Abstract CT161: Phase I clinical trials of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors
Authors: Paul C. McDonald, Stephen Chia, Philippe L. Bedard, Qunicy Chu, Michael Lyle, Liren Tang, Madhu Singh, Zaihui Zhang, Claudiu T. Supuran, Daniel J. Renouf, Shoukat Dedhar
Journal: Cancer Research (2020)

Abstract Carbonic anhydrase IX (CAIX) is a cell surface, HIF-1A-inducible enzyme that is highly expressed in many solid tumors, is considered to be an endogenous marker of hypoxia and is a prominent biomarker of poor patient prognosis. In contrast, CAIX expression in normal human normal tissue is highly restricted, making it an attractive therapeutic target and driving the development of CAIX-specific inhibitors. SLC-0111 is an ureido-substituted benzenesulfonamide small molecule inhibitor of CAIX. We have shown previously that targeting CAIX activity with SLC-0111, alone and in combination with chemotherapy or immune checkpoint blockade, results in anti-tumor efficacy in multiple solid tumor models in vivo. Here, we report the findings of a multi-center, open-label, first-in-human phase I clinical trial investigating the safety and tolerability of SLC-0111 in patients with previously treated, advanced solid tumors (NCT02215850). Using a 3+3 design, dose escalation started at 500 mg oral daily dosing of SLC-0111 in cohort 1 and increased to 1000 mg and 2000 mg in cohorts 2 and 3. Drug-related adverse events (AEs) were monitored to determine safety and tolerability. Pharmacokinetic analyses assessed plasma concentrations of single and repeated doses of SLC-0111. RECIST 1.1 criteria were used to assess disease progression. No DLTs were reported and patients dosed at 1000 mg and below exhibited fewer drug-related AEs ≥ grade 3 and fewer AEs such as nausea and vomiting, compared to the 2000 mg cohort. 41% of patients experienced dose interruptions or discontinuation and the majority (71%) of these occurred in the 2000 mg cohort. Mean Cmax and AUC(0-24) values for single doses were similar at the 1000 mg and 2000 mg dose levels. Mean Tmax and T1/2 values of SLC-0111 were similar after single and repeated dosing. Power-law analysis of Cmax and AUC(0-24) showed that exposure to SLC-0111 was generally dose proportional. No objective responses were observed, but stable disease greater than 24 weeks was observed in 2 patients. These data show that SLC-0111 is safe in patients and support 1000 mg/day as the recommended phase II dose (RP2D). Based on these encouraging results, a phase Ib clinical trial to evaluate SLC-0111 in combination with chemotherapy in a defined population of CAIX-positive pancreatic cancer patients (NCT03450018) is now open and future clinical development will include investigation of SLC-0111 in combination with chemotherapy in patients with glioblastoma. Citation Format: Paul C. McDonald, Stephen Chia, Philippe L. Bedard, Qunicy Chu, Michael Lyle, Liren Tang, Madhu Singh, Zaihui Zhang, Claudiu T. Supuran, Daniel J. Renouf, Shoukat Dedhar. Phase I clinical trials of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT161.