrolled in the colorectal cohort of the phase 2 study. These patients had a median age of 64 years, an Eastern Cooperative Oncology Group (ECOG) performance status of 1, and had received a median of 6 prior lines of therapy.

Nine of the 16 patients in this cohort had KRAS-mutant disease including the patient with an objective response. Interestingly, of the 10 patients with tumor specimens tested for the presence of O-6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry, only the patient who achieved a PR had MGMT-negative disease.

Grade 3 and grade 4 treatment-related toxicities included thrombocytopenia, hemolysis, and diarrhea. While 1 patient underwent a dose reduction due to thrombocytopenia, no patients discontinued treatment due to toxicity.  

“Assessing tumor MGMT status may help identify patients who could benefit from this combination and pharmacodynamic studies are under way to assess drug activity in responding and nonresponding patients,” the researchers noted in conclusion.

Read more of Cancer Therapy Advisor‘s coverage of AACR 2019 meeting by visiting the conference page.

Reference

1. O’Sullivan Coyne G, Monge BonillaC, ZlottJ, et al. A phase II trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed metastatic colorectal carcinoma. Presented at: American Association for Cancer Research (AACR) Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract LB293/10.