Rachael A. Vaubel, Wenjuan Zhang, Ju-Hee Oh, Ann C. Mladek, Tugce I. Pasa, Jennifer K. Gantchev, Katie L. Waller, Gerard Baquer, Sylwia A. Stopka, Michael S. Regan, Md Amin Hossain, Paul A. Decker, Matthew L. Kosel, Shiv K. Gupta, Sonia Jain, Paige P. Sarkaria, Zeng Hu, Lauren L. Ott, Brett L. Carlson, Katrina K. Bakken, Surabhi Talele, Wenqiu Zhang, Keith L. Ligon, Eudocia Q. Lee, Jeanette E. Eckel Passow, Danielle M. Burgenske, Nathalie Y.R. Agar, William F. Elmquist, Jann N. Sarkaria
{"title":"Navtemadlin在idh野生型胶质母细胞瘤中的药代动力学、药效学和疗效的临床前建模","authors":"Rachael A. Vaubel, Wenjuan Zhang, Ju-Hee Oh, Ann C. Mladek, Tugce I. Pasa, Jennifer K. Gantchev, Katie L. Waller, Gerard Baquer, Sylwia A. Stopka, Michael S. Regan, Md Amin Hossain, Paul A. Decker, Matthew L. Kosel, Shiv K. Gupta, Sonia Jain, Paige P. Sarkaria, Zeng Hu, Lauren L. Ott, Brett L. Carlson, Katrina K. Bakken, Surabhi Talele, Wenqiu Zhang, Keith L. Ligon, Eudocia Q. Lee, Jeanette E. Eckel Passow, Danielle M. Burgenske, Nathalie Y.R. Agar, William F. Elmquist, Jann N. Sarkaria","doi":"10.1158/1078-0432.ccr-25-0244","DOIUrl":null,"url":null,"abstract":"Background: Navtemadlin is a potent small molecule inhibitor of MDM2, which has completed a Phase 0 window of opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient derived xenografts (PDXs). Methods: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53 wild-typeGBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX, compared to 100 mg/kg in a non-amplified PDX. CNS distribution was limited by blood-brain barrier efflux (Kp_brain=0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood-brain barrier efflux (Rag-/-Abcb1a-/- Abcg2-/-), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in 3 (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusion: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of GBM patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"2 1","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pre-clinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-wildtype Glioblastoma\",\"authors\":\"Rachael A. Vaubel, Wenjuan Zhang, Ju-Hee Oh, Ann C. Mladek, Tugce I. Pasa, Jennifer K. Gantchev, Katie L. Waller, Gerard Baquer, Sylwia A. Stopka, Michael S. Regan, Md Amin Hossain, Paul A. Decker, Matthew L. Kosel, Shiv K. Gupta, Sonia Jain, Paige P. Sarkaria, Zeng Hu, Lauren L. Ott, Brett L. Carlson, Katrina K. Bakken, Surabhi Talele, Wenqiu Zhang, Keith L. Ligon, Eudocia Q. Lee, Jeanette E. Eckel Passow, Danielle M. Burgenske, Nathalie Y.R. Agar, William F. Elmquist, Jann N. Sarkaria\",\"doi\":\"10.1158/1078-0432.ccr-25-0244\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Background: Navtemadlin is a potent small molecule inhibitor of MDM2, which has completed a Phase 0 window of opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient derived xenografts (PDXs). Methods: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53 wild-typeGBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX, compared to 100 mg/kg in a non-amplified PDX. CNS distribution was limited by blood-brain barrier efflux (Kp_brain=0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood-brain barrier efflux (Rag-/-Abcb1a-/- Abcg2-/-), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in 3 (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusion: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of GBM patients.\",\"PeriodicalId\":10279,\"journal\":{\"name\":\"Clinical Cancer Research\",\"volume\":\"2 1\",\"pages\":\"\"},\"PeriodicalIF\":10.2000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1078-0432.ccr-25-0244\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.ccr-25-0244","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Pre-clinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-wildtype Glioblastoma
Background: Navtemadlin is a potent small molecule inhibitor of MDM2, which has completed a Phase 0 window of opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient derived xenografts (PDXs). Methods: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53 wild-typeGBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX, compared to 100 mg/kg in a non-amplified PDX. CNS distribution was limited by blood-brain barrier efflux (Kp_brain=0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood-brain barrier efflux (Rag-/-Abcb1a-/- Abcg2-/-), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in 3 (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusion: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of GBM patients.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.