Circulating Tumor DNA Enriched, Genomically Directed Post-neoadjuvant Trial for Patients With Residual Triple Negative Breast Cancer (PERSEVERE)

• Written informed consent and HIPAA authorization for release of personal health. NOTE: HIPAA authorization may be included in the informed consent or maybe obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status 0 or 1 within 21 days prior to study registration.
• Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-)vasive breast cancer per pathology report. NOTE: ER and PR will be consideredgative if ≤ 10% of cells stain weakly positive. HER2 will be considered negative ifd 0 or 1+ by immunohistochemistry (IHC) or 2+ by IHC associated with auorescence in situ hybridization (FISH) ratio of < 2.0 or < 6 copies per cell.
• Must have clinical stage I-III at diagnosis (AJCC 8th edition) based on initialvaluation by physical examination and/or breast imaging prior to neoadjuvanthemotherapy.
• Must have completed preoperative (neoadjuvant) chemotherapy for this index case. NOTE:Acceptable preoperative regimens include an anthracycline or a taxane, or both.Participants who received preoperative therapy as part of a clinical trial may enroll.Participants may not have received adjuvant chemotherapy after surgery prior togistration. Bisphosphonate use is allowed.
• Subjects receiving pembrolizumab are eligible and may continue treatment during theg process. Subjects assigned to Arm 1 will require a 3 week wash out periodudy treatment. Subjects assigned to Arm 2 and Arm 3 mayue pembrolizumab treatment during the study based on investigator discretion.
• Must have significant residual invasive disease at the time of definitive surgerywing preoperative chemotherapy. Significant residual disease is defined as athe following:
  • Residual invasive disease in the breast measuring at least 1 cm. The presence ofDCIS without invasion does not qualify as residual disease in the breast.
  • Any macroscopic, ≥ 2mm, lymph node involvement regardless of primary tumor sitevolvement (includes no residual disease in the breast).
  • Residual cancer burden (RCB) score 2 or 3.
• Must have completed definitive resection of primary tumor. Participants must begin
  assigned arm therapy no later than 84 days from the last local therapy. NOTE: Negativegins for both invasive and ductal carcinoma in situ (DCIS) are desirable, howeverwith positive margins may enroll if the study site treatment teambelieves no further surgery is possible and participant has received radiotherapy.Participants with margins positive for lobular carcinoma in situ (LCIS) are eligible.her mastectomy or breast conserving surgery (including lumpectomy or partialy) is acceptable.
• Breast Radiotherapy
  • Radiotherapy is required for participants who underwent breast-conservingherapy, including lumpectomy or partial mastectomy.
  • Post mastectomy radiation is at the discretion of the treating physician.
  • If radiation was given prior to surgery, additional radiation after surgery isquired.
  • In all cases participants must begin arm assigned therapy no later than 84 dayshe last local therapy
  • Any acute toxicity must have resolved to grade < 2 prior to starting arm specificherapy.
• Must consent to allow submission of blood and archived tumor tissue sample from
  definitive surgery for next generation sequencing of the tumor. Tumor block isd however 14 slides + 1H&E can be submitted if necessary. NOTE: Due toble false positives, ctDNA should not be drawn before completing radiation orhan 14 days from surgery if radiation is not required.
• Adequate laboratory values must be obtained within 21 days prior to studygistration.
  • Hemoglobin (Hgb) ≥ 9.0 g/dL
  • Platelets ≥ 100 K/mm3
  • Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
  • Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula
  • Bilirubin ≤ 1.5 ULN (except in participants with documented Gilbert's disease,who must have a total bilirubin ≤ 3.0 mg/dL)
  • Aspartate aminotransferase (AST, SGOT) ≤ 2.5 ULN
  • Alanine aminotransferase (ALT, SGPT) ≤ 2.5 ULN
• Women of childbearing potential and their partners and male subjects and their
  partners must be willing to use effective contraception (as outlined in protocol) fromhe time consent is signed until after protocol therapy discontinuation based onkage insert or investigator brochure guidelines (See protocol for timeframes).
• Women of childbearing potential must have a negative pregnancy test at screening andwithin 7 days prior to study registration. Women should be counseled regardingble birth control methods to utilize. If prior to treatment after discussionwith the subject it is felt by the treating physician there is a possibility theubject is pregnant a pregnancy test should be repeated. NOTE: Women are consideredhildbearing potential if they are surgically sterile (they have undergone ahysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they areusal for at least 12 consecutive months.
• Women must not be breastfeeding from the time of treatment initiation until the numberdays after protocol therapy discontinuation based on package insert or investigatorbrochure guidelines (See protocol for timeframes).

        Inclusion Criteria for Patients Assigned to Arm 1c ONLY -Adequate laboratory values must bebtained within 21 days prior to starting arm therapy.Fasting total glucose ≤ 126 mg/dLHbA1C ≤ 5.7%Cholesterol < 300 mg/dL; 10.34 mmol/LTriglycerides < 300 mg/dL; 3.42 mmol/LGeneral Exclusion CriteriaClinically significant infections as judged by the treating physician. NOTE: Forwho are exhibiting symptoms consistent with COVID-19 or have testedve using a test consistent with the institutional standard of care, enrollmentd protocol treatment should not be initiated until resolution of symptoms as pervestigator discretion.ge IV (metastatic) disease, however no specific staging studies are required in thebsence of symptoms or physical exam findings that would suggest distant disease.HIV-infected patients on effective anti-retroviral therapy with undetectable virald within 6 months of registration are eligible for this trial. NOTE: Patientswithout a known history of being HIV positive do not require testing at screening.Patients who are known to be HIV positive will require testing as described to begible for this trial. Testing should be considered standard of care.Patients with evidence of chronic hepatitis B virus (HBV) infection, with undetectableHBV viral load within 6 months of registration are eligible for this trial. Theyhould be on suppressive therapy, if indicated. Patients with a history of hepatitis Cvirus (HCV) infection must have been treated and cured. For patients with HCVwho are currently on treatment, the HCV viral load must be undetectablewithin 6 months of registration to be eligible for this trial. NOTE: Patients withoutknown history of being hepatitis positive do not require testing at screening.Patients who are known to be hepatitis positive will require testing as described tobe eligible for this trial. Testing should be considered standard of care.Participants with unstable angina or a myocardial infarction within 12 months of studygistration.Active second malignancy (except non-melanomatous skin cancer or incidental prostateund on cystectomy): Active second malignancy is defined as a current need forherapy or a high possibility (> 30%) of recurrence during the study. Previousbreast cancer is allowable unless it meets "active" criteria as statedbove.History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenicganizing pneumonia), or evidence of active pneumonitis on screening chestuterized tomography (CT) scan. History of radiation pneumonitis in the radiationd (fibrosis) is permitted.History of interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis,Aspergillosis, active tuberculosis, or history of opportunistic infections(pneumocystis pneumonia or cytomegalovirus pneumonia).History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative) or active bowel inflammation (e.g., diverticulitis).History of autoimmune disease, including but not limited to myasthenia gravis,yositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoidhritis, inflammatory bowel disease, vascular thrombosis associated withhospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome,Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.Patients with the following are eligible:history of autoimmune-related hypothyroidism on a stable dose ofhyroid-replacement hormoned Type 1 diabetes mellitus on a stable insulin dosing regimenzema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologicy (e.g. patients with psoriatic arthritis would be excluded)d provided that they meet the following conditions:h must cover less than 10% of body surface areadisease is well controlled prior to arm assignment and only requires lowy topical steroidsute exacerbations of underlying condition within the previous 12 months(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate,ds, biologic agents, oral calcineurin inhibitors, or high potency ords).Treatment with systemic corticosteroids or other systemic immunosuppressivedications (including but not limited to prednisone, dexamethasone, cyclophosphamide,zathioprine, methotrexate, thalidomide, mycophenolate and anti-tumor necrosis factor[TNF] agents) within 2 weeks prior to arm assignment, or anticipated requirement forystemic immunosuppressive medications during the trial. Patients who have receivedute, low dose, systemic immunosuppressant medications (e.g. one-time dose ofdexamethasone) may be enrolled in the study. The use of inhaled corticosteroids forhronic obstructive pulmonary disease, mineralocorticoids (e.g. fludrocortisone) forwith orthostatic hypotension, and low dose supplemental corticosteroids (<10g prednisone or equivalent) for adrenocortical insufficiency are allowed. Patientswith a history of allergic reaction to IV contrast requiring steroid pre-treatmenthould have screening and subsequent tumor assessments performed using magneticging (MRI).bility to swallow pills.vidence of significant uncontrolled concomitant disease that could affect compliancewith the protocol, safety of participation, or interpretation of results. Thisudes significant liver disease (such as cirrhosis, uncontrolled major seizuredisorder, or superior vena cava syndrome) or any other serious medical condition orbnormality in clinical laboratory tests that meet these criteria in thevestigator's opinion.Prior history of stem cell or solid organ transplantation.History of severe allergic, anaphylactic, or other hypersensitivity reactions to anyhe study medications being used in this study.Treatment with any investigational agent within 30 days prior to study registration.usion Criteria for Patients Assigned to Arm 1c ONLYAny concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy)hat, in the opinion of the investigator, would require medical or surgical interventionduring the study period to prevent or treat vision loss that might result from thatdition.