Neoadjuvant Angiogenesis-Targeting Bispecific Chemoimmunotherapy for TNBC

Inclusion Criteria: Ability of participant OR Legally Authorized Representative (LAR) to understand this study, and participant or LAR willingness to sign a written informed consent 18 years of age or older Histologically confirmed cT1c-T3 N0 or cT1-T3 N1-N2 triple-negative breast cancer * The invasive tumor must be hormone receptor poor, defined as both estrogen receptor (ER) and progesterone receptor staining in ≤ 10% of invasive cancer cells by IHC. * The invasive tumor must be HER2-negative based on the current ASCO-CAP guidelines 79. * Subjects with bilateral synchronous triple-negative breast cancer are eligible if they meet other eligibility criteria. No previous ipsilateral breast surgery for the current breast cancer No previous chemotherapy, immunotherapy, targeted therapy, endocrine therapy, or radiotherapy for the current breast cancer ECOG Performance Status 0 or 1, documented within 21 days prior to the start of study treatment (Appendix A) Breast and axillary imaging (including MRI and either mammogram and/or ultrasound, per standard of care) within 56 days (8 weeks) prior to treatment initiation Subjects with clinically and/or radiographically abnormal axillary or internal mammary lymph nodes should have pathologic assessment of disease status with image-guided biopsy or fine needle aspiration unless deemed medically unsafe Co-enrollment in the PROGECT (HSC #12614) observational registry protocol Archival breast tumor tissue has been obtained or has been requested for use, which should include either a formalin-fixed paraffin-embedded (FFPE) block, or sixteen slides (fourteen 5-micron uncharged unstained slides plus either two H\&E slides or two 5-micron charged unstained slides) - from primary breast tumor only. Neuropathy: No baseline grade 2 or above neuropathy Not pregnant, not breastfeeding, and at least one of the following applies: * Not a woman of reproductive potential as defined by institutional standards and treating physician's discretion * A woman of reproductive potential who agrees to follow contraceptive guidelines per institutional standards during the treatment period and for at least 3 months after the last dose of ivonescimab, or until 6 months after last dose of carboplatin or doxorubicin, 2 months after last dose of docetaxel, or 12 months after last dose of cyclophosphamide (whichever is longer). Adequate organ function, defined as follows: Hematologic (assessed ≤ 21 days of treatment initiation): * Absolute neutrophil count ≥ 1,500/μL (with the exception of patients with documented Fy(a-/b-) (Duffy null) immunophenotype, in which case absolute neutrophil count ≥1,200/uL is allowed) * Platelets ≥ 100,000/μL * Leukocytes ≥ 3,000/μL * Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (must be met without erythropoietin dependency and without erythrocyte transfusion within the last two weeks) Coagulation (assessed ≤ 21 days of treatment initiation): For patients who are not on therapeutic anti-coagulation: * Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5x ULN * Partial prothrombin time (PTT) or activated partial prothrombin time (aPTT) ≤ 1.5x ULN (unless abnormalities are unrelated to coagulopathy). Patients receiving therapeutic anti-coagulation should be on a stable dose. Renal (assessed ≤ 21 days of treatment initiation): * Creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 60 mL/min * Urine protein test \<2+ or 24-hour urine protein quantification \<1.0 g Hepatic (assessed ≤ 21 days of treatment initiation): * Total bilirubin ≤ 1.5x ULN * AST(SGOT) and ALT(SPGT) ≤ 2x ULN * Serum albumin ≥ 3.0 g/dL Cardiac (assessed ≤ 56 days of treatment initiation): * Subjects with heart failure are not eligible, nor are patients with myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke, or transient ischemic attack within the past 12 months, uncontrolled hypertension (systolic BP \> 150 mmHg, diastolic BP \> 100 mmHg), uncontrolled or symptomatic arrythmia, or greater than grade 2 peripheral vascular disease * LVEF ≥ 50% by echocardiogram or MUGA scan, per standard of care Exclusion Criteria: Current or anticipated use of other investigational agents while participating in this study Clinically or radiographically detected metastatic disease Inflammatory breast cancer Prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the treatment regimen. \- Note: Patients with squamous cell or basal cell carcinoma of the skin, ductal carcinoma in situ (DCIS) of the breast, or carcinoma in situ (CIS) of the uterine cervix who have undergone definitive therapy are not excluded from participation History of allergic reactions attributed to carboplatin, docetaxel, doxorubicin, or cyclophosphamide History of severe (≥ grade 3) hypersensitivity to ivonescimab or any of its excipients, or to any other monoclonal antibody Prior treatment with a VEGF inhibitor or with an anti-PD-1, anti-PD-L1, anti-PD-L2 inhibitor or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA4, OX40, CD137) History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to starting study treatment, including but not limited to: * Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots). Note: Transient hemoptysis associated with diagnostic bronchoscopy is allowed. * Nasal bleeding /epistaxis (bloody nasal discharge is allowed) * Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to starting study treatment. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to institutional guidelines. Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy Major surgical procedures or serious trauma within 4 weeks prior to start of study treatment, major surgical procedures planned for within 4 weeks after the first dose of study treatment, or minor local procedures within 3 days prior to start of study treatment (as determined by the investigator). \- Note: Central venous catheterization and port implantation within 3 days prior to start of study treatment are allowed. Subject has received a live vaccine within 30 days prior to treatment initiation * Live vaccines include (but are not limited to) measles, mumps, rubella, varicella/zoster (chicken pox and shingles), yellow fever, rabies, Bacillus-Calmette-Guérin (BCG), typhoid. * Note: Seasonal injectable influenza vaccines are killed virus and are allowed Subject is currently receiving treatment or has received treatment with an investigational agent within four weeks prior to treatment initiation, or has used an investigational device within four weeks prior to treatment initiation Has a diagnosis of immunodeficiency or is receiving chronic steroid therapy (in doses exceeding 10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment Active autoimmune or lung disease that has required systemic treatment (e.g., disease-modifying agents, corticosteroids in doses exceeding 10 mg daily prednisone equivalent, immunosuppressive drugs) in the past two years. * Note: Patients using replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid therapy) are eligible * Note: Intermittent use of bronchodilators, inhaled corticosteroids, topical corticosteroids, or local corticosteroid injections is permitted History of major diseases before starting study treatment, specifically any of the following: * Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association \[NYHA\] classification ≥ grade 2) or unstable vascular disease (e.g., aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to starting study treatment, or other cardiac impairment that may affect the safety evaluation of the study drug (e.g., poorly controlled arrhythmias, myocardial ischemia) * History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before starting study treatment * History of any grade arterial thromboembolic event, Grade 3 and above venous thromboembolic event, as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to starting study treatment * Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before starting study treatment * History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to starting study treatment Currently has or has history of (within the past one year) non-infectious pneumonitis requiring steroids Non-infectious pneumonia requiring systemic corticosteroids within the past 30 days, or current interstitial lung disease Infection requiring systemic therapy within 2 weeks prior to starting study treatment (excluding antiviral therapy for hepatitis B or C) Peripheral neuropathy grade 2 or higher by CTCAE version 6 Current or history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation Known history of human immunodeficiency virus (HIV) infection. \- Note: Patients with controlled viral load are eligible. Active hepatitis B (defined as HBsAg reactive) or hepatitis C (detectable HCV RNA or positive for HCV antibody) * Note: Patients with active hepatitis B are eligible if on appropriate antiviral therapy with acceptable tolerability for 4 weeks prior to starting study treatment, with stable or declining levels of hepatitis B DNA by polymerase chain reaction testing. * Note: Testing for hepatitis B and C is not required unless mandated by local health authority History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of this study, interfere with the subject's participation for the full duration of the study, or it is not in the best interest of the subject to participate, in the opinion of the treating investigator Pregnancy, breastfeeding or planning to breastfeed during study treatment, or expecting to conceive within the projected duration of the study, starting with the screening visit through 90 days after the last dose of trial treatment. There is a potential for congenital abnormalities and for this regimen to harm breastfeeding infants. Subject is a female of reproductive potential per institutional guidelines and treating physician's discretion and within 24 hours of starting treatment: * Serum pregnancy test is positive, or * Urine pregnancy test is positive or cannot be confirmed as negative, and serum pregnancy test has not been done or is positive * Note: In the event that 24 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.