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. MeanC(max)and AUC((0-24))values for single doses were similar at the 1000-mg and 2000-mg dose levels. MeanT(max)andT(1/2)values of SLC-0111 were similar after single and repeated dosing. Power-law analysis ofC(max)and AUC(0-24)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.

A Phase 1 Study of SLC-0111, a Novel Inhibitor of Carbonic Anhydrase IX, in Patients With Advanced Solid Tumors / McDonald, Paul C; Chia, Stephen; Bedard, Philippe L; Chu, Quincy; Lyle, Michael; Tang, Liren; Singh, Madhu; Zhang, Zaihui; Supuran, Claudiu T; Renouf, Daniel J; Dedhar, Shoukat. - In: AMERICAN JOURNAL OF CLINICAL ONCOLOGY: CANCER CLINICAL TRIALS. - ISSN 0277-3732. - ELETTRONICO. - 43:(2020), pp. 0-0. [10.1097/COC.0000000000000691]

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

Supuran, Claudiu T;
2020

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. MeanC(max)and AUC((0-24))values for single doses were similar at the 1000-mg and 2000-mg dose levels. MeanT(max)andT(1/2)values of SLC-0111 were similar after single and repeated dosing. Power-law analysis ofC(max)and AUC(0-24)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.
2020
43
0
0
McDonald, Paul C; Chia, Stephen; Bedard, Philippe L; Chu, Quincy; Lyle, Michael; Tang, Liren; Singh, Madhu; Zhang, Zaihui; Supuran, Claudiu T; Renouf, Daniel J; Dedhar, Shoukat
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1308084
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