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A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors

Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on...

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Autores principales: Adjei, Alex A., LoRusso, Patricia, Ribas, Antoni, Sosman, Jeffrey A., Pavlick, Anna, Dy, Grace K., Zhou, Xiaofei, Gangolli, Esha, Kneissl, Michelle, Faucette, Stephanie, Neuwirth, Rachel, Bózon, Viviana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306265/
https://www.ncbi.nlm.nih.gov/pubmed/27650277
http://dx.doi.org/10.1007/s10637-016-0391-2
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author Adjei, Alex A.
LoRusso, Patricia
Ribas, Antoni
Sosman, Jeffrey A.
Pavlick, Anna
Dy, Grace K.
Zhou, Xiaofei
Gangolli, Esha
Kneissl, Michelle
Faucette, Stephanie
Neuwirth, Rachel
Bózon, Viviana
author_facet Adjei, Alex A.
LoRusso, Patricia
Ribas, Antoni
Sosman, Jeffrey A.
Pavlick, Anna
Dy, Grace K.
Zhou, Xiaofei
Gangolli, Esha
Kneissl, Michelle
Faucette, Stephanie
Neuwirth, Rachel
Bózon, Viviana
author_sort Adjei, Alex A.
collection PubMed
description Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1–21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2–22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median T(max) was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2–22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46–97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-016-0391-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-53062652017-02-27 A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors Adjei, Alex A. LoRusso, Patricia Ribas, Antoni Sosman, Jeffrey A. Pavlick, Anna Dy, Grace K. Zhou, Xiaofei Gangolli, Esha Kneissl, Michelle Faucette, Stephanie Neuwirth, Rachel Bózon, Viviana Invest New Drugs Phase I Studies Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1–21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2–22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median T(max) was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2–22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46–97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-016-0391-2) contains supplementary material, which is available to authorized users. Springer US 2016-09-21 2017 /pmc/articles/PMC5306265/ /pubmed/27650277 http://dx.doi.org/10.1007/s10637-016-0391-2 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Phase I Studies
Adjei, Alex A.
LoRusso, Patricia
Ribas, Antoni
Sosman, Jeffrey A.
Pavlick, Anna
Dy, Grace K.
Zhou, Xiaofei
Gangolli, Esha
Kneissl, Michelle
Faucette, Stephanie
Neuwirth, Rachel
Bózon, Viviana
A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors
title A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors
title_full A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors
title_fullStr A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors
title_full_unstemmed A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors
title_short A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors
title_sort phase i dose-escalation study of tak-733, an investigational oral mek inhibitor, in patients with advanced solid tumors
topic Phase I Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306265/
https://www.ncbi.nlm.nih.gov/pubmed/27650277
http://dx.doi.org/10.1007/s10637-016-0391-2
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