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

• ClinicalTrials.gov Identifier: NCT00999804
• Recruitment Status: Active, not recruiting
• First Posted: October 22, 2009
• Results First Posted: December 12, 2016
• Last Update Posted: June 18, 2023
• Sponsor: Baylor Breast Care Center
• Collaborators: Translational Breast Cancer Research Consortium; GlaxoSmithKline
• Information provided by (Responsible Party): Mothaffar Rimawi, Baylor Breast Care Center

Tracking Information

• First Submitted Date: October 21, 2009
• First Posted Date: October 22, 2009
• Results First Submitted Date: December 29, 2015
• Results First Posted Date: December 12, 2016
• Last Update Posted Date: June 18, 2023
• Actual Study Start Date: October 2011
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2016)

Pathologic Complete Response [ Time Frame: 12 or 24 week depending the arm assignment ]

Pathologic complete response was defined as no residual invasive cancer in the breast, after 12 or 24 weeks of lapatinib/trastuzumab with or without endocrine therapy. This outcome is based on patient's pathological report. We are not measuring the clinical response. Participants who have received at least one cycle of therapy (defined as one dose of trastuzumab and 21 days of lapatinib), and have had their response classified were evaluable.

• Original Primary Outcome Measures (submitted: October 21, 2009): The primary endpoint of the study is clinical efficacy, as determined by clinical tumor measurements and pathologic response. [ Time Frame: 5 years ]

Current Secondary Outcome Measures (submitted: October 19, 2016)

• Number of Participants With Adverse Events [ Time Frame: 12 week or 24 weeks depending on arm assignment ]
  the safety and tolerability of an extended regimen of lapatinib + trastuzumab, with or without endocrine therapy
• Total Pathologic Complete Response [ Time Frame: 12 weeks or 24 weeks depending on arm assignment ]
  pathologic complete response was defined as no residual invasive cancer in the breast and the axillary lymph nodes.
• Clinical Response [ Time Frame: 12 weeks or 24 weeks depending on arm assignment ]

• Original Secondary Outcome Measures (submitted: October 21, 2009): Safety analyses will include summaries of adverse event rates (both frequency and incidence tables), baseline laboratory parameters and changes from baseline, frequency of CTC toxicity grades for both laboratory and non-laboratory data. [ Time Frame: 8 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy
• 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

Brief Summary

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.

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Lapatinib
  1000 mg of Lapatinib by mouth daily
  Other Name: TyKerb
• Drug: Letrozole
  Letrozole, 2.5 mg by mouth daily (for hormone receptor positive participants only)
  Other Name: Femara
• Drug: Trastuzumab
  6 mg/kg intravenously, every 3 weeks
  Other Name: Herceptin

Study Arms

• Experimental: 24-week arm
  Participants will receive 24-weeks of lapatinib plus trastuzumab. Participants who are estrogen receptor (ER) and/or progesterone receptor (PR) positive will also receive endocrine therapy.
  Interventions:

  • Drug: Lapatinib
  • Drug: Letrozole
  • Drug: Trastuzumab
• Active Comparator: 12-week arm
  Participants will receive 12-weeks of lapatinib plus trastuzumab. Participants who are estrogen receptor (ER) and/or progesterone receptor (PR) positive will also receive endocrine therapy.
  Interventions:

  • Drug: Lapatinib
  • Drug: Letrozole
  • Drug: Trastuzumab

• Publications *: Rimawi MF, Niravath P, Wang T, Rexer BN, Forero A, Wolff AC, Nanda R, Storniolo AM, Krop I, Goetz MP, Nangia JR, Jiralerspong S, Pavlick A, Veeraraghavan J, De Angelis C, Gutierrez C, Schiff R, Hilsenbeck SG, Osborne CK; Translational Breast Cancer Research Consortium. TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 versus 24 Weeks in Patients with HER2-Positive Breast Cancer. Clin Cancer Res. 2020 Feb 15;26(4):821-827. doi: 10.1158/1078-0432.CCR-19-0851. Epub 2019 Oct 29.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 19, 2016): 128
• Original Estimated Enrollment (submitted: October 21, 2009): 55
• Estimated Study Completion Date: January 2024
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00999804
• Other Study ID Numbers: H-25846
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Mothaffar Rimawi, Baylor Breast Care Center
• Original Responsible Party: Jenny C. N. Chang, MD, Baylor College of Medicine
• Current Study Sponsor: Baylor Breast Care Center
• Original Study Sponsor: Same as current

Collaborators

• Translational Breast Cancer Research Consortium
• GlaxoSmithKline

Investigators

• Principal Investigator: Mothaffar Rimawi, MD; Baylor College of Medicine

• PRS Account: Baylor Breast Care Center
• Verification Date: June 2023