Lapatinib Ditosylate and Akt Inhibitor MK2206 in Treating Women With Metastatic Breast Cancer
|ClinicalTrials.gov Identifier: NCT01281163|
Recruitment Status : Terminated
First Posted : January 21, 2011
Last Update Posted : August 27, 2015
|Condition or disease||Intervention/treatment||Phase|
|Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Positive Progesterone Receptor Negative Progesterone Receptor Positive Recurrent Breast Carcinoma Stage IV Breast Cancer||Drug: Akt Inhibitor MK2206 Other: Laboratory Biomarker Analysis Drug: Lapatinib Ditosylate Other: Pharmacogenomic Study Other: Pharmacological Study||Phase 1|
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.
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 (Clinical Trial)|
|Actual Enrollment :||4 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1b Dose-Escalation Study of the AKT Inhibitor MK-2206 (NSC# 749607) Plus Lapatinib (NSC# 727989) Administered in Patients With HER2 Positive Metastatic Breast Cancer|
|Study Start Date :||January 2011|
|Primary Completion Date :||December 2013|
|Study Completion Date :||December 2013|
Experimental: Treatment (Akt inhibitor MK2206 and lapatinib ditosylate)
Patients receive lapatinib ditosylate PO 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.
Drug: Akt Inhibitor MK2206
Other Name: MK2206Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Lapatinib Ditosylate
Other Name: TykerbOther: Pharmacogenomic Study
Other Name: PHARMACOGENOMICOther: Pharmacological Study
- 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 [ Time Frame: Baseline and after 2 weeks ]The percent change in BCSCs in tumor biopsies will be evaluated.
- 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 [ Time Frame: Up to 30 days after completion of study treatment ]Summarized with descriptive statistics appropriate to such distributions.
- Percent change in BCSCs within the tumor [ Time Frame: Baseline to 2 weeks of treatment ]Summarized with standard descriptive statistics.
- 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 [ Time Frame: Days 1, 2, 8, 9, 10, 22, 23, 24 of course 1 and day 1 of course 2 ]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).
- Tumor response assessed by RECIST [ Time Frame: Up to 30 days ]Described by point estimates and exact 90% confidence intervals (CIs).
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01281163
|United States, Connecticut|
|New Haven, Connecticut, United States, 06520|
|United States, Massachusetts|
|Dana-Farber Cancer Institute|
|Boston, Massachusetts, United States, 02115|
|United States, Michigan|
|University of Michigan Comprehensive Cancer Center|
|Ann Arbor, Michigan, United States, 48109|
|Wayne State University/Karmanos Cancer Institute|
|Detroit, Michigan, United States, 48201|
|United States, Tennessee|
|Vanderbilt University/Ingram Cancer Center|
|Nashville, Tennessee, United States, 37232|
|Principal Investigator:||Patricia LoRusso||Barbara Ann Karmanos Cancer Institute|