PMID- 32251122 OWN - NLM STAT- MEDLINE DCOM- 20201023 LR - 20221005 IS - 1537-453X (Electronic) IS - 0277-3732 (Print) IS - 0277-3732 (Linking) VI - 43 IP - 7 DP - 2020 Jul TI - A Phase 1 Study of SLC-0111, a Novel Inhibitor of Carbonic Anhydrase IX, in Patients With Advanced Solid Tumors. PG - 484-490 LID - 10.1097/COC.0000000000000691 [doi] AB - 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 /= 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 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 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. FAU - McDonald, Paul C AU - McDonald PC AD - BC Cancer. FAU - Chia, Stephen AU - Chia S AD - BC Cancer. FAU - Bedard, Philippe L AU - Bedard PL AD - Department of Medicine, Princess Margaret Cancer Centre, Division of Medical Oncology & Hematology, University of Toronto, Toronto, ON. FAU - Chu, Quincy AU - Chu Q AD - Cancer Cross Institute, Edmonton, AB, Canada. FAU - Lyle, Michael AU - Lyle M AD - Welichem Biotech Inc., Burnaby. FAU - Tang, Liren AU - Tang L AD - Welichem Biotech Inc., Burnaby. FAU - Singh, Madhu AU - Singh M AD - Welichem Biotech Inc., Burnaby. FAU - Zhang, Zaihui AU - Zhang Z AD - SignalChem Lifesciences Inc., Richmond, BC. FAU - Supuran, Claudiu T AU - Supuran CT AD - Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy. FAU - Renouf, Daniel J AU - Renouf DJ AD - BC Cancer. FAU - Dedhar, Shoukat AU - Dedhar S AD - BC Cancer. AD - Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver. LA - eng GR - FDN-143318/CIHR/Canada PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Clin Oncol JT - American journal of clinical oncology JID - 8207754 RN - 0 (Antigens, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (Enzyme Inhibitors) RN - 0 (Phenylurea Compounds) RN - 0 (SLC-0111) RN - 0 (Sulfonamides) RN - EC 4.2.1.1 (CA9 protein, human) RN - EC 4.2.1.1 (Carbonic Anhydrase IX) SB - IM MH - Adult MH - Aged MH - Antigens, Neoplasm MH - Antineoplastic Agents/*therapeutic use MH - Carbonic Anhydrase IX/*antagonists & inhibitors MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/therapeutic use MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy MH - Phenylurea Compounds/*therapeutic use MH - Sulfonamides/*therapeutic use PMC - PMC7323835 COIS- Disclosures: P.C.M., C.T.S., and S.D. are inventors of SLC-0111. M.L and L.T. are currently employees of Welichem Biotechnology Inc. Z.Z. and M.S. were employees of SignalChem Lifesciences Inc. during the study. Z.Z. is currently an employee of SignalChem Lifesciences Inc. P.L.B. reports grants from Seattle Genetics during the conduct of the study; grants and other from BristolMyersSquibb, grants and other from Sanofi, grants and other from Genentech/Roche, grants from Novartis, grants from GlaxoSmithKline, grants from Nektar Therapeutics, grants from Merck, grants from Lilly, grants from Servier, grants from PTC Therapeutics, other from Pfizer, outside the submitted work; and Past Chair, Investigational New Drug Committee, Canadian Clinical Trials Group; Executive Board Member, Breast International Group; Steering Committee Member, American Association for Cancer Research Project GENIE; Member, NCI-BIO Breast Cancer Immunotherapy Task Force. The other authors declare no conflicts of interest. EDAT- 2020/04/07 06:00 MHDA- 2020/10/24 06:00 PMCR- 2020/06/29 CRDT- 2020/04/07 06:00 PHST- 2020/04/07 06:00 [pubmed] PHST- 2020/10/24 06:00 [medline] PHST- 2020/04/07 06:00 [entrez] PHST- 2020/06/29 00:00 [pmc-release] AID - 00000421-202007000-00005 [pii] AID - 10.1097/COC.0000000000000691 [doi] PST - ppublish SO - Am J Clin Oncol. 2020 Jul;43(7):484-490. doi: 10.1097/COC.0000000000000691.