Neoadjuvant Ixabepilone/Carboplatin/Trastuzumab in HER2-Positive Locally Advanced Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Ixabepilone; Trastuzumab; Carboplatin
Intervention description: Ixabepilone 40mg/m2 IV infusion over 3 hours on day 1 of cycles 1-6 (all treatment cycles are 21 days in length); Trastuzumab 8mg/kg IV over 90 minutes for the first infusion (Cycle 1, Day 1) with a 60 minute post-infusion observation period. Subsequent infusions (Day 1 of Cycles 2-6 with all cycles being 21 days in length) 6mg/kg over 30 minutes if the previous dose was well tolerated; peri-operative trastuzumab 6mg/kg IV every 3-4 weeks; post-operative trastuzumab 6mg/kg IV day 1 every 3 weeks until week 52; Carboplatin AUC=6 IV per institutional guidelines on Day 1 of Cycles 1-6 (all treatment cycles are 21 days in length)
Intervention MeSH terms: Carboplatin; Trastuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer; Neoadjuvant; Ixabepilone; Carboplatin; Trastuzumab

Summary:

      In this phase II trial the investigators propose to evaluate ixabepilone in combination with
      carboplatin and trastuzumab as neoadjuvant therapy in locally advanced breast cancer
      patients. Patients with early stage, HER2-positive breast cancer will receive six cycles of
      neoadjuvant treatment with ixabepilone, carboplatin, and trastuzumab every three weeks prior
      to surgery; after surgery, patients will continue treatment with trastuzumab every three
      weeks until week 52. Concomitant with the post-operative trastuzumab treatment, patients with
      hormone receptor-positive tumors will receive anti-estrogen treatment. Also, after the
      completion of chemotherapy, patients may receive radiation treatment at the discretion of
      their physician.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Female and male patients ≥18 years of age.

          2. Histologically confirmed 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 (clinical T2-T3, N0-N1, M0). For patients with clinically
             suspicious axillary adenopathy, the primary breast tumor can be any size (clinical
             T1-T3, N1-N2, M0). (T1N0M0 lesions are excluded.)

          4. Patients who have no clearly defined palpable breast mass or axillary lymph nodes but
             are radiographically measurable are eligible. Accepted procedures for measuring breast
             disease are mammography, MRI, and breast ultrasound. In these patients, radiographic
             tumor measurements need to be repeated after 3 cycles and prior to surgery.

          5. Positive HER2 status (overexpression and/or amplification of HER2 in the primary
             tumor) as defined by: IHC 3+ or fluorescence in situ hybridization (FISH) positive
             (ratio >2.2) testing. Documentation of the HER2 results must be available at the time
             of study enrollment.

          6. An ECOG (Eastern Cooperative Oncology Group) performance score of ≤2

          7. Normal bone marrow function as defined by:

               -  absolute neutrophil count (ANC) >1,500/µL;

               -  platelets >100,000/µL;

               -  hemoglobin >10 g/dL.

          8. Normal hepatic and renal function.

          9. Left ventricular ejection fraction (LVEF) within the institutional limits of normal,
             whichever is lower, as measured by multi-gated acquisition (MUGA) scan or
             echocardiogram (ECHO).

         10. Life expectancy > 12 weeks.

         11. Estrogen and progesterone (or estrogen alone) receptor status in the primary tumor
             known or pending at the time of study enrollment.

         12. For women of childbearing potential, negative serum pregnancy test within 7 days prior
             to starting treatment.

         13. For women of childbearing potential, agreement to use a method of contraception that
             is acceptable to their physician from time of first signing the informed consent until
             at least 3 months after the last dose of study drug. If a woman becomes pregnant or
             suspects she is pregnant while participating in this study, she must agree to inform
             her treating physician immediately. Patient agreement to discontinue breast-feeding,
             if applicable, during study treatment. Men enrolled in the study must also agree to
             use a method of contraception that is acceptable to their physician during their study
             participation.

         14. For patients with previous invasive cancers (including breast cancer) treated with
             curative intent, completion of chemotherapy or radiation therapy more than 5 years
             prior to enrollment for this study and no evidence of recurrent disease. Patients may
             be receiving anti-estrogen hormonal therapy prescribed for previous invasive breast
             cancer as long as the diagnosis of invasive cancer was made more than 5 years prior to
             study enrollment. Patients may be using anti-estrogen hormonal therapy at the time of
             current diagnosis but must discontinue this therapy before beginning study treatment.

         15. 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.

         16. Ability to understand and willingness to sign a written informed consent document.

        Exclusion Criteria:

          1. Previous treatment for this breast cancer.

          2. Evidence of metastatic disease.

          3. Prior radiation that included ≥30% of major bone marrow-containing areas.

          4. Women who are pregnant or breastfeeding.

          5. Neuropathy (motor or sensory) ≥grade 1 at study entry.

          6. History of significant cardiac disease or cardiac risk factors or the following:

               -  uncontrolled arrhythmias

               -  poorly controlled hypertension (e.g., systolic blood pressure [BP]> 150 mmHg or
                  diastolic BP >100 mmHg) in spite of optimal medical management

               -  angina pectoris requiring antianginal medication or unstable angina within the
                  previous 6 months

               -  history of documented congestive heart failure (CHF)

               -  any documented myocardial infarction within the previous 6 months

               -  clinically significant valvular heart disease

               -  current use of medications (e.g., digitalis, beta-blockers, calcium
                  channel-blockers) that alter cardiac conduction, if these medications are
                  administered for the management of cardiac arrhythmia, angina, or CHF. If these
                  medications are administered for other reasons (e.g., hypertension), the patient
                  may be eligible.

               -  patients with cardiomegaly on chest x-ray or ventricular hypertrophy on ECG
                  unless ECHO or MUGA scan within the last 3 months demonstrates that the LVEF is ≥
                  institutional lower limit of normal.

          7. Symptomatic intrinsic lung disease.

          8. Active malignancy, other than superficial basal cell carcinoma, superficial squamous
             (skin) cell carcinoma, carcinoma in situ, or non-invasive breast cancer, within the
             past 5 years.

          9. Uncontrolled intercurrent illness including (but not limited to) ongoing or active
             infection >grade 2.

         10. Mental condition or psychiatric disorder rendering the subject unable to understand
             the nature, scope, and possible consequences of the study or that would limit
             compliance with study requirements.

         11. Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving a reasonable suspicion of a disease or condition that
             contraindicates the use of a study agent or that may affect the interpretation of the
             results or renders the subjects at high risk from treatment complications.

         12. Chronic use of CYP3A4 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 must be discontinued at least 72 hours prior to
             initiation of study treatment.

         13. Received chemotherapy for any indication within the 5 years preceding study
             enrollment.

         14. Prior treatment with trastuzumab or any other anti-HER2 agent for any indication.

         15. Concurrent treatment with any other anti-cancer therapy.

         16. Concurrent radiation therapy during neoadjuvant study treatment.

         17. Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must
             be stopped prior to study enrollment.

         18. Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other
             selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention
             of breast cancer. These agents must be discontinued prior to study enrollment.

         19. Participation within the previous 30 days in a study with an experimental drug.

         20. Known or suspected allergy to Cremophor EL (polyoxyethylated castor oil), a drug
             formulated in Cremophor EL such as paclitaxel, or any other agent given in the course
             of this trial.

         21. Inability or unwillingness to comply with study procedures including those for
             follow-up.