This phase I trial studies the side effects and best dose of Akt inhibitor MK2206 and lapatinib ditosylate when given together with trastuzumab in treating patients with locally advanced or metastatic human epidermal growth factor receptor-2 (HER2)-positive breast, gastric, or gastroesophageal cancer that cannot be removed by surgery. Akt inhibitor MK2206 and lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for tumor growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving Akt inhibitor MK2206 and lapatinib ditosylate together with trastuzumab may kill more tumor cells.
PRIMARY OBJECTIVES: I. To define maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of MK-2206 (Akt inhibitor MK2206) in combination with trastuzumab and lapatinib (lapatinib ditosylate) in adult patients with locally advanced or metastatic HER2-positive breast or gastric cancer; two schedules of lapatinib administration will be examined-continuous daily dosing and pulsatile dosing. SECONDARY OBJECTIVES: I. To provide preliminary assessment of the safety and tolerability of MK-2206 administered in combination with epidermal growth factor receptor (EGFR)/HER2 blockade via trastuzumab and lapatinib in adult patients with a locally advanced or metastatic HER2-positive breast or gastric tumor. II. To explore the anti-tumor activity of MK-2206 in combination with trastuzumab and lapatinib in patients with advanced HER2-positive solid tumor. TERTIARY OBJECTIVES: I. To correlate the anti-tumor activity of MK-2206 in combination with trastuzumab and lapatinib in HER2-positive solid tumor patients with phosphoinositide 3-kinase (PI3K) pathway activation events, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) or phosphatase and tensin homolog (PTEN) and other related gene mutations and expressions; to compare the HER2 and PI3K-PTEN mutation status of the primary tumor to metastatic tumor biopsy when available. OUTLINE: This is a dose-escalation study of Akt inhibitor MK2206 and lapatinib ditosylate. Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, and 15; lapatinib ditosylate PO once daily (QD) on days 1-21 or on days 1-3, 8-10, and 15-17; and trastuzumab intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
MTD of Akt inhibitor MK-2206 and lapatinib ditosylate in combination with trastuzumab determined by dose limiting toxicities as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4
Described by frequency and grade, by course and over all courses, with the maximum grade over all courses used as the summary measure per patient.
Time frame: 21 days
Median progression free survival (PFS)
Estimated using Kaplan-Meier estimates along with 95% confidence intervals.
Time frame: Up to 3 years
Median and range of duration of response
Estimated using Kaplan-Meier estimates along with 95% confidence intervals.
Time frame: Up to 3 years
Overall response rate (ORR), evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Calculated and presented with 95% confidence intervals. Kaplan-Meier methods or the Chi-square test will be used to assess whether PI3K-PTEN mutation status of metastatic tissue is correlated with PFS or ORR. In addition, comparisons of the HER-2 status and PI3K-PTEN mutation status of the primary tumor will be compared with that from metastatic tissue using paired tests, such as the Mc Nemar's Chi-square test.
Time frame: 21 days
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