Triple-Negative Breast Cancer Clinical Trials

• Age ≥ 18 years, inclusive of all genders.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 2.

• Patients must have histologically confirmed TNBC (ER/PR ≤ 10% allowed, HER2- as defined by ASCO guidelines). HER2 negative permitted to enroll as IHC 0, 1, or 2+ with negative ISH.

• Primary breast tumor measurable by ultrasound and at least 1cm.

• Clinically appropriate to receive neoadjuvant pembrolizumab plus chemotherapy (e.g. Keynote-522) planned for curative intent per standard of care (as indicated following study therapy however not mandated on trial for Option 2).

• Multifocal/multicentric disease is allowed. If clinically indicated per the standard of care, suspicious sites that do not appear to be part of the same disease process should be biopsied with reconfirmation of ER/PR/HER2 status. Up to 20 slides or 1 block may be submitted to conduct biomarkers studies on remaining tissue.

• No prior therapy of any kind for TNBC.

• Willingness to undergo serial ultrasounds, serial biopsies, and blood draws.

• Patients must have adequate organ function as defined below. Specimens must be collected within 28 days prior to the start of study treatment.

‣ Absolute neutrophil count (ANC) ≥1500/µL

⁃ Platelets ≥100 000/µL

⁃ Hemoglobin ≥8.0 g/dL or ≥5.0 mmol/L

⁃ Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN

⁃ Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN. Patients with elevated LFTs that are suggestive of Gilbert's disease (a benign process) are eligible.

⁃ AST (SGOT) and ALT (SGPT) ≤2.5 × ULN

⁃ 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

⁃ TSH and free T4 levels should be drawn within 14 days prior to start of treatment. Patients must have adequate thyroid function as demonstrated by free T4 values, regardless of TSH.

⁃ Fertile male patients and female patients of childbearing potential must agree to avoid impregnating a partner or becoming pregnant, respectively. They must be willing to employ highly effective contraception methods (with a failure rate of less than 1% when used consistently and correctly) at least 28 days before the first dose of study treatment until 4 months after the last dose of study treatment.

⁃ A woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

⁃ Acceptable methods of contraception presented below are in compliance with the Clinical Trial Facilitation and Coordination Group (CTFG) recommendations related to contraception and pregnancy testing in clinical trials, Version 1.1 (September, 2020). However, if a contraception method listed below is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception in that country/region. Local guidelines should be followed.

‣ Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Oral. Intravaginal. Transdermal.

‣ Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral. Injectable. Implantable.

‣ Intrauterine device (IUD).

‣ Intrauterine hormone-releasing system (IUS).

‣ Bilateral tubal occlusion.

‣ Vasectomized partner. (Only considered to be highly effective contraception if he is the sole sexual partner of the female patient of childbearing potential and if the vasectomized partner has received medical assessment of the surgical success.)

‣ Sexual abstinence. (Only considered to be highly effective contraception if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient and if considered acceptable by local regulatory agencies and IRBs/IECs.

⁃ WOCBP must have a negative urinary or serum pregnancy test within 72 hours prior to start of treatment. If screening serum pregnancy test collected outside of 72 hours prior to start of treatment, this may be accepted for determination of eligibility but must be re-checked prior to treatment C1D1. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The following age-specific requirements apply:

⁃ Women \< 50 years of age are considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

⁃ Women ≥ 50 years of age are considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

⁃ To be eligible by H\&E, the tumor must have a stromal tumor infiltrating lymphocytes (sTILs) score of at least 1% on diagnostic biopsy as defined by the International TILs Working Group (https://www.tilsinbreastcancer.org/), ascertained by local pathologist or study pathologist.