This phase I trial studies the side effects and the best dose of lapatinib ditosylate and Akt inhibitor MK2206 in treating women with metastatic breast cancer. Lapatinib ditosylate and Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of continuous daily administration of lapatinib (lapatinib ditosylate) in combination with weekly administration of MK2206 (AKT inhibitor MK2206) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. II. To determine the dose-limiting toxicity (DLT) and identify the maximum-tolerated dose (MTD) and/or recommended phase II dose (RP2D) for this administration schedule. SECONDARY OBJECTIVES: I. To determine the pharmacokinetics (PK) of MK2206 and lapatinib, each given alone and in the combination. II. To evaluate potential pharmacogenetic influence of the candidate drug metabolizing enzymes and transporters on the PK of MK2206 and lapatinib. III. To evaluate the change in select breast cancer biomarkers in the phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathways, (e.g., phosphorylated \[p\]PTEN, PTEN, pAkt, Akt, phosphorylated glycogen synthase kinase (pGSK)3-beta, GSK3-beta), Wnt/beta-catenin pathway (e.g., activated beta-catenin (ABC), beta-catenin), and pHER2. IV. To evaluate the change in breast cancer stem cell (BCSC) biomarkers, aldehyde dehydrogenase (ALDH)1 and cluster of differentiation (CD) 44+/CD24-, before and after 2 weeks of treatment with the combination of MK2206 and lapatinib at the MTD. The percent change in BCSCs in tumor biopsies will also be evaluated. V. To determine tumor response in patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), and by percent change in BCSCs within the tumor before vs after 2 weeks of combination treatment. VI. To perform genomic profiling of the tumor cell and BCSC populations before and after 2 weeks of treatment with the combination of MK2206 and lapatinib at the MTD. OUTLINE: This is a phase I, dose-escalation study followed by an expansion cohort study. Patients receive lapatinib ditosylate orally (PO) once daily (QD) on days 1 and 15-28 of course 1 and on days 1-28 of subsequent courses. Patients also receive AKT inhibitor MK2206 PO QD on days 8, 15, and 22 of course 1 and on days 1, 8, 15, and 22 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
4
Given PO
Correlative studies
Given PO
Correlative studies
Correlative studies
Yale University
New Haven, Connecticut, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States
MTD based on the dose-limiting toxicity, occurrence of adverse events and the associated NCI CTCAE grade of continuous daily administration of lapatinib ditosylate in combination with weekly administration of MK-2206
Time frame: 28 days
Change in breast cancer stem cell (BCSC) biomarkers in serial tumor biopsies by aldefluor assay and flow cytometry
The percent change in BCSCs in tumor biopsies will be evaluated.
Time frame: Baseline and after 2 weeks
Change in selected breast cancer biomarkers in serial tissue biopsies using immunohistochemistry (IHC) and automated quantitative immunofluorescence system (AQUA) assay
Time frame: Baseline and after 2 weeks
Genomic profiling of the tumor cells and BCSC populations
Summarized with descriptive statistics appropriate to such distributions.
Time frame: Up to 30 days after completion of study treatment
Percent change in BCSCs within the tumor
Summarized with standard descriptive statistics.
Time frame: Baseline to 2 weeks of treatment
Pharmacogenetic influence of the candidate drug-metabolizing enzymes and transporters on the PK of MK2206 and lapatinib
Time frame: Up to 30 days
Pharmacokinetics of MK-2206 in combination with lapatinib
Including, but not limited to, maximum observed plasma concentration (Cmax), time to maximum plasma concentration (tmax), plasma terminal half-life (t1/2), area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf), AUC from time 0 to the next dose (AUCtlast), accumulation index (AI = AUCtlast/AUC0-inf), maximum observed plasma concentration at steady state (Css, max), and minimum observed plasma concentration at steady state (Css, min).
Time frame: Days 1, 2, 8, 9, 10, 22, 23, 24 of course 1 and day 1 of course 2
Tumor response assessed by RECIST
Described by point estimates and exact 90% confidence intervals (CIs).
Time frame: Up to 30 days
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.