Lapatinib Ditosylate and Akt Inhibitor MK2206 in Treating Women With Metastatic Breast Cancer

NCT01281163 | Terminated Phase 1

• 8 other identifiers: NCI-2011-02574WSU# 2010-109CDR00006937292010-1098747P30CA022453U01CA062487U01CA062490
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Positive; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IV Breast Cancer

Outcome Measures

Primary Outcomes (1)

• 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

  28 days

Secondary Outcomes (7)

• Change in breast cancer stem cell (BCSC) biomarkers in serial tumor biopsies by aldefluor assay and flow cytometry

  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

  Baseline and after 2 weeks

• Genomic profiling of the tumor cells and BCSC populations

  Up to 30 days after completion of study treatment

• Percent change in BCSCs within the tumor

  Baseline to 2 weeks of treatment

• Pharmacogenetic influence of the candidate drug-metabolizing enzymes and transporters on the PK of MK2206 and lapatinib

  Up to 30 days

Study Arms (1)

Treatment (Akt inhibitor MK2206 and lapatinib ditosylate)

EXPERIMENTAL

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: Laboratory Biomarker Analysis; Drug: Lapatinib Ditosylate; Other: Pharmacogenomic Study; Other: Pharmacological Study

Interventions

Akt Inhibitor MK2206 DRUG

Given PO

Also known as: MK2206

Treatment (Akt inhibitor MK2206 and lapatinib ditosylate)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (Akt inhibitor MK2206 and lapatinib ditosylate)

Lapatinib Ditosylate DRUG

Given PO

Also known as: Tykerb

Treatment (Akt inhibitor MK2206 and lapatinib ditosylate)

Pharmacogenomic Study OTHER

Correlative studies

Also known as: PHARMACOGENOMIC

Treatment (Akt inhibitor MK2206 and lapatinib ditosylate)

Pharmacological Study OTHER

Correlative studies

Treatment (Akt inhibitor MK2206 and lapatinib ditosylate)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be women with histologically or cytologically confirmed Her2 positive (3+ by immunohistochemistry \[IHC\] or fluorescence in situ hybridization \[FISH\] ratio \>= 2.0) advanced breast cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
• Patients must have estrogen receptor (ER) and progesterone receptor (PR) negative metastatic breast cancer or have had progressive disease following at least 1 prior hormonal therapy for ER or PR positive metastatic breast cancer
• Patients enrolled in the expansion cohort at the MTD dose of MK-2206/lapatinib combination must agree to undergo two biopsies for research purposes (Note: we will only biopsy the MTD cohort and their tumor must be accessible for biopsy)
• Patients with brain metastases will be eligible if the brain mets have been stable for at least one month and the patients are steroid-independent
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan; patients with skin-only disease not measurable by RECIST are eligible but must have disease for which unilateral dimensions can be measured and must have monthly photographs with measurements available
• Leukocytes \>= 3,000/mcL
• Absolute neutrophil count \>= 1,500/mcL
• Platelets \>= 100,000/mcL
• Total bilirubin within normal institutional limits
• Magnesium within normal institutional limits
• Potassium within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal
• Creatinine =\< 1.2 x institutional upper limit of normal OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional norm
• Lapatinib has been reported to decrease left ventricle ejection fraction (LVEF); patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure will not be eligible; normal LVEF will be confirmed before starting lapatinib, and evaluations (echocardiogram \[ECHO\]/multi gated acquisition scan \[MUGA\]) continued every 3 cycles during treatment; repeat LVEF determination will be performed for any signs or symptoms suggestive of congestive heart failure
• Patients must have developed progressive disease following at least 1 prior systemic therapy for metastatic breast cancer

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for those who received radiation therapy of \> 5% of their total marrow volume; 6 weeks for nitrosoureas or mitomycin C) prior to entering the study; or those who have not recovered to =\< CTCAE grade 1 toxicities related to prior therapy are not eligible to participate in this study with the exception of grade 2 peripheral neuropathy if it has been stable, and not worsening, for at least 30 days
• Patients may not have received any other investigational agents or immunotherapies within the preceding 30 days or five half-lives of the drug (whichever is less)
• Patients must not have received prior treatment with either an AKT inhibitor or lapatinib with the exception of patients who have been administered an AKT inhibitor or lapatinib as part of a single or extremely limited dosing study, such as a phase 0 study
• Patients must not receive any other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) while on this study except for medications that are prescribed for supportive care but may potentially have an anti-cancer effect (i.e. megestrol acetate, bisphosphonates); these medications must have been started 1 month prior to enrollment on this study; erythropoietin (Epo) and darbepoetin (Darbepo) are allowed
• Patients may not be receiving any other investigational agents
• Any patient requiring chronic maintenance of white blood cell counts or granulocyte counts through the use of growth factor support (e.g. Neulasta, Neupogen)
• Patients with a prior history of seizures
• Patients with known brain metastases are excluded from this clinical trial if the mets have been stable for less than one month and/or if they are on active steroid treatment
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206, lapatinib, or other agents used in study
• Preclinical studies demonstrated the potential of MK-2206 for induction of hyperglycemia in all preclinical species tested; patients with diabetes or at risk for hyperglycemia are not to be excluded from trials with MK-2206, but the hyperglycemia should be well controlled on oral agents before the patient enters the trial
• Preclinical studies indicated transient changes in corrected QT (QTc) interval during MK-2206 treatment; prolongation of QTc interval is potentially a safety concern while on MK-2206 therapy; patients with baseline QTcF \> 450 msec (male) or QTcF \>470 msec (female) will be excluded from entry on study; a list of medications that may cause QTc interval prolongation are listed, and should be avoided by patients entering on trial
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK-2206; these potential risks may also apply to other agents used in this study
• HIV-positive patients on combination antiretroviral therapy are ineligible
• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

Yale University

New Haven, Connecticut, 06520, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

MK 2206; Lapatinib; Pharmacogenomic Testing

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Genetic Testing; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Patricia LoRusso

  Barbara Ann Karmanos Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 20, 2011
• First Posted: January 21, 2011
• Study Start: January 1, 2011
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: August 27, 2015

Record last verified: 2015-04

Locations

US (5)