Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy (HELEX)
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.
|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|
- 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.
- Clinical Response [ Time Frame: 8 years ] [ Designated as safety issue: Yes ]
- To establish the safety and tolerability of an extended regimen of lapatinib + trastuzumab, with or without endocrine therapy
- To evaluate the rate of pathologic complete response, defined as no residual invasive cancer in the breast and the axillary lymph nodes.
- To evaluate the overall response rate and clinical benefit rate.
- 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.
- To evaluate overall survival
|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)|
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
Patients that er ER/PR positive will be in this arm
Other Name: Femarra, Letrozole
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.
|Contact: Anne Pavlick, BSfirstname.lastname@example.org|
|Contact: Ashley Whittington, BAemail@example.com|
|United States, Alabama|
|University of Alabama - Birmingham||Recruiting|
|Birmingham, Alabama, United States, 35294|
|Contact: Val Caterinicchia, RN 205-934-0309 firstname.lastname@example.org|
|Principal Investigator: Andres Forero-Torres, MD|
|United States, Illinois|
|University of Chicago||Recruiting|
|Chicago, Illinois, United States, 60637|
|Contact: Jean Gibson, RN 773-834-2167 email@example.com|
|Principal Investigator: Rita Nanda, MD|
|United States, Indiana|
|Indianapolis, Indiana, United States, 46202|
|Contact: Kisha Horan 317-274-4262|
|Principal Investigator: Anna Maria Storniolo, M.D.|
|United States, Maryland|
|Baltimore, Maryland, United States, 21231|
|Contact: Hopkins Clinical Trials Specialist 410-955-8804 firstname.lastname@example.org|
|Principal Investigator: Antonio Wolff, MD|
|United States, Massachusetts|
|Dana Farber Cancer Institute||Recruiting|
|Boston, Massachusetts, United States, 02130|
|Principal Investigator: Ian Krop, M.D.|
|United States, North Carolina|
|Durham, North Carolina, United States, 27705|
|Contact: Kim Riley 919-660-1278|
|Principal Investigator: Nicole Kuderer, M.D.|
|United States, Tennessee|
|Vanderbilt University Medical Center||Recruiting|
|Nashville, Tennessee, United States, 37212|
|Contact: VICC Clinical Information Program 800-811-8480|
|Principal Investigator: Brent Rexer, M.D.|
|United States, Texas|
|Baylor College of Medicine Lester and Sue Smith Breast Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Anne Pavlick, BS 713-798-1999 email@example.com|
|Contact: Brenda Reusser, BA 713-798-1929 firstname.lastname@example.org|
|Sub-Investigator: Mothaffar Rimawi, MD|
|Sub-Investigator: Kent Osborne, MD|
|Principal Investigator:||Mothaffar Rimawi, MD||Baylor College of Medicine|