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Invest New Drugs. 2017 Feb;35(1):47-58. doi: 10.1007/s10637-016-0391-2. Epub 2016 Sep 21.

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

Author information

1
Department of Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN, 55905, USA. Adjei.Alex@Mayo.edu.
2
Roswell Park Cancer Institute, Buffalo, NY, USA. Adjei.Alex@Mayo.edu.
3
Yale University, New Haven, CT, USA.
4
University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
5
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
6
New York University Langone Medical Center, New York, NY, USA.
7
Roswell Park Cancer Institute, Buffalo, NY, USA.
8
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
9
AstraZeneca Pharmaceuticals, Waltham, MA, USA.
10
Present address: Array BioPharma Inc., Boulder, CO, USA.

Abstract

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 Tmax 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.

KEYWORDS:

MEK inhibition; Phase 1; Solid tumor; TAK-733

PMID:
27650277
PMCID:
PMC5306265
DOI:
10.1007/s10637-016-0391-2
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Compliance with ethical standards Conflicts of interest AR has acted as a consultant for and has received honoraria from Amgen, Compugen, Flexus, GSK, Genentech, and Merck, and holds stock in Novartis and Kite Pharma. JAS has acted as a consultant for Millennium Pharmaceuticals, Inc., Merck, and Amgen, and has received honorarium from Millennium Pharmaceuticals, Inc. The institution of JAS has also received grants from Bristol-Myers Squibb, GSK, and Millennium Pharmaceuticals, Inc. XZ, SF, RN, MK, EG and VB were employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. AAA, PL, AP, and GKD have no conflicts of interest to disclose. Funding The work was supported by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

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