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Effects of MK-3475 (Pembrolizumab) on the Breast Tumor Microenvironment in Triple Negative Breast Cancer (Pembro/IORT)

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: NCT02977468
Recruitment Status : Recruiting
First Posted : November 30, 2016
Last Update Posted : September 24, 2019
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Eileen Connolly, Columbia University

Brief Summary:

Assess response to pembrolizumab in both primary tumor, normal breast stroma, circulating lymphocytes and serum exosomes in treatment naive triple negative breast cancer (TNBC) patients.

Assess for change in tumor-infiltrating lymphocytes (TILS) both stromal (sTILS) and intraepithelial (iTILS) in newly diagnosed early stage TNBC patients treated with two doses of MK-3475 prior to lumpectomy.

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: Merck 3475 Pembrolizumab Radiation: Intraoperative radiation therapy (IORT) Phase 1

Detailed Description:

This is an open-label, single-arm, single institution pre-operative "window of opportunity study" of pembrolizumab in subjects with newly diagnosed triple-negative, < 3 cm, node negative breast cancer. Subjects may not have received any prior neo/adjuvant chemotherapy, definitive surgery or radiation treatment prior to enrollment.

The goal of this project is to determine if immune modulation through treatment with MK-3475 (Pembrolizumab) in triple negative breast cancer (TNBC) patients will alter expression of immune tolerant markers [including PD-L1], within the primary tumor. Investigators hope to determine if MK-3475 exposure will change the molecular signature of breast stroma from "normal" adjacent breast tissue (non-tumor tissue) obtained prospectively at the time of breast conserving surgery (BCS) in TNBC patients. Finally, investigators will investigate how pembrolizumab alters breast stromal response to high dose radiation delivered by intraoperative radiation therapy (IORT).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effects of MK-3475 (Pembrolizumab) on the Breast Tumor Microenvironment in Triple Negative Breast Cancer With and Without Intra-operative RT: a Window of Opportunity Study
Actual Study Start Date : October 25, 2017
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Single Arm open label

Participants receive 'Merck 3475 Pembrolizumab' by vein one to two times before Intraoperative radiation therapy (IORT).

The Intrabeam® Photon Radiosurgery System is a miniature electron beam-driven X-ray source which provides a point source of low energy X-rays (50 kV maximum) at the tip of a 3.2 mm diameter tube. The radiation source can be inserted into the area of interest immediately after excision of the tumor and switched on for 20-35 minutes to provide intraoperative radiotherapy accurately targeted to the tissues that are at the highest risk of local recurrence. The dosimetric characteristics and early clinical applications of this device have been well studied and this is the device which was utilized in the international TARGIT trial.

Drug: Merck 3475 Pembrolizumab
Participants receive Pembrolizumab by vein over about 30 minutes on Day 1 of one to two cycles.
Other Names:
  • Keytruda
  • SCH-900475
  • MK-3475

Radiation: Intraoperative radiation therapy (IORT)
Participants will receive Intraoperative radiation therapy (IORT) on the day of surgery.
Other Names:
  • IORT
  • Zeiss Intrabeam

Primary Outcome Measures :
  1. Number of subjects with significant mean percent change in TILs [ Time Frame: 3 months ]
    This outcome measure is designed to determine if immune modulation therapy with MK-3475 will increase TILs in newly diagnosed TNBC tumors. The mean percent change in TILS in tumor tissue from initial core biopsy samples will be compared with pathology samples from definitive surgery after two cycles of MK-3475.

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:   21 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Be willing and able to provide written informed consent/assent for the trial.
  2. Be > or = 21 years of age on day of signing informed consent.
  3. Histologically proven invasive breast carcinoma with triple negative receptor status (Estrogen receptor, Progesterone receptor and HER2 negative by IHC and FISH). Patients who are weekly positive for the estrogen or progesterone receptor (i.e., < or = 10%) are eligible.
  4. Clinically ≤ 3 cm unifocal lesion by imaging or physical examination.
  5. Clinically node negative, no evidence of metastatic disease.
  6. No prior anti-cancer therapy including investigational agents, radiation therapy, or breast resection within 6 months of study entry.
  7. Breast size B cup or larger, to allow for IORT procedure.
  8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  9. Demonstrate adequate organ function.
  10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  11. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication.

Exclusion Criteria:

  1. Multifocal disease within the breast.
  2. Has primary lesion > 3 cm in size radiographically or by physical examination. Pathologically proven nodal disease at diagnosis is not allowed.
  3. Has metastatic disease.
  4. Has a known additional malignancy that is progressing or requires active treatment in the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, DCIS of the breast, or in situ cervical cancer that has undergone potentially curative therapy.
  5. Patients for whom radiotherapy for breast cancer is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation).
  6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  7. Has a known history of active TB (Bacillus Tuberculosis).
  8. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or any of its excipients.
  9. Has 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.
  10. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  11. Has an active infection requiring systemic therapy.
  12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  14. Is pregnant or breastfeeding, or expected to conceive children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

    The effects of MK-3745 on the developing human fetus are unknown. For this reason and because monoclonal antibody neoplastic agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

  15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
  16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  17. Has received a live vaccine within 30 days of planned start of study therapy.
  18. Has a medical history of allogenic stem cell transplant
  19. Has received a solid organ transplant

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): NCT02977468

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Contact: Eileen Connolly, MD 212-305-5050
Contact: Radiation Oncology Research Department 212-305-5050

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United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Eileen Connolly, MD    212-305-5050   
Contact: Mariamne Reyna    646-317-4244   
Principal Investigator: Eileen Connolly, MD, PhD         
Sponsors and Collaborators
Eileen Connolly
Merck Sharp & Dohme Corp.
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Principal Investigator: Eileen Connolly, MD Assistant Professor Of Radiation Oncology
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Responsible Party: Eileen Connolly, Assistant Professor of Radiation Oncology, Columbia University Identifier: NCT02977468    
Other Study ID Numbers: AAAQ7863
First Posted: November 30, 2016    Key Record Dates
Last Update Posted: September 24, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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 Eileen Connolly, Columbia University:
triple negative breast cancer
tumor microenvironment
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents