This phase I trial studies the side effects and the best dose of Akt inhibitor MK2206 and lapatinib ditosylate in treating patients with solid tumors or breast cancer that has spread to other places in the body. Akt inhibitor MK2206 and lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of MK-2206 (Akt inhibitor MK2206) in combination with lapatinib (lapatinib ditosylate) in adult subjects with advanced solid tumors. (Dose Escalation Cohort) II. To further evaluate the safety of MK-2206 in combination with lapatinib administered to patients with locally advanced and unresectable or metastatic human epidermal growth factor receptor 2 positive (HER2+) breast cancer, previously treated with trastuzumab. (Dose Expansion Cohort) SECONDARY OBJECTIVES: I. To determine the clinical activity of MK-2206 in combination with lapatinib administered to subjects with advanced solid tumors. (Dose Escalation Cohort) II. To describe the dose-limiting toxicities (DLTs) of combined MK-2206 and lapatinib. (Dose Escalation Cohort) III. To determine the safety of MK-2206 and lapatinib administered in combination. (Dose Escalation Cohort) IV. To determine the pharmacokinetic and pharmacogenomic profile of MK-2206 in combination with lapatinib. (Dose Escalation Cohort) V. To assess for target (HER2-phosphoinositide 3-kinase \[PI3K\]-protein kinase B \[AKT\] pathway) inhibition via peripheral blood mononuclear cells (PBMCs) in the dose escalation cohort. (Dose Escalation Cohort) VI. 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. (Dose Expansion Cohort) VII. 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). (Dose Expansion Cohort) VIII. To determine the pharmacokinetic and pharmacogenomic profiles of MK-2206 in combination with lapatinib. (Dose Expansion Cohort) IX. To assess for mechanisms of lapatinib resistance by evaluating tumor tissue for phosphatase and tensin homolog (PTEN) loss using immunohistochemistry. (Dose Expansion Cohort) X. To assess for mechanisms of lapatinib resistance by evaluating tumor tissue for oncogenic mutations in PI3K. Tumor response to combination therapy with lapatinib and MK-2206 will be correlated with presence/absence of PI3K activating mutations and PTEN loss. (Dose Expansion Cohort) XI. To assess for mechanisms of lapatinib resistance by assessing for target (HER2-PI3K-AKT pathway) inhibition via peripheral blood mononuclear cells (PBMCs). (Dose Expansion Cohort) OUTLINE: This is a dose-escalation study. Patients receive Akt inhibitor MK2206 orally (PO) every other day (QOD) for 28 days (35 days for course 1) and lapatinib ditosylate PO once daily (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. After completion of study treatment, patients are followed up for 4 weeks and patients on the expanded cohort are followed up every 3 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
28
Given PO
Given PO
Correlative studies
Correlative studies
Sanford Cancer Center-Oncology Clinic
Sioux Falls, South Dakota, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
MTD of Akt inhibitor MK-2206 and lapatinib ditosylate, defined as the dose level at which less than one-third of patients experience a DLT as graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4 (Part I)
Time frame: 35 days
Incidence of adverse reactions to Akt inhibitor MK2206 and lapatinib ditosylate in patients with advanced and unresectable or metastatic HER2+ breast cancer previously treated with trastuzumab as assessed by NCI CTCAE v. 4 (Part II)
Possible adverse events will be reported in tabular format.
Time frame: Up to 4 years
Response rate (complete or partial response or stable disease) measured by Response Evaluation Criteria in Solid Tumors (RECIST) (Part I)
Two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed.
Time frame: Up to 4 weeks
Incidence of DLTs assessed by NCI CTCAE v. 4 (Part I)
The toxicities observed will be summarized by type and severity using the most recent version of the NCI CTCAE v.4 terminology. Both the number and severity of toxicity and adverse events will be analyzed in descriptive manner and presented in tabular format.
Time frame: Up to 4 weeks
Incidence of adverse events, graded using NCI CTCAE v. 4 (Part I)
Possible adverse events will be reported in tabular format.
Time frame: Up to 4 weeks
Response rates using RECIST guidelines (Part II)
Responses will be summarized by means of descriptive statistics and frequency tables. Confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed in the expansion cohort.
Time frame: Up to 4 years
Disease progression using RECIST guidelines (Part II)
Time frame: Up to 4 years
Progression-free survival (PFS) rates (Part II)
PFS times will be presented in a tabular format. If enough events will be observed, a Kaplan-Meier curve will be displayed.
Time frame: Up to 4 years
Pharmacokinetic (PK) parameters of Akt inhibitor MK-2206 in combination with lapatinib ditosylate (Part II)
All PK parameters will be summarized by using means, standard deviations and ranges. PK parameters of patients with severe toxicities (grade \>= 3) will be compared to PK parameters of patients with no severe toxicities using Wilcoxon's rank sum test. Given the exploratory nature of these analyses, no multiplicity adjustments will be made.
Time frame: Pre-dose, 0 and 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours on days 1, 9, and 15 of course 1, and day 1 of subsequent courses
Quantitative expression of proteins in tumor specimens (Part II)
Expressions for total HER2, PTEN, and AKT will all be presented descriptively (mean, standard deviation, median, range) in tabular format and correlated with response or clinical benefit using regression models.
Time frame: Baseline
Oncogenic mutations in PI3K (Part II)
Genotypes will all be presented descriptively in tabular format and correlated with pharmacokinetics and clinical responses via regression models. PK data means and standard deviations will be summarized by genotype and compared using a series of pairwise two-sample t-tests. Genotype analyses are exploratory, hence no multiplicity adjustments will be made.
Time frame: Baseline
Change in PBMC counts (Part II)
Paired t-tests will be used to compare baseline values to each PBMC assessment timepoint post-baseline. Means and standard deviations will be tabulated at each timepoint and for each dose level. Given the exploratory nature of these analyses, no multiplicity adjustments will be made.
Time frame: Baseline to up day 1 of last course of treatment
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