The purpose of this research study is to look at the safety and side effects of combining the
drug pembrolizumab with imiquimod, GM-CSF, and cryotherapy to treat breast cancer that
includes skin lesions.
- Histologically confirmed locally advanced unresectable or metastatic breast cancer
with cutaneous metastasis with progression after one or more therapies including
endocrine therapies for estrogen receptor positive breast cancer.
- Failed at least 1 prior therapies
- Patients can have concurrent maintenance therapy (including endocrine therapy,
pertuzumab, or trastuzumab) if they have had stable or progressive cutaneous disease
for 2 months prior to study entry and there is no anticipated change in maintenance
therapy drug during the study period.
- Patients that are starting a new systemic therapy must receive the new systemic
therapy for at least 2 weeks before enrolling in this study.
- Have measurable disease based on RECIST 1.1. Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
- Be willing to provide serial tumor and blood specimens (week 0, 2, 5, 10, and 18).
Baseline biopsy should be performed within 2 weeks of 1st treatment.
- At least 18 years of age on the day of signing informed consent.
- Have a performance status of 0 or 1 on the ECOG Performance Scale. Evaluation of ECOG
PS is to be performed within 7 days prior to the date of allocation.
- Demonstrate adequate organ function (performed within 10 days of treatment
initiation), defined as:
- Absolute neutrophil count (ANC) ≥1,500 /mcL
- Platelets ≥100,000 / mcL
- Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L without erythropoietin dependency and without
packed red blood cell transfusion within the last 2 weeks
- Creatinine ≤1.5 X upper limit of normal (ULN) OR
- Measured or calculateda creatinine clearance (GFR can also be used in place of
creatinine or CrCl) ≥30 mL/min for subject with creatinine levels > 1.5 X
- Total bilirubin ≤ 1.5 X ULN OR
- Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN (≤ 5 X ULN for subjects with liver
- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN 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 X ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for at least 12 days after the last dose of study treatment.
- A male participant must agree to use contraception during the treatment period and for
at least 120 days after the last dose of study treatment and refrain from donating
sperm during this period.
- Ability to understand and willingness to sign an IRB approved written informed consent
- Has large, ulcerated, bulky tumors (defined as total volume greater than 4 x 4 x 4
cm^3 with > 50% ulceration).
- Has life expectancy of < 6 months.
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks of the first dose of
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.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in doses
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive
therapy within 7 days prior to the first dose of trial treatment.
- Has a known history of active TB (Bacillus Tuberculosis)
- Has severe hypersensitivity (≥ grade 3) to pembrolizumab or any of its excipients.
- Patients that have received prior systemic anti-cancer therapy including
investigational agents within 2 weeks prior to study Day 1. or who.
- Note: Participants must have recovered from all AEs due to a previous therapies
to ≤ grade 1 or baseline. Subjects with ≤ Grade 2 neuropathy may be eligible.
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
- Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
- Has a known additional malignancy that is progressing or requires 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) that have undergone potentially curative therapy are not excluded.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are radiologically stable i.e. without evidence of progression by imaging for at
least four weeks prior by repeat imaging (note that the repeat imaging should be
performed during study screening), clinically stable and without requirement of
steroid treatment for at least 14 days prior to first dose of study treatment.
- Has 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 (e.g., thyroxin, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
- Has a history of (non-infectious) pneumonitis that required steroids or has current
- Has an active infection requiring systemic therapy.
- 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.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- 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. A WOCBP who has a positive
urine pregnancy test within 72 hours prior to allocation. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- 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 (e.g.
CTLA-4, OX-40, CD137).
- Has a known history of Human Immunodeficiency Virus (HIV).
- Has known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C (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.
- Has received a live vaccine within 30 days of planned start of study therapy. 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 (eg, FluMist®) are live attenuated vaccines and are not allowed.