Effect of Trastuzumab on Disease Free Survival in Early Stage HER2-Negative Breast Cancer Patients With ERBB2 Expressing Disseminated Tumor Cells

Study Overview
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Brief Summary
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This phase II trial studies the efficacy of trastuzumab treatment in breast cancer patients with stage II-III human epidermal growth factor receptor 2 (HER2)-negative tumors and HER2-expressing bone marrow disseminated tumor cells (DTCs). Administering targeted trastuzumab therapy to these patients may result in the elimination of HER2 expressing disseminated tumor cells and improved disease free survival.

Official Title
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A Phase II Randomized Trial Evaluating the Effect of Trastuzumab on Disease Free Survival in Early Stage HER2-Negative Breast Cancer Patients With ERBB2 Expressing Bone Marrow Disseminated Tumor Cells

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Doxorubicin
* Biological: Trastuzumab
* Drug: Cyclophosphamide
* Drug: Paclitaxel
* Drug: Epirubicin
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Pre-Registration Inclusion Criteria: Histologically confirmed HER2-negative primary invasive ductal or invasive lobular breast carcinoma. For patients enrolling for neoadjuvant treatment, diagnosis must be clinical stage II or III; for patients enrolling for adjuvant treatment, diagnosis must be pathologic stage IIA to IIIC. Standard HER2 testing will be performed in the surgical specimen at Washington University according to the standard of care in the Department of Pathology. A HER2-negative primary breast cancer sample from a patient eligible for randomization should have a HER2 IHC score of 0 or 1+ Those patients with IHC score of 2+ should be HER2 FISH-negative in standard testing. Patient will have undergone staging studies including a CT of the chest/abdomen/pelvis and bone scan and/or PET scan either prior to the initiation of treatment or prior to entry into the trial. In addition, patients with non-metastatic, HER2-negative, recurrent tumors who need chemotherapy are eligible. Planning to receive best practice adjuvant or neoadjuvant chemotherapy according to institutional guidelines. Adjuvant tamoxifen or aromatase inhibitors treatment will be allowed for hormone receptor-positive patients. Patients who have failed neoadjuvant endocrine therapy will also be eligible. At least 18 years old. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Patient (or legally authorized representative) must be able to understand and willing to sign a written informed consent document. Pre-Registration Exclusion Criteria: Prior chemotherapy for this cancer (excluding initiation of best practice chemotherapy to be given as standard of care as described in this protocol, which may be initiated after the pre-registration bone marrow collection but before final confirmation of eligibility and randomization). Previous treatment with trastuzumab or any other Her2 targeted therapy. Presence of an uncontrolled intercurrent 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. Registration Inclusion Criteria Presence of bone marrow ERBB2 overexpressing DTCs at the time of diagnosis; bone marrow aspiration will be performed in consented patients to evaluate DTCs following pre-registration provided patients meet all eligibility criteria as described in this section. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Adequate cardiac function as demonstrated by LVEF of >55% performed no more than 4 weeks prior to randomization. Normal organ and marrow function as defined below: leukocytes ≥3,000/mcL absolute neutrophil count ≥1,500/mcL platelets ≥100,000/mcL hemoglobin ≥ 10 g/dL total bilirubin within institutional upper limits of normal unless related to primary disease AST(SGOT)/ALT(SGPT) ≤2.0 X institutional upper limit of normal Creatinine ≤ 1.5 institutional upper limits of normal OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal If a woman of childbearing potential, patient must use two forms of effective contraception for a minimum of 6 months following trastuzumab. Effective methods of birth control include use of established oral, injected, or implanted hormonal methods of birth control, IUD, IUS, and condoms. Registration Exclusion Criteria Evidence of distant metastasis present by CT scan, bone scan, or physical exam. History of allergic reactions attributed to compounds of similar chemical or biologic composition to trastuzumab. Prior chemotherapy for this cancer (excluding initiation of best practice chemotherapy to be given as standard of care described in this protocol, which may be initiated after the pre-registration bone marrow collection but before final confirmation of eligibility and randomization). History of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix. Pregnant or breastfeeding. Patient must have a negative serum pregnancy test ≤ 7 days from date of registration (if a woman of childbearing potential). Clinically important history of active liver disease, including viral or other hepatitis or cirrhosis. Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation. Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.

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 I (definitive therapy)<br>Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel docetaxel plus cyclophosphamide single-agent paclitaxel docetaxel plus carboplatin fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel | Drug: Doxorubicin<br> <br> * Other names: Adriamycin®, Rubex®, Hydroxydaunomycin Hydrochloride, Hydroxydoxorubicin Hydrochloride;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan®, CPM, CTX, CYT;Drug: Paclitaxel<br> <br> * Other names: Abraxane®, Onxol®;Drug: Epirubicin<br> <br> * Other names: Ellence, Pharmorubicin, Epirubicin ebewe;Drug: Docetaxel<br> <br> * Other names: Taxotere, Docefrez;Drug: Fluorouracil<br> <br> * Other names: 5-FU, Adrucil;|
| Experimental: Arm II (definitive therapy, trastuzumab)<br>Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are: doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel docetaxel plus cyclophosphamide single-agent paclitaxel docetaxel plus carboplatin fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: Doxorubicin<br> <br> * Other names: Adriamycin®, Rubex®, Hydroxydaunomycin Hydrochloride, Hydroxydoxorubicin Hydrochloride;Biological: Trastuzumab<br> <br> * Other names: •Herceptin®;Drug: Cyclophosphamide<br> <br> * Other names: Cytoxan®, CPM, CTX, CYT;Drug: Paclitaxel<br> <br> * Other names: Abraxane®, Onxol®;Drug: Epirubicin<br> <br> * Other names: Ellence, Pharmorubicin, Epirubicin ebewe;Drug: Docetaxel<br> <br> * Other names: Taxotere, Docefrez;Drug: Carboplatin<br> <br> * Other names: cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II), Paraplatin, Paraplatin-AQ;Drug: Fluorouracil<br> <br> * Other names: 5-FU, Adrucil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Disease Recurrence | -Disease recurrence is defined as the documented appearance of local (breast, chest wall, axillary, supraclavicular nodes) or distant disease. | Up to 3 years after completion of treatment (estimated to be 4 years) | 
| Death Rate |  | Up to 3 years after completion of treatment (estimated to be 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Elimination of ERBB2 Overexpressing Bone Marrow DTCs | Bone marrow disseminated tumor cells (DTCs) are evaluated by RT-PCR performed on specimens collected 6-18 months apart (one before and one after therapy). The proportion of samples turned negative after therapy will be calculated. Samples will be considered negative for ERBB2-expression if expression from bone marrow collected from each iliac crest is less than 2 standard deviations above the ERBB2-level in pooled normal bone marrow specimens. | Before treatment and after treatment (estimated to be 6-18 months) |