Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck
© 2023 EMD Serono and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:115 |
|---|---|
| Enthalten in: |
Clinical pharmacology and therapeutics - 115(2024), 1 vom: 01. Jan., Seite 52-61 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Vugmeyster, Yulia [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antineoplastic Agents |
|---|
| Anmerkungen: |
Date Completed 18.12.2023 Date Revised 11.04.2024 published: Print-Electronic ClinicalTrials.gov: NCT02022098 Citation Status MEDLINE |
|---|
| doi: |
10.1002/cpt.3065 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM362737150 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM362737150 | ||
| 003 | DE-627 | ||
| 005 | 20240412232516.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/cpt.3065 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1373.xml |
| 035 | |a (DE-627)NLM362737150 | ||
| 035 | |a (NLM)37777832 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Vugmeyster, Yulia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.12.2023 | ||
| 500 | |a Date Revised 11.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02022098 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 EMD Serono and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | ||
| 520 | |a Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Cisplatin |2 NLM | |
| 650 | 7 | |a Q20Q21Q62J |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 700 | 1 | |a Ravula, Abhigyan |e verfasserin |4 aut | |
| 700 | 1 | |a Rouits, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Diderichsen, Paul Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Kleijn, Huub Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Koenig, Andre |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, XiaoZhe |e verfasserin |4 aut | |
| 700 | 1 | |a Schroeder, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Goteti, Kosalaram |e verfasserin |4 aut | |
| 700 | 1 | |a Venkatakrishnan, Karthik |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Clinical pharmacology and therapeutics |d 1960 |g 115(2024), 1 vom: 01. Jan., Seite 52-61 |w (DE-627)NLM000015318 |x 1532-6535 |7 nnns |
| 773 | 1 | 8 | |g volume:115 |g year:2024 |g number:1 |g day:01 |g month:01 |g pages:52-61 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/cpt.3065 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 115 |j 2024 |e 1 |b 01 |c 01 |h 52-61 | ||