Abstract CT146: A phase IB study of the combination of AZD6244 hydrogen sulfate (selumetinib) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC)
Bibliographic record
Abstract
Abstract Background: Targeting MEK is of great interest in the development of novel agents for treatment of a variety of malignancies. Resistance to MEK inhibitors has delayed the development of novel agents, and better strategies are needed to overcome acquired resistance. Preclinical studies performed at the University of Colorado in KRAS mutant cell lines have shown that several members of the Wnt pathway are overexpressed in cell lines resistant to the MEK inhibitor, selumetinib. Gene set enrichment analysis and synthetic lethal screens demonstrated that genes involved in the canonical and non-canonical Wnt pathways were upregulated in selumetinib-resistant CRC cell lines, whereas the combination of selumetinib and cyclosporin A (CsA), a WNT pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We are conducting an NCI CTEP-approved Phase I/IB trial of the combination of selumetinib and CsA. Biomarkers of response to therapy are being co-developed in a preclinical trial of MEK/WNT inhibition in PDX models. We hypothesize that this combination will be safe, potentially effective in patients with mCRC and that upregulation of FZD2 may predict for sensitivity. Methods: This is a dose-escalation phase I trial investigating the combination of selumetinib and CsA in patients with solid tumors with an expansion cohort in patients with mCRC (n = 20). The expansion cohort will utilize a “run-in” of MEK inhibition alone to evaluate adaptive mechanisms of resistance that may identify those patients most likely to respond to the combination. An adaptive statistical design will be used to assess both KRAS/NRAS wild-type and mutant CRC to determine whether either or both subsets should be studied further in phase II trials. Results: As of January 15, 2016, a total of 18 patients have been enrolled and treated with selumetinib and CsA in the escalation phase. One DLT was reported in cohort 1 (G3 hypertension), and three DLTs (G3 hypertension, rash and elevated creatinine) were reported in cohort 2 (n = 12). Grade 1 or 2 nausea (67%) and rash (50%) were reported as the most common AEs. One unconfirmed partial response was noted (CRC KRAS mut), and 9 patients exhibited stable disease as their best response. One patient maintained stable disease for over 9 months. Disease control rate was 56% in the escalation cohort. Preclinical studies are currently being performed using next-generation MEK and WNT inhibitors in CRC PDX models. Conclusions: The combination of selumetinib and CsA is well tolerated with evidence of preliminary anti-tumor activity. Selumetinib at 75mg/kg BID and CsA at 2mg/kg was selected as the recommended phase 2 dose. The dose expansion in patients with metastatic CRC is underway. Preclinical studies and tissue acquisition for correlative studies are ongoing. Citation Format: Anna Capasso, Arvind Dasari, A. Craig Lockhart, Mark Stein, Hanna Sanoff, James Lee, Aaron Hansen, Tanios Bekaii-Saab, Sarah Rippke, James Yao, Funda Meric-Bernstam, S Gail Eckhardt, Christopher h. Lieu. A phase IB study of the combination of AZD6244 hydrogen sulfate (selumetinib) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT146.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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".