Phase I study of TRC102 in combination with cisplatin and pemetrexed in patients with advanced solid tumors/Phase II study of TRC102 with pemetrexed in patients with mesothelioma refractory to pemetrexed and cisplatin or carboplatin.

Abstract

9055 Background: Treatment options remain limited in malignant pleural mesothelioma refractory to pemetrexed +/- platinum. TRC102 (methoxyamine hydrochloride) is a novel biochemical inhibitor of the BER pathway. Available data support the hypothesis that TRC102 bound DNA is a substrate for topoisomerase II, which cleaves TRC102-bound DNA sites to produce strand breaks in cancer cells that cause cellular apoptosis and enhance the cytotoxic effects of chemotherapy. Methods: This was a parallel cohort trial of a Phase I of TRC102 in combination with cisplatin (CDDP) and pemetrexed in patients with advanced solid tumors (Arm A) and a Phase II of TRC102 with pemetrexed in patients with mesothelioma refractory to platinum and pemetrexed (Arm B). Results: In Arm A dose escalation, 16 pts (11M/5F) were treated; 9 evaluable through 3 TRC102 dose levels (50, 75, and 100 mg/day, PO), with CDDP 60 mg/m2 and pemetrexed 500 mg/m2 (levels 1- 3); and 5 evaluable at TRC102 100 mg/day PO, CDDP 75 mg/m2, pemetrexed 500 mg/m2 (level 4). Cycles were every 21 days. There were no DLT’s, establishing level 4 as the RP2D. The only grade 4 treatment-related AE was thrombocytopenia on cycle 22 (level 2). Cycle 1 grade 3 AEs were 1 hypophosphatemia (level 1) and 1 leukopenia (level 2). There were 3 PRs (all parotid salivary gland tumors). Median PFS (95%CI) = 7.1% (1.4 – 15.5) mos. Arm B was designed as the first stage of a two stage Gehan design trial of patients with mesothelioma who had progressed on or recurred within 6 months of pemetrexed + platinum frontline treatment. 14 pts were treated with TRC102 50 mg/day D1-4 and pemetrexed 500 mg/m2 every 21 days. There were 2 PRs (both in epithelioid cancer of which 1 was confirmed), meeting the pre-specified criteria for continued interest ( > 0/14). mPFS (95% CI) was 4.3 (1.4 - 6.8) mos. 8 pts had stable disease for at least 1 cycle (4 stable at cycles 6, 9, 10 and 12). There were 1 grade 4 neutropenia and 5 grade 3 AE’s (1 each – anemia, neutropenia, leukopenia, fatigue, hyponatremia). Conclusions: TRC102 in combination with CDDP and pemetrexed exhibited antitumor activity, particularly in salivary gland tumors, and a tolerable safety profile at the doses tested. The combination of TRC102 and pemetrexed demonstrated activity in malignant mesothelioma that progressed on prior pemetrexed. Additional studies are warranted to confirm preliminary signals of activity. Clinical trial information: NCT02535312.