Abstract
A phase I study of MK-2206 in combination with lapatinib in patients (pts) with advanced solid tumors
Journal of clinical oncology, Vol.31(15_suppl), pp.2607-2607
05/20/2013
DOI: 10.1200/jco.2013.31.15_suppl.2607
Abstract
Abstract only
2607
Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of <75% of drug. The most common AEs at least possibly related to therapy included diarrhea (gr 3-4 in 3 pts; gr 1-2 in 16 pts), nausea (gr 3 in 2 pts; gr 1-2 in 14 pts) and rash (gr 3 in 2 pts; gr 1-2 in 12 pts). The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib, exceeding biologically active doses for each agent. One pt with adrenal cortical carcinoma was on study for 6 months with stable disease (SD) and 1 pt with colorectal cancer was on study for 5 months with significant tumor marker decline and SD. PK analyses are ongoing. Conclusions: MK-2206 in combination with lapatinib is well-tolerated at biologically active single agent doses. Anti-tumor activity will be evaluated further in a dose expansion cohort in pts with advanced HER2-positive breast cancer. Clinical trial information: NCT01245205.
Details
- Title: Subtitle
- A phase I study of MK-2206 in combination with lapatinib in patients (pts) with advanced solid tumors
- Creators
- Kari Braun Wisinski - University of Wisconsin Carbone Cancer CenterAmye Tevaarwerk - University of Wisconsin Carbone Cancer CenterMaria Bell - Sanford USD Medical CenterMark E. Burkard - University of Wisconsin Carbone Cancer CenterJens C. Eickhoff - University of Wisconsin–MadisonGeorge Wilding - University of Wisconsin Carbone Cancer CenterNoelle K. LoConte - University of Wisconsin Carbone Cancer CenterAnne M. Traynor - University of Wisconsin Carbone Cancer CenterTien Hoang - University of Wisconsin Carbone Cancer CenterJennifer Heideman - University of Wisconsin Carbone Cancer CenterJill Kolesar - University of Wisconsin Carbone Cancer CenterGlenn Liu - University of Wisconsin Carbone Cancer Center
- Resource Type
- Abstract
- Publication Details
- Journal of clinical oncology, Vol.31(15_suppl), pp.2607-2607
- DOI
- 10.1200/jco.2013.31.15_suppl.2607
- ISSN
- 0732-183X
- eISSN
- 1527-7755
- Language
- English
- Date published
- 05/20/2013
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics; Internal Medicine
- Record Identifier
- 9984695801002771
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