Journal
CLINICAL CANCER RESEARCH
Volume 22, Issue 11, Pages 2659-2667Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-2365
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Funding
- NCI Cancer Center [P30 CA014520]
- NCI [U01CA062491]
- Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427, KL2TR000428]
- [T32 CA009614]
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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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