Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy (HELEX)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Translational Breast Cancer Research Consortium
GlaxoSmithKline
Information provided by (Responsible Party):
Baylor Breast Care Center
ClinicalTrials.gov Identifier:
NCT00999804
First received: October 21, 2009
Last updated: July 22, 2014
Last verified: July 2014
  Purpose

Breast cancer is the most common malignancy in the U.S. Targeted therapies such as tamoxifen have been revolutionary in reducing tumor recurrences and mortality in early breast cancer. Using this successful paradigm, there has been a continued search for other targeted biologic therapies directed at receptors with known potential for promoting tumor growth.

The estrogen receptor (ER) and/or the HER signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. Molecular targets of these pathways provide the most effective therapies in appropriately selected patients. However, de novo and acquired resistance remain major obstacles to successful treatment, and understanding the molecular pathways responsible for this resistance would enable the discovery of new strategies to overcome it.

The superiority of multi-drug HER2-targeted therapy over single agent therapy has been demonstrated in the preclinical setting using mouse xenografts. Trastuzumab, pertuzumab, lapatinib, and gefitinib, represent a group of therapeutic agents that target the HER family by different molecular mechanisms. Used as single agents in the MCF7/HER2-18 xenograft model, these drugs restored or enhanced sensitivity to tamoxifen. However, tumor growth inhibition lasted only 2-3 months before resistance to treatments occurred. However, when gefitinib, a HER1 inhibitor, was added to the two-antibody (T+P) regimen to block signals from HER1 dimers, a complete disappearance of nearly all xenograft tumors was observed; moreover, there was evidence of complete tumor eradication in 50% of the mice. The combination of lapatinib + trastuzumab was also highly effective in eradication of tumor burden, with no evidence of re-growth after 200 days. These xenograft models demonstrate that multi-drug HER2-targeted therapy more effectively induces apoptosis and inhibits proliferation, thereby resulting in tumor regression. Furthermore, HER2 combination therapy appears to more effectively reduce levels of phosphorylated pAKT and MAPK, thus resulting in sustained tumor inhibition.


Condition Intervention Phase
Breast Cancer
Drug: Herceptin / Lapatinib
Drug: Letrozole
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: TBCRC 023: A Randomized Multicenter Phase II Neoadjuvant Trial of Lapatinib Pus Trastuzumab, With or Without Endocrine Therapy for 12 Weeks vs. 24 Weeks in Patients With HER2 Overexpressing Breast Cancer

Resource links provided by NLM:


Further study details as provided by Baylor Breast Care Center:

Primary Outcome Measures:
  • To evaluate the rate of pathologic complete response, defined as no residual invasive cancer in the breast, after 12 or 24 weeks of lapatinib/trastuzumab with or without endocrine therapy. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    We propose a randomized multicenter neoadjuvant clinical trial in HER-2 overexpressing breast cancer patients with 12 vs. 24 weeks of lapatinib plus trastuzumab, with or without endocrine therapy, during which serial cancer tissue samples will be obtained for molecular studies in relation to tumor response. The patients will receive either 12 or 24 weeks of therapy to determine the pathologic complete response rate to this combined targeted therapy regimen, without the addition of any cytotoxic chemotherapy.


Secondary Outcome Measures:
  • Clinical Response [ Time Frame: 8 years ] [ Designated as safety issue: Yes ]
    1. To establish the safety and tolerability of an extended regimen of lapatinib + trastuzumab, with or without endocrine therapy
    2. To evaluate the rate of pathologic complete response, defined as no residual invasive cancer in the breast and the axillary lymph nodes.
    3. To evaluate the overall response rate and clinical benefit rate.
    4. To evaluate time to progression and site of first progression in patients treated with an extended regimen of lapatinib + trastuzumab with or without endocrine therapy.
    5. To evaluate overall survival


Estimated Enrollment: 96
Study Start Date: October 2011
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: HER2 Positive
Patients that are HER2 Positive will be in this Arm
Drug: Herceptin / Lapatinib
biologic dosed mg per kg
Other Name: Herceptin
Experimental: Endocrine
Patients that er ER/PR positive will be in this arm
Drug: Letrozole
2.5 mg
Other Name: Femarra, Letrozole

Detailed Description:

Breast cancer cells have certain characteristics or traits--these traits are called biomarkers. There are three biomarkers that help doctors decide which treatment to give any given patient. These biomarkers are the estrogen receptor (ER), progesterone receptor (PgR), and HER2 protein. Breast cancer cells that have a large number of estrogen or progesterone receptors are called ER and/or PgR positive. Cancers that are ER and/or PgR positive use the hormones estrogen and progesterone to help them grow. Not all breast cancers are ER or PgR positive. Patients are being asked to take part in this study that have a special type of breast cancer called HER2 positive breast cancer. HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor-2 (HER2). HER2 is located on the outer surface of a cancer cell. The HER2 protein sends a signal to the inside of the cancer cells telling it to grow and divide.

Two medications that directly target this HER2 protein. One is called trastuzumab(Herceptin), and the other is called lapatinib (Tykerb). Both medications are FDA-approved for the treatment of women with HER2+ breast cancer. Each medication attaches to the protein so that it can no longer function. Once the protein stops working, the cancer cells can no longer make copies of themselves. This makes cancer shrink. Both drugs target HER2; however each drug works a little bit differently.

Some patients respond better to Herceptin, and some patients respond better to Tykerb. Right now, we are not sure why some patients respond to one drug but do not respond to the other drug. One possibility is that in some patients, the HER2 protein finds another way to send its message to the inside of the cell (similar to a road detour). For example, when one path is "closed" because the drug is blocking it, the HER2 protein finds a different way to send its signal. We think that we can completely block the HER2 protein by giving patients both Tykerb and Herceptin.

Some patients with HER positive breast cancer are also ER and/or PgR positive. Even after HER2 is completely blocked, these types of cancer cells can still grow by using the estrogen or progesterone receptor. If a patient is told they are ER and/or PgR positive, they will also take an anti-estrogen pill along with Tykerb and Herceptin. We think that we can stop cancer growth more completely by blocking both the HER2 protein and the ER/PR receptors.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All patients must be female and at least 18 years of age.
  2. Signed informed consent.
  3. Locally advanced breast cancers are eligible. Locally advanced cancers must be of clinical and/or radiologic size >3 cm, or >2 cm with clinical evidence of axillary nodal involvement*. (If tumors are less than 3 cm, we will use the radiologically measured tumor size to determine if the tumor meets the minimal size requirements.)
  4. Patients must have histologically confirmed invasive mammary carcinoma that is HER2 overexpressing, defined as 3+ by immunohistochemistry, or a FISH/CEP ratio greater than 2.
  5. Negative serum pregnancy test (HCG) within 7 days of starting study drug, if of child-bearing potential.
  6. Kidney and liver function tests - all within 1.5 times the institutional upper limit of normal.
  7. Performance status (WHO/ECOG scale) 0-1 and life expectancy >6 months.
  8. No evidence of brain or leptomeningeal disease, or any other Stage IV disease.
  9. No previous or current malignancies at other sites within the last 5 years, with exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.

Exclusion Criteria:

  1. Patients with bilateral breast cancer.
  2. Pregnancy or unwillingness to use a reliable contraceptive method in women of child-bearing potential.
  3. Severe underlying chronic illness or disease.
  4. Cardiomyopathy or baseline LVEF less than 50%.
  5. Other investigational drugs while on study.
  6. Severe or uncontrolled hypertension, history of congestive heart failure or severe coronary arterial disease.
  7. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded
  8. Taking any lapatinib prohibited medication(s)
  9. Inability or unwillingness to comply with, or follow study procedures.
  10. Patients who have received any form of treatment for breast cancer within the past five years, including surgical resection, chemotherapy, endocrine therapy, or biologic therapy.
  11. Patients with a prior history of ipsilateral invasive breast cancer or carcinoma in situ who present with a new primary.
  12. Patients with known active, infectious Hepatitis B, Hepatitis C, or HIV.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00999804

Locations
United States, Alabama
University of Alabama - Birmingham
Birmingham, Alabama, United States, 35294
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202
United States, Maryland
Johns Hopkins
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02130
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27705
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37212
United States, Texas
Baylor College of Medicine Lester and Sue Smith Breast Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor Breast Care Center
Translational Breast Cancer Research Consortium
GlaxoSmithKline
Investigators
Principal Investigator: Mothaffar Rimawi, MD Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Baylor Breast Care Center
ClinicalTrials.gov Identifier: NCT00999804     History of Changes
Other Study ID Numbers: H-25846
Study First Received: October 21, 2009
Last Updated: July 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Baylor Breast Care Center:
Locally Advanced Breast Cancer Neoadjuvant Endocrine

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Lapatinib
Letrozole
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Aromatase Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014