A Phase 1 Study of SLC-0111, a Novel Inhibitor of Carbonic Anhydrase IX, in Patients With Advanced Solid Tumors

Author:

McDonald Paul C.1,Chia Stephen1,Bedard Philippe L.2,Chu Quincy3,Lyle Michael4,Tang Liren4,Singh Madhu4,Zhang Zaihui5,Supuran Claudiu T.6,Renouf Daniel J.1,Dedhar Shoukat17

Affiliation:

1. BC Cancer

2. Department of Medicine, Princess Margaret Cancer Centre, Division of Medical Oncology & Hematology, University of Toronto, Toronto, ON

3. Cancer Cross Institute, Edmonton, AB, Canada

4. Welichem Biotech Inc., Burnaby

5. SignalChem Lifesciences Inc., Richmond, BC

6. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy

7. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver

Abstract

Objectives: SLC-0111 is an ureido-substituted benzenesulfonamide small molecule inhibitor of carbonic anhydrase IX. The objectives of this first-in-human Phase 1 study were to determine the safety and tolerability of SLC-0111 in patients with advanced solid tumors and to establish the recommended Phase 2 dose for future clinical investigations. Materials and Methods: Using a 3+3 design, dose escalation started at 500 mg oral daily dosing of SLC-0111 in cohort 1 and increased to 1000 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. Results: No dose-limiting toxicities were reported and patients dosed at ≤1000 mg exhibited fewer drug-related AEs ≥ grade 3 and fewer AEs such as nausea and vomiting, compared with the 2000-mg cohort. Forty-one percent of patients experienced dose interruptions or discontinuation and the majority (71%) of these occurred in the 2000-mg cohort. Mean C max and AUC(0-24) values for single doses were similar at the 1000-mg and 2000-mg dose levels. Mean T max and T 1/2 values of SLC-0111 were similar after single and repeated dosing. Power-law analysis of C max and AUC0-24 showed that exposure to SLC-0111 was generally dose proportional. No objective responses were observed, but stable disease >24 weeks was observed in 2 patients. Conclusions: SLC-0111 was safe in patients with previously treated, advanced solid tumors. The safety and pharmacokinetic data support 1000 mg/d as the recommended phase 2 dose for SLC-0111.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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