Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212
Primary Purpose
Breast Cancer
Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
GSK1120212
Sponsored by
About this trial
This is an interventional basic science trial for Breast Cancer focused on measuring GSK1120212, TNBC, Triple Negative Breast Cancer, Surgical Resection
Eligibility Criteria
Inclusion Criteria:
- Histologically confirmed TNBC (i.e., ER negative, PR negative (each <10% staining by immunohistochemistry) and Her2 negative (0-1+ or FISH non-amplified; by clinical assay on primary tumor)
Stage I-IIIc disease:
- Scheduled for lumpectomy or mastectomy
- No prior or current therapy for breast cancer
- Not considered candidate for therapeutic neoadjuvant treatment
For stage IV disease:
- Scheduled for surgical resection of oligometastatic disease
- Previously untreated for breast cancer
- Subject enrolls into LCCC9819
- ECOG Performance Status 0-2
Normal end organ function as defined by the following:
- Absolute neutrophil count (ANC)≥ 1.2 X 109/L;
- Hemoglobin ≥ 9 g/dL;
- Platelets ≥ 75 X 109/L;
- PT/INR and PTT ≤ 1.2 X upper limit of normal (ULN);
- Albumin ≥ 2.5 g/dL
- Total bilirubin ≤ 1.5 x ULN mg/dL
- AST and ALT ≤ 2.5 X ULN
- Creatinine ≤ 1.5 X ULN OR Calculated creatinine clearance ≥50 mL/min OR 24-hour urine creatinine clearance ≥50 mL/min;
- Ejection fraction ≥ LLN by ECHO (preferred) or MUGA
- Age ≥18 years
- Willing to use adequate contraception if applicable, and to continue use for 4 weeks post last dose of GSK1120212
- Sufficient fresh or frozen tissue remaining from pre-treatment core incisional biopsy or willing to undergo biopsy for research purposes only (approximately 10mg or one core's worth of tissue needed)
- Surgeon and Medical Oncologist agree one week window trial appropriate/safe for trial candidate and that surgery appointment can accommodate a 7 day (one week) treatment schedule
- Able to swallow oral medications
Exclusion Criteria
- Pregnant or lactating female
- Currently active GI disease, or prior surgery that may affect ability to absorb oral medications
- Prior radiation therapy to the target lesion
History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):
- History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
- Current use of a prohibited medication or requires any of these medications during treatment with GSK1120212 (see section 4.6).
- Use of an investigational anti-cancer drug within 28 days or five half-lives, whichever is shorter, prior to the first dose of GSK1120212. A minimum of 10 days between termination of the investigational drug and administration of GSK1120212 is required. In addition, any drug-related toxicity should have recovered to Grade 1 or less.
- Prior treatment with MEK or BRAF inhibitors
- Any major radiotherapy, or immunotherapy within the last four weeks; use of erythropoietin replacement or bisphosphonates is considered supportive care and their use is permitted
- Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease)
History or evidence of cardiovascular risk including any of the following:
- QTc interval >/= 480 msecs.
- Clinically significant uncontrolled arrhythmias Exception: subjects with controlled atrial fibrillation for >30 days prior to day 1 of treatment with GSK1120212 are eligible
- History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 24 weeks
- ≥Class II heart failure as defined by the New York Heart Association (NYHA) functional classification system (see Appendix C)
- Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed)
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, dimethyl sulfoxide (DMSO), or excipients
- Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
- Any other concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol
Sites / Locations
- Lineberger Comprehensive Cancer Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
GSK1120212
Arm Description
Outcomes
Primary Outcome Measures
the number and type of kinases in participant tissue sample prior to administration of drug compared to post-treatment.
use of pan kinase inhibitors immobilized on beads to capture expressed kinases in cells and tumors. The activation state of more than 60% of the expressed kinome, defined by RNA-seq, will be analyzed using mass spectrometry analysis of the captured kinases.
Secondary Outcome Measures
the number and type of kinases that produce a compensatory response to MEK inhibitor
The activation state of more than 60% of the expressed kinome, defined by RNA-seq, will be analyzed using mass spectrometry analysis of the captured kinases. For each activated kinase, a drug therapy that combines an inhibitor of that kinase with a MEK inhibitor will be identified.
the number of participants with adverse events
Identify any safety issues in subjects treated with drug GSK1120212
Full Information
NCT ID
NCT01467310
First Posted
October 13, 2011
Last Updated
September 1, 2020
Sponsor
UNC Lineberger Comprehensive Cancer Center
Collaborators
GlaxoSmithKline, National Cancer Institute (NCI), Susan G. Komen Breast Cancer Foundation
1. Study Identification
Unique Protocol Identification Number
NCT01467310
Brief Title
Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212
Official Title
Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212
Study Type
Interventional
2. Study Status
Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
January 2012 (undefined)
Primary Completion Date
March 21, 2016 (Actual)
Study Completion Date
March 21, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
UNC Lineberger Comprehensive Cancer Center
Collaborators
GlaxoSmithKline, National Cancer Institute (NCI), Susan G. Komen Breast Cancer Foundation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Research into treatments for breast cancer relies more and more on an understanding of how the cells of tumor tissue act when they are exposed to a new or different drug. To find these new or different drugs to treat cancer, researchers are looking at proteins that help cancer cells grow, such as a group of proteins called Kinases. In this study the investigators want to look at the activity of kinases when a particular experimental drug called GSK1120212 is administered. GSK1120212 blocks a kinase called MEK. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators want to give subjects GSK1120212 for a short period of time (one week) to see how MEK and the other kinases function in cancer cells both before and after the study drug is given. This study is not intended to treat cancer, it is looking at ways that the investigators may treat cancer in the future.
Detailed Description
In this study the investigators want to look at the activity of kinases when a particular experimental drug called GSK1120212 is administered. GSK1120212 blocks a kinase called MEK. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators want to give subjects GSK1120212 for a short period of time (one week) to see how MEK and the other kinases function in cancer cells both before and after the study drug is given. The investigators are giving this drug for research purposes only. The length of time it is being given is not intended to treat cancer.
Research into treatments for breast cancer relies more and more on an understanding of how the cells of tumor tissue act when they are exposed to a new or different drug. To find these new or different drugs to treat cancer, researchers are looking at proteins that help cancer cells grow, such as a group of proteins called Kinases. This is important because many of the newest cancer drugs are designed to block kinases causing the cancer cells to die and the tumors to shrink. However, blocking only one of the kinases at a time is often less effective than the investigators expected because when you block one kinase another can take its place. For this reason, the investigators may need to treat breast cancer with more than one kinase-blocking drug at a time. However, the investigators don't yet know what the best combination of drugs should be, because it is hard to measure all the possible kinases. Previous studies have only been able to identify less than 10% of the hundreds of kinases in cancer cells.
Recently researchers here at UNC have developed a process that can identify may (more than half) of these kinases. This can tell us which kinases need to be blocked at the same time to make tumors shrink so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are fewer drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
GSK1120212, TNBC, Triple Negative Breast Cancer, Surgical Resection
7. Study Design
Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
GSK1120212
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
GSK1120212
Intervention Description
1.5 to 2.0 mg taken orally every day for seven days.
Primary Outcome Measure Information:
Title
the number and type of kinases in participant tissue sample prior to administration of drug compared to post-treatment.
Description
use of pan kinase inhibitors immobilized on beads to capture expressed kinases in cells and tumors. The activation state of more than 60% of the expressed kinome, defined by RNA-seq, will be analyzed using mass spectrometry analysis of the captured kinases.
Time Frame
Two years
Secondary Outcome Measure Information:
Title
the number and type of kinases that produce a compensatory response to MEK inhibitor
Description
The activation state of more than 60% of the expressed kinome, defined by RNA-seq, will be analyzed using mass spectrometry analysis of the captured kinases. For each activated kinase, a drug therapy that combines an inhibitor of that kinase with a MEK inhibitor will be identified.
Time Frame
Two years
Title
the number of participants with adverse events
Description
Identify any safety issues in subjects treated with drug GSK1120212
Time Frame
Two years
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed TNBC (i.e., ER negative, PR negative (each <10% staining by immunohistochemistry) and Her2 negative (0-1+ or FISH non-amplified; by clinical assay on primary tumor)
Stage I-IIIc disease:
Scheduled for lumpectomy or mastectomy
No prior or current therapy for breast cancer
Not considered candidate for therapeutic neoadjuvant treatment
For stage IV disease:
Scheduled for surgical resection of oligometastatic disease
Previously untreated for breast cancer
Subject enrolls into LCCC9819
ECOG Performance Status 0-2
Normal end organ function as defined by the following:
Absolute neutrophil count (ANC)≥ 1.2 X 109/L;
Hemoglobin ≥ 9 g/dL;
Platelets ≥ 75 X 109/L;
PT/INR and PTT ≤ 1.2 X upper limit of normal (ULN);
Albumin ≥ 2.5 g/dL
Total bilirubin ≤ 1.5 x ULN mg/dL
AST and ALT ≤ 2.5 X ULN
Creatinine ≤ 1.5 X ULN OR Calculated creatinine clearance ≥50 mL/min OR 24-hour urine creatinine clearance ≥50 mL/min;
Ejection fraction ≥ LLN by ECHO (preferred) or MUGA
Age ≥18 years
Willing to use adequate contraception if applicable, and to continue use for 4 weeks post last dose of GSK1120212
Sufficient fresh or frozen tissue remaining from pre-treatment core incisional biopsy or willing to undergo biopsy for research purposes only (approximately 10mg or one core's worth of tissue needed)
Surgeon and Medical Oncologist agree one week window trial appropriate/safe for trial candidate and that surgery appointment can accommodate a 7 day (one week) treatment schedule
Able to swallow oral medications
Exclusion Criteria
Pregnant or lactating female
Currently active GI disease, or prior surgery that may affect ability to absorb oral medications
Prior radiation therapy to the target lesion
History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):
History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
Current use of a prohibited medication or requires any of these medications during treatment with GSK1120212 (see section 4.6).
Use of an investigational anti-cancer drug within 28 days or five half-lives, whichever is shorter, prior to the first dose of GSK1120212. A minimum of 10 days between termination of the investigational drug and administration of GSK1120212 is required. In addition, any drug-related toxicity should have recovered to Grade 1 or less.
Prior treatment with MEK or BRAF inhibitors
Any major radiotherapy, or immunotherapy within the last four weeks; use of erythropoietin replacement or bisphosphonates is considered supportive care and their use is permitted
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease)
History or evidence of cardiovascular risk including any of the following:
QTc interval >/= 480 msecs.
Clinically significant uncontrolled arrhythmias Exception: subjects with controlled atrial fibrillation for >30 days prior to day 1 of treatment with GSK1120212 are eligible
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 24 weeks
≥Class II heart failure as defined by the New York Heart Association (NYHA) functional classification system (see Appendix C)
Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed)
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, dimethyl sulfoxide (DMSO), or excipients
Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
Any other concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lisa Carey, MD
Organizational Affiliation
UNC Lineberger Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Lineberger Comprehensive Cancer Center
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
12. IPD Sharing Statement
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Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212
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