P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer

This research trial is studying a combination of neoadjuvant radiotherapy (RT), immunotherapy
(pembrolizumab) and chemotherapy for lymph node-positive, triple negative (TN) or hormone
receptor positive/HER2-negative breast cancer.

The names of the study interventions involved in this study are:

- Radiation Therapy (RT)

- Immunotherapy: Pembrolizumab (MK-3475)

- Chemotherapies:

- Paclitaxel

- Doxorubicin (also called Adriamycin)

- Cyclophosphamide

- Carboplatin (optional, and in TN only)

- Capecitabine (optional, and in TN only)

Inclusion Criteria:

- Age ≥18 years old

- Participant has non-metastatic, T1*-T2 and N1-3 and one of the following
histologically confirmed disease subtypes:

-- Triple negative breast cancer is defined as ER-negative (<1% cells), PR-negative
(<1% cells) and HER2-negative (<2+ HER2 IHC or <2.2 HER2/CEP17 ratio by FISH), as per
testing at local institution

- High-risk HR+/HER2-negative breast cancer is defined as ER≥1%, HER2-negative (<2+
Her2 IHC or <2.2 HER2/CEP17 ratio by FISH) and either histologic grade II-III or
a high-risk genomic assay score (Oncotype RS>25, high risk Mammaprint, PAM-50,
EndoPredict or ProSigna score).

- Note: Eligibility requires primary tumor size ≥1.0 cm in maximum diameter and
axillary node-positive breast cancer

- Primary breast tumor measuring ≥1.5 cm in maximal diameter as measured by any
available standard of care imaging (mammogram, breast ultrasound, breast MRI).

- Biopsy-proven, axillary lymph node-positive breast cancer at diagnosis. Note:
Clinically node-positive disease is classified as cN1-3. cN1: without matted nodes,
even if several/multiple appear matted on ultrasound or MRI; cN2: clinically fixed or
matted nodes on examination or clinically or imaging-detected internal mammary node
involvement.

- Clips or fiducial placement within the biopsy-proven axillary lymph node and breast
primary tumor are required.

- Multifocal and multicentric disease is permitted; however only one breast tumor may be
preoperatively boosted.

--Note: For patients with multifocal disease and are randomized to receive a
preoperative RT boost, all sites of multifocal disease should be contained within the
pre-operative boost volume. Subsequently, these patients will not need a post-op
boost.

- Synchronous bilateral invasive breast cancer is permitted; however only one breast
tumor may be preoperatively boosted.

- No indication of distant metastases. Staging scans are not required and are per the
discretion of the treating physician.

- Neoadjuvant chemotherapy (NAC) with paclitaxel, dose-dense doxorubicin and
cyclophosphamide (dd AC) is planned. Note: For TNBC patients, administration of
carboplatin is optional, as per MD choice. For HR+ patients, carboplatin will not be
administered.

- The boost volume is determined to be able to meet study dose constraints by the
treating radiation oncologist.

- Breast-conserving surgery or mastectomy +/- reconstruction is planned following NAC.

- ECOG performance status score of 0 or 1.

- Have adequate organ function as defined in the following table. Bloodwork must be
collected within 10 days prior to the start of study treatment.

- Hematological --- Absolute neutrophil count (ANC) ≥1500/µL

- Platelets ≥100 000/µL

- Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

- Renal

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

- Hepatic

- Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with
total bilirubin levels >1.5 × ULN

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

- Coagulation

- 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

- ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic
transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

- Criteria must be met without erythropoietin dependency and without packed
red blood cell (pRBC) transfusion within last 2 weeks.

- Creatinine clearance (CrCl) should be calculated per institutional standard.

- Note: This table includes eligibility-defining laboratory value requirements for
treatment; laboratory value requirements should be adapted according to local
regulations and guidelines for the administration of specific chemotherapies.

- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:

-- a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow
the contraceptive guidance throughout the study and for at least 4 months after the
last dose of pembrolizumab in such a manner that the risk of pregnancy is minimized.

- A male participant must agree to use a contraception as detailed in Appendix A of this
protocol during the treatment period and for at least 4 months after the last dose of
after the last dose of study treatment and refrain from donating sperm during this
period.

- Willingness to adhere to the study visit schedule and the prohibitions and
restrictions specified in this protocol.

- Willingness to undergo mandatory research biopsy of the breast tumor between weeks 2-3
of Cycle 1.

- Written informed consent obtained from participant and ability for participant to
comply with the requirements of the study.

- Patients unable to read/write English are eligible to participate in the overall
study, but will not be required to participate in the Patient-Reported Outcome
questionnaires.

Exclusion Criteria:

- HER2-positive breast cancer by ASCO/CAP guidelines (HER2 IHC 3+ or ≥ 2.2 HER2/CEP17
ratio by FISH)

- Inflammatory (cT4d) breast cancer

- Metastatic breast cancer (M1)

- Contraindication(s) to breast-conserving therapy or mastectomy

- Contraindication to radiation therapy including: prior ipsilateral breast or mantle
RT, active scleroderma, systemic lupus erythematosis and pregnancy.

--Note: All cardiac implantable electronic devices are permitted, provided that
methods to assess radiation doses and minimize damage to the devices during RT is
planned, per institutional guidelines.

- Prior ipsilateral breast, chest wall or thoracic radiotherapy

- Prior ipsilateral invasive breast cancer, contralateral breast cancer or a known
additional, invasive malignancy that is progressing or required active treatment in
the last 5 years.

--Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of
the skin or cervical carcinoma in situ that has undergone potentially curative therapy
and a previous diagnosis of ductal carcinoma in situ are not excluded.

- Has a known history of active tuberculosis (Bacillus tuberculosis

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
OX 40, CD137).

- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to randomization.

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

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

- Has known severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its
excipients.

- Participants with active, known or suspected autoimmune disease. Participants with
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are permitted to enroll.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- Known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required
unless mandated by local health authorities.

- Known active Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or
known active hepatitis C virus (defined as HCV RNA [qualitative] is detected). Note:
Testing for hepatitis B or hepatitis C is not required, unless mandated by local
health authorities or institutional guidelines.

- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.

- Has had an allogenic tissue/solid organ transplant

- A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose
of study treatment (see Appendix A). If the urine test cannot be confirmed as
negative, a serum pregnancy test is required. In such cases, the participant must be
excluded from participation if the serum pregnancy result is positive.

- Prohibited Treatments and/or Therapies:Use of immunosuppressants and/or systemic
corticosteroids is exclusionary, except the following in the absence of active
autoimmune disease:

- As premedication for chemotherapy

- For the prevention of nausea in the three days following chemotherapy

- Participants are permitted the use of corticosteroids with minimal systemic
absorption (e.g. topical, ocular, intra-articular, intranasal and inhaled)

- Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
equivalent permitted

- Adrenal replacement steroid doses including doses >10 mg daily prednisone is
permitted

- A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT
scan premedication against contrast dye allergy) or for treatment of
non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by
a contact allergen is permitted (used in the management of cancer or
non-cancer-related illnesses). However, use of corticosteroids is allowed for the
treatment of immune-related Adverse Events (irAEs), or adrenal insufficiency.