Overview

The primary objective is to determine the feasibility of combining pembrolizumab with a single fraction radiation boost in patients with early/ operable breast cancer. The secondary objectives are to assess clinical response on pre- and post-treatment clinical, imaging, and histology exams, and to assess immune response on pre and post treatment blood and tissue samples by tracking change in Ki67 + CD8 T cells in peripheral blood and in extent of tumor infiltrating lymphocytes. A clinically significant partial response is defined as >30% tumor shrinkage post-clinical trial intervention.

Eligibility

Inclusion Criteria:

        Men and women age ≥ 18 years old (unless otherwise specified) Willing and able to provide
        written informed consent/assent ECOG Performance Status 0 - 1
        Patients with:
        Newly diagnosed breast cancer with tumor size < 5 cm who are not eligible for I-SPY2 (to
        prevent recruitment competition), or not recommended to undergo standard of care
        neoadjuvant chemotherapy with at least one of the following features:
          -  Triple negative breast cancer (TNBC) defined using the ASCO CAP guidelines with the
             following modification supported by a recent publication as ER ≤ 10%, PR ≤ 10%, HER2-
             determined by immunohistochemistry and/or fluorescence in situ hybridization analyses
             and with tumor size ≤ 2.5 cm;
          -  HR+ HER2- breast cancer regardless of nodal status and age of diagnosis ≥ 50
          -  HR+ HER2- breast cancer and age of diagnosis <50 with tumor size ≤ 2.5 cm and
             clinically node (+)
          -  HR+ or HR- and HER2+ breast cancer with tumor size ≤ 2.5 cm
          -  Ductal carcinoma in situ (DCIS) with microinvasion
        OR
          -  Locally recurrent breast cancer of any receptor subtype with no prior radiation, not
             recommended to receive neoadjuvant chemotherapy and expecting surgical excision as
             part of treatment.
        A female participant 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) as defined in Appendix 2 of the study
             protocol OR
          2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the
             treatment period and for at least 120 days for study treatments with risk of
             genotoxicity after the last dose of study treatment.
               -  Female participants of childbearing potential should be willing to use 2 methods
                  of birth control or be surgically sterile, or abstain from heterosexual activity
                  for the course of the study through 120 days after the last dose of study
                  medication. Medically accepted methods of birth control include a diaphragm,
                  cervical cap, latex condoms, surgical sterility, intrauterine devices (IUDs),
                  hormonal implants, injectable contraceptives, or birth control pills.
                  Participants of childbearing potential are those who have not been surgically
                  sterilized or have not been free from menses for > 1 year.
               -  Ability to tolerate radiation therapy (e.g., lie flat and hold position)
               -  Demonstrate adequate hematologic, renal, hepatic, thyroid, and bone marrow
                  function
        Inclusion Criteria:
          -  Men and women age ≥ 18 years old (unless otherwise specified)
          -  Willing and able to provide written informed consent/assent
          -  ECOG Performance Status 0 - 1
          -  Patients with:
               -  Newly diagnosed breast cancer with tumor size < 5 cm who are not eligible for
                  I-SPY2 (to prevent recruitment competition), or not recommended to undergo
                  standard of care neoadjuvant chemotherapy with at least one of the following
                  features:
                    -  Triple negative breast cancer (TNBC) defined using the ASCO CAP guidelines
                       with the following modification supported by a recent publication as ER ≤
                       10%, PR ≤ 10%, HER2- determined by immunohistochemistry and/or fluorescence
                       in situ hybridization analyses and with tumor size ≤ 2.5 cm;
                    -  HR+ HER2- breast cancer regardless of nodal status and age of diagnosis ≥ 50
                    -  HR+ HER2- breast cancer and age of diagnosis <50 with tumor size ≤ 2.5 cm
                       and clinically node (+)
                    -  HR+ or HR- and HER2+ breast cancer with tumor size ≤ 2.5 cm
                    -  Ductal carcinoma in situ (DCIS) with microinvasion
        OR
          -  Locally recurrent breast cancer of any receptor subtype with no prior radiation, not
             recommended to receive neoadjuvant chemotherapy and expecting surgical excision as
             part of treatment.
             • A female participant is eligible to participate if she is not pregnant (see Appendix
             2), not breastfeeding, and at least one of the following conditions applies:
               1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 2. OR
               2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the
                  treatment period and for at least 120 days for study treatments with risk of
                  genotoxicity after the last dose of study treatment.
                  • Female participants of childbearing potential should be willing to use 2
                  methods of birth control or be surgically sterile, or abstain from heterosexual
                  activity for the course of the study through 120 days after the last dose of
                  study medication. Medically accepted methods of birth control include a
                  diaphragm, cervical cap, latex condoms, surgical sterility, intrauterine devices
                  (IUDs), hormonal implants, injectable contraceptives, or birth control pills.
                  Participants of childbearing potential are those who have not been surgically
                  sterilized or have not been free from menses for > 1 year.
                    -  Ability to tolerate radiation therapy (e.g., lie flat and hold position)
                    -  Demonstrate adequate hematologic, renal, hepatic, thyroid, and bone marrow
                       function
                  Exclusion criteria:
                  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to
                  allocation. If the urine test is positive or cannot be confirmed as negative, a
                  serum pregnancy test will be required.
                  • A history of prior radiotherapy to the ipsilateral breast/chest wall that
                  precludes delivery of hypofractionated radiotherapy.
                  • 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).
                  • Has received prior systemic anti-cancer therapy including investigational
                  agents within 4 weeks
                  • Has not adequately recovered from major surgery or has ongoing surgical
                  complications
                  • Has a known additional malignancy that is progressing or requires active
                  treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
                  carcinoma of the skin, or in situ cervical cancer that has undergone potentially
                  curative therapy.
                  • Has active autoimmune disease that has required systemic treatment in the past
                  2 years except replacement therapy (eg., thyroxine, insulin, or physiologic
                  corticosteroid)
                  • Participants with vitiligo or resolved childhood asthma/atopy would be an
                  exception to this rule. Participants that require intermittent use of
                  bronchodilators or local steroid injections would not be excluded from the study.
                  Participants with hypothyroidism stable on hormone replacement or Sjogren's
                  syndrome will not be excluded from the study. Steroid prep due to dye allergies
                  prior to staging scans or use in anti-emetic prophylaxis is allowed.
                  • Has a history of (non-infectious) pneumonitis/interstitial lung disease that
                  required steroids or has current pneumonitis/interstitial lung disease.
                  • Has an active infection requiring systemic therapy.
                  • Has a history or current evidence of any condition, therapy, or laboratory
                  abnormality that might confound the results of the trial, interfere with the
                  participant's participation for the full duration of the trial, or is not in the
                  best interest of the participant to participate, in the opinion of the treating
                  investigator.
                  • Has known psychiatric or substance abuse disorders that would interfere with
                  cooperation with the requirements of the trial.
                    -  Is pregnant or breastfeeding or expecting to conceive or father children
                       within the projected duration of the trial, starting with the pre-screening
                       or screening visit through 120 days after the last dose of trial treatment.
                    -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2
                       antibodies).
                    -  Has a known history of Hepatitis B (defined as Hepatitis B surface antigen
                       [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA
                       [qualitative] is detected) infection.
                  Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by
                  local health authority.
                  • Has received a live vaccine or live-attenuated vaccine within 30 days before
                  the first dose of study intervention. Administration of killed vaccines is
                  allowed.
                  Note: please refer to Section 5.7 for information on COVID-19 vaccines • Has
                  severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
                  • Has had an allogenic tissue/solid organ transplant.