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TAC Chemotherapy and Pembrolizumab Plus Interleukin-12 Gene Therapy and L-NMMA in Triple Negative Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04095689
Recruitment Status : Not yet recruiting
First Posted : September 19, 2019
Last Update Posted : September 23, 2019
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
The Methodist Hospital System

Brief Summary:
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 preoperative (neoadjuvant) chemotherapy.

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: Docetaxel Drug: Doxorubicin Drug: Cyclophosphamide Drug: Pembrolizumab Drug: IL-12 gene therapy Drug: L-NMMA Phase 2

Detailed Description:

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 chemotherapy treatment.

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 L-NMMA.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 43 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of TAC Chemotherapy and Pembrolizumab Plus Interleukin-12 Gene Therapy Followed by TAC Chemotherapy and Pembrolizumab Plus L-NMMA in Patients With Triple Negative Breast Cancer
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Experimental
docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy and pembrolizumab plus IL-12 gene therapy followed by TAC chemotherapy and pembrolizumab plus the pan-nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA)
Drug: Docetaxel
Microtubule-targeting drug (inhibits microtubule depolymerization)
Other Name: Taxotere

Drug: Doxorubicin
Topoisomerase inhibitor
Other Name: Adriamycin

Drug: Cyclophosphamide
DNA crosslinking drug
Other Name: Cytoxan

Drug: Pembrolizumab
Programmed cell death-1 (PD-1) inhibitor
Other Name: Keytruda

Drug: IL-12 gene therapy
Adenoviral-mediated IL-12

Drug: L-NMMA
pan-NOS inhibitor
Other Name: NG-monomethyl-L-arginine

Primary Outcome Measures :
  1. pathological complete response (pCR) rate of TAC chemotherapy and pembrolizumab plus IL-12 gene therapy followed by TAC chemotherapy and pembrolizumab plus L-NMMA [ Time Frame: 18 weeks ]
    To determine the pCR rate of TAC chemotherapy and pembrolizumab plus IL-12 gene therapy followed by TAC chemotherapy and pembrolizumab plus L-NMMA in patients with TNBC

Secondary Outcome Measures :
  1. pCR rate of TAC chemotherapy and pembrolizumab plus IL-12 gene therapy [ Time Frame: 18 weeks ]
    To estimate the pCR rate of TAC chemotherapy and pembrolizumab plus IL-12 gene therapy

  2. Number of participants with treatment-related adverse events [ Time Frame: 18 weeks ]
    To determine the number of participants with treatment-related adverse events, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  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.

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.

  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 eligible.
    • NOTE: 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. 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) infection.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04095689

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Contact: Houston Methodist Cancer Center 713-441-0629
Contact: Jenny Chang, M.D. 713-441-0629

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United States, Texas
Houston Methodist Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
The Methodist Hospital System
Merck Sharp & Dohme Corp.
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Principal Investigator: Jenny Chang Houston Methodist Cancer Center
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Responsible Party: The Methodist Hospital System Identifier: NCT04095689    
Other Study ID Numbers: Merck IIS
First Posted: September 19, 2019    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by The Methodist Hospital System:
triple negative breast cancer, neoadjuvant, pembrolizumab
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological