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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00422903
First received: January 16, 2007
Last updated: July 26, 2012
Last verified: July 2012
  Purpose

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


Condition Intervention Phase
Neoplasms, Breast
Drug: lapatinib
Drug: letrozole
Other: placebo
Phase 2

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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Percentage of Participants With Clinical Objective Response (cOR) in the Breast, Evaluated by an Independent Radiological Evaluation Monitoring Committee [ Time Frame: From Baseline (Day 1) up to 6 months, evaluated every 12 weeks ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria [ Time Frame: From Baseline (Day 1) up to 6 months, evaluated every 12 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants With Pathological Complete Response (pCR) in the Breast and Axillary Nodes, Evaluated Using Miller and Payne Criteria [ Time Frame: At the point of definitive surgery (up to 6 months after Baseline) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Breast Tumors Per Pathological Stage at Surgery [ Time Frame: At the point of definitive surgery (up to 6 months after Baseline) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With the Indicated Nodal Status at Surgery [ Time Frame: At the point of definitive surgery (up to 6 months after Baseline) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With the Indicated Type of Surgery [ Time Frame: At the point of definitive surgery (up to 6 months after Baseline 1) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Conversion From Planned Mastectomy at Baseline to BCS at Surgery [ Time Frame: At the point of definitive surgery (up to 6 months after Baseline) ] [ Designated as safety issue: No ]
    The percentage of participants who were planned to undergo a mastectomy at baseline but later underwent BCS was measured.

  • Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 [ Time Frame: From Baseline (Day 1) up to 6 months (until definitive surgery) ] [ Designated as safety issue: No ]
    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.

  • Mean Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Baseline (Day 1), after 12 weeks, and after 24 weeks ] [ Designated as safety issue: No ]
    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.

  • Time to Treatment Failure From the Start of the Primary Therapy [ Time Frame: From Baseline (Day 1) up to 6 months (until definitive surgery) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With the Indicated Percentage of Inhibition of Intermediate and Final Biomarkers of the Proliferative and Apoptosis Pathways of Tumor Gene Expression [ Time Frame: At Screening (Day -28) and at surgery; up to 6 months ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With a Correlation Between Tumor Gene Expression at Diagnosis and Pathological Response [ Time Frame: At Screening (Day -28) and at surgery; up to 6 months ] [ Designated as safety issue: No ]

Enrollment: 92
Study Start Date: April 2007
Study Completion Date: April 2011
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Letrozole plus placebo
Letrozole 2.5 mg administered orally fro 6 mos. plus placebo 1500 mg administered orally throughout the study until definitive surgery
Drug: letrozole
2.5 mg administered orally daily
Other: placebo
1500 mg administered orally daily
Experimental: Letrozole plus lapatininb
Letrozole 2.5 mg administered orally fro 6 mos. plus lapatinib 1500 mg administered orally throughout the study until definitive surgery
Drug: lapatinib
1500 mg administered orally daily
Other Name: lapatinib
Drug: letrozole
2.5 mg administered orally daily

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00422903

Locations
Italy
GSK Investigational Site
Carpi (MO), Emilia-Romagna, Italy, 41012
GSK Investigational Site
Forlì, Emilia-Romagna, Italy, 47100
GSK Investigational Site
Modena, Emilia-Romagna, Italy, 41100
GSK Investigational Site
Piacenza, Emilia-Romagna, Italy, 29100
GSK Investigational Site
Rimini, Emilia-Romagna, Italy, 47900
GSK Investigational Site
Treviglio (BG), Lombardia, Italy, 24047
GSK Investigational Site
Brindisi, Puglia, Italy, 72100
GSK Investigational Site
Pisa, Toscana, Italy, 56126
GSK Investigational Site
Chieti, Italy, 66100
GSK Investigational Site
Cremona, Italy, 26100
GSK Investigational Site
Perugia, Italy, 06156
GSK Investigational Site
Reggio Emilia, Italy, 42100
GSK Investigational Site
Varese, Italy, 21100
Spain
GSK Investigational Site
Badalona, Spain, 08916
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00422903     History of Changes
Other Study ID Numbers: EGF107692
Study First Received: January 16, 2007
Results First Received: April 6, 2012
Last Updated: July 26, 2012
Health Authority: Italy: Ministry of Health
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
neo-adjuvant
letrozole
lapatinib
primary breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Lapatinib
Letrozole
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Aromatase Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014