L-NMMA Plus Docetaxel in Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients

This is a Phase Ib/II study assessing the maximum tolerated dose (MTD), dose-limiting
toxicities (DLTs), recommended Phase 2 dose (RP2D), and efficacy of L-NMMA when combined with
docetaxel in refractory locally advanced or metastatic triple negative breast cancer
patients. The Phase Ib portion of the study is designed to investigate the combination at two
dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5,
15, 17.5, and 20 mg/kg). The starting dose of L-NMMA will be 7.5 mg/kg. L-NMMA dose will
escalate/de-escalate based on DLT occurrence. For the 5, 7.5, 10, 12.5, and 15 mg/kg L-NMMA
doses, docetaxel will be administered at 75 mg/m2. For the 17.5 and 20 mg/kg L-NMMA doses,
docetaxel will be administered at 100 mg/m2. In the Phase II portion of the study, the
starting dose will be the RP2D determined in the Phase Ib portion of the study. Patients will
receive up to 6 (21-day) cycles of the L-NMMA and docetaxel combination. L-NMMA will be
administered via 2-hour intravenous (IV) infusion on Days 1-5 of each cycle. Docetaxel will
be administered via 1-hour IV infusion approximately 15 minutes after the Day 1 L-NMMA
infusion. For L-NMMA-induced hypertension, amlodipine (10 mg) and enteric-coated low-dose
aspirin (81 mg) will be orally administered. Amlodipine will be administered for 6 days at
each cycle, starting 24 hours before the first dose of L-NMMA. Enteric-coated low-dose
aspirin will be administered once daily during the 6 21-day cycles. For docetaxel-induced
leukopenia, pegfilgrastim (6 mg) will be administered via subcutaneous injection
approximately 24 hours after every dose of docetaxel.

Inclusion Criteria:

Patient must meet all of the following criteria:

• Female patients with pathologically determined advanced (progressive disease or
refractory to 3 cycles of standard chemotherapy) or metastatic (any line) triple negative
breast cancer (TNBC). TNBC is defined as: Estrogen receptor negative and progesterone
receptor negative (<10% staining by immunohistochemistry [IHC]).

Human epidermal growth factor receptor 2 (HER2) negative. HER2 negativity must be confirmed
by one of the following:

- Fluorescence in situ hybridization (FISH)-negative (FISH ratio <2), or

- IHC 0-1+, or

- IHC 2+ AND FISH-negative (FISH ratio <2). Eastern Cooperative Oncology Group
performance status of ≤ 2

- Age ≥ 18 years

- Laboratory values within the following ranges:

- Hemoglobin ≥9.0 g/dL (transfusions permitted)

- Absolute neutrophil count ≥1500/mm3 (1.5 x 109/L)

- Platelet count ≥100,000/mm3 (100 x 109/L)

- Total bilirubin <2 X upper limit of normal (ULN)

- Creatinine (Cr) <2 X ULN and Cr clearance (CrCl) ≥30 by Cockcroft and Gault

- Alanine transaminase (ALT) and aspartate transaminase (AST) <2 X ULN (if liver
metastases are present then ALT and AST must be <5 X ULN)

- Have adequate organ function (cardiac ejection fraction of ≥ 45%)

- Negative serum pregnancy test within 7 days of the administration of the first
treatment dose for women of childbearing potential (WOCBP). For WOCBP, adequate
contraception must be used throughout the study.

- Ability to understand the requirements of the study, provide written informed
consent and authorization of use and disclosure of protected health information,
and agree to abide by the study restrictions and return for the required
assessments.

- Patient must be willing to undergo biopsies as required by the study protocol.
Biopsies will be based on acceptable clinical risks as judged by investigator.
Tissue from a previous biopsy will be accepted in the form of tissue slides.

Exclusion Criteria:

History of poorly controlled hypertension (defined as systolic blood pressure >150 mmHg at
baseline)

- Patients with metastatic disease who have received radiation therapy, chemotherapy, or
non-cytotoxic investigational agents within 2 weeks of study treatment initiation.

- Patients who received docetaxel at any line of treatment within the past 12 months

- Evidence of New York Heart Association class III or greater cardiac disease

- History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic
conduction abnormality within the past 12 months

- History of congenital QT prolongation

- Absolute corrected QT interval of >480 msec in the presence of potassium >4.0
milliequivalent/L and magnesium >1.8 mg/dL

- Any medical or psychiatric condition that would prevent informed consent or limit
expected survival to less than 4 weeks

- Symptomatic central nervous system metastases

- Pregnant or nursing women

- Hypersensitivity or intolerance to L-NMMA, docetaxel, amlodipine, pegfilgrastim, or
their components

- Use of amlodipine or another calcium channel blocker in the past 14 days

- Alcoholism or hepatic disease with the exception of liver metastases

- Severe renal insufficiency (CrCl <30 mL/min [Cockcroft and Gault])

- History of gastrointestinal bleeding, ulceration, or perforation

- Concurrent use of potent cytochrome P450 (CYP)3A4 inhibitors

- Concurrent use of potent CYP3A4 inducers

- Concurrent use of medications that interact with nitrate/nitrites

- Use of an investigational drug within 14 days preceding the first dose of study
medication.

- Concurrent use of any complementary or alternative medicines

- Patients with > Grade 2 neuropathy

- Inability to take aspirin