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 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. 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.
|Number of pages
|Clinical Cancer Research
|Published - Jun 1 2016
Bibliographical noteFunding Information:
This work was supported by the NCI Cancer Center Support Grant P30 CA014520 and NCI U01CA062491 Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis. A.J. Tevaarwerk and M.E. Burkard have received support from the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grants UL1TR000427 and KL2TR000428, while M. Rampurwala has received support from T32 CA009614.
© 2016 American Association for Cancer Research.
ASJC Scopus subject areas
- Medicine (all)