BreastVAX: Radiation Boost to Enhance Immune Checkpoint Blockade Therapy

Inclusion Criteria:

All (male and female) participants must meet the following criteria during screening to be enrolled in the study:

Is willing and able to provide written informed consent/assent for the trial.
Is ≥ 18 years of age on day of signing informed consent.
Have an ECOG Performance Status 0 - 1 at screening.
Patients with:

Newly diagnosed clinical T1-2 N0-1 M0 breast cancer not eligible for I-SPY2 (to prevent recruitment competition) or not undergoing neoadjuvant chemotherapy with at least one of the following features:

Triple negative breast cancer defined using the ASCO CAP guidelines1 with the following modification supported by a recent publication as ER ≤ 10%, PR ≤ 10%, and HER2(-) determined by immunohistochemistry and/or fluorescence in situ hybridization analyses and with tumor size ≤ 2.0 cm via breast ultrasound if deemed appropriate by the PI, any nodal status, and not undergoing neoadjuvant chemotherapy.

Hormone receptor(+) HER2(-) (HR+ HER2[-]) breast caner with nodal involvement (node+ disease) confirmed on fine needle aspiration (FNA) or core needle biopsy and clinical T1 or T2 tumor determined by breast ultrasound if deemed appropriate by the PI. FNA or core needle biopsy of axilla node are standard diagnostic procedure to confirm nodal involvement.

HR+ or HR- and HER2(+) breast cancer with clinical T1 tumor (tumor size ≤ 2 cm via breast ultrasound if deemed appropriate by the PI), any nodal status, and not undergoing neoadjuvant chemotherapy OR

Locally recurrent breast cancer with no prior radiation expecting surgical excision as part of treatment • A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 of the study protocol

OR

Locally recurrent breast cancer with no prior radiation expecting surgical excision as part of treatment.

A female participant is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR
A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the treatment period and for at least 30 days (corresponding to time needed to eliminate the study drug pembrolizumab plus 30 days [a menstruation cycle] for study treatments with risk of genotoxicity) after the last dose of study treatment.
Female participants of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication Medically accepted methods of birth control include a diaphragm, cervical cap, latex condoms, surgical sterility, intrauterine devices (IUDs), hormonal implants, injectable contraceptives, or birth control pills. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Ability to tolerate radiation therapy (e.g., lie flat and hold position).

Demonstrate adequate hematologic, renal, hepatic, thyroid and bone marrow function. All screening labs should be performed within 21 days of treatment initiation. Adequate organ function defined as follows:

ANC ≥1500/mcL
Platelets ≥100,000 / mcL
Hemoglobin ≥9g/dL
Serum Creatinine ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/ min for participant with creatinine levels > 1.5 X institutional ULN Total
Bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 ULN
AST & ALT ≤ 2.5 X ULN

Exclusion Criteria:

1. A history of prior radiotherapy that precludes delivery of hypofractionated radiotherapy.

2. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to [randomization / allocation].

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.

Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

3. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.

4. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study. Steroid prep due to dye allergies prior to staging scans or use in anti-emetic prophylaxis is allowed.

5. Has evidence of interstitial lung disease or active, non-infectious pneumonitis or has as a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

6. Has an active infection requiring systemic therapy. 7. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

8. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

9. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

10. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

11. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.

- Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

12. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

13. History of allergy to pembrolizumab.