Abstract
Abstract P5-19-20: A phase I study of MK-2206 in combination with lapatinib in patients with advanced solid tumors followed by dose-expansion in advanced HER2+ breast cancer
Cancer research (Chicago, Ill.), Vol.75(9_Supplement), pp.P5-P5-19-20
05/01/2015
DOI: 10.1158/1538-7445.SABCS14-P5-19-20
Abstract
Abstract
Background : AKT mediates 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. MK-2206 is an oral selective inhibitor of AKT. This study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), adverse events (AEs), clinical activity, pharmacokinetic (PK) parameters and explore potential biomarkers of the combination of MK-2206 with lapatinib.
Methods : The dose escalation cohort included adult patients (pts) with solid tumors treated with 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. MK-2206 plasma concentrations were evaluated on day 1, 9 (steady state) and 15 (steady state in combination with lapatinib). Lapatinib plasma concentrations were evaluated on day 9 (first dose) and day 15 (steady state in combination with MK-2206). Both used a validated LC-MSMS assay. Pharmacokinetic parameters were calculated using non-compartmental methods with WinNonLin Phoenix version. The dose expansion cohort included women with advanced HER2+ breast cancer treated at the MTD. Peripheral blood mononuclear cells (PBMCs) and archived tumor samples were collected for all pts.
Results : In the dose escalation cohort, 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. Cancers were colorectal (8 pts), lung (4 pts), breast (3 pts) and other (8 pts). 19 evaluable pts were treated a median of 8 weeks (range 3-35). At dose level four, 1 pt had grade 4 hyponatremia, grade 3 rash and hypocalcemia and 1 pt had intolerable grade 2 mucositis with delivery of <75% of drug. The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib. The most common AEs at least possibly related to therapy included diarrhea (grade 3-4 in 3 pts; grade 1-2 in 16 pts), nausea (grade 3 in 2 pts; grade 1-2 in 14 pts) and rash (grade 3 in 2 pts; grade 1-2 in 12 patients). PK analyses demonstrated lapatinib half-life was approximately 18 hours on both day 9 and 15. MK-2206 half-life was 65± 119 hours on day 1, 104± 84 on day 9 and 59.1±25 on day 15. Dose adjusted MK-2206 AUC (hr*ng/mL/mg) was 26.6± 31 of day 1, 100.6± 78 on day 9 and 62.8± 58 on day 15. In the dose expansion cohort, five HER2+ women were enrolled (median age 43 yrs [range 33-56]). The majority were heavily pretreated: all had prior progression on trastuzumab and 2 with prior lapatinib. They were on study for a median of 8 weeks (range 4-24 weeks). One pt had stable disease for 6 months and another pt had clinical benefit with non-measurable skin disease and she remains on study. Exploration of PBMCs for evidence of target inhibition in HER2-PI3K-AKT signaling and tumor tissue for PTEN loss, PI3K mutations will be presented.
Conclusions : Continuous dosing of MK-2206 in combination with lapatinib is well-tolerated. Preliminary results of pharmacokinetic analysis indicate a potential for a drug interaction. Clinical benefit was seen in patients with HER2+ breast cancer.
Citation Format: Moniba Nazeef, Amye J Tevaarwerk, Jens Eickhoff, Mark E Burkard, Jennifer Heideman, Glenn Liu, Chris Flynn, Jill M Kolesar, Kari B Wisinski. A phase I study of MK-2206 in combination with lapatinib in patients with advanced solid tumors followed by dose-expansion in advanced HER2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-20.
Details
- Title: Subtitle
- Abstract P5-19-20: A phase I study of MK-2206 in combination with lapatinib in patients with advanced solid tumors followed by dose-expansion in advanced HER2+ breast cancer
- Creators
- Moniba NazeefAmye J Tevaarwerk - University of Wisconsin–MadisonJens Eickhoff - University of Wisconsin–MadisonMark E Burkard - University of Wisconsin–MadisonJennifer Heideman - University of Wisconsin–MadisonGlenn Liu - University of Wisconsin–MadisonChris Flynn - University of Wisconsin–MadisonJill M Kolesar - University of Wisconsin–MadisonKari B Wisinski - University of Wisconsin–Madison
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.75(9_Supplement), pp.P5-P5-19-20
- Publisher
- AMER ASSOC CANCER RESEARCH
- DOI
- 10.1158/1538-7445.SABCS14-P5-19-20
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 05/01/2015
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Internal Medicine; Pharmacy
- Record Identifier
- 9984696549502771
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