Abstract B62: A phase 1 study of oral TRC102 (methoxyamine), an inhibitor of base-excision repair, to potentiate the therapeutic effects of pemetrexed in patients with advanced refractory cancer
Authors: Gordon Michael S. , Weiss Glen J. , Rosen Lee S. , Mendelson David S. , Ramanathan Ramesh K. , Goldman Jonathan , Adams Bonne J. , Alvarez Delia , Liu Lili , Gerson Stanton L. , Theuer Charles P. , Leigh Bryan R. 
Published: June 2012

Abstract
Background: TRC102 is a small molecule inhibitor of base-excision repair (BER) that is highly water soluble and nearly completely bioavailable after oral administration. TRC102 potentiates the cytotoxicity of alkylator and antimetabolite chemotherapy and reverses chemotherapy resistance by rapidly and covalently binding to chemotherapy-induced abasic sites. TRC102-bound DNA is no longer a substrate for BER enzymes and is instead cleaved by topoisomerase II resulting in double-strand breaks that trigger apoptosis.
Methods: This Phase 1 trial evaluated the safety, PK, and PD of oral TRC102 combined with intravenous pemetrexed in patients with advanced refractory cancer. Patients were required to have ECOG PS ≤ 1 and adequate organ function. TRC102 was escalated in cohorts of 3–6 evaluable patients in combination with standard-dose pemetrexed. All patients received TRC102 alone on Days 1–4 of a 2-week cycle followed by the combination of TRC102 (D1–4) and pemetrexed (D1) every 3 weeks thereafter.
Results: 20 patients were treated with a total of 65 cycles of TRC102 at 15 mg/m2 (n=4), 30 mg/m2 (n=7), 60 mg/m2 (n=3) and 100 mg/m2 (n=6). 18 of the 20 patients were evaluable for safety. No adverse events were attributed to TRC102 alone up to 60 mg/m2. One of six patients treated at 100 mg/m2 experienced dose-limiting Grade 3 anemia with TRC102 alone in Cycle 1. The patient remains on study in Cycle 3 with a 50% dose-reduction of TRC102. Adverse events considered possibly related to the combination of TRC102 + pemetrexed included Grade 3–4 neutropenia without fever, Grade 3 thrombocytopenia, and Grade 1–2 fatigue and asthenia. The only other DLT was Grade 3 anemia in a patient who received 30 mg/m2 TRC102 + pemetrexed in Cycle 2. The patient remained on study through Cycle 5 with a 50% dose-reduction of TRC102. Clinical PK analyses indicated that TRC102 plasma concentrations required for in vivo activity were achieved with daily oral administration at all dose levels (Cmax &gt; 50 ng/mL, t½ &gt; 24 hr). PD studies confirmed that TRC102 binds pemetrexed-induced abasic sites in these patients. One patient with squamous cell carcinoma of the tonsillar fossa recurrent in the right lung and right hilum had RECIST-defined partial response after 2 cycles of 30 mg/m2 TRC102 + pemetrexed that is ongoing in Cycle 10. One patient with epithelial clear cell cancer of the ovary metastatic to the liver had a mixed response after 2 cycles of 30 mg/m2 TRC102 + pemetrexed. Stable disease for 9 cycles was observed in a patient with metastatic squamous cell lung cancer at 30 mg/m2 TRC102 + pemetrexed as 3rd line therapy.
Conclusion: Daily oral TRC102 for 4 days is tolerated at doses that may potentiate the clinical activity of pemetrexed in patients with advanced refractory cancer. Phase 2 studies are planned in multiple indications.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B62.