Abstract B155: A phase I study of the MEK inhibitor GSK1120212 (GSK212) in combination with PI3K/mTOR inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors.
Bibliographic record
Abstract
Abstract Background: This is a Phase I, open-label, dose escalation, pharmacokinetic (PK), pharmacodynamic (PD) and safety study in patients (pts) with advanced solid tumors exploring the combination of the investigational drugs GSK458 and GSK212. GSK212 is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinases 1 and 2 (MEK1 and MEK2). GSK458 is a potent, reversible, ATP-competitive, pan-phosphoinositide-3 kinase (PI3K) inhibitor, which also inhibits the mammalian target of rapamycin (mTOR), and the common activating mutations of catalytic isoform p110α. The MTD for daily, continuous dosing of monotherapy GSK458 is 2.5mg and GSK212 is 2.0mg. Methods: The study consists of two parts: dose escalation in Part 1 (ongoing) uses a zone design (3+3 rules) to study safety, tolerability, PK, PD and clinical activity, and to establish the maximum tolerated doses (MTDs) and schedules for the combination. Adult pts with relapsed or refractory solid tumors are receiving oral doses of GSK458+GSK 212 once daily until disease progression or toxicity. Efficacy is assessed using RECIST 1.1. Part 2 will examine safe dose combinations from Part 1 in patients with tumors likely to respond to MEK/PI3K pathway inhibition. Genetic and protein profiles collected from blood and tumor samples will be used to explore relationships between predictive biomarkers of response and efficacy. Results: 34 pts(45% female) with a mean age of 58y (range 37–82y) have enrolled. Safety data includes31 subjects who have received ≥1 dose of GSK458+GSK212. Most commonly reported drug-related AEs >10%, n=31) include rash (68%; G3/4, 3%), diarrhea (42%; G3/4, 6%), nausea (29%; G3/4, 0%), vomiting (23%; G3/4, 3%), decreased appetite (19%; G3/4, 0%), stomatitis (13%; G3/4, 3%) and fatigue (13%; G3/4; 3%). Of 21 serious adverse events (SAEs) reported in 14 pts, 3 were considered related to study drug. Stable disease has been observed in several patients with the longest being at 6 months (renal cell carcinoma and colorectal cancer). The combination of GSK458 0.5 mg + GSK212 2.0 mg exceeded the MTD. However, once daily and continuous combination dosing of GSK458 (0.5, 1.0 or 1.5mg) + GSK212 ≤ 2.0 mg were well tolerated. Conclusions: The preliminary safety profile and anti-tumor activity of this combination warrants further investigation in continued dose escalation and planned expansion cohorts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B155.
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".