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A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma
AIM: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. PATIENTS & METHODS: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients w...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Future Medicine Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134932/ https://www.ncbi.nlm.nih.gov/pubmed/35575067 http://dx.doi.org/10.2217/cns-2022-0005 |
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author | de Groot, John Ott, Martina Wei, Jun Kassab, Cynthia Fang, Dexing Najem, Hinda O'Brien, Barbara Weathers, Shiao-Pei Matsouka, Carlos Kamiya Majd, Nazanin K Harrison, Rebecca A Fuller, Gregory N Huse, Jason T Long, James P Sawaya, Raymond Rao, Ganesh MacDonald, Tobey J Priebe, Waldemar DeCuypere, Michael Heimberger, Amy B |
author_facet | de Groot, John Ott, Martina Wei, Jun Kassab, Cynthia Fang, Dexing Najem, Hinda O'Brien, Barbara Weathers, Shiao-Pei Matsouka, Carlos Kamiya Majd, Nazanin K Harrison, Rebecca A Fuller, Gregory N Huse, Jason T Long, James P Sawaya, Raymond Rao, Ganesh MacDonald, Tobey J Priebe, Waldemar DeCuypere, Michael Heimberger, Amy B |
author_sort | de Groot, John |
collection | PubMed |
description | AIM: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. PATIENTS & METHODS: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. RESULTS: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T(1/2) was 2–3 h with a dose dependent increase in the C(max). Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. CONCLUSION: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients. |
format | Online Article Text |
id | pubmed-9134932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Future Medicine Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-91349322022-06-04 A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma de Groot, John Ott, Martina Wei, Jun Kassab, Cynthia Fang, Dexing Najem, Hinda O'Brien, Barbara Weathers, Shiao-Pei Matsouka, Carlos Kamiya Majd, Nazanin K Harrison, Rebecca A Fuller, Gregory N Huse, Jason T Long, James P Sawaya, Raymond Rao, Ganesh MacDonald, Tobey J Priebe, Waldemar DeCuypere, Michael Heimberger, Amy B CNS Oncol Research Article AIM: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. PATIENTS & METHODS: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. RESULTS: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T(1/2) was 2–3 h with a dose dependent increase in the C(max). Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. CONCLUSION: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients. Future Medicine Ltd 2022-05-16 /pmc/articles/PMC9134932/ /pubmed/35575067 http://dx.doi.org/10.2217/cns-2022-0005 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Research Article de Groot, John Ott, Martina Wei, Jun Kassab, Cynthia Fang, Dexing Najem, Hinda O'Brien, Barbara Weathers, Shiao-Pei Matsouka, Carlos Kamiya Majd, Nazanin K Harrison, Rebecca A Fuller, Gregory N Huse, Jason T Long, James P Sawaya, Raymond Rao, Ganesh MacDonald, Tobey J Priebe, Waldemar DeCuypere, Michael Heimberger, Amy B A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma |
title | A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma |
title_full | A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma |
title_fullStr | A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma |
title_full_unstemmed | A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma |
title_short | A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma |
title_sort | first-in-human phase i trial of the oral p-stat3 inhibitor wp1066 in patients with recurrent malignant glioma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134932/ https://www.ncbi.nlm.nih.gov/pubmed/35575067 http://dx.doi.org/10.2217/cns-2022-0005 |
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