Low or High Dose Radiation with Pembrolizumab and Preoperative Chemotherapy for the Treatment of Non-Metastatic Node Positive Triple Negative Breast Cancer, P-RAD(+)TN Trial

Inclusion Criteria

• Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information. Subjects is willing and able to comply with study procedures based on the judgement of the investigator
• Age ≥ 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Status of 0 or 1
• Participant has non-metastatic, N1-3* and has histologically confirmed triple negative breast cancer, defined as estrogen receptor (ER) < 10% cells, progesterone receptor (PR) < 10% cells) and HER2- negative (<2+ HER2 immunohistochemistry [IHC] or <2.2 HER2/CEP17 ratio by Fluorescence In Situ Hybridization [FISH]), as per testing at local institution. * Primary breast tumor ≥ 1.0 cm in maximal diameter as measured by any available standard of care (SoC) breast imaging (e.g. mammogram, ultrasound, MRI). * Biopsy-proven, axillary lymph node-positive triple negative (TN) breast cancer at diagnosis. ** Note: Clinically node-positive disease is classified as cN1-3. *** cN1: without matted nodes, even if several/multiple appear matted on ultrasound or MRI; *** cN2: clinically fixed or matted nodes on examination or clinically or imaging detected internal mammary node involvement; *** cN3: Lymph node involvement to ipsilateral level 3 axillary nodes with or without level 1-2; or involvement of ipsilateral internal mammary nodes with level 1 and/or level 2 axillary nodes; or involvement of ipsilateral supraclavicular nodes. * Multifocal and multicentric disease is permitted; more than one breast tumor may be boosted per MD discretion. ** Note: All sites of multifocal/multicentric disease do not have to be contained within the pre-operative boost volume. MDs may decrease coverage of multifocal/multicentric tumors in the boost volume in order to meet suggested normal tissue constraints as needed. * Synchronous bilateral invasive breast cancer is permitted after discussion with the Investigator. * No indication of distant metastases. Staging scans are not required and are per the discretion of the treating physician. * Patients with ER and PR expression of 1-10% by IHC with documented confirmation that the investigator considers the patient to be an appropriate candidate for treatment as per KEYNOTE 522
• Subject already has or is planned for clips or fiducial placement within the biopsy proven axillary lymph node and breast primary tumor prior to RT simulation
• Subject has available and sufficient archival tissue from diagnostic core biopsy of the tumor and lymph node. If archival baseline tissue is not available, a mandatory biopsy is required
• Neoadjuvant chemotherapy (NAC) is planned per standard of care
• The boost volume is determined to be able to meet study dose constraints by the treating radiation oncologist
• Breast-conserving surgery or mastectomy ± reconstruction is planned following NAC
• Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen and/or in remission for 5 years are eligible for this trial
• Hemoglobin (Hgb) ≥ 9.0 g/dL or ≥ 5.6 mmol/L * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Absolute Neutrophil Count (ANC) ≥ 1.5 × 10^9/L * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Platelets ≥ 100 × 10^9/L * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Creatinine ≤ 1.5 × upper limit of normal (ULN) OR calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault Formula * Creatinine clearance (CrCl) should be calculated per institutional standard * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN. Subjects with Gilbert’s Syndrome may be enrolled despite a total bilirubin level > 1.5 mg/dL if their conjugated bilirubin is < 1.5 × ULN. * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Aspartate Aminotransferase (AST) ≤ 2.5 × ULN * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Alanine Aminotransferase (ALT) ≤ 2.5 × ULN * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• International normalized ratio (INR) or prothrombin time (PT) activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants * Note: Hematology and other lab parameters that are ≥ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to study treatment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally post-menopausal for at least 12 consecutive months. Documentation of post-menopausal status must be provided
• Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 4 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label
• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 4 months after the last dose of study therapy

Exclusion Criteria

• Active infection requiring systemic therapy
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Prior ipsilateral invasive breast, chest wall or thoracic radiotherapy
• Prior ipsilateral invasive breast cancer, contralateral breast cancer or a known additional, invasive malignancy that is progressing or required active treatment in the last 5 years. * Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or cervical carcinoma in situ that has undergone potentially curative therapy and a previous diagnosis of ductal carcinoma in situ are not excluded
• 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 with 4 weeks prior to randomization * Note: Participants must have recovered from all AEs due to previous therapies to ≤ grade 1 or baseline. Participants with ≤ grade 2 neuropathy may be eligible. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has known severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients
• Known absolute contraindications to radiotherapy including inherited syndromes associated with hypersensitivity to ionizing radiation (e.g., Ataxia Telangiectasia, Nijmegen Breakage Syndrome, Fanconi Anemia)
• Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• 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
• Known history of human immunodeficiency virus (HIV). * Note: No HIV testing is required unless mandated by local health authorities
• Known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). * Note: No testing for hepatitis B or hepatitis C is required, unless mandated by local health authorities or institutional guidelines
• Has received a live vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed
• Has had an allogenic tissue/solid organ transplant
• Subject is receiving prohibited medications or treatments that cannot be discontinued/replaced by an alternative therapy prior to initiating treatment