This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
In this research study, the investigators are evaluating the safety and effectiveness of
palliative radiotherapy ("radiation therapy") in combination with pembrolizumab in
HR-positive, HER2-negative breast cancer. This study is designed to test how well radiation
therapy in combination with pembrolizumab treats this type of cancer.
The FDA has approved radiation therapy as a treatment option for this type of breast cancer.
The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this
specific disease but it has been approved in the United Sates for other types of cancer.
Pembrolizumab is a drug that may treat cancer by working with the immune system. The immune
system is the body's natural defense against disease. The immune system sends types of cells
called "T cells" throughout the body to detect and fight infections and diseases, including
cancer. For some types of cancer, the T cells do not work as they should and are prevented
from attacking the tumors. Pembrolizumab is thought to work by blocking a protein in the T
cells called PD-1 ("programmed death 1"), which then allows these cells and other parts of
the immune system to attack tumors.
The combination of pembrolizumab and radiation therapy is investigational. The study drug and
radiation therapy, when given separately, work in different waysto help stop the cancer cells
from growing and spreading. However, it is not known if giving the study drug and radiation
therapy at the same time will have a better anti-cancer effect than giving each treatment on
- Participants must have histologically or cytologically confirmed invasive breast
cancer, with metastatic disease. Participants without pathologic or cytologic
confirmation of metastatic disease should have unequivocal evidence of metastasis from
physical examination or radiologic evaluation.
- Invasive disease must have been tested for ER, PR and HER2. Participants must have
hormone-receptor positive, HER2-negative breast cancer defined as:
- ER>1% or PR>1%
- HER2-negative per ASCO CAP guidelines, 2013 [Wolff et al., 2013]
- Participant must be a candidate for palliative radiation treatment to at least one
bone, lymph node, or soft tissue lesion. Radiation of visceral lesions (such as lung
or hepatic lesions) is not permitted.
- Participant must have measurable disease outside the field of radiation as defined by
- If tumor is accessible and outside the field of radiation, the participant must be
willing to undergo a research biopsy at baseline and after 2 cycles of pembrolizumab.
Participants for whom newly-obtained samples cannot be provided (e.g. inaccessible or
safety concern) must be willing to submit an archival specimen.
- Prior systemic therapy:
- Participant must be at least 14 days from the last dose of prior chemotherapy,
endocrine therapy, biological agents (including small molecule targeted therapy)
or any investigational drug product with adequate recovery of toxicity to
baseline, or grade 1(with the exception of alopecia and hot flashes) at the time
- There is no limit to the number of prior lines of therapy, including endocrine or
cytotoxic agents. Systemic treatment naive patients for metastatic disease are
- Participants may initiate or continue bisphosphonate therapy on study.
- Continuation of ovarian suppression is allowed.
- Prior radiation therapy:
- Patients must be at least 3 months from prior radiation therapy
- Re-irradiation of the same field is not allowed
- Concurrent administration of other cancer specific therapy during the course of this
study is not allowed.
- The subject is ≥18 years old
- ECOG performance status ≤1 (See Appendix A for details)
- Participants must have normal organ and marrow function as defined below:
- absolute neutrophil count ≥1,500/mcL
- platelets ≥100,000/mcL
- hemoglobin ≥ 8 g/dl
- total bilirubin ≤1.5 × institutional upper limit of normal (ULN)
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or ≤ 5 × institutional ULN for
participants with documented liver metastases
- creatinine ≤1.5 ×within normal institutional ULN (or 2.0 x ULN in patients with
documented Gilbert's Syndrome) OR creatinine clearance ≥60 mL/min/1.73 m2 for
participants with creatinine levels above institutional ULN.
- International normalized ratio (INR) or Prothrombin Time (PT) <1.5 times the
upper limit of normal unless subject is receiving anticoagulant therapy, as long
as PT or PTT is within therapeutic range of intended use of anticoagulants.
- Activated Partial Thromboplastin Time (aPTT) <1.5 times the upper limit of normal
unless subject is receiving anticoagulant therapy, as long as PT or PTT is within
therapeutic range of intended use of anticoagulants.
- Female subjects of childbearing potential must have a negative pregnancy test at
- Female and male subjects of childbearing potential must agree to use an adequate
method of contraception as outlined in section 5.4.1. Contraception is required
starting with the first dose of study medication through 120 days after the last dose
of study medication Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject.
- Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1
severity or lower, except for stable sensory neuropathy (≤ Grade 2) and alopecia.
- The subject is capable of understanding and complying with the protocol and has signed
the informed consent document
- Participants who are receiving any other investigational agents.
- Previous treatment with any anti-PD-1, PD-L1, or PD-L2 agent.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pembrolizumab.
- Known brain metastases that are untreated, symptomatic, or require therapy to control
symptoms. Participants with previously diagnosed brain metastases are eligible if they
- completed treatment (whole brain radiotherapy, radiosurgery, or a combination) at
least 3 months prior to trial therapy initiation,
- are neurologically stable, and
- have recovered from effects of radiotherapy or surgery. Any corticosteroid use
for brain metastases must have been discontinued without the subsequent
appearance of symptoms for ≥2 weeks before prior to registration.
- Radiologic or clinical evidence of Spinal Cord Compression.
- Spinal Instability Neoplastic Score ≥ 7 unless lesion reviewed by a neurosurgical
service and considered stable.
- Participants with bone lesions requiring surgical fixation to provide mechanical
stability are ineligible. Participants with previously fixed lesions are allowed.
- The participant has an uncontrolled intercurrent illness, including, but not limited
to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac
arrhythmia, congestive heart failure-New York Heart Association Class III or IV,
active ischemic heart disease, myocardial infarction within the previous six months,
uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the
previous 6 months, severe malnutrition or psychiatric illness/social situations that
would limit compliance with study requirements.
- Clinically significant electrocardiogram (ECG) abnormality, including a marked
baseline prolonged QT/QTc ([QT interval/corrected QT interval], eg, a repeated
demonstration of a QTc interval >500 ms).
- Participant has a medical condition that requires chronic systemic steroid therapy or
on any other form of immunosuppressive medication. For example, patients with
autoimmune disease that requires systemic steroids or immunosuppression agents should
be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment.
- Has history of (non-infectious) pneumonitis that required steroids or current
- Has a history of interstitial lung disease.
- The participant is known to be positive for the human immunodeficiency virus (HIV),
HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic interactions with
- Individuals with a history of different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 3 years or are deemed by the investigator
to be at low risk for recurrence of that malignancy.
- Has received a live vaccine within 30 days of planned start of study therapy.
- The participant is pregnant or breast-feeding