Jump to: Authorized Access | Attribution | Authorized Requests

Study Description

In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer.

Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance 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 no targeted 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.

In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

Authorized Access
Publicly Available Data
  Link to other NCBI resources related to this study
Study Inclusion/Exclusion Criteria

Ages Eligible for Study: 18 Years and older (Adult, Senior)
Sexes Eligible for Study: Female
Accepts Healthy Volunteers: No
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

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
RNAseq Illumina HiSeq 2000 N/A N/A
Study History

Study Start Date: January 2012
Study Completion date: April 2016

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
Authorized Data Access Requests
Study Attribution
  • Principal Investigator
    • Lisa A. Carey, MD. University of North Carolina at Chapel Hill, NC, USA.
    • Shelton Earp, MD. University of North Carolina at Chapel Hill, NC, USA.
  • Co-Principal Investigator
    • Kristalyn Gallagher, DO. University of North Carolina at Chapel Hill, NC, USA.
  • Funding Source
    • IIR12-225201. Susan G. Komen.
    • Supplied trametinib. GlaxoSmithKline.
    • GM101141. National Institutes of Health, MD, USA.
    • CA058223. National Cancer Institute SPORE Grant, Natioanl Health Institute, MD, USA.