Abstract CT161: Phase I clinical trials of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".