Breast Cancer Study of Preoperative Pembrolizumab + Radiation

Study Overview
=================
Brief Summary
-----------------
This study is being done to assess the feasibility of pembrolizumab (study drug) combined with standard radiation to the tumor (tumor boost) before patients undergo standard treatment that can consist of one or more of the following: breast-conserving surgery, radiation to the entire breast/chest wall after surgery, and chemotherapy. Study participants will receive two doses of the study drug intravenously (through the vein) before their planned breast surgery or chemotherapy. The study drug will be administered three weeks apart. At the time of the second dose, radiation to the tumor in the affected breast will be given. This type of radiation treatment is called a tumor boost, which is a standard part of radiation therapy for breast cancer that may occur either before or after planned breast-conserving surgery. Patients will receive breast surgery or begin chemotherapy approximately six weeks after your first dose of the study drug.

Detailed Description
-----------------
With more than 1 million new cases diagnosed yearly worldwide, breast cancer is a global public health burden. Over the past decade, molecular subtyping of breast cancer has identified intrinsic subtypes that may be at enhanced risk for both local and distant recurrence. This study focuses on the immunogenicity of high-risk breast cancer subtypes that are likely to display a dense lymphocytic infiltration including including TNBC and HR+/HER2- tumors. Immune build up via immune co-stimulatory molecules permits the ensuing immune response to strengthen and destroy cancer systemically. Thus, the effect of the anti-tumor immune response initiated by the radiation to an intact tumor by combination with checkpoint blockade is increased. Pembrolizumab is an optimal immunotherapy agent to study, as this agent has recently been FDA approved for use in multiple tumor types. It is therefore ready to be tested for efficacy in other disease sites and in combination with other treatments.

Official Title
-----------------
Preoperative Combination of Pembrolizumab and Radiation Therapy in Patients With Operable Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Radiation: RT Boost


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed histologic diagnosis of invasive adenocarcinoma of the breast, and ER, PR and HER2 testing (on outside or Cedars-Sinai biopsy report), and High-risk, ER-positive and HER2-negative breast cancer patients. ER-positive disease is defined as ER>10%, any PR and HER2-negative by ASCO CAP guidelines. High-risk disease will be defined by the presence of at least 2 of the following 3 criteria: histologic grade II-III, Ki-67 > 20%, ER expression < 75% by IHC) TNBC patients (defined as ER<10%, PR<10%, HER2-neu 0-1+ by IHC or FISH-negative; or as per MD discretion) Operable tumor measuring ≥2 cm in maximal diameter as measured by any available standard of care imaging (mammogram, breast ultrasound, breast MRI) Any nodal status Multifocal disease is permitted; largest focus must measure ≥2 cm Synchronous bilateral invasive breast cancer is permitted No indication of distant metastases Breast-conserving therapy is planned Tumor amenable to preoperative radiation therapy boost as determined by radiation oncologist ECOG performance status score of 0 or 1 Screening laboratory values must meet the following criteria: i. White blood cells (WBCs) ≥ 2000/μL ii. Absolute neutrophil count (ANC) ≥ 1500/μL iii. Platelets ≥ 100 x 103/μL iv. Hemoglobin ≥ 11.0 g/dL v. Serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 40 ml/min) vi. AST ≤ 2.5 x upper limit of normal (ULN) vii. ALT ≤ 2.5 x ULN viii. Total bilirubin within normal limits (except subjects with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL) ix. INR ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulant(s) x. Negative HIV screening test xi. Negative screening tests for Hepatitis B and Hepatitis C. Patients with positive results that do not indicate true active or chronic infection may enroll after discussion and consensus agreement by the treating physician and principal investigator. Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy 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. WOCBP must have a negative serum pregnancy test within 14 days prior to the first dose of pembrolizumab. Women must not be breastfeeding. Willingness to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol. Willingness to undergo mandatory Week 4 research biopsy Written informed consent obtained from subject and ability for subject to comply with the requirements of the study. Exclusion Criteria: HER2-positive breast cancer defined as IHC3+ or IHC2+ with FISH>2 AND copy number >4 OR FISH <2 AND copy number >6 Inflammatory breast cancer Contraindication(s) to breast-conserving therapy Contraindication to radiation therapy or planned partial breast irradiation Patients with cosmetic breast augmentations, specifically sub glandular implants with altered breast tissue, at the time of diagnosis Evidence of metastatic disease. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Medical history and concurrent diseases Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Active infection requiring systemic therapy. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C (e.g., HCV RNA [qualitative] is detected). Prohibited Treatments and/or Therapies Chronic use of immunosuppressants and/or systemic corticosteroids (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. Live vaccines within 30 days prior to the first dose of study treatment and while participating in the study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Prior treatment 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) Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study start. 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. Prior radiotherapy within 2 weeks of start of study treatment to sites outside the breast. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. For subjects who agree to the research breast MRI sub-study: Four or more previous gadolinium contrast scans due to the risk of brain deposits following repeated use of gadolinium-based contrast agents.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single Arm with Two Cohorts Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm Cohort 2: TNBC patients with primary tumors measuring at least 2cm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab with RT Boost<br>Study drug plus tumor boost before standard of care treatment | Drug: Pembrolizumab<br>* checkpoint inhibitor<br>* Other names: MK-3475;Radiation: RT Boost<br>* The second dose of pembrolizumab will be given in conjunction with an RT boost, consisting of 8 Gy for 3 fractions.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who do Not Necessitate a Delay in Standard of Care Treatment After Receiving the Investigational Combination of Preoperative Pembrolizumab and Radiation | Feasibility of preoperative radiation and Pembrolizumab in newly diagnosed, non-metastatic patients with triple negative breast cancer. | 8 weeks after trial initiation | 
| Changes in Tumor Infiltrating Lymphocytes (TIL) | An increase in the tumor-infiltrating lymphocyte score (TILs) as measured by Salgado criteria. An increase in TILs is an indicator of immune system engagement (range is 0-100 in percent), therefore increase indicates better outcome. A lead in with pembrolizumab alone followed by the combination of pembrolizumab with RT will allow for serial assessment of TILs. This will establish the contribution of RT to the immune response generated by pembrolizumab. The working group's consensus for Salgado criteria is that TILs may provide more biological relevant information when scored as a continuous variable. The percentage of stromal TILs is a semi quantitative parameter for this assessment (0%-100%). No formal recommendation for a clinically relevant TIL threshold(s) can be given at this stage. The consensus was that a valid methodology is currently more important than issues of thresholds for clinical use, which will be determined once a solid methodology is in place. | 8 weeks after trial initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pembrolizumab-related Adverse Events | Treatment toxicities. Number of AEs attributed to Pembrolizumab (considered at least possibly related, probably related, or related). | 15 weeks after trial initiation | 
| Immune-related Adverse Events | Treatment toxicities. Number of immune-related AEs (irAEs). | Assessed up to one year post-treatment | 
| Invasive Disease-free Survival After Preoperative Radiation and Pembrolizumab | Disease-free survival, as described from time from occurrence of surgery to time from first recurrence from or death from breast cancer | From treatment start date until date of documented recurrence or death from breast cancer, assessed up to 19 weeks after start of treatment | 
| Pathological Complete Response Rate | Absence of invasive disease in the breast and lymph nodes at the time of curative-intent surgery. | From treatment start date until the time of curative-intent surgery, approximately 8 weeks. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
invasive adenocarcinoma of the breast, ER-positive and HER2-negative breast cancer, Triple negative breast cancer (TNBC), immunotherapy, checkpoint inhibitor, HR-positive