Ixabepilone + Carboplatin Metastatic Breast Cancer

Ixabepilone adds significantly to the antitumor effectiveness of capecitabine in both ER+ and triple negative breast cancer. Ixabepilone has substantial antitumor activity in taxane-refractory patients and novel combinations are needed in this poor prognosis population. Carboplatin in combination with gemcitabine or paclitaxel has activity in metastatic breast cancer (MBC); there is also demonstrated activity of the gemcitabine/carboplatin combination in the ER+ versus triple negative subsets. A Phase I study of ixabepilone plus carboplatin in solid tumor patients demonstrated the safety of this combination at the doses and schedule proposed for this Phase II trial (BMS data on file).

This is a Phase II, open label, nonrandomized, parallel, noncomparative, study of 2 groups (as stratified below). All patients will receive ixabepilone 20 mg/m2 on Days 1 and 8 and carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. Patients will be stratified by either hormone receptor positive \[ER+/PR+/HER2-, ER+/PR-/HER2-, ER-/PR+/HER2-\]- (n=50) or triples negative ER-/PR-/HER2- (n=53). If one group fulfills their accrual goal first, registration into that strata will be stopped and only patients meeting stratification requirements for the other group will be registered.

Eligibility Criteria:
Inclusion Criteria:

Male or female patients will be eligible for inclusion in this study if they meet all of the following criteria:

1. Has measurable metastatic and or locally unresectable breast cancer with documented HER2 negative (-) disease
2. Has at least 1 measurable lesion per RECIST criteria (lesions that can be accurately measured in at least 1 dimension (longest diameter (LD) to be recorded) as ≥20 mm with conventional techniques (CT, MRI, X-ray) or as ≥10 mm with spiral CT scan). Irradiated lesions cannot be used to assess response but can be used to assess progression.
3. Has received up to 2 (0 to 2) prior chemotherapy regimens for metastatic disease with the following conditions:

   •Has had no prior treatment with ixabepilone or platinum agents
4. Has had no adjuvant chemotherapy within the 6 months prior to study, but may have received prior anthracyclines and/or taxanes as adjuvant chemotherapy
5. 3 weeks or more have elapsed since last chemotherapy treatment and any related toxicities have resolved to \<Grade 1; at least 30 days must have passed since any investigational product has been administered and associated toxicities must have resolved to \<Grade 1 (if applicable).
6. Has an ECOG Performance Status (PS) 0-2
7. Is ≥18 years of age
8. Has a life expectancy of at least 12 weeks
9. Has laboratory values of:

   White blood cell (WBC) count ≥3000 x 106/L Absolute neutrophil count (ANC) ≥1500 x 106/L Hemoglobin ≥9 g/dL Total bilirubin ≤1x upper limit of normal (ULN) AST and ALT ≤2.5 x ULN Alkaline phosphatase ≤2.5 x ULN; up to 5xULN if elevation is due to bone disease Serum creatinine ≤1.5 mg/dL Calculated creatinine clearance \>50 mL/min (based on Cockroft and Gault method \[Appendix III\]) Platelet count ≥100,000 x 106/L
10. If patient has had radiation therapy, it has been completed \>3 weeks prior to the start of study treatment. NOTE: Previously irradiated lesions will not be evaluable. However, these patients will still be eligible.
11. Has a negative serum pregnancy test within 7 calendar days prior to registration (female patients of childbearing potential \[not surgically sterilized and between menarche and 1 year postmenopause
12. If fertile, patient (male or female) has agreed to use an acceptable method of birth control to avoid pregnancy for the duration of the study and for a period of 3 months thereafter
13. Has signed the most recent Patient Informed Consent Form
14. Has signed a Patient Authorization Form Note: Having tissue available is not an inclusion criterion in this study; however, available tissue will be collected (see Section 8) if possible.

Exclusion Criteria:

A patient will be excluded from this study if he or she meets any of the following criteria:

1. Had prior treatment with ixabepilone or other epothilones
2. Had prior radiation to ≥30% of major bone marrow containing areas (pelvis, lumbar spine)
3. Has ER+ and/or PR+ disease that has not progressed on hormone therapy, unless the patient has life-threatening or rapidly progressing visceral disease
4. Has HER2+ disease (IHC staining of 3+ \[uniform, intense membrane staining of \>30% of invasive tumor cells\]), a FISH result of more than 6 HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals of \>2.2)
5. Has only lytic bone disease or nonmeasurable disease only
6. Has a known, prior, severe (NCI CTCAE Grade 3-4) history of hypersensitivity reaction to a drug formulated in Cremophor®EL (polyoxyethylated castor oil) or has history of severe allergic reactions to cisplatin or other platinum-containing compounds
7. Has been treated previously with a platinum-containing agent
8. Is receiving concurrent immunotherapy, hormonal therapy, or radiation therapy. Washout periods for these prior therapies are specified in Section 5.
9. Is receiving concurrent investigational therapy or has received such therapy within the 30 days prior to dosing Day 1
10. Has neuropathy (motor or sensory) \>Grade 1
11. Has evidence of CNS involvement requiring radiation or steroid treatment. Patients with stable brain metastases who are off steroids at least 2 weeks are eligible.
12. Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection
13. Has clinically relevant coagulopathy either secondary to hepatic dysfunction or an underlying condition requiring therapeutic anticoagulation (specifically, A-fib, history of DVT). A daily aspirin or Plavix for CAD are permitted.
14. Has a history of other malignancy within the last 5 years (except cured basal cell carcinoma of skin and carcinoma in situ of uterine cervix), which could affect the diagnosis or assessment of any of the study drugs
15. Is a pregnant or breast feeding woman
16. Is unable to comply with the requirements of the study