Letrozole In Combination With Lapatinib In Neoadjuvant Treatment Of Early Breast Cancer

Study Overview
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Brief Summary
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Evaluate the percentage of clinical objective responses (cOR) in patients with HER2 negative early breast cancer treated with pre operative (neoadjuvant)lapatinib and letrozole

Official Title
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Letrozole Versus Letrozole Plus Lapatinib (GW572016) in Hormone-sensitive, HER-2 Negative Operable Breast Cancer. A Double Blind Randomized Phase II Study With Biomarker Evaluation.

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: lapatinib
* Drug: letrozole
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically confirmed infiltrating primary breast cancer of 2.0 cm or more in largest clinical diameter ER and/or PgR positive cancer (> 10% of positive cancer cell assessed by IHC) Postmenopausal status, defined by at least one of the following: ≥ 60 years of age < 60 years of age and amenorrheic for ≥ 12 months prior to day 1 < 60 years of age and amenorrheic for < 12 months prior to day, or without a uterus: luteinizing hormone (LH) and follicle stimulating hormone (FSH) values within postmenopausal range Prior bilateral oophorectomy Prior radiation castration with amenorrhea for at least 6 months HER2 negative tumors (IHC 0-2+, or FISH negative) Availability of tumor tissue suitable for biological and molecular examination before starting primary treatment Age over 18 years ECOG PS 0-1 Normal organ and marrow function as defined below: leukocytes > 3000/mL absolute neutrophil count > 1,500/mL platelets > 100,000/mL total bilirubin within normal institutional limits AST (SGOT)/ALT(SGPT)< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram or MUGA scan. Eligibility of patients receiving medications or substances known to affect, or with the potential to affect the activity or pharmacokinetics of lapatinib will be determined following review of their use by the Principal Investigator. A list of medications and substances known or with the potential to interact with CYP450 isoenzymes is provided Ability to understand and the willingness to sign a written informed consent document. Ability to swallow and retain oral medication. Exclusion criteria: Stage IIIB, IIIC, and inflammatory breast cancer Stage IV breast cancer Contraindication to the treatment with letrozole Prior treatment with chemotherapy, endocrine therapy or radiotherapy. Prior treatment with EGFR targeting therapies Treatment with any other investigational agents, or with all herbal (alternative) medicines History of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements HIV-positive patients receiving combination anti-retroviral therapy GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis) Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors (See section 3.7.4.2 Other concomitant treatments)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Letrozole plus placebo<br>Letrozole 2.5 mg administered orally fro 6 mos. plus placebo 1500 mg administered orally throughout the study until definitive surgery | Drug: letrozole<br>* 2.5 mg administered orally daily<br>Other: placebo<br>* 1500 mg administered orally daily<br>|
| Experimental: Letrozole plus lapatininb<br>Letrozole 2.5 mg administered orally fro 6 mos. plus lapatinib 1500 mg administered orally throughout the study until definitive surgery | Drug: lapatinib<br>* 1500 mg administered orally daily<br>Drug: letrozole<br>* 2.5 mg administered orally daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Objective Response (cOR) in the Breast, Evaluated by an Independent Radiological Evaluation Monitoring Committee | cOR is defined as the documented evidence of complete response (CR) and partial response (PR) as assessed by ultrasound examination using Response Evaluation Criteria In Solid Tumors (RECIST). CR is defined as the disappearance of all target lesions (TLs) and non-TLs and the appearance of no new lesions (NLs). PR for TLs is defined as a >=30% decrease in the sum of the longest diameter (LD) of TLs, taking as a reference the Baseline sum LD. For non-TLs, it is defined as the persistence of >=1 non-TL and no new TLs or non-TLs. | From Baseline (Day 1) up to 6 months, evaluated every 12 weeks | 
| Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria | Complete clinical response=nodule not detectable; all ultrasound abnormalities detected at diagnosis have disappeared. Partial clinical response=the tumor's longest diameter (LD) is reduced by 50% or more; ultrasound characteristics of the tumor persist. Minimal response=the tumor's LD is reduced by 25%-49%. Stable disease=the tumor's LD is decreased by less than 25% and is increased by no more than 25% from the starting value. Progressive disease=the tumor's LD is increased by more than 25% from the starting value. Participants who were not evaluable did not have data available. | From Baseline (Day 1) up to 6 months, evaluated every 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathological Complete Response (pCR) in the Breast and Axillary Nodes, Evaluated Using Miller and Payne Criteria | pCR is defined as the complete absence of infiltrating tumor cells (TCs) in the breast and lymph nodes. Miller and Payne criteria: Grade 1, no change/some alteration to individual malignant cells, but no reduction in overall cellularity; Grade 2, up to a 30% loss in TCs; Grade 3, between an estimated 30% and 90% reduction in TCs; Grade 4, more than a 90% reduction in TCs, only small cluster/dispersed cells remaining; Grade 5, no malignant identifiable cells; carcinoma in the milk ducts may be present. Grades 1 and 2 = No response; Grades 3 and 4= PR; Grade 5 = CR. | At the point of definitive surgery (up to 6 months after Baseline) | 
| Number of Participants With Breast Tumors Per Pathological Stage at Surgery | Tumors were categorized as follows: T0, no evidence of primary tumor, but carcinoma of the milk ducts, accumulation of abnormal cells in the breast lobules, or Paget disease (cancer condition that appears like a skin disease involving the breast nipple) with no associated tumor mass; T1, tumor was <=2 centimeters (cm) across; T2, tumor was >2 cm but <5 cm across; T3, tumor was >5 cm across; T4, tumor of any size growing into the chest wall or skin, including inflammatory breast cancer. | At the point of definitive surgery (up to 6 months after Baseline) | 
| Number of Participants With the Indicated Nodal Status at Surgery | The nodal status of cancer indicates the involvement of lymph nodes in the participant with cancer. N0 indicates no involvement of lymph nodes, and N+ indicates involvement of lymph nodes. | At the point of definitive surgery (up to 6 months after Baseline) | 
| Number of Participants With the Indicated Type of Surgery | Mastectomy is the medical term for the surgical removal of one or both breasts. Breast-conserving surgery (BCS) involves removing only the affected part of the breast tissue during surgery, as opposed to removal of the entire breast. | At the point of definitive surgery (up to 6 months after Baseline 1) | 
| Percentage of Participants With Conversion From Planned Mastectomy at Baseline to BCS at Surgery | The percentage of participants who were planned to undergo a mastectomy at baseline but later underwent BCS was measured. | At the point of definitive surgery (up to 6 months after Baseline) | 
| Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 | Toxicity was measured in grades (severity of the AE) as per National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI CTCAE) version (v) 3.0. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening/disabling; Grade 5, death related to the AE. Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, and hypertension is high blood pressure. | From Baseline (Day 1) up to 6 months (until definitive surgery) | 
| Mean Left Ventricular Ejection Fraction (LVEF) | Cardiac safety was evaluated as any signs or symptoms of deterioration in LVEF. LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. LVEF was evaluated using NCI CTCAE. | Baseline (Day 1), after 12 weeks, and after 24 weeks | 
| Time to Treatment Failure From the Start of the Primary Therapy | Time to treatment failure is calculated as the interval between the date of randomization and the occurrence of local tumor progression (including ipsilateral [on the same side] and controlateral breast tumor progression), distant tumor progression, permanent treatment discontinuation (either for the experimental or conventional treatment arm), or death for any cause. | From Baseline (Day 1) up to study withdrawal (approx. 66 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neo-adjuvant, letrozole, lapatinib, primary breast cancer