Abraxane With or Without Tigatuzumab in Patients With Metastatic, Triple Negative Breast Cancer

The study is an open-label randomized, multi-institutional, phase II clinical trial of
Abraxane in combination with tigatuzumab or Abraxane as a single agent in patients with TNBC.
Randomization (2:1) will be made from these two categories: TBNC patients with no prior
chemotherapy for metastatic disease or TBNC patients with prior taxane (except Abraxane)
therapy for metastatic disease. Patients randomized to Abraxane alone may be allowed to cross
over to the combination of Abraxane + tigatuzumab if there is disease progression.

Inclusion Criteria:

- Patients must have pathologically documented Stage IV breast cancer. If blocks
(paraffin-embedded tissue) from original diagnosis are available, they will be
obtained to confirm the diagnosis and for correlative studies. Fifteen slides can be
obtained from the block if the block is not available to be sent or released.

- Tumor must be HER-2-neu negative (defined as 0 or 1+ staining by immunohistochemistry
or gene amplification ratio less than or equal to 2.0, by fluorescent in situ
hybridization - FISH), estrogen and progesterone receptors negative (<10%).

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded)

- Biopsy of a metastatic lesion is not required for protocol entry but all patients with
reasonably accessible lesions (chest wall, breast, skin, subcutaneous, superficial
lymph nodes, bones and liver metastases) must agree to biopsy.

1. Biopsies may be done with local anesthesia or intravenous conscious sedation,
according to standard institutional guidelines.

2. If a biopsy requires general anesthesia, then it is only allowed if acquisition
of tissue is necessary for clinical reasons and excess tissue that would
otherwise have been discarded is then used for research purposes. If a biopsy
requires general anesthesia, then a biopsy of that site for research purposes
only, without a coexisting clinical indication is not allowed on this protocol.

3. Patients with reasonably accessible lesions as described above, who will not
agree with the biopsy, will not be enrolled in the trial.

4. Patients with NO reasonably accessible lesions as described above can be enrolled
in the trial.

Prior Therapy:

- There is no restriction as to the number of prior regimens for metastatic disease as
long as patients have adequate performance status. Patients with no prior chemotherapy
for metastatic disease and patients who have received prior therapy with taxanes for
metastatic disease (taxol or taxotere) are eligible. Stratification will be used for
randomization of these two categories (no prior chemotherapy for metastatic disease or
prior taxane therapy for metastatic disease).

- Chemotherapy treatment prior to enrollment must be discontinued for at least 3 weeks
prior to study entry.

- Patients must have completed radiation therapy at least 7 days prior to beginning
protocol treatment.

- Patients must have recovered from all reversible toxicities related to prior therapy
before beginning protocol treatment, and may not have any pre- existing
treatment-related toxicities in excess of grade 1. Patients must have < grade 2
pre-existing peripheral neuropathy.

- Patients may receive bisphosphonates; however, if used, bone lesions may not be used
for progression or response.

- At least 18 years of age (19 in Alabama).

- Life expectancy of greater than 12 weeks.

- ECOG performance status < or equal to 2.

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count: > or equal to 1,500/mcL,

- Hemoglobin: > or equal to 9 mg/dL,

- Platelets: > or equal to 100,000/mcL,

- Total bilirubin: < or equal to 1.5 X institutional upper limit of normal,

- AST(SGOT)/ALT(SGPT): < or equal to 2.5 X institutional upper limit of normal
without liver metastases, OR < or equal to 5 X institutional upper limit of
normal if documented liver metastases,

- Creatinine: < or equal to 2.0 mg/dL, OR calculated creatinine clearance greater
than or equal to 50 mL/min (calculated by the Cockcroft and Gault method).

- Ability to understand and the willingness to sign a written informed consent document.

- Both men and women are eligible.

- Use of an effective means of contraception in subjects of child-bearing potential.

- Negative serum or urine beta-HCG pregnancy test at screening for patients with
childbearing potential.

Exclusion Criteria:

- Patients may not be receiving any other investigational agents.

- Prior use of Abraxane for metastatic disease or in the adjuvant setting.

- Metastatic lesions identifiable only by PET.

- Patients may not be receiving concurrent chemotherapy for treatment of metastatic
disease.

- Active brain metastases: evidence of progression < or equal to 3 months after local
therapy (patients should be asymptomatic and off corticosteroids and anticonvulsants
for at least 3 months prior to study entry).

- Patients with brain metastases must have at least one site of measurable disease
outside of the central nervous system.

- Uncontrolled concurrent illness including, but not limited to, ongoing or active
infection, history of recent myocardial infarction, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements.

- Pregnant or lactating women are excluded. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother,
breastfeeding should be discontinued if the mother is treated. These potential risks
may also apply to other agents used in this study.

- A prior invasive malignant disease within five years except for skin cancer (squamous
cell or basal cell carcinoma).

- Patients with known history of HIV or Hepatitis B because of potential for added
toxicity from treatment regimen.

- Dementia or altered mental status that would prohibit the understanding of informed
consent.