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Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

PURPOSE: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to...

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Autores principales: Kim, Tae Min, Lee, Keun-Wook, Oh, Do-Youn, Lee, Jong-Seok, Im, Seock-Ah, Kim, Dong-Wan, Han, Sae-Won, Kim, Yu Jung, Kim, Tae-You, Kim, Jee Hyun, Han, Hyesun, Kim, Woo Ho, Bang, Yung-Jue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Cancer Association 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056959/
https://www.ncbi.nlm.nih.gov/pubmed/28859471
http://dx.doi.org/10.4143/crt.2017.303
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author Kim, Tae Min
Lee, Keun-Wook
Oh, Do-Youn
Lee, Jong-Seok
Im, Seock-Ah
Kim, Dong-Wan
Han, Sae-Won
Kim, Yu Jung
Kim, Tae-You
Kim, Jee Hyun
Han, Hyesun
Kim, Woo Ho
Bang, Yung-Jue
author_facet Kim, Tae Min
Lee, Keun-Wook
Oh, Do-Youn
Lee, Jong-Seok
Im, Seock-Ah
Kim, Dong-Wan
Han, Sae-Won
Kim, Yu Jung
Kim, Tae-You
Kim, Jee Hyun
Han, Hyesun
Kim, Woo Ho
Bang, Yung-Jue
author_sort Kim, Tae Min
collection PubMed
description PURPOSE: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. MATERIALS AND METHODS: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort. RESULTS: A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer). CONCLUSION: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.
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spelling pubmed-60569592018-07-27 Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors Kim, Tae Min Lee, Keun-Wook Oh, Do-Youn Lee, Jong-Seok Im, Seock-Ah Kim, Dong-Wan Han, Sae-Won Kim, Yu Jung Kim, Tae-You Kim, Jee Hyun Han, Hyesun Kim, Woo Ho Bang, Yung-Jue Cancer Res Treat Original Article PURPOSE: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. MATERIALS AND METHODS: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort. RESULTS: A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer). CONCLUSION: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers. Korean Cancer Association 2018-07 2017-08-29 /pmc/articles/PMC6056959/ /pubmed/28859471 http://dx.doi.org/10.4143/crt.2017.303 Text en Copyright © 2018 by the Korean Cancer Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Kim, Tae Min
Lee, Keun-Wook
Oh, Do-Youn
Lee, Jong-Seok
Im, Seock-Ah
Kim, Dong-Wan
Han, Sae-Won
Kim, Yu Jung
Kim, Tae-You
Kim, Jee Hyun
Han, Hyesun
Kim, Woo Ho
Bang, Yung-Jue
Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
title Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
title_full Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
title_fullStr Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
title_full_unstemmed Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
title_short Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
title_sort phase 1 studies of poziotinib, an irreversible pan-her tyrosine kinase inhibitor in patients with advanced solid tumors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056959/
https://www.ncbi.nlm.nih.gov/pubmed/28859471
http://dx.doi.org/10.4143/crt.2017.303
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