Docetaxel Chemotherapy and Pembrolizumab Plus Interleukin-12 Gene Therapy in Triple Negative Breast Cancer

The purpose of this research study is to test the safety and effectiveness of docetaxel chemotherapy and pembrolizumab plus adenoviral-mediated interleukin-12 (ADV/IL-12) gene therapy in patients with anthracycline-refractory, triple negative breast cancer (TNBC).

The purpose of this study is to learn how triple negative breast cancer (TNBC) responds to the use of chemotherapy, pembrolizumab, and gene therapy together in patients who have previously not responded to treatment. We will also look at the effects, good or bad, the study therapy has on you and your TNBC.

Chemotherapy given before breast cancer surgery is called neoadjuvant chemotherapy. It shrinks the breast tumor, so it is easier to remove during surgery. Docetaxel is often used for the neoadjuvant treatment of breast cancer. Unfortunately, a lot of breast tumors do not shrink with docetaxel chemotherapy treatment. Docetaxel chemotherapy is standard care for TNBC.

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 help increase the tumor-shrinking activity of docetaxel chemotherapy and pembrolizumab, you will be given more treatments, Interleukin-12 (IL-12) gene therapy This treatments will be used to boost the cancer-fighting ability of your immune system. Thus, the use of IL-12 gene therapy with docetaxel chemotherapy and pembrolizumab may make your immune system work harder to shrink your tumor. IL-12 is a substance that is normally made by certain immune cells in the body. IL-12 stimulates T cells, a special type of immune cell in the blood, to respond to threats to your body like cancer.

After you finish the study treatment, you will have your breast cancer surgery.

Eligibility Criteria:
Inclusion Criteria:

Patients are eligible to be included in the trial only if all of the following criteria apply:

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. Histologically confirmed triple negative breast cancer is defined as estrogen receptor (ER), progesterone receptor (PR), and HER2 negative. ER/PR negativity is defined as \<10% IHC staining of any intensity.

HER2 negativity is defined as the following per the 2018 American Society of Clinical Oncology and College of American Pathologists guidelines.

4. Refractory to standard neoadjuvant anthracycline-containing chemotherapy regimen, demonstrated on MRI.

5. Bilateral breast cancers that individually meet eligibility criteria are allowed.

6. Prior immunotherapy treatment allowed. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8. Adequate organ function as defined in Table 1. All screening labs should be performed within 28 days of trial treatment initiation.

9. Cardiac ejection fraction ≥45%. 10. 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 follow the contraceptive guidance in 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 \[β-HCG\]) within 72 hours prior to trial treatment administration.

   11. Willing to provide biopsy tissue as required by the trial. 12. Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations.

   Exclusion Criteria:
   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 administration.

   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 investigational agent.

   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 (docetaxel chemotherapy, gene vector, pembrolizumab).

   13. Patients must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Patients with ≤ Grade 2 neuropathy may be eligible. If patient received major surgery, she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting the trial treatment.

   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 excluded.

   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. Known history of human immunodeficiency virus (HIV). 22. 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) infection.

   23. 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.