Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER-2 Negative Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Ixabepilone; Cyclophosphamide
Intervention description: 40 mg/m2 IV infusion over 3 hours on day 1 of a 21 day cycle for 6 cycles; 600 mg/m2 IV infusion per institutional guidelines on day 1 of a 21 day cycle for 6 cycles
Intervention MeSH terms: Cyclophosphamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 168.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer; Ixabepilone; Ixempra; Cyclophosphamide; Cytoxan; Neoadjuvant Therapy

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Female patients, age ≥18 years.

          2. Histologically confirmed invasive adenocarcinoma of the breast.

          3. 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.)

          4. 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.

          5. Eastern Cooperative Oncology Group performance status (ECOG

             PS) 0-2.

          6. No metastatic disease, as documented by complete staging workup

               -  6 weeks prior to initiation of study treatment.

          7. No previous treatment for breast cancer.

          8. 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).

          9. Adequate hematologic function with:

               -  Absolute neutrophil count (ANC) >1500/μL.

               -  Platelets ≥100,000/μL.

               -  Hemoglobin ≥10 g/dL.

         10. 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.

         11. Adequate renal function with serum creatinine ≤1.5 x ULN.

         12. Estrogen and progesterone receptor status in the primary tumor

             known or pending at the time of study registration.

         13. Knowledge of the investigational nature of the study and ability to

             provide consent for study participation.

         14. 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

         15. Bilateral, synchronous breast cancer is allowed if one primary

             tumor meets the inclusion criteria.

         16. Sufficient archived breast tumor specimen available at baseline

        for the Oncotype DX assay.

        -

        Exclusion Criteria:

          1. Inflammatory breast cancer.

          2. Peripheral neuropathy (motor or sensory) ≥ grade 1 by the

             Common Terminology Criteria for Adverse Events version 3.0

             (CTCAE v 3.0).

          3. Prior radiation that included ≥30% of major bone marrow containing

             areas (pelvis, lumbar, spine).

          4. 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.

          5. 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.

          6. 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.

          7. 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.

          8. 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.

          9. 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.

         10. Uncontrolled intercurrent illness including (but not limited to)

             ongoing or active infection.

         11. 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).

         12. Use of any investigational agent within 30 days of administration

             of the first dose of study drug.

         13. Requirement for radiation therapy concurrent with neoadjuvant

             study chemotherapy.

         14. Concurrent treatment with any anti-cancer therapy other than

             those agents used in this study.

         15. Inability or unwillingness to comply with study procedures

             including follow-up visits.

         16. 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.

         17. 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

        -