title: Phase I Study of an AKT Inhibitor (MK-2206) Combined with Lapatinib in Adult Solid Tumors Followed by Dose Expansion in Advanced HER2+ Breast Cancer.
abstract: Preclinical data support combining AKT inhibitors with HER2-targeted therapies to overcome resistance to treatment. This phase I study combined the investigational AKT inhibitor, MK-2206, with lapatinib to determine the MTD.
  
  
  
  The dose escalation cohort enrolled adults with advanced solid tumors, who received MK-2206 dosed 30 to 60 mg every other day and lapatinib 1,000 to 1,500 mg daily continuously, escalated using a 3+3 design. Cycles were 28 days except cycle 1 (35 days, including an initial 8 days of MK-2206 alone to evaluate pharmacokinetic interactions). The dose expansion cohort enrolled adults with advanced HER2(+) breast cancer.
  
  
  
  Twenty-three participants enrolled in the dose escalation cohort. Dose-limiting toxicities were hyponatremia, fatigue, rash, hypocalcemia, and mucositis. Common toxicities included diarrhea, nausea, and rash. The MTD was reached at MK-2206 45 mg orally every other day and lapatinib 1,500 mg orally daily. Two participants maintained stable disease for >4 months, including a colorectal cancer participant with substantial carcinoembryonic antigen decrease. Of 5 participants in the dose expansion cohort, 2 maintained stable disease for >6 months, including one with prior progression on single-agent lapatinib. Plasma MK-2206 concentrations decreased after addition of lapatinib, but in vitro studies indicate lapatinib increases the intracellular levels of MK-2206.
  
  
  
  MK-2206 combined with lapatinib can be tolerated with both drugs above biologically active single-agent doses. Overlapping toxicities result in significant diarrhea and rash, which can be managed medically. Antitumor activity was promising and supports evaluation of AKT inhibitors combined with HER2-targeted therapies. Clin Cancer Res; 22(11); 2659-67. ©2016 AACR.
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. kbwisinski@medicine.wisc.edu.
authors.forename: Kari B
authors.initials: KB
authors.lastname: Wisinski
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Amye J
authors.initials: AJ
authors.lastname: Tevaarwerk
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Burkard
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Murtuza
authors.initials: M
authors.lastname: Rampurwala
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.affiliation: Sanford Cancer Center, Sioux Falls, South Dakota.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Bell
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Christopher
authors.initials: C
authors.lastname: Flynn
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism; D018567:Breast Neoplasms, Male / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D000077341:Lapatinib; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C548887:MK 2206; C508053:ERBB2 protein, human