Abstract CT161: Phase I clinical trials of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors
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Bibliographic record
Abstract
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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it