Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Breast Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/21/2019 |
| Start Date: | October 2011 |
| End Date: | January 2020 |
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
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.
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.
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.
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.
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.
We found this trial at
8
sites
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University of Alabama at Birmingham The University of Alabama at Birmingham (UAB) traces its roots...
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University of Chicago One of the world's premier academic and research institutions, the University of...
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Duke University Younger than most other prestigious U.S. research universities, Duke University consistently ranks among...
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Indiana University INDIANA UNIVERSITY is a major multi-campus public research institution, grounded in the liberal...
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1211 Medical Center Dr
Nashville, Tennessee 37232
Nashville, Tennessee 37232
(615) 322-5000
Vanderbilt Univ Med Ctr Vanderbilt University Medical Center (VUMC) is a comprehensive healthcare facility dedicated...
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Johns Hopkins The Johns Hopkins University opened in 1876, with the inauguration of its first...
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Dana-Farber Cancer Institute Since it’s founding in 1947, Dana-Farber has been committed to providing adults...
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