Phase 1 Concentration‐QTc and Cardiac Safety Analysis of the MDM2 Antagonist KRT‐232 in Patients With Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia
Open accessAbstract
Cardiac safety and plasma concentration‐QTc interval analyses were completed using data from 2 phase 1 studies of the selective mouse double minute chromosome 2 antagonist, KRT‐232, in patients with solid tumors or multiple myeloma and acute myeloid leukemia (AML) who received KRT‐232 doses of 15 to 480 mg once daily (QD; N = 130). A linear mixed‐effects model related change from baseline Fridericia‐corrected QT interval (ΔQTcF) to KRT‐232 plasma concentrations. The final model included parameters for the intercept (with between‐subject variability), KRT‐232 concentration–ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. Mean (90% confidence interval) predicted ΔQTcF values at the maximum clinical dose (480 mg QD) were 2.04 (0.49‐3.60) milliseconds for patients with solid tumors and 4.52 (2.35‐6.69) milliseconds for patients with AML. Because the 90% confidence interval upper bound of the mean ΔQTcF was predicted to be below 10 milliseconds at doses up to 480 mg QD in patients with solid tumors, multiple myeloma, or AML, KRT‐232 does not result in clinically meaningful QT prolongation at the doses currently under investigation in clinical trials. No significant cardiac safety concerns were identified at these doses.
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In vitro experiments demonstrated that AMG-232 induced p53 signal transduction and inhibited tumor cell proliferation in three p53 wild tumor cell lines (SJSA-1, HCT116, and ACHN).
“In vitro experiments demonstrated that AMG-232 induced p53 signal transduction and inhibited tumor cell proliferation in three p53 wild tumor cell lines (SJSA-1, HCT116, and ACHN).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [385]
AMG-232 is more selective than RG-7112 for p53 wild cells.
“Studies have shown that AMG-232 is more selective than RG-7112 for p53 wild cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [385]
In vivo experiments showed that AMG-232 (10, 25, 75 mg kg−1, orally, once a day) activated the p53 pathway, effectively inhibited the growth of xenogeneic tumors in mice, blocked viral DNA synthesis, induced apoptosis, and caused dose-dependent tumor growth inhibition (ED50 = 16 mg kg−1).
“In vivo experiments showed that AMG-232 (10, 25, 75 mg kg−1, orally, once a day) activated the p53 pathway, effectively inhibited the growth of xenogeneic tumors in mice, blocked viral DNA synthesis, induced apoptosis, and caused dose-dependent tumor growth inhibition (ED50 = 16 mg kg−1).385–387”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [385]
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References 17 · Cited by 12
Research works printed but not linked: 1
- [14]Allard MWD, Krejsa CM, Slatter JG. Exposure–macrophage inhibitory cytokine‑1 (MIC‑1) response analysis of the MDM2 antagonist KRT‑232 in patients with advanced solid tumors, multiple myeloma, or acute myeloid leukemia. HemaSphere. 2020; 4:S1, Abstract EP519.
- Authors
- Taylor, A., Lee, D., Allard, M., Poland, B., & Greg Slatter, J.
- Affiliations
- Certara (United States) (US)
- Kartos Therapeutics, Inc. (United States) (US)
- Kartos Therapeutics, Inc. Bellevue Washington USA
- Corresponding author
- Taylor, Adekemi
- Venue
- Clinical Pharmacology in Drug Development
- Publisher
- Wiley
- Published
- 2021-01-18
- Volume
- 10
- Issue
- 8
- Pages
- 918-926
- ISSN
- 2160-763X (ISSN-L)
- 2160-7648
- PMC
- PMC8451834
- OpenAlex
- W3125373932
- Cited by
- 12
- References
- 17
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 6 · 2021: 1
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Pharmacology in Drug Development (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- MDM2 inhibitors, cardiac safety, QTc prolongation, solid tumors, multiple myeloma, acute myeloid leukemia, linear mixed models, pharmacokinetics
- MeSH terms
- Carboxylic Acids, Dose-Response Relationship, Drug, Drug Administration Schedule, Electrocardiography, Heart Function Tests, Humans, Male, Multiple Myeloma, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-mdm2
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