Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER-2 Negative Breast Cancer

Study Overview
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Brief Summary
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We propose to evaluate ixabepilone in combination with cyclophosphamide for the neoadjuvant treatment of locally advanced breast cancer. In this regimen, ixabepilone is substituted for docetaxel, since preclinical and clinical studies suggest that ixabepilone is more active than either docetaxel or paclitaxel. The combination of ixabepilone and cyclophosphamide could further improve the efficacy of non-anthracycline neoadjuvant therapy.

Detailed Description
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In this study, patients with early stage, HER2-negative breast cancer will receive neoadjuvant treatment with ixabepilone and cyclophosphamide given every three weeks for a total of six cycles. Following surgery patients with hormone receptor-positive tumors will receive anti-estrogen treatment. Patients may receive local regional radiation therapy after surgery per institutional guidelines at the investigator's discretion. Baseline tumor tissue and tumor tissue removed at the time of surgery will be tested by Oncotype Detailed Description (DX) assay to determine whether it is predictive of response to this neoadjuvant treatment regimen. This study will be one of the first investigations of the combination of ixabepilone and cyclophosphamide as neoadjuvant treatment for HER2-negative breast cancer. It will examine this treatment regimen for potential advantages gained from substitution of ixabepilone for a taxane and use of non-anthracycline agents.

Official Title
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Phase II Study of Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER2-Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ixabepilone
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients, age ≥18 years. Histologically confirmed invasive adenocarcinoma of the breast. Primary palpable disease confined to a breast and axilla on physical examination. For patients without clinically suspicious axillary adenopathy, the primary tumor must be larger than 2 cm in diameter by physical exam or imaging studies (clinical T2-T3, N0-N1, M0). For patients with clinically suspicious axillary adenopathy, the primary breast tumor can be any size (clinical T1-3, N1-2, M0). (T1N0M0 lesions are excluded.) Patients without clearly defined palpable breast mass or axillary lymph nodes but radiographically measurable tumor masses are acceptable. Accepted procedures for measuring breast disease are mammography, MRI, and breast ultrasound. This will need to be re-evaluated after 3 cycles and prior to surgery. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. No metastatic disease, as documented by complete staging workup 6 weeks prior to initiation of study treatment. No previous treatment for breast cancer. HER2-negative tumor status. HER2-negative is defined as: Immunohistochemical (IHC) 0, IHC 1+ OR IHC 2+ or IHC 3+ must be confirmed as FISH (fluorescence in situ hybridization) negative (defined by ratio <2.2). Adequate hematologic function with: Absolute neutrophil count (ANC) >1500/μL. Platelets ≥100,000/μL. Hemoglobin ≥10 g/dL. Adequate hepatic function with: Serum bilirubin ≤ the institutional upper limit of normal (ULN). Aspartate aminotransferase (AST) ≤2.5 x institutional ULN. Alanine aminotransferase (ALT) ≤2.5 x institutional ULN. Adequate renal function with serum creatinine ≤1.5 x ULN. Estrogen and progesterone receptor status in the primary tumor known or pending at the time of study registration. Knowledge of the investigational nature of the study and ability to provide consent for study participation. For patients who had, or will have sentinel lymph node and/or axillary dissection prior to initiation of study treatment, completion at least 4 weeks prior to starting study treatment and well-healed wound Bilateral, synchronous breast cancer is allowed if one primary tumor meets the inclusion criteria. Sufficient archived breast tumor specimen available at baseline for the Oncotype DX assay. - Exclusion Criteria: Inflammatory breast cancer. Peripheral neuropathy (motor or sensory) ≥ grade 1 by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v 3.0). Prior radiation that included ≥30% of major bone marrow containing areas (pelvis, lumbar, spine). Chronic use of cytochrome P450 (CYP) 3A4 inhibitors and use of the following strong CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, and voriconazole. Use of these agents should be discontinued at least 72 hours prior to initiation of study treatment. Chemotherapy within 5 years of starting study treatment except for low doses of agents used for anti-inflammatory indications such as rheumatoid arthritis, psoriasis, and connective tissue disorders. Although such doses and schedules cannot result in myelosuppression, patients must discontinue this therapy while they are receiving study treatment. Known or suspected hypersensitivity to Cremophor®EL (polyoxyethylated castor oil) or a drug formulated in Cremophor®EL such as paclitaxel, or any other agent given in the course of this study. Pregnancy or breast-feeding. A negative serum pregnancy test within 7 days prior to first study treatment (Day 1, Cycle 1) for all women of childbearing potential is required. Patients of childbearing potential must agree to use a birth control method that is approved by their study physician while receiving study treatment and for 3 weeks after their last dose of study treatment. Patients must agree to not breast-feed while receiving study treatment. Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator (SERM). Patients must have discontinued use of such agents prior to beginning study treatment. History of malignancy treated with curative intent within the previous 5 years with the exception of skin cancer, cervical carcinoma in situ, or follicular thyroid cancer. Patients with previous invasive cancers (including breast cancer) are eligible if the treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease. Uncontrolled intercurrent illness including (but not limited to) ongoing or active infection. Chronic treatment with corticosteroid unless treatment was begun >6 months prior to study treatment and is at a low dose (≤20 mg methylprednisolone or equivalent). Use of any investigational agent within 30 days of administration of the first dose of study drug. Requirement for radiation therapy concurrent with neoadjuvant study chemotherapy. Concurrent treatment with any anti-cancer therapy other than those agents used in this study. Inability or unwillingness to comply with study procedures including follow-up visits. Mental condition or psychiatric disorder that would prevent patient comprehension of the nature, scope, and possible consequences of the study or that would limit compliance with study requirements. Any other disease(s), metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that would cause reasonable suspicion of a disease or condition that contraindicates the use of study drugs, that may affect the interpretation of the results, or that renders the patient at high risk from treatment complications -

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: Ixabepilone/Cyclophosphamide<br>Systemic Therapy followed by surgery and possible radiation therapy | Drug: Ixabepilone<br>* 40 mg/m2 IV infusion over 3 hours on day 1 of a 21 day cycle for 6 cycles<br>* Other names: Ixempra;Drug: Cyclophosphamide<br>* 600 mg/m2 IV infusion per institutional guidelines on day 1 of a 21 day cycle for 6 cycles<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate (pCR) | Pathologic complete response (pCR) rate will be determined by the pathologic evaluation of breast and lymph node samples collected at the time of surgery. pCR is defined as no residual disease in breast or lymph nodes in resected tissue samples. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absence of Grade-4 Non-hematologic Toxicity Excluding, Alopecia, Nausea, Vomiting and Bone Pain | Non hematologic treatment-related grade 4 toxicities measured according to CTCAE 3.0 | 3 months | 
| Overall Survival | Overall survival (OS) determined as the time between day 1 cycle 1 to the date of death from any cause. The percentage of patients who were alive at 3 years, estimated by Kaplan Meier method as the probability of being event free at 3 years is reported here. | 36 months | 
| Disease Free Survival | Defined as the time between Day 1 Cycle 1, and date of first documented recurrence, initiation of additional chemotherapy, or death. | 36 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ixempra, Breast Cancer, Ixabepilone, Cyclophosphamide, Cytoxan, Neoadjuvant Therapy