A Phase I Study of MK-2206 in Combination With Lapatinib in Refractory Solid Tumors Followed by Dose-expansion in Advanced HER2+ Breast Cancer
I. To determine the maximum-tolerated dose (MTD) of MK2206 in combination with lapatinib in
adult subjects with advanced solid tumors.
II. To further evaluate the safety of MK2206 in combination with lapatinib in patients with
locally advanced and unresectable or metastatic HER2+ breast cancer previously treated with
I. To determine the clinical activity of MK2206 in combination with lapatinib administered
to subjects with advanced solid tumors.
II. To describe the dose-limiting toxicities (DLTs) of combined MK2206 and lapatinib.
(advanced solid tumors) III. To determine the safety of MK-2206 and lapatinib administered
in combination. (advanced solid tumors) IV. To determine the pharmacokinetic and
pharmacogenomic profile of MK2206 in combination with lapatinib. (advanced solid tumors) V.
To determine the clinical activity of MK-2206 and lapatinib administered in combination to
patients with locally advanced and unresectable or metastatic HER2+ breast cancer.
VI. To determine the progression-free rate following MK-2206 in combination with lapatinib
when administered at the MTD level to subjects with HER2+ metastatic breast cancer (MBC).
VII. To determine the pharmacokinetic and pharmacogenomics profiles of MK2206 in combination
with lapatinib. (HER2+ MBC)
VIII. To assess for mechanisms of lapatinib resistance by performing:
- Automated Quantitative Analysis (AQUA) analyses for total EGFR, HER2, PTEN, AKT, and
P-glycoprotein, and phosphoepitopes generated by EGFR, HER2, PI3K, and AKT for
quantitative expression of these epitopes in metastatic tumor samples.
- Evaluating tumor tissue for oncogenic mutations in PI3K and KRAS via microdissection,
DNA isolation, and pyrosequencing with primers specific for common activating mutations
including PIK3CA 1633G>A, 3140A>G/T, and 1624G>A, and KRAS 34G>C/T, 35G>T/A, 38G>8.
Tumor response to combination therapy with lapatinib and MK-2206 will be correlated
with presence/absence of mutations.
- Assess for target (AKT, EGFR, HER2) inhibition via peripheral blood mononuclear cells
(PBMCs) in the dose escalation cohort.
OUTLINE: This is a dose-escalation study followed by an expansion study in patients with
HER2+ advanced breast cancer.
Patients receive Akt inhibitor MK2206 orally (PO) once daily (QD), every other day (QOD) for
28 days (35 days for course 1) and lapatinib tosylate PO QD or twice daily (BID) on days
1-28 (days 9-35 for course 1). Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
Once the maximum-tolerated dose is determined, a cohort of patients with breast cancer
receive MK2206 PO QD, QOD for 28 days and lapatinib tosylate PO QD or BID on days 1-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed up for 4 weeks and patients on the
expanded cohort are followed up every 3 months.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose (MTD) defined as the dose level at which less than one-third of patients experience a dose-limiting toxicity (DLT) using NCI CTCAE v.4 (Part I)
University of Wisconsin Hospital and Clinics
United States: Food and Drug Administration
|University of Wisconsin Hospital and Clinics||Madison, Wisconsin 53792-0001|
|Sanford Cancer Center-Oncology Clinic||Sioux Falls, South Dakota 57104|