title: A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors.
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 Tmaxwas 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.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN, 55905, USA. Adjei.Alex@Mayo.edu.|Roswell Park Cancer Institute, Buffalo, NY, USA. Adjei.Alex@Mayo.edu.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.affiliation: Yale University, New Haven, CT, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: New York University Langone Medical Center, New York, NY, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.|AstraZeneca Pharmaceuticals, Waltham, MA, USA.
authors.forename: Esha
authors.initials: E
authors.lastname: Gangolli
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kneissl
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Faucette
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Neuwirth
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.|Present address: Array BioPharma Inc., Boulder, CO, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Bózon
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000097:blood; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C558666:TAK 733; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: MEK inhibition; Phase 1; Solid tumor; TAK-733