T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA

Study Overview
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Brief Summary
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This research study is studying a combination of drugs as a possible treatment for breast cancer that has tested positive for a protein called HER2. The names of the study interventions involved in this study are: Trastuzumab emtansine (also called T-DM1) Pertuzumab

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for pre-operative use in breast cancer but it has been approved for other uses in breast cancer. The FDA has approved pertuzumab as a pre-operative treatment.

Official Title
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The Impact of HER2 Heterogeneity on the Treatment of Early-stage HER2-positive Breast Cancer: a Phase II Study of T-DM1 in Combination With Pertuzumab in the Preoperative Setting

Conditions
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HER-2 Positive Breast Cancer, Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer

Intervention / Treatment
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* Drug: T-DM1
* Drug: Pertuzumab
* Procedure: Excision of tumor/mastectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have HER2-positive Stage II or III histologically confirmed invasive carcinoma of the breast. A minimum tumor size of 2 cm determined by physical exam or imaging is required. HER-2 positive, confirmed by central testing (Clarient labs): IHC 3+ and/or FISH positive based on one of the three following criteria: Single-probe average HER2 copy number≥6.0 signals/cell OR Dual-probe HER2/CEP17 <2.0 with an average HER2 copy number ≥6.0 signals/cell OR Dual-probe HER2/CEP17 ratio ≥2.0 ER/PR determination is required. Bilateral breast cancers are allowed if both cancers are HER2-positive. Patients with multifocal or multicentric disease are eligible as long as one area meets eligibility criteria. Breast imaging should include the ipsilateral axilla. For subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either before or after preoperative therapy at the discretion of the subject's physicians. For subjects with a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be performed to determine the presence of metastatic disease in the lymph nodes. Men and women (with any menopausal status) ≥ 18 years of age ECOG performance status 0 or 1 Required laboratory values: ANC ≥1500/mm3 Hemoglobin ≥ 9 g/dl Platelets ≥100,000/mm3 Serum creatinine < 1.5 X ULN (institutional) Total bilirubin ≤ 1.0 X ULN (institutional) For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range. AST and ALT ≤ 1.5x ULN (institutional) Alkaline phosphatase ≤1.5x ULN (institutional) Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B core antibody (HBcAb) in addition to HCV antibody testing. Only for patients who test positive for hep B/C virus: PTT/INR < ULN (institutional) Left ventricular ejection fraction (LVEF) ≥ 55% Premenopausal women must have a negative serum pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause. Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment. Potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment period with T-DM1. Excessive alcohol intake should be avoided (occasional use is permitted). Patients with a history of ipsilateral DCIS are eligible. Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy. Willing and able to sign informed consent. Willing to provide tissue for research purposes. Exclusion Criteria: Pregnant or nursing women due to the teratogenic potential of the study drugs. Active, unresolved infection. Receipt of intravenous antibiotics for infection within 7 days prior to enrollment. Patients with active liver disease, for example, due to hepatitis B virus, hepatitis C virus, autoimmune hepatic disorder, or sclerosing cholangitis. Uncontrolled hypertension (systolic >180 mm Hg and/or diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher, or serious cardiac arrhythmia requiring medication. Significant symptoms (Grade ≥2) peripheral neuropathy. Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes. Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-DM1 and Pertuzumab<br>T-DM1 3.6 mg per kg of body weight via IV every 3 weeks for 6 doses and Pertuzumab loading dose of 840 mg via IV on Cycle 1 Day 1 followed by maintenance dose of 420 mg via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor within 42 days of the last cycle of therapy. | Drug: T-DM1<br>* Neoadjuvant treatment is for a total of 18 weeks.<br>* Other names: Kadcyla;Drug: Pertuzumab<br>* Neoadjuvant treatment is for a total of 18 weeks.<br>* Other names: Perjeta;Procedure: Excision of tumor/mastectomy<br>* Definitive breast cancer surgery (excision or mastectomy) marks the end of protocol mandated therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous | The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pathologic Complete Response (pCR) | The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer_RCB). | Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment. | 
| Hormone Receptor (HR) Status by HER2 Amplification Status | HR status classified by estrogen receptor (ER) and/or progesterone receptor (ER) positive versus ER negative and PR negative determined by immunohistochemical methods according to the local institution's standard protocol. | Day 0 (baseline/at study entry) | 
| Median Disease-Free Survival | Disease-free survival (DFS) based on the Kaplan-Meier method is defined as the duration of time from study entry to the occurrence of the first of the following events: local/regional recurrence, contralateral invasive breast cancer, distant recurrence or death from any cause. In situ cancer is not included as DFS event. Participants alive without an event are censored at date of last disease assessment. | Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10. | 
| Median Overall Survival | Overall survival (OS) based on Kaplan-Meier methods is defined as the interval from the date of registration to death from any cause. Patients are censored at date last known alive. | Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10. | 
| Clinical Response Rate (Complete Response) | Clinical response rate was defined as the percentage of participants achieving complete response (CR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions | Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment. | 
| Clinical Response Rate (Partial Response) | Clinical response rate was defined as the percentage of participants achieving partial response (PR) based on RECIST 1.1 criteria on treatment up to surgery. Per RECIST 1.1 for target lesions: PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. | Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment. | 
| Number of Participants With a Dose Reduction | Number of participants with ever having dose reduction on neoadjuvant therapy up to surgery. | Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment. | 
| Treatment-Emergent Fatigue Rate | Treatment-emergent fatigue rate is the percentage of participants who experienced grade 1-2 fatigue based on the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as reported on the adverse event case report form. CTCAE severity scale ranges from 0 (none) to 5 (death): Grade 1=mild and Grade 2=moderate. | Adverse events are assessed every cycle of neoadjuvant therapy prior to surgery, up to approximately 18 weeks (6 cycles) from study enrollment. |