Clinical Trials /

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

NCT04095689

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 preoperative (neoadjuvant) chemotherapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: Merck IIS
  • NCT ID: NCT04095689

Conditions

  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
DocetaxelTaxotereExperimental
DoxorubicinAdriamycinExperimental
CyclophosphamideCytoxanExperimental
PembrolizumabKeytrudaExperimental
IL-12 gene therapyExperimental
L-NMMANG-monomethyl-L-arginineExperimental

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
ExperimentalExperimentaldocetaxel, 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)
  • Docetaxel
  • Doxorubicin
  • Cyclophosphamide
  • Pembrolizumab
  • IL-12 gene therapy
  • L-NMMA

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:pCR rate of TAC chemotherapy and pembrolizumab plus IL-12 gene therapy
Time Frame:18 weeks
Safety Issue:
Description:To estimate the pCR rate of TAC chemotherapy and pembrolizumab plus IL-12 gene therapy
Measure:Number of participants with treatment-related adverse events
Time Frame:18 weeks
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:The Methodist Hospital System

Trial Keywords

  • triple negative breast cancer, neoadjuvant, pembrolizumab

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