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

Neoplasms, Breast Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00422903
• Other study ID #: EGF107692
• Status: Completed
• Phase: Phase 2
• First received: January 16, 2007
• Last updated: June 4, 2015
• Start date: April 2007
• Est. completion date: April 2011

Study information

• Verified date: July 2012
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of HealthUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: April 2011
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 80 Years

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms, Breast

Intervention

Drug:
• lapatinib
1500 mg administered orally daily
• letrozole
2.5 mg administered orally daily

Other:
• placebo
1500 mg administered orally daily

Locations

Country	Name	City	State
Italy	GSK Investigational Site	Brindisi	Puglia
Italy	GSK Investigational Site	Carpi (MO)	Emilia-Romagna
Italy	GSK Investigational Site	Chieti
Italy	GSK Investigational Site	Cremona
Italy	GSK Investigational Site	Forlì	Emilia-Romagna
Italy	GSK Investigational Site	Modena	Emilia-Romagna
Italy	GSK Investigational Site	Perugia
Italy	GSK Investigational Site	Piacenza	Emilia-Romagna
Italy	GSK Investigational Site	Pisa	Toscana
Italy	GSK Investigational Site	Reggio Emilia
Italy	GSK Investigational Site	Rimini	Emilia-Romagna
Italy	GSK Investigational Site	Treviglio (BG)	Lombardia
Italy	GSK Investigational Site	Varese
Spain	GSK Investigational Site	Badalona

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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 6 months (until definitive surgery)	No
Secondary	Number of Participants With the Indicated Percentage of Inhibition of Intermediate and Final Biomarkers of the Proliferative and Apoptosis Pathways of Tumor Gene Expression	The percentage of inhibition of biomarkers of proliferation/apoptosis was calculated as the difference between the staining scores before and after treatment. Biomarkers (EGFR, HER2, pTEN, pAKT, pMAPK, apoptosis with TUNEL Test, and Ki67) were evaluated to define the inhibition of the down-stream pathways of members of the EGFr family. Changes in immunohistochemical Ki67 expression were used as a marker of effect on proliferation.	At Screening (Day -28) and at surgery; up to 6 months	No
Secondary	Number of Participants With a Correlation Between Tumor Gene Expression at Diagnosis and Pathological Response		At Screening (Day -28) and at surgery; up to 6 months	No