Study of Chemotherapy in Combination With IDO Inhibitor in Metastatic Breast Cancer

It is estimated that 232,340 US women will be diagnosed with and 40,030 women will die of
breast cancer in 2013. Metastatic breast cancer is a terminal condition and treatments are
palliative in nature. The median survival for patients with metastatic breast cancer is
approximately 2.5 years. The standard therapies currently in use include anti-estrogen
therapies (anastrazole, letrozole, fulvestrant, tamoxifen), chemotherapy agents (taxanes,
capecitabine, navelbine, gemcitabine, eribulin, ixabepilone), targeted therapies
(trastuzumab, lapatinib), and supportive care agents (zolendronic acid, denosumab). While
breast cancer typically responds well to treatment, the response is transient and their
disease becomes more refractory with continued therapy. Also, quality of life is a
significant issue for these patients as many of these therapies are associated with
significant side effects. Well tolerated, novel agents which improve the efficacy of existing
chemotherapy agents would prove quite useful in managing metastatic breast cancer.

Preclinical data derived from MMTV-Neu mice with autochthonous tumors studied the interaction
between indoximod and various chemotherapeutic agents. Mice with 5-10mm tumors were enrolled
into control and treatment groups. Mice were treated with indoximod alone, chemotherapy alone
(paclitaxel, doxorubicin, cyclophosphamide, and others), and the combination of indoximod and
chemotherapy. treatment with indoximod or paclitaxel alone caused retardation of tumor growth
in this model but no regressions were seen. the combination of indoximod plus paclitaxel
caused 30% tumor regression and histologically there was significantly enhanced tumor cell
death with the combination versus either agent alone. This synergism was abrogated when the
mice underwent CD4+ T cell depletion prior to treatment with the combination, suggesting the
immune response played a role in the observed effect. Based on this data and other reports
suggesting systemic immunomodulating drugs like indoximod can synergize with chemotherapy
agents such as taxanes, the decision was made to devise this combination of therapy of
docetaxel or paclitaxel with indoximod in metastatic breast cancer.

Inclusion Criteria:

- Histologically or cytologically confirmed estrogen/progesterone receptors (ER/PR) +/-;
human epidermal growth factor receptor 2 (HER2)-, metastatic breast cancer.

- Metastatic disease that is evaluable on imaging. May have measureable disease, defined
as at least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded for non-nodal lesions and short axis for nodal
lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI,
or calipers by clinical exam. Patients can also have non-measurable disease including
bone only metastatic disease, evaluated by bone scan, PET or MRI.

- Any number of prior endocrine therapies in the metastatic setting are allowed. The
patient must not have received any prior chemotherapy agents in the metastatic
setting. Prior treatment with adjuvant docetaxel or paclitaxel is allowed if disease
relapse occurred greater than 12 months from the completion of adjuvant therapy.

- Age ≥18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Karnofsky ≥60%).

- Life expectancy of greater than 4 months.

- Patients must have normal organ and marrow function as defined below: leukocytes
≥3,000/mcL, absolute neutrophil count ≥1,500/mcL, platelets ≥100,000/mcL, total
bilirubin within normal institutional limits, aspartate aminotransferase AST(SGOT)/
alanine aminotransferase ALT(SGPT) ≤2.5 X institutional upper limit of normal,
creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73
m^2 for patients with creatinine levels above institutional normal.

- Patients with known brain metastases will only be eligible after their tumors have
been treated with definitive resection and/or radiotherapy and they are neurologically
stable for at least 1 month off steroids.

- Male and female subjects of child producing potential must agree to use adequate forms
of contraception or avoidance of pregnancy measures prior to study entry, while
enrolled on study and for a minimum of one month after completion of the study.

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

Exclusion Criteria:

- Patients who have had chemotherapy for the treatment of metastatic breast cancer are
not eligible. Patients who have had radiotherapy within 3 weeks prior to entering the
study or those who have not recovered from adverse events due to agents administered
more than 3 weeks earlier are not eligible.

- Patients who are currently receiving any other investigational agents.

- Patients with known active, untreated brain metastases should be excluded from this
clinical trial. Those with previously treated inactive brain metastases with no
evidence of active disease documented on brain MRI at least 4 weeks after radiation
and off all steroids may be eligible.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to docetaxel or tryptophan containing substances. This would include
L-tryptophan or 5-hydroxy-tryptophan supplements. Also patients with a history of
severe hypersensitivity reactions to docetaxel or to other drugs formulated with
polysorbate 80 are excluded.

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

- Pregnant women are excluded from this study because indoximod is an immunoregulatory
agent with the potential for abortifacient effects due to fetal rejection by the
maternal immune system. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with indoximod,
breastfeeding should be discontinued if the mother is treated with indoximod. Also,
docetaxel and paclitaxel are category D cytotoxic agents and are not administered to
pregnant females.

- Known HIV-positive patients and those with other acquired/inherited immunodeficiencies
are ineligible due to the possibility of affecting the response to indoximod and the
higher risk of active opportunistic infections.

- Patients with more than one active malignancy at the time of enrollment.

- Patients who have received any prior experimental active immunotherapy consisting of
targeted monoclonal antibodies (ipilimumab) or pharmaceutical compounds are excluded.

- Patients with any active autoimmune disease (i.e. psoriasis, extensive atopic
dermatitis, asthma, inflammatory bowel disease (IBD), multiple sclerosis (M.S.),
uveitis, vasculitis), chronic inflammatory condition, or any condition requiring
concurrent use of any systemic immunosuppressants or steroids for any reason would be
excluded from the study. Any patient with an allo-transplant of any kind would be
excluded as well. This would include those with a xenograft heart valve to avoid the
potential risk of any immune reaction causing valvular degeneration. Mild-intermittent
asthma requiring only occasional beta-agonist inhaler use or mild localized eczema
will not be excluded.