Clinical trial NCT00548184: Lapatinib and Trastuzumab With or Without Endocrine Therapy
Official title: A Phase II Trial of Lapatinib and Trastuzumab With or Without Endocrine Therapy in Locally Advanced HER2 Overexpressing Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: primary breast cancers
Locally advanced breast cancers
Lead sponsor: Baylor Breast Care Center
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2007-10-23
Enrollment: 65
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: We think that lapatinib will help to shrink your tumor when given prior to the main or primary therapy for the kind of breast cancer you have been diagnosed with. When treatment is given before the main or primary therapy, it is called neoadjuvant therapy. We will compare lapatinib with lapatinib plus trastuzumab (herceptin) for 12 weeks. If your tumor is estrogen receptor positive (ER positive), estrogen deprivation will also be given to you. Tumors that are ER positive have a lot of estrogen receptors found in them. This is also called "over expression" or amplification of estrogen receptors.

The most important information we will get from this study is to see the response to "neoadjuvant" (treatment given before the main treatment), lapatinib with trastuzumab (herceptin) in your tumor tissue sample.

Detailed description: The neoadjuvant setting is especially attractive for studies of predictive biologic correlates for several reasons including early assessment of response to therapy, access to the primary tumor, and reduced patient numbers compared to those required in the adjuvant setting. Response to neoadjuvant therapy is a validated surrogate marker for improved survival; it may be used to test the overall efficacy of neoadjuvant treatment regimens and response in the primary tumor mirrors the effect of therapy on micrometastases.

Trastuzumab is an efficacious agent in HER2 overexpressing breast cancers. Our results with neoadjuvant trastuzumab indicate that its efficacy may be better in patients with treatment-naïve tumors compared to metastatic disease, with 26% of patients showing a partial response after only 3 weeks of therapy. No patients progressed during this 3-week period. We have also conducted a neoadjuvant lapatinib study given as a single agent for 6 weeks. The response rates in this second study have been impressive with greater than 80% responses in patients with HER2 positive locally advanced breast cancers. It is likely that the true response rate to HER2 blockade would be higher had therapy been continued for longer. We therefore hypothesize that lapatinib, a dual tyrosine kinase inhibitor, together with trastuzumab, will result in tumor regression when given as neoadjuvant therapy in HER2 overexpressing breast cancer. We will compare lapatinib plus trastuzumab for 12 weeks, and if the tumors express ER, estrogen deprivation will also be administered.

This is a phase II trial. Clinical efficacy will be assessed by bidimensional tumor measurements of the primary cancer at baseline, and at the end of week 12. Objective tumor response rate defined as objective bidimensional tumor measurements after neoadjuvant treatment at 12 weeks will be calculated, and assessed according to standard RECIST criteria. Pathologic responses will be graded as pathologic complete response if there is no invasive cancer in the residual breast at the time of surgery. Near pathologic complete response will also be documented as residual disease of less than 1 cm.

Eligibility criteria: Inclusion Criteria:

* All patients must be female.
* Signed informed consent.
* Locally advanced breast cancers or primary 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 radiologically measured tumor size to determine the minimal tumor size for eligibility and in assessing tumor size during follow-up).
* HER2 overexpressing tumors defined as HercepTest score of 3+, or \> 10% cells moderately or strongly HER2 positive by other methods, or Allred semi-quantitative score of \>5, or gene amplified.
* Negative serum pregnancy test (HCG) within 7 days of starting study, if of child-bearing potential.
* Kidney and liver function tests - all within 1.5 times the institution's upper limit of normal.
* Performance status (WHO scale) less than 2 and life expectancy more than 6 months.
* Age at least 18 years.
* No brain or leptomeningeal 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.

Note: The presence of pathological involvement of axillary nodes will be assessed and agreed upon by two investigators.

Exclusion Criteria:

* 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 within 7 days of first dose of study medications. (See Prohibited Medications List in protocol.)

Primary outcomes:
measure: Pathologic Assessment After Study Treatment
timeFrame: 12 weeks
Secondary outcomes:
Other outcomes:
measure: Data Analysis of the Biomarkers: Immunohistochemical Staining of Cells From Breast Biopsies and Skin Biopsies Will be Performed.
timeFrame: one year
Locations:
city: Birmingham
country: United States
facility: UAB Cancer Center
state: Alabama
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bunting-Blaustein Cancer Research
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine, Lester and Sue Smith Breast Center
state: Texas
Study officials:
affiliation: Baylor Breast Center
name: Mothaffar Rimawi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Veeraraghavan J, De Angelis C, Mao R, Wang T, Herrera S, Pavlick AC, Contreras A, Nuciforo P, Mayer IA, Forero A, Nanda R, Goetz MP, Chang JC, Wolff AC, Krop IE, Fuqua SAW, Prat A, Hilsenbeck SG, Weigelt B, Reis-Filho JS, Gutierrez C, Osborne CK, Rimawi MF, Schiff R. A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Ann Oncol. 2019 Jun 1;30(6):927-933. doi: 10.1093/annonc/mdz076.
citation: Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, Schiff R, Osborne CK, Chang JC. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013 May 10;31(14):1726-31. doi: 10.1200/JCO.2012.44.8027. Epub 2013 Apr 8.