Akt Inhibitor MK2206 in Combination With Lapatinib Ditosylate in Patients With Advanced or Metastatic Solid Tumors or Breast Cancer
This phase I clinical trial is studying the side effects and the best dose of giving Akt inhibitor MK2206 (MK2206) together with lapatinib ditosylate (lapatinib) in treating patients with advanced or metastatic solid tumors or breast cancer. MK2206 and lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
HER2-positive Breast Cancer
Male Breast Cancer
Recurrent Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: Akt inhibitor MK2206
Drug: lapatinib ditosylate
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of MK-2206 in Combination With Lapatinib in Refractory Solid Tumors Followed by Dose-expansion in Advanced HER2+ Breast Cancer|
- 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) [ Time Frame: 35 days ] [ Designated as safety issue: Yes ]
- 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) [ Time Frame: Up to 3 months ] [ Designated as safety issue: Yes ]Possible adverse events will be reported in tabular format.
- Response rate (complete or partial response or stable disease) measured by RECIST (Part I) [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]Two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed.
- DLTs assessed by NCI CTCAE v. 4 (Part I) [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]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.
- Safety of Akt inhibitor MK2206 and lapatinib ditosylate assessed by NCI CTCAE v. 4 (Part I) [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: Yes ]Data analyses will be performed using SAS version 9.2 or greater. All demographic variables (e.g., gender, age, weight, etc.) will be summarized by standard descriptive statistics: means, standard deviations, medians, and ranges for variables on a continuous scale, and frequency tables for variables on a categorical scale.
- Response rates using RECIST guidelines (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]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.
- Disease progression using RECIST guidelines (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
- Progression-free survival rates (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]PFS times will be presented in a tabular format. Given the reduced sample size, statistical inference might not be possible. However, if enough events will be observed, a Kaplan-Meier curve will be displayed.
- Pharmacokinetic (PK) parameters (Part II) [ Time Frame: Pre-dose, 0 and 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours ] [ Designated as safety issue: No ]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.
- Mechanisms of lapatinib ditosylate resistance (Part II) [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]Expressions will all be presented descriptively (mean, standard deviation, median, range) in tabular format and correlated with response or clinical benefit using regression models.
|Study Start Date:||November 2010|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (Akt inhibitor MK2206 and lapatinib tosylate)
Patients receive Akt inhibitor MK2206 PO QD, QOD for 28 days (35 days for course 1) and lapatinib tosylate PO QD or 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 Akt inhibitor 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.
Drug: Akt inhibitor MK2206
Other Name: MK2206Drug: lapatinib ditosylate
Other Names:Other: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
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|United States, South Dakota|
|Sanford Cancer Center-Oncology Clinic|
|Sioux Falls, South Dakota, United States, 57104|
|United States, Wisconsin|
|University of Wisconsin Hospital and Clinics|
|Madison, Wisconsin, United States, 53792|
|Principal Investigator:||Amye Tevaarwerk||University of Wisconsin Hospital and Clinics|