Neoadjuvant Study With Chemotherapy, Lapatinib And Trastuzumab In Breast Cancer

Study Overview
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Brief Summary
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Evaluate the activity of Trastuzumab, Lapatinib, and a combination of both agents with chemotherapy in the preoperative (neoadjuvant) treatment of early breast cancer.

Official Title
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Chemotherapy Plus Lapatinib or Trastuzumab or Both in Her2+ Primary Breast Cancer. A Randomized Phase IIb Study With Biomarker Evaluation.

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: lapatinib
* Biological: trastuzumab
* Drug: paclitaxel
* Drug: fluorouracil
* Drug: epidoxorubicin
* Drug: cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically confirmed infiltrating primary breast cancer of > 2.0 cm in largest clinical diameter HER2 positive tumor (either IHC 3+ or FISH+) Availability of tumor tissue suitable for biological and molecular examination before starting primary treatment Age >18, < 65 years ECOG PS 0-1 Normal organ and marrow function as defined below: leukocytes ³ 3000/microL absolute neutrophil count ³ 1,500/microL platelets ³ 100,000/microL total bilirubin <= 1.5x ULN. In case of Gilbert's syndrome, <2 x ULN is allowed AST (SGOT)/ALT(SGPT)<= 2.5 X institutional upper limit of normal Alkaline phosphatase <= 2.5 x ULN 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 The effects of lapatinib on the developing human fetus at the recommended therapeutic dose are unknown; women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately, the patient should be apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy 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 anthracycline, paclitaxel and/or trastuzumab 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 Pregnancy or breastfeeding; (breast feeding should be discontinued to be enrolled in the study) Women of childbearing potential that refusal to adopt adequate contraceptive measures 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 A<br>Chemotherapy plus trastuzumab | Biological: trastuzumab<br>* First dose 4mg/kg in 60mins, then weekly 2mg/kg in 30 mins<br>* Other names: Herceptin;Drug: paclitaxel<br>* 80mg/sqm 1 hour infusion for 12 weeks<br>* Other names: Taxol;Drug: fluorouracil<br>* 600mg/sqm iv day 1 q21 days for four coursess<br>Drug: epidoxorubicin<br>* 75mg/sqm iv day 1 q21 days for four courses<br>Drug: cyclophosphamide<br>* 600mg/sqm day 1 q21 days for four courses<br>|
| Experimental: Arm B<br>Chemotherapy plus lapatinib | Drug: lapatinib<br>* Arm B 1250mg/d PO Arm C 750mg/d PO<br>* Other names: Tyverb/Tykerb;Drug: paclitaxel<br>* 80mg/sqm 1 hour infusion for 12 weeks<br>* Other names: Taxol;Drug: fluorouracil<br>* 600mg/sqm iv day 1 q21 days for four coursess<br>Drug: epidoxorubicin<br>* 75mg/sqm iv day 1 q21 days for four courses<br>Drug: cyclophosphamide<br>* 600mg/sqm day 1 q21 days for four courses<br>|
| Active Comparator: Arm C<br>Chemotherapy plus trastuzumab plus lapatinib | Drug: lapatinib<br>* Arm B 1250mg/d PO Arm C 750mg/d PO<br>* Other names: Tyverb/Tykerb;Biological: trastuzumab<br>* First dose 4mg/kg in 60mins, then weekly 2mg/kg in 30 mins<br>* Other names: Herceptin;Drug: paclitaxel<br>* 80mg/sqm 1 hour infusion for 12 weeks<br>* Other names: Taxol;Drug: fluorouracil<br>* 600mg/sqm iv day 1 q21 days for four coursess<br>Drug: epidoxorubicin<br>* 75mg/sqm iv day 1 q21 days for four courses<br>Drug: cyclophosphamide<br>* 600mg/sqm day 1 q21 days for four courses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathological Complete Response (pCR) in the Breast and in the Lymph Nodes | Pathological Complete Response (pCR) is defined by the complete absence of infiltrating tumor cells in the breast and in the lymph nodes. The pathological response in the breast was evaluated according to the criteria of Miller and Payne as follows: Grade 1, no change or some alteration to individual malignant cells, but no reduction in overall cellularity; Grade 2, a minor loss in tumor cells (up to 30%); Grade 3, between an estimated 30% and 90% reduction in tumor cells; Grade 4, marked disappearance of tumor cells, with only a small cluster or a dispersed cell remaining (more than 90% loss); Grade 5, no identifiable malignant cells. Ductal carcinoma in situ (DCIS) may be present. Grades were interpreted as follows: Grade 1-2=no response; Grade 3-4=partial response; Grade 5=complete response. pCR was defined by comparing specimens obtained at Baseline (biopsy) to those obtained upon surgery. | At Baseline and surgery (within 5 weeks after the last chemotherapy administration) (assessed up to Study Week 29) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography | The clinical response was evaluated by comparing the tumor size (largest tumor diameter) before (at Baseline [biopsy]) and after treatment (before surgery), as assessed by ultrasonography examination. The clinical response was scored by Response Evaluation Criteria in Solid Tumors (RECIST) as follows: complete clinical response: the nodule is not detectable and all the ultrasound abnormality detected at diagnosis disappeared (margins circumscribed, round oval shape, parallel orientation, isoechoic echo pattern, no posterior acoustic features, echogenic lesion boundary, and tumor vascularity not present); partial clinical response: the longest diameter of the tumor has been reduced by >50%, and the ultrasound characteristics of the tumor persist; no response (stable disease): the longest diameter of the tumor has been reduced by <50% or has increased by no more than 20% from the starting value; progressive disease: tumor longest diameter has increased >20% from the starting value. | At Baseline and after primary treatment (within 2 weeks before surgery; up to Study Week 27) | 
| Percentage of Participants Who Had Breast-conserving Surgery (BCS), Mastectomy, and Conversion From Mastectomy to BCS | The percentage of participants who had BCS and mastectomy and who were initiallycandidates for mastectomy and who actually had BCS was measured. At Baseline, the surgeon stated, within 4 weeks before starting the primary treatment, which type of surgical treatment he would perform in the absence of primary therapy and in the case of primary therapy (if the tumor size was reduced by the primary treatment to less than 3 centimeters), and the reasons for these choices. The rules for choosing the type of surgical treatment are reported in the Consensus Conference on Primary Treatment of Early Breast Cancer. The surgeon was to have re-evaluated the participant after primary treatment. In cases in which the type of surgical procedure was different from that originally programmed, the reason for this chance was to have been reported. | At Baseline and at surgery (up to Study Week 29) | 
| Time to Treatment Failure From the Start of Primary Therapy | Time to treatment failure (TTF) is defined as the interval of time between the date of randomization and the earliest date of disease progression, premature treatment discontinuation and death due to any cause. The overall disease progression date is the earlier of the two disease progression dates from ultrasonography and mammography assessments. For ultrasonography, disease progression is defined as at least 20% increase in the longest diameter of the primary lesion at pre-surgery comparing to Baseline. For mammography, disease progression is defined as at least 20% increase in the larger nodule dimension at pre-surgery comparing to Baseline. For participants who has neither progressed, pre-maturely withdrawn or died, time to treatment failure will be censored at the latest date of ultrasonography and mammography tumor assessments. | From randomization up to Study Week 307 | 
| Number of Participants With Treatment Failure | Treatment failure is defined as the occurrence of local tumor progression (including ipsilateral and controlateral breast), distant tumor progression, permanent treatment discontinuation (either for the experimental or conventional arm), or death due to any cause. | From randomization up to 29 weeks | 
| Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment | The percentage of inhibition of intermediate (EGFR, HER2, pMAPK, pAKT, PTEN, and PI3KCA) and final (TUNEL and Ki67) biomarkers of the proliferation and apoptosis pathways was calculated as the difference between the staining scores before (Baseline [biopsy]) and after treatment (withdrawal). | At Baseline and Withdrawal (assessed up to Study Week 29) | 
| Number of Participants With Any Adverse Event (AE), Including Serious Adverse Events (SAEs), Occurring in >=5% of Participants | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment had been exercised in deciding whether reporting was appropriate in other situations. | From the first dose of randomized therapy to 30 days after the last dose of randomized therapy (assessed up to Study Week 29) | 
| Number of Variations/Somatic Mutation in PI3KCA at Baseline | Analysis of mutations in the PI3KCA gene was performed from RNA extracted from frozen tumor tissue samples (sections). A gene is either a wild-type (no mutation) or mutated (presence of a mutation). Exons 9 and 20 of the PI3KCA gene were accessed (high frequency mutation at these two spots). | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neo-adjuvant trastuzumab early breast cancer lapatinib