The purpose of this research study is to test the safety and effectiveness of adding
interleukin 12 (IL-12) gene therapy and L-NMMA to pembrolizumab in patients with early-stage
triple negative breast cancer (TNBC) receiving standard of care neoadjuvant chemotherapy.
Chemotherapy given before breast cancer surgery is called neoadjuvant chemotherapy. It
shrinks the breast tumor so it is easier to remove during surgery. Docetaxel, doxorubicin,
and cyclophosphamide chemotherapy (called TAC chemotherapy) is often used for the neoadjuvant
treatment of breast cancer. Unfortunately, a lot of breast tumors do not shrink with TAC
Pembrolizumab is a type of treatment that stimulates your own immune system to attack cancer
cells. Your immune system is normally your body's first defense against threats like cancer.
However, sometimes cancer cells produce signals that prevent the immune system from detecting
and killing them. Pembrolizumab helps your immune system so it can detect and attack cancer
cells. Chemotherapy plus pembrolizumab has been shown to be better than chemotherapy alone
for shrinking breast tumors before surgery. To increase the cancer-fighting ability of your
immune system, you will be given 1 or 2 more treatments. These include IL-12 gene therapy and
1. The patient (or legally acceptable representative if applicable) provides written
informed consent for the trial.
2. Female ≥18 years of age on the day of informed consent signing.
3. Newly diagnosed histologically confirmed TNBC.
4. Bilateral breast cancers that individually meet eligibility criteria are allowed.
5. Eastern Cooperative Oncology Group performance status of 0 or 1.
6. Adequate organ function:
- Absolute neutrophil count ≥1500/µL
- Platelets ≥100,000/µL
- Hemoglobin≥9.0 g/dL (met without transfusion within last 2 weeks)
- White blood cell count >2,500/µL and <15,000/µL
- Lymphocyte count ≥500/µL
- Creatinine OR measured calculated creatinine clearance ≤1.5 × upper limit of
normal (ULN) OR
≥30 mL/min for patient with creatinine levels >1.5 × institutional ULN
- Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for patients with total
bilirubin levels >1.5 × ULN (Patients with known Gilbert's disease who have serum
bilirubin level ≤3 × ULN may be enrolled)
- Aspartate transaminase and alanine transaminase ≤2.5 × ULN with normal alkaline
phosphatase (ALP) OR ≤1.5 × ULN in conjunction with ALP >2.5 × ULN
- International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 × ULN unless
patient is receiving anticoagulant therapy as long as PT OR aPTT is within
therapeutic range of intended use of anticoagulants
7. Cardiac ejection fraction ≥45%.
8. A female patient is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to use highly effective contraception during the treatment
period and for at least 120 days after the last dose of trial treatment. WOCBP
must have a negative serum pregnancy test (β-human chorionic gonadotropin) within
72 hours prior to trial treatment administration.
9. Willing to provide biopsy tissue as required by the trial.
10. Willing and able to comply with the protocol for the duration of the trial including
undergoing treatment and scheduled visits and examinations.
1. History of poorly controlled hypertension (defined as systolic blood pressure >150
mmHg). Patients whose hypertension has been well controlled on the same treatment for
1 year prior to Cycle 1, Day 1 are eligible. Only patients on single-agent
antihypertensive therapy are allowed.
2. History of New York Heart Association class III or greater cardiac disease..
3. History of myocardial infarction, stroke, ventricular arrhythmia, or greater than
first-degree conduction defect within the past 12 months.
4. History of congenital QT prolongation.
5. Absolute corrected QT interval of >480 msec in the presence of potassium >4.0 mEq/L
and magnesium >1.8 mg/dL.
6. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to trial treatment
NOTE: Patients who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous
7. Concurrent use of medications that interact with nitrate/nitrite.
8. Concurrent use of any complementary or alternative medicines.
9. Concurrent use of inhibitors or inducers of cytochrome P450 (CYP)3A4 and CYP2D6.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(dose exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to trial treatment administration.
11. Known history of active tuberculosis (Bacillus Tuberculosis).
12. Known or suspected hypersensitivity to any component or excipient of the proposed
regimen (TAC chemotherapy, gene vector, L-NMMA, pembrolizumab).
13. Has had prior chemotherapy, targeted small molecule therapy, radiation therapy, or
surgery within 4 weeks prior to trial treatment administration.
- NOTE: Patients must have recovered from all adverse events due to previous
therapies to ≤ Grade 1 or baseline. Patients with ≤ Grade 2 neuropathy may be
- NOTE: If patient received major surgery, she must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting the
14. Known additional malignancy that is progressing or requires active treatment. NOTE:
Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin,
or cervical cancer in situ that have undergone potentially curative therapy are not
15. Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
16. History of (noninfectious) pneumonitis that required steroids or current pneumonitis.
17. Active infection requiring systemic therapy.
18. History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with the patient's participation
for the full duration of the trial, or is not in the best interest of the patient to
participate, in the opinion of the treating investigator.
19. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.
20. Pregnant or breastfeeding, or expecting to conceive children within the projected
duration of the trial, starting with the prescreening or screening visit through 120
days after the last dose of trial treatment.
21. Received prior therapy with an immuno-oncology agent.
22. Known history of human immunodeficiency virus.
23. Known history of hepatitis B (defined as hepatitis B surface antigen reactive) or
known active hepatitis C virus (HCV; defined as HCV RNA [qualitative] is detected)
24. Received a live vaccine within 30 days prior to trial treatment administration.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.