Tykerb Evaluation After Chemotherapy (TEACH): Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer

Study Overview
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Brief Summary
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This study was designed to evaluate and compare the safety and efficacy of an oral dual tyrosine kinase inhibitor, lapatinib, versus placebo in women with early-stage ErbB2-overexpressing breast cancer who have completed their primary neoadjuvant or adjuvant chemotherapy and have no clinical or radiographic evidence of disease.

Official Title
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A Randomized, Double-blind, Multicenter, Placebo-controlled Study of Adjuvant Lapatinib (GW572016) in Women With Early-Stage ErbB2 Overexpressing Breast Cancer

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: lapatinib
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically or cytologically confirmed ErbB2-overexpressing invasive carcinoma (TX or T1-4) of the breast at the time of the initial diagnosis and have undergone adequate excision of tumor; Had tumors that overexpress ErbB2 defined as 3+ by IHC or c-erbB2 gene amplification by FISH (ErbB2 expression/amplification must be documented prior to study entry; however, a tumor tissue sample must be sent to a central laboratory for subsequent re-analysis of ErbB2 status); Have Stage I through Stage IIIc disease according to the American Joint Committee on Cancer (6th edition) staging criteria for breast cancer and meet one of the following criteria: node-positive disease defined as: one positive lymph node by sentinel node biopsy OR at least 1 positive lymph node found among at least 6 axillary nodes examined on axillary node dissection OR status post axillary radiotherapy for sterilization if clinically evaluated as cN1 or cN2 (if sentinel node biopsy is positive, subject may either undergo an axillary node dissection or radiotherapy to the axilla). node-positive disease evaluated as: ipsilateral axillary lymph nodes cN0-2 by clinical evaluation and axillary lymph nodes pNX, pN0(i+), or pN1-3 by pathological evaluation [patients with pN3 (Stage IIIc disease) must be disease free following completion of neoadjuvant or adjuvant chemotherapy for at least 12 months and must not have been lost to follow up]. OR node-negative disease defined as: negative sentinel node biopsy OR no positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection OR status post axillary radiotherapy for sterilization if clinically evaluated as cN0. node-negative disease categorized as: high-risk disease (tumor >2.0 cm if ER and/or progesterone receptor (PgR) positive disease is present or tumor >1.0 cm if ER and PgR negative disease) OR intermediate-risk disease (tumor 1.0-2.0 cm and ER and/or PgR positive disease). Women with synchronous bilateral invasive breast cancer or synchronous DCIS of either the contralateral or ipsilateral breast at the time of the initial diagnosis are also eligible; Have undergone either mastectomy OR lumpectomy; Have received and completed treatment with a neoadjuvant or adjuvant chemotherapy regimen containing either an anthracycline or a taxane; or any cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen; May continue to receive endocrine therapy while taking study medication, if endocrine therapy was initiated as either adjuvant therapy for treatment of the initial diagnosis of invasive breast cancer or for ovarian function suppression; however, endocrine therapy may not be initiated while taking study medication. Endocrine therapy agents may be switched while participating in this study (e.g., stop tamoxifen and start letrozole); May have received prior radiotherapy as treatment for primary tumor; however, is not required for study entry; May continue to receive radiotherapy while taking study medication, if radiotherapy was initiated as adjuvant therapy for treatment of the initial diagnosis of invasive breast cancer; May continue to receive bisphosphonates only for treatment of documented osteoporosis, but not as treatment or prophylaxis of bone metastases; All women eligible for adjuvant treatment with trastuzumab, including those diagnosed and treated within the last six months, must be considered for such treatment prior to being offered participation in this study. Participation in this study will be allowed only if the physician and patient have considered and discussed at length the advantages of trastuzumab, but have mutually decided against initiating trastuzumab therapy. Have clinical and radiologic assessments that are negative for local or regional recurrence of disease or metastatic disease at the time of study entry; if signs or symptoms suggestive of either recurrence of disease or metastatic disease are present, the appropriate radiological imaging must be performed if the following laboratory results are present, the appropriate radiological imaging must be performed: for AST/ALT ≥2×ULN or ALP ≥2×ULN (not in the bone fraction), an abdominal CT or MRI must be done for ALP≥2×ULN in the bone fraction, a bone scan must be done; a confirmatory x-ray, CT scan or MRI scan or biopsy is required if the results of the bone scan are inconclusive Have a unilateral/bilateral mammogram within 12 months prior to study entry; Have an analysis of both ER and PgR on the primary tumor prior to study entry; Have a cardiac ejection fraction within institutional range of normal as measured by either echocardiogram or multigated acquisition scans; Have an Eastern Cooperative Oncology Group Performance Status of 0 to 1; Women with a history of non-breast malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence. Women with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical carcinoma in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin; Are able to swallow and retain oral medication; Have a paraffin-embedded tissue block from an archived tumor tissue from the primary tumor or twenty (20) slides of paraffin-embedded tissue available for biomarker analysis; Have adequate organ function defined as: absolute neutrophil count ≥1.5× 10^9/L; hemoglobin ≥9 g/dL; platelets ≥75 × 10^9/L; albumin ≥2.5 g/dL; serum bilirubin ≤1.25 ×ULN; aspartate aminotransferase and alanine aminotransferase ≤3 × ULN and serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥40 mL/min Have signed the informed consent form (ICF); Women of child-bearing potential must have a negative serum pregnancy test at screening and agree to complete abstinence from intercourse or consistent and correct use of an acceptable methods of birth control from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication: Exclusion Criteria: Have clinical and radiologic evidence of local or regional recurrence of disease or metastatic disease at the time of study entry; Had metachronous invasive breast cancer (breast cancers diagnosed at different times); Have a prior history of other breast cancer malignancies, including DCIS; Are unable to provide archived tumor tissue samples for assay; Had prior therapy with an ErbB1 and/or ErbB2 inhibitor; women who experienced a hypersensitivity or allergic reaction to trastuzumab during the first infusion and were unable to complete this infusion are eligible; Receive concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication; Have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment; Have malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Women with ulcerative colitis are also excluded; Have a concurrent disease or condition that would make the woman inappropriate for study participation, or any serious medical disorder that would interfere with the woman's safety; Have an active or uncontrolled infection; Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent; Have a known history of uncontrolled or symptomatic angina, arrhythmias, or CHF; Are pregnant or breastfeeding; Receive concurrent treatment with an investigational agent; women, who are in follow-up in another clinical trial where the primary endpoint has been met and the interval between assessments is ≥12 months and radiological imaging is not required at these assessments, are eligible; Receive concurrent treatment with a selected list of strong inducers and inhibitors of CYP3A4; Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication; Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lapatinib or excipients;

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>6 tablets daily for 12 months | Other: placebo<br>* 6 tablets daily for 12 months<br>|
| Experimental: Lapatinib<br>Lapatinib 1500 mg (6 tablets) daily for 12 months | Drug: lapatinib<br>* Lapatinib 1500 mg (6 tablets) daily for 12 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) With Any Recurrence of the Initial Disease, Second Primary Cancer, Contralateral Breast Cancer, or Death (Disease-free Survival [DFS]) | DFS=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause. The date of the event is the earliest date of the occurrence of any of the following: local recurrence (LR) following mastectomy; LR in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including ductal carcinoma in situ; other second primary cancer (excluding squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast); death from any cause without a prior event. Par. who started additional anti-cancer adjuvant therapy prior to the recurrence of their disease were to be censored. Par. who did not withdraw from the study and did not experience a specified event or death were to be censored (follow-up ongoing) at the last visit date available at which progression was assessed. | From randomization until date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause (assessed up to 6 years; 1 year of treatment, 5 years of follow-up [median of 5.3 years for final analysis]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died (Overall Survival) | Overall Survival (OS) is defined as the time from randomization until death from any cause. Data are presented as the number of participants who died. For participants who did not die, time to death was censored at the last date the participant was known to be alive. | From the date of randomization until death from any cause (assessed up to 6 years; 1 year of treatment and 5 years of follow-up [median of 5.3 years for final analysis]) | 
| Percentage of Participants With the Indicated Period of Recurrence-free Survival (Time to First Recurrence) | Recurrence is defined as experiencing a recurrence of initial disease or contralateral breast cancer after randomization. Time to first recurrence is defined as the interval between the date of randomization and the date of the first occurrence of an objective disease recurrence or contralateral breast cancer. Time to first recurrence included the first occurrence at one of the following sites as an event: local recurrence following mastectomy; local recurrence in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including ductal carcinoma in situ (DCIS). | From the date of randomization until the date of the first occurrence of an objective disease recurrence or contralateral breast cancer (assessed up to 6 years; 1 year of treatment and 5.3 years of follow-up [median of 5 years for final analysis]) | 
| Percentage of Participants With the Indicated Period of Distant Recurrence-free Survival (Time to Distant Recurrence) | Distant recurrence (metastatic disease) is defined as a tumor in any area of the body not including those defined as local or regional recurrence. Sites of distant recurrence include: skin, subcutaneous tissue, and lymph nodes (excluding those described for local and regional recurrence); bone marrow; skeletal; lungs and pleural; ascites and pleural effusions; liver and other viscera; and central nervous system (CNS). Time to distant recurrence is defined as the interval between the date of randomization and the date of the first occurrence of a distant recurrence. | From the date of randomization until the date of the first occurrence of a distant recurrence (assessed up to 6 years; 1 year of treatment and 5 years of follow-up [median of 5.3 years for final analysis]) | 
| Time to Central Nervous System (CNS) Recurrence | Time to CNS recurrence is defined as the interval between the date of randomization and the date of the occurrence of a CNS recurrence if noted as part of the participant's first recurrence. Time to CNS recurrence was not calculated; data are presented as the number of participants with CNS recurrence in the subsequent outcome measure table. | From the date of randomization until the date of the first occurrence of a CNS recurrence (assessed up to 6 years [1 year of treatment and 5 years of follow-up; median of 5.3 years for final analysis]) | 
| Number of Participants With CNS Recurrence | The number of participants experiencing a CNS recurrence was summarized. | From the date of randomization until the date of the first occurrence of a CNS recurrence (assessed up to 6 years [1 year of treatment and 5 years of follow-up; median of 5.3 years for final analysis]) | 
| Modified Disease-free Survival (MDFS) | Modified disease recurrence=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause. The date of the event=the earliest date of the occurrence of any of the following events: local recurrence following mastectomy; local recurrence in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including DCIS; death from any cause without a prior event. MDFS was not calculated; data are presented as the number of participants with any recurrence of the initial disease, contralateral breast cancer, or death (disease-free survival) in the subsequent outcome measure table. | From the date of randomization until the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause (assessed up to 6 years) | 
| Number of Participants With Any Recurrence of the Initial Disease, Contralateral Breast Cancer, or Death (Disease-free Survival [DFS]) | DFS=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause. The date of the event is the earliest date of the occurrence of any of the following: local recurrence (LR) following mastectomy; LR in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence and contralateral breast cancer, including ductal carcinoma in situ; or death from any cause without a prior event. Participants who started additional anti-cancer adjuvant therapy prior to the recurrence of their disease were to be censored. Participants who did not withdraw from the study and did not experience a specified event or death were to be censored (follow-up ongoing) at the last visit date available at which progression was assessed. | From the date of randomization until the date of the first occurrence of an objective disease recurrence, contralateral breast cancer, or death from any cause (assessed up to 6 years) | 
| Change From Baseline in Short Form-36 Version 2 (SF-36 v2) Scores for the Physical Component Summary (PCS) | The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health. Each domain is scored from 0 (poorer health) to 100 (better health).The PCS score is a summary score representing overall physical health, which is derived from the 8 domain scores. As with each domain score, the PCS score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the last observation carried forward (LOCF) method. The scores were analyzed using an analysis of covariance (ANCOVA) model, adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement. | Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years) | 
| Change From Baseline in SF-36 v2 Scores for the Mental Component Summary (MCS) | The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health. Each domain is scored from 0 (poorer health) to 100 (better health).The MCS score is a summary score representing overall mental health, which is derived from the 8 domain scores. As with each domain score, the MCS score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the LOCF method. The scores were analyzed using an ANCOVA model adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement. | Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years) | 
| Change From Baseline in the SF-36 v2 Domain Scores for Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (MH) | The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH) perceptions, vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH). Each domain is scored from 0 (poorer health) to 100 (better health); higher scores represent better health. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Missing post-Baseline data were imputed using the LOCF method. The scores were analyzed using an ANCOVA model, adjusting for Baseline sub-scale score, treatment, and country. Positive changes from Baseline indicate improvement. | Baseline, Month 6, Month 12, and every 6 months after discontinuation of study treatment for 24 months (up to a maximum of 3 study years) | 
| Number of Participants With Hematology Values Outside the Reference Range for the Indicated Parameters | The hematology parameters assessed were: basophils (Bs) in giga (10^9) per liter (GI/L) and in percentage (%), eosinophils (Eo) in GI/L and %, hematocrit, hemoglobin, lymphocytes (Lmph) in GI/L and %, monocytes (Mono) in GI/L and %, platelet count, Red Blood Cell (RBC) count, total neutrophil count (TNC) in GI/L and %, and White Blood Cell (WBC) count. The Baseline (BL) value is the last available pre-treatment result recorded. Any post-Baseline value was based on results recorded at any scheduled or unscheduled post-Baseline visits. The prevalence of values lying outside the reference (ref.) range (high or low) is presented for BL and any post-Baseline (APBL) visit. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm. Data for the primary analysis (conducted in 2011) are reported. | At Baseline and every 3 months thereafter up to Month 12/Early Withdrawal Visit | 
| Number of Participants With Clinical Chemistry Values Outside the Reference Range for the Indicated Parameters | The clinical chemistry parameters assessed were: alanine amino transferase (ALT), albumin, alkaline phosphatase (ALP), aspartate amino transferase (AST), bicarbonate, blood urea nitrogen (BUN), bone alkaline phosphatase (Bone ALP), calcium, chloride, creatinine, creatinine clearance (Cr. Clearance), creatinine clearance estimated (Cr. Clrnc. est.), glucose, potassium, sodium, total bilirubin (Total Bln), total protein, urea, and uric acid. The Baseline (BL) value is the last available pre-treatment result recorded. Any post-Baseline value was based on results recorded at scheduled or unscheduled post-Baseline visits. The prevalence of values lying outside the reference (ref.) range (high or low) was presented for BL and any post-Baseline (APBL) visit. Two participants were randomized to placebo but received lapatinib; therefore, they are included in the lapatinib treatment arm. | At Baseline and every 6 weeks thereafter up to Month 12/Early Withdrawal Visit | 
| Number of Participants With Non-laboratory Toxicities of the Indicated Toxicity Grades | Non-laboratory toxicities are defined as adverse events (AEs). The number of partcipants with any treatment-emergent AE of the indicated toxicity grade are summarized. Toxicity grading was according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 as follows: Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life threatening; Grade 5=death. The events that were not given a toxicity grade are categorized as Not Applicable. | From the first dose of study treatment up to 12 months | 
| Number of Participants Experiencing Primary or Secondary Cardiac Events | A cardiac event is classified as a primary cardiac endpoint (PCE) or a secondary cardiac endpoint (SCE). PCE is defined as: cardiac death (cardiac death due to heart failure, myocardial infarction, or arrhythmia;or probable cardiac death defined as sudden, unexpected death within 24 hours of a definite or probable cardiac event); severe symptomatic congestive heart failure (CHF) (as per New York Heart Association [NYHA] Class III or IV and an absolute decrease in left ventricular ejection fraction [LVEF] of more than 10 percentage points from Baseline and to a left ventricular ejection fraction [LVEF] value below 50%). SCE is defined as asymptomatic or mildly symptomatic cardiac events (NYHA Class I or II) and a significant decrease in LVEF, defined as an absolute decrease in LVEF of more than 10 percentage points from Baseline and to an LVEF value below 50%. | From the date of randomization up to 12 months | 
| Number of Participants With the Indicated Electrocardiogram (ECG) Findings | 12-lead ECG measurements were taken at Screening and at study conclusion/withdrawal. The number of participants with normal, abnormal clinically significant (CS), and abnormal not clinically significant (NCS) ECG findings, as classified by the investigator, were summarized. Participants with missing values were categorized as missing. Data for the primary analysis (conducted in 2011) are reported. | Screening and Month 12/Early Withdrawal Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, ErbB2-overexpressing, early-stage breast cancer, adjuvant