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

Kari B. Wisinski; Amye J. Tevaarwerk; Mark E. Burkard; Murtuza Rampurwala; Jens Eickhoff; Maria C. Bell; Jill M. Kolesar; Christopher Flynn; Glenn Liu

doi:10.1158/1078-0432.CCR-15-2365

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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

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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

Kari B. Wisinski, Amye J. Tevaarwerk, Mark E. Burkard, Murtuza Rampurwala, Jens Eickhoff, Maria C. Bell, Jill M. Kolesar, Christopher Flynn and Glenn Liu

Clinical cancer research, Vol.22(11), pp.2659-2667

06/01/2016

DOI: 10.1158/1078-0432.CCR-15-2365

PMCID: PMC4891227

PMID: 27026198

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Abstract

Purpose: 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. Experimental Design: 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 pharmacokinetic interactions). The dose expansion cohort enrolled adults with advanced HER2(+) breast cancer. Results: 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. Conclusions: 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.

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Title: Subtitle: 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
Creators: Kari B. Wisinski - University of Wisconsin Carbone Cancer Center
Amye J. Tevaarwerk - University of Wisconsin Carbone Cancer Center
Mark E. Burkard - University of Wisconsin Carbone Cancer Center
Murtuza Rampurwala - University of Wisconsin Carbone Cancer Center
Jens Eickhoff - University of Wisconsin–Madison
Maria C. Bell - Sanford Canc Ctr, Sioux Falls, SD USA
Jill M. Kolesar - University of Wisconsin Carbone Cancer Center
Christopher Flynn - University of Wisconsin Carbone Cancer Center
Glenn Liu - University of Wisconsin Carbone Cancer Center
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.22(11), pp.2659-2667
DOI: 10.1158/1078-0432.CCR-15-2365
PMID: 27026198
PMCID: PMC4891227
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Publisher: Amer Assoc Cancer Research
Number of pages: 9
Grant note: UL1TR000427; KL2TR000428 / Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) T32CA009614 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30 CA014520 / NCI Cancer Center; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000427 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) KL2RR025012 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) U01CA062491 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
Language: English
Date published: 06/01/2016
Academic Unit: Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics; Internal Medicine
Record Identifier: 9984696550702771

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