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

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ClinicalTrials.gov Identifier: NCT00422903
Recruitment Status : Completed
First Posted : January 17, 2007
Results First Posted : August 29, 2012
Last Update Posted : May 12, 2016
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Neoplasms, Breast
Interventions Drug: lapatinib
Drug: letrozole
Other: placebo
Enrollment 92

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery. Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Period Title: Overall Study
Started 49 43
Completed 45 38
Not Completed 4 5
Reason Not Completed
Disease Progression             3             1
Adverse Event             0             2
Informed Consent Withdrawn             1             2
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib Total
Hide Arm/Group Description Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery. Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery Total of all reporting groups
Overall Number of Baseline Participants 49 43 92
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 49 participants 43 participants 92 participants
70
(47 to 88)
70
(49 to 88)
70
(47 to 88)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 49 participants 43 participants 92 participants
Female
49
 100.0%
43
 100.0%
92
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Percentage of Participants With Clinical Objective Response (cOR) in the Breast, Evaluated by an Independent Radiological Evaluation Monitoring Committee
Hide Description 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.
Time Frame From Baseline (Day 1) up to 6 months, evaluated every 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population: all participants who entered the study and received at least one dose of letrozole. Three participants withdrew consent and were not included in the efficacy analysis.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 48 41
Measure Type: Number
Unit of Measure: percentage of participants
CR 2 12
PR 58 54
2.Primary Outcome
Title Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria
Hide Description 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.
Time Frame From Baseline (Day 1) up to 6 months, evaluated every 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Three participants withdrew consent and were not included in the efficacy analysis.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 48 41
Measure Type: Number
Unit of Measure: percentage of participants
Complete Response 2 12
Partial Response 27 34
Minimal Response 40 24
Stable Disease 33 20
Progressive Disease 6 2
Not Evaluable 2 7
3.Secondary Outcome
Title Percentage of Participants With Pathological Complete Response (pCR) in the Breast and Axillary Nodes, Evaluated Using Miller and Payne Criteria
Hide Description 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.
Time Frame At the point of definitive surgery (up to 6 months after Baseline)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 49 43
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
0
(0.0 to 7.3)
0
(0.0 to 8.2)
4.Secondary Outcome
Title Number of Participants With Breast Tumors Per Pathological Stage at Surgery
Hide Description 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.
Time Frame At the point of definitive surgery (up to 6 months after Baseline)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants contributing data were analyzed.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 47 42
Measure Type: Number
Unit of Measure: participants
T0 1 0
T1 20 26
T2 24 12
T3 2 2
T4 0 2
5.Secondary Outcome
Title Number of Participants With the Indicated Nodal Status at Surgery
Hide Description 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.
Time Frame At the point of definitive surgery (up to 6 months after Baseline)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants contributing data were analyzed.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 47 42
Measure Type: Number
Unit of Measure: participants
N0 19 21
N+ 28 21
6.Secondary Outcome
Title Number of Participants With the Indicated Type of Surgery
Hide Description 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.
Time Frame At the point of definitive surgery (up to 6 months after Baseline 1)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants contributing data were analyzed.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 49 43
Measure Type: Number
Unit of Measure: participants
Mastectomy 13 15
BCS 34 27
Not done 2 1
7.Secondary Outcome
Title Percentage of Participants With Conversion From Planned Mastectomy at Baseline to BCS at Surgery
Hide Description The percentage of participants who were planned to undergo a mastectomy at baseline but later underwent BCS was measured.
Time Frame At the point of definitive surgery (up to 6 months after Baseline)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants contributing data were analyzed.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 49 43
Measure Type: Number
Unit of Measure: percentage of participants
56 46
8.Secondary Outcome
Title Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2
Hide Description 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.
Time Frame From Baseline (Day 1) up to 6 months (until definitive surgery)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants contributing data were analyzed.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 49 43
Measure Type: Number
Unit of Measure: participants
Musculoskeletal pain 4 2
Diarrhea 2 10
Mucositis 0 8
Liver toxicity 1 4
Skin disorders 1 18
Hypertension 1 2
9.Secondary Outcome
Title Mean Left Ventricular Ejection Fraction (LVEF)
Hide Description 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 Frame Baseline (Day 1), after 12 weeks, and after 24 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants contributing data were analyzed.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 49 43
Mean (Full Range)
Unit of Measure: Percent volume
Baseline
61
(50 to 78)
61
(54 to 76)
After 12 weeks
62
(50 to 76)
60
(52 to 75)
After 24 weeks
61
(50 to 84)
59
(50 to 75)
10.Secondary Outcome
Title Time to Treatment Failure From the Start of the Primary Therapy
Hide Description 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.
Time Frame From Baseline (Day 1) up to study withdrawal (approx. 66 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants contributing data were analyzed.
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description:
Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.
Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Number of Participants Analyzed 13 6
Median (95% Confidence Interval)
Unit of Measure: Months
32.2
(6.3 to 38.5)
22.2 [1] 
(NA to NA)
[1]
The confidence limits for the median value are not estimable because there are no time points that satisfy the condition using the method of Klein and Moeschberger (1997).
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Letrozole + Placebo Letrozole + Lapatinib
Hide Arm/Group Description Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery. Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
All-Cause Mortality
Letrozole + Placebo Letrozole + Lapatinib
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Letrozole + Placebo Letrozole + Lapatinib
Affected / at Risk (%) Affected / at Risk (%)
Total   1/49 (2.04%)   3/43 (6.98%) 
Cardiac disorders     
Myocardial infarction  1  1/49 (2.04%)  0/43 (0.00%) 
Cardiac failure  1  0/49 (0.00%)  1/43 (2.33%) 
Hepatobiliary disorders     
Sphincter of Oddi dysfunction  1  0/49 (0.00%)  1/43 (2.33%) 
Injury, poisoning and procedural complications     
Overdose  1  0/49 (0.00%)  1/43 (2.33%) 
Nervous system disorders     
Spinal cord compression  1  0/49 (0.00%)  1/43 (2.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Letrozole + Placebo Letrozole + Lapatinib
Affected / at Risk (%) Affected / at Risk (%)
Total   20/49 (40.82%)   36/43 (83.72%) 
Gastrointestinal disorders     
Diarrhea  1  5/49 (10.20%)  26/43 (60.47%) 
Dyspepsia  1  5/49 (10.20%)  5/43 (11.63%) 
Nausea  1  6/49 (12.24%)  0/43 (0.00%) 
General disorders     
Astenia/Fatigue  1  6/49 (12.24%)  7/43 (16.28%) 
Injury, poisoning and procedural complications     
Mucositis  1  0/49 (0.00%)  7/43 (16.28%) 
Investigations     
LFT transaminases  1  0/49 (0.00%)  8/43 (18.60%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal pain  1  9/49 (18.37%)  6/43 (13.95%) 
Skin and subcutaneous tissue disorders     
Dermatology/Skin  1  0/49 (0.00%)  25/43 (58.14%) 
Nail changes  1  0/49 (0.00%)  5/43 (11.63%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00422903     History of Changes
Other Study ID Numbers: EGF107692
First Submitted: January 16, 2007
First Posted: January 17, 2007
Results First Submitted: April 6, 2012
Results First Posted: August 29, 2012
Last Update Posted: May 12, 2016