Study of Neoadjuvant Carboplatin, Eribulin and Trastuzumab for Operable HER2 Positive Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of eribulin in combination with carboplatin and trastuzumab in the neoadjuvant setting in subjects who are human epidermal growth factor receptor (HER)2 positive and are clinically stage IIA to IIIB. The study regimen will be administered every 3 weeks for a total of 6 cycles followed by definitive surgery.

Detailed Description
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During Phase I, the eribulin dose will be assigned upon study enrollment. The maximum tolerated dose (MTD) determined in Phase I will be the dose used for Phase II. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of each cycle. Carboplatin area under the curve (AUC) 6 will be administered IV over 15 to 30 minutes on Day 1 of each cycle. Trastuzumab will be administered as an IV infusion on Day 1 of each cycle. A loading dose of 8 mg/kg of trastuzumab will be administered over 90 minutes on Cycle 1 Day 1. Then, a maintenance dose of 6 mg/kg of trastuzumab will be administered over 30 to 90 minutes on Day 1 of Cycles 2 - 6. eribulin: During Phase I, the eribulin dose will be assigned upon study enrollment. The maximum tolerated dose (MTD) determined in Phase I will be the dose used for Phase II. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of each cycle. carboplatin: Carboplatin area under the curve

Official Title
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Phase I/II Study of Neoadjuvant Carboplatin, Eribulin Mesylate and Trastuzumab (ECH) for Operable HER2 Positive Breast Cancer

Conditions
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HER-2 Positive Breast Cancer

Intervention / Treatment
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* Drug: eribulin
* Drug: carboplatin
* Drug: trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Females; 18 years of age or greater Histologically proven invasive breast cancer American Joint Committee on Cancer (AJCC) clinical stage IIA - IIIB Tumor size greater than 10 millimeters HER2 positive Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Estrogen receptor (ER) positive or negative Ejection fraction greater than or equal to lower limit of normal for the institution by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) Less than or equal to Grade 1 neuropathy according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Planned lumpectomy or mastectomy Eligible for radiation therapy No prior treatment for invasive breast cancer Adequate organ system function per protocol as determined within 7 days prior to first dose of study treatment Women of childbearing potential must have a negative pregnancy test within 7 days prior to the first dose of study treatment and must agree to use adequate contraception methods during study treatment and for a minimum of 6 months following trastuzumab discontinuation Female subjects who are lactating should discontinue nursing prior to the first dose of study treatment and should refrain from nursing throughout the treatment period Exclusion Criteria: Fine needle cytology only without other histologic evidence of invasive breast cancer Inflammatory breast cancer AJCC clinical stage T1a-b breast cancer (primary tumor less than or equal to 10 millimeters) Evidence of metastatic disease HER2 negative Ejection fraction less than lower limit of normal for the institution by ECHO or MUGA Corrected QT interval greater than 480 milliseconds Pre-existing cardiac dysfunction Prior history of invasive cancer within the past 3 years Synchronous bilateral breast cancer Pre-existing CTCAE v4.0 Grade 2 or greater neuropathy Hypersensitivity to halichondrin B or halichondrin B chemical derivative History of severe allergic reactions to cisplatin or other platinum containing compounds, or mannitol Mild, moderate, or severe hepatic impairment Moderate or severe renal impairment Hypokalemia or hypomagnesemia if it cannot be corrected prior to the first dose of study treatment Organ allografts requiring immunosuppression Known positive human immunodeficiency virus (HIV) status Prior major surgery within 28 days prior to the first dose of study treatment and/or presence of any non-healing wound, fracture, or ulcer Minor surgery or radiation therapy within 14 days prior to the first dose of study treatment Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eribulin, carboplatin, and trastuzumab<br>During Phase I, the eribulin dose will be assigned upon study enrollment. The maximum tolerated dose (MTD) determined in Phase I will be the dose used for Phase II. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of each cycle. Carboplatin area under the curve (AUC) 6 will be administered IV over 15 to 30 minutes on Day 1 of each cycle. Trastuzumab will be administered as an IV infusion on Day 1 of each cycle. A loading dose of 8 mg/kg of trastuzumab will be administered over 90 minutes on Cycle 1 Day 1. Then, a maintenance dose of 6 mg/kg of trastuzumab will be administered over 30 to 90 minutes on Day 1 of Cycles 2 - 6. | Drug: eribulin<br>* During Phase I, the eribulin dose will be assigned upon study enrollment. The maximum tolerated dose (MTD) determined in Phase I will be the dose used for Phase II. Eribulin will be administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of each cycle.<br>* Other names: HALAVEN;Drug: carboplatin<br>* Carboplatin area under the curve (AUC) 6 will be administered IV over 15 to 30 minutes on Day 1 of each cycle.<br>Drug: trastuzumab<br>* Trastuzumab will be administered as an IV infusion on Day 1 of each cycle. A loading dose of 8 mg/kg of trastuzumab will be administered over 90 minutes on Cycle 1 Day 1. Then, a maintenance dose of 6 mg/kg of trastuzumab will be administered over 30 to 90 minutes on Day 1 of Cycles 2 - 6.<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Response | Definitive surgery will be performed 3 to 8 weeks after completion of study treatment. The pathology report will be scored for pathologic response: complete pathologic response (no invasive cancer in breast or lymph nodes; residual DCIS or LCIS is acceptable), partial pathologic response (residual invasive cancer in breast and/or lymph nodes), or no response (pathologic staging is equal to or worse than pretreatment clinical staging). | Assessed at time of definitive surgery, approximately 21-26 weeks from study treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response | Clinical assessment of response will be performed 3 weeks after completion of study treatment. The treating physician will assess clinical response using physical examination and radiologic evaluation. Clinical response options are complete response (no invasive tumor in breast and lymph nodes), partial response (> 50% reduction in longest diameter of pretreatment tumor), no response (< 50% response to 10% growth of tumor as determined by longest diameter of pretreatment tumor size), and progression. | Assessed prior to definitive surgery, approximately 18 weeks from study treatment start. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant Treatment, HER-2 Positive Breast Cancer