Abstract 3516: AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML.
Bibliographic record
Abstract
Abstract PIM kinases have been shown to play a key role as downstream effectors of growth factor signalling pathways including Flt3 and the Jak-STAT signalling pathways in AML, NHL and other solid tumors. AZD1208 is a novel, orally bioavailable, highly selective PIM kinase inhibitor with single nanomolar potency against all three PIM kinases and is currently undergoing Phase I testing and dose escalation studies in AML. Here we describe a multiplexed biomarker strategy measuring pBAD, p4EBP1 and p-p70S6K as downstream pharmacodynamic biomarkers for PIM kinase inhibition in clinical trials. Patient bone marrow aspirates and peripheral blood samples were collected pre- and post-AZD1208 treatment in AML patients during the Phase I dose escalation and expansions. Primary patient samples were analyzed for quantitative changes in pBAD, p4EBP1 by NanoPro and MesoScale assay platforms as well as a qualitative evaluation of p-p70S6K and other exploratory endpoints. Preclinical PK-PD modeling data with AZD1208 had suggested that greater than a 50% decrease in the levels of one of these phosphorlyated substrates would be indicative of efficacy and PIM pathway inhibition. Following a single dose of AZD1208 at 120mg, the first dose level, approximately 60-70% inhibition of pBAD, S112 was seen in the bone marrow and peripheral blasts. Taken together, the data presented here provide evidence for single agent AZD1208 activity in AML patients based on quantitative reduction in these biomarkers. Correlations of these biomarker endpoints with Phase I pharmacokinetic data underscore the therapeutic potential of Pim kinase inhibition by AZD1208 for the treatment of AML, and strongly support further investigation of this agent in other indications where PIM signaling may play a role in tumorigenesis and survival. Citation Format: Kristen A. McEachern, Yichen Cao, Rachel DuPont, Lourdes Pablo, Patricia McCoon, Jorge E. Cortes, Daniel J. DeAngelo, Mark D. Minden, Becker Hewes, Jeffrey L. Brown, Carl Barrett. AZD1208 PIM kinase inhibitor - Preliminary evidence of target pathway inhibition in Phase I clinical trials of AML. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3516. doi:10.1158/1538-7445.AM2013-3516
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".