Lapatinib +/- Trastuzumab In Addition To Standard Neoadjuvant Breast Cancer Therapy.

Study Overview
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Brief Summary
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This study will examine safety and efficacy of Lapatinib in combination with a standard neoadjuvant chemotherapy including 5FU, Epirubicin, Cyclophosphamide and Paclitaxel. Tumor tissue will be obtained at 3 timepoints (optional 4th) to evaluate tumor response to treatment.

Official Title
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Phase II Randomized Trial of Neoadjuvant Trastuzumab and/or Lapatinib Plus Chemotherapy (Sequential FEC75 and Paclitaxel) in Women With ErbB2- (HER2/Neu-) Overexpressing Invasive Breast Cancer

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Paclitaxel
* Drug: FEC75
* Drug: Lapatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have signed an informed consent form (ICF) and a Patient Authorization Form (HIPAA). Have histologically or cytologically confirmed ErbB2- (HER2/neu-) overexpressing invasive breast cancer (T2-4, N0-2). ErbB2 overexpressing breast cancer, defined as one of the following definitions: 3+ staining by immunohistochemistry (IHC), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus a FISH ratio of more than 2.2. Have either measurable or evaluable disease. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 (Refer to Section 11.4). Have LVEF within the institutional range of normal as measured by either echocardiogram (ECHO) or MUGA scans. The same modality must be used consistently throughout the study. Be deemed able to tolerate 8 cycles of preoperative chemotherapy, including 4 cycles with an anthracycline (epirubicin). Must be willing to undergo 2 mandatory core biopsies (4 passes each) after diagnosis to obtain tissue for biologic expression profiling. Any subject with clinically palpable residual disease may undergo an optional third biopsy to allow identification of presumed pathways of resistance to therapy. This information might be useful in providing the subject with options for other targeted therapies if definitive surgery confirms residual disease. Definitive local therapy with surgery and radiation therapy as indicated will be performed after completion of 12 weeks of paclitaxel-based chemotherapy. Are able to swallow and retain oral medication (intact pill). Are able to complete all screening assessments as outlined in the protocol. Have adequate organ function as defined in Table 4: Table 1 Baseline Laboratory Values Hematologic: ANC (absolute neutrophil count) >1.5 x 109/L hemoglobin >9 g/dL platelets >75 x 109/L Hepatic: albumin >2.5 g/dL serum bilirubin <1.25 x ULN AST / ALT <3 x ULN if no documented liver metastases AST / ALT <3 x ULN with documented liver metastases Renal: serum creatinine <2.0 mg/dL OR - calculated creatinine clearance >40 mL/min Are subjects aged >18 years with any menopausal status: Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are postmenopausal) Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following: Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or Consistent and correct use of one of the following acceptable methods of birth control: male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only) where not contraindicated for this subject population or per local practice.; or barrier methods, including diaphragm or condom with a spermicide. Please note that breast cancer subjects on this trial cannot receive injectable levonorgestrel or injectable progestogen due to the potential for an adverse effect of anti-hormonal therapies on chemotherapy administered for breast cancer [Albain, 2002]. Progestogen may also affect the proliferative rate of endocrine-responsive tumors. Exclusion Criteria: Have received any prior chemotherapy. Had prior therapy with an ErbB1 and/or ErbB2 inhibitor. Are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication. 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 active cardiac disease, defined as one or more of the following: History of uncontrolled or symptomatic angina History of arrhythmias requiring medications, or clinically significant Myocardial infarction <6 months from study entry Uncontrolled or symptomatic congestive heart failure Ejection fraction below the institutional normal limit Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient Are pregnant or breastfeeding. Have received concurrent treatment with an investigational agent or participate in another clinical trial. Have received concurrent treatment with prohibited medications (refer to Section 5.8.2 for details on prohibited medications). Have 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 any of the agents used in this study or their excipients. Are receiving therapeutic anti-coagulation therapy (i.e. warfarin, heparin).

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>Trastuzumab alone for 2 weeks then in combination with FEC75 for 4 (21 Day) cycles and Paclitaxel for 4 (21 day) cycles then continued trastuzumab until time of definitive surgery | Drug: Trastuzumab<br>* 4mg/kg IV loading dose followed by 2mg/kg IV weekly<br>Drug: Paclitaxel<br>* 80mg/m2 IV weekly for 4 (21 day) cycles<br>Drug: FEC75<br>* 5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles<br>|
| Experimental: Arm 2<br>Lapatinib alone for 2 weeks then in combination with FEC75 for 4 (21 Day) cycles followed by Paclitaxel for 4 (21 day) cycles then continued lapatinib until time of definitive surgery | Drug: Paclitaxel<br>* 80mg/m2 IV weekly for 4 (21 day) cycles<br>Drug: FEC75<br>* 5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles<br>Drug: Lapatinib<br>* 1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3<br>|
| Experimental: Arm 3<br>Trastuzumab + Lapatinib for 2 weeks then added FEC75 for 4 (21 Day) cycles followed by Paclitaxel for 4 (21 day) cycles then continued trastuzumab + lapatinib until time of definitive surgery | Drug: Trastuzumab<br>* 4mg/kg IV loading dose followed by 2mg/kg IV weekly<br>Drug: Paclitaxel<br>* 80mg/m2 IV weekly for 4 (21 day) cycles<br>Drug: FEC75<br>* 5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles<br>Drug: Lapatinib<br>* 1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy | A pCR in the breast was defined as no pathologic evidence of invasive disease (residual ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS] was allowed). A pCR in the axillary lymph node(s) was defined as no evidence of breast cancer cells in the lymph node (including subcapsular sinus). Overall pCR was defined as the sum of pCR in the breast and pCR in the lymph nodes. 26 weeks of therapy comprised the 2-week run-in phase, 12 weeks of treatment with FEC, and 12 weeks of treatment with Paclitaxel. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal | cCR was defined as the percentage of participants achieving either a Complete Response (CR) or a Partial Response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. | Week 26 or EOT or Early withdrawal | 
| Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization | Percentage is the Kaplan Meier estimate of DFS. DFS is time from randomization until disease recurrence (contralateral breast cancer; second primary cancer; progression during neo-adjuvant treatment; or death from any cause). Par. who experienced progression during treatment and were withdrawn were considered to have a DFS event at withdrawal. | From first dose date until disease progression, assessed up to a maximum of 5 years | 
| Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal | 12-lead ECGs were performed, and participants were classified as having normal ECG, abnormal- not clinically significant (NCS) ECG, and abnormal-clinically significant (CS) ECG per investigator opinion and reported result. | Baseline and EOT (up to Week 26) or Early withdrawal | 
| Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline | 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 and is used to determine cardiac function. LVEF was measured by performing echocardiogram (ECHO). If ECHO could not be performed or if the investigator believed that it was not conclusive to evaluate LVEF, then a multigated acquisition (MUGA) scan was performed. | Weeks 3, 9, and 15; EOT or early withdrawal; and 3- and 6-month survival follow-up after last chemotherapy course | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ErbB2 Overexpressing, ErbB2 Positive, Lapatinib, Invasive Breast Cancer