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

This is an interventional treatment trial for Breast Cancer Read More

General Inclusion Criteria

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or may be 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-) invasive breast cancer per pathology report. NOTE: ER and PR will be considered negative if ≤ 10% of cells stain weakly positive. HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence 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 initial evaluation by physical examination and/or breast imaging prior to neoadjuvant chemotherapy.
• 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 to registration. Bisphosphonate use is allowed.
• Subjects receiving pembrolizumab are eligible and may continue treatment during the screening process. Subjects assigned to Arm 1 will require a 3 week wash out period prior to initiation of study treatment. Subjects assigned to Arm 2 and Arm 3 may continue pembrolizumab treatment during the study based on investigator discretion.

• Must have significant residual invasive disease at the time of definitive surgery following preoperative chemotherapy. Significant residual disease is defined as at least one of the following:

  • Residual invasive disease in the breast measuring at least 1 cm. The presence of DCIS without invasion does not qualify as residual disease in the breast.
  • Any macroscopic, ≥ 2mm, lymph node involvement regardless of primary tumor site involvement (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: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however participants with positive margins may enroll if the study site treatment team believes no further surgery is possible and participant has received radiotherapy. Participants with margins positive for lobular carcinoma in situ (LCIS) are eligible. Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable.

• Breast Radiotherapy

  • Radiotherapy is required for participants who underwent breast-conserving therapy, 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 is not required.
  • In all cases participants must begin arm assigned therapy no later than 84 days from the last local therapy
  • Any acute toxicity must have resolved to grade < 2 prior to starting arm specific therapy.
• Must consent to allow submission of blood and archived tumor tissue sample from definitive surgery for next generation sequencing of the tumor. Tumor block is preferred however 14 slides + 1H&E can be submitted if necessary. NOTE: Due to possible false positives, ctDNA should not be drawn before completing radiation or less than 14 days from surgery if radiation is not required.

• Adequate laboratory values must be obtained within 21 days prior to study registration.

  • 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) from the time consent is signed until after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes).
• Women of childbearing potential must have a negative pregnancy test at screening and within 7 days prior to study registration. Women should be counseled regarding acceptable birth control methods to utilize. If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a pregnancy test should be repeated. NOTE: Women are considered not of childbearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they are postmenopausal for at least 12 consecutive months.
• Women must not be breastfeeding from the time of treatment initiation until the number of days after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes).

Inclusion Criteria for Patients Assigned to Arm 1c ONLY -Adequate laboratory values must be obtained within 21 days prior to starting arm therapy.

• Fasting total glucose ≤ 126 mg/dL
• HbA1C ≤ 5.7%
• Cholesterol < 300 mg/dL; 10.34 mmol/L
• Triglycerides < 300 mg/dL; 3.42 mmol/L

General Exclusion Criteria

• Clinically significant infections as judged by the treating physician. NOTE: For participants who are exhibiting symptoms consistent with COVID-19 or have tested positive using a test consistent with the institutional standard of care, enrollment and protocol treatment should not be initiated until resolution of symptoms as per investigator discretion.
• Stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. NOTE: Patients without 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 be eligible for this trial. Testing should be considered standard of care.
• Patients with evidence of chronic hepatitis B virus (HBV) infection, with undetectable HBV viral load within 6 months of registration are eligible for this trial. They should be on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable within 6 months of registration to be eligible for this trial. NOTE: Patients without a known history of being hepatitis positive do not require testing at screening. Patients who are known to be hepatitis positive will require testing as described to be eligible for this trial. Testing should be considered standard of care.
• Participants with unstable angina or a myocardial infarction within 12 months of study registration.
• Active second malignancy (except non-melanomatous skin cancer or incidental prostate cancer found on cystectomy): Active second malignancy is defined as a current need for cancer therapy or a high possibility (> 30%) of recurrence during the study. Previous contralateral breast cancer is allowable unless it meets "active" criteria as stated above.
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (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 colitis) or active bowel inflammation (e.g., diverticulitis).

• History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 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 of thyroid-replacement hormone
  • controlled Type 1 diabetes mellitus on a stable insulin dosing regimen

  • eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g. patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

    • rash must cover less than 10% of body surface area
    • disease is well controlled prior to arm assignment and only requires low potency topical steroids
    • no acute exacerbations of underlying condition within the previous 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral steroids).
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, mycophenolate and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to arm assignment, or anticipated requirement for systemic immunosuppressive medications during the trial. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g. one-time dose of dexamethasone) may be enrolled in the study. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g. fludrocortisone) for patients with orthostatic hypotension, and low dose supplemental corticosteroids (<10 mg prednisone or equivalent) for adrenocortical insufficiency are allowed. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have screening and subsequent tumor assessments performed using magnetic resonance imaging (MRI).
• Inability to swallow pills.
• Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol, safety of participation, or interpretation of results. This includes significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome) or any other serious medical condition or abnormality in clinical laboratory tests that meet these criteria in the investigator's opinion.
• Prior history of stem cell or solid organ transplantation.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study medications being used in this study.
• Treatment with any investigational agent within 30 days prior to study registration.

Exclusion Criteria for Patients Assigned to Arm 1c ONLY

-Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition.