Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy

NCT00999804 | Active Not Recruiting Phase 2 Results DMC

• 1 other identifier: H-25846
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 8

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.

Conditions

Breast Cancer

Keywords

Locally Advanced Breast Cancer Neoadjuvant Endocrine

Outcome Measures

Primary Outcomes (1)

• Pathologic Complete Response

  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.

  12 or 24 week depending the arm assignment

Secondary Outcomes (3)

• Number of Participants With Adverse Events

  12 week or 24 weeks depending on arm assignment

• Total Pathologic Complete Response

  12 weeks or 24 weeks depending on arm assignment

• Clinical Response

  12 weeks or 24 weeks depending on arm assignment

Study Arms (2)

24-week arm

EXPERIMENTAL

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.

Drug: Lapatinib; Drug: Letrozole; Drug: Trastuzumab

12-week arm

ACTIVE COMPARATOR

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.

Drug: Lapatinib; Drug: Letrozole; Drug: Trastuzumab

Interventions

Lapatinib DRUG

1000 mg of Lapatinib by mouth daily

Also known as: TyKerb

12-week arm; 24-week arm

Letrozole DRUG

Letrozole, 2.5 mg by mouth daily (for hormone receptor positive participants only)

Also known as: Femara

12-week arm; 24-week arm

Trastuzumab DRUG

6 mg/kg intravenously, every 3 weeks

Also known as: Herceptin

12-week arm; 24-week arm

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients must be female and at least 18 years of age.
• Signed informed consent.
• 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.)
• 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.
• Negative serum pregnancy test (HCG) within 7 days of starting study drug, if of child-bearing potential.
• Kidney and liver function tests - all within 1.5 times the institutional upper limit of normal.
• Performance status (WHO/ECOG scale) 0-1 and life expectancy \>6 months.
• No evidence of brain or leptomeningeal disease, or any other Stage IV disease.
• 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.

You may not qualify if:

• Patients with bilateral breast cancer.
• Pregnancy or unwillingness to use a reliable contraceptive method in women of child-bearing potential.
• Severe underlying chronic illness or disease.
• Cardiomyopathy or baseline LVEF less than 50%.
• Other investigational drugs while on study.
• Severe or uncontrolled hypertension, history of congestive heart failure or severe coronary arterial disease.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded
• Taking any lapatinib prohibited medication(s)
• Inability or unwillingness to comply with, or follow study procedures.
• 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.
• Patients with a prior history of ipsilateral invasive breast cancer or carcinoma in situ who present with a new primary.
• Patients with known active, infectious Hepatitis B, Hepatitis C, or HIV.

Sponsors & Collaborators

• Baylor Breast Care Center: lead
• Translational Breast Cancer Research Consortium: collaborator
• GlaxoSmithKline: collaborator

Study Sites (8)

University of Alabama - Birmingham

Birmingham, Alabama, 35294, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02130, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

Location

Baylor College of Medicine Lester and Sue Smith Breast Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• 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.

  PMID: 31662331 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Lapatinib; Letrozole; Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Mothaffar Rimawi
• Organization: Baylor College of Medicine

rimawi@bcm.edu

7137981311

Study Officials

• Mothaffar Rimawi, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 21, 2009
• First Posted: October 22, 2009
• Study Start: October 1, 2011
• Primary Completion: November 1, 2014
• Study Completion: January 1, 2026
• Last Updated: March 12, 2025
• Results First Posted: December 12, 2016

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (8)