PRIMARY OBJECTIVES:
I. To gain preliminary data of the anti-tumor activity and safety profile of the combination
of imiquimod and pembrolizumab in patients with unresectable cutaneous melanoma.
SECONDARY OBJECTIVES:
I. To compare and contrast (in a hypothesis generating manner) the biomarker profiles of
patients who have a confirmed complete response (CR) or partial response (PR) by Response
Evaluation Criteria in Solid Tumors (RECIST) criteria with patients who do not.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) on day 1 and apply imiquimod cutaneously on
days 1-5 (Monday - Friday). Courses repeat every 21 days for up to 2 years (approximately 35
courses) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks for 2 years.
Inclusion Criteria:
- Histological confirmation of stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c that is not
suitable for surgical resection
- Patients must not have received prior pembrolizumab or other anti-PD1/PDL1 therapies
for their metastatic disease
- At least one cutaneous lesion that is amenable to treatment with topical imiquimod
- Measurable disease by RECIST
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- Absolute neutrophil count (ANC) >= 1500/mm^3
- Platelet count >= 100,000/mm^3
- Hemoglobin > 9.0 g/dL or >= 5.6 mmol/L without transfusion or (EPO) erythropoietin
dependency (within 7 days of assessment)
- Serum total bilirubin =< 1.5 X upper limit of normal (ULN) or direct bilirubin =<
(ULN) for subjects with total bilirubin levels > 1.5 ULN
- Aspartate transaminase (AST) =< 2.5 x ULN or =< 5 x ULN for subjects with liver
metastases
- Albumin >= 2.5mg/dL
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants
- Creatinine =< 1.5 X upper limit of normal (ULN)
- NOTE: measured or calculated (per institutional standard) creatinine clearance is
acceptable >= 60 mL/min for subject with creatinine levels > 1.5 X institutional
ULN
- Negative urine or serum pregnancy test done =< 72 hours prior to first treatment, for
women of childbearing potential only
- If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- Provide informed written consent
- Willing to return to enrolling institution for follow-up
- Willing to provide tissue from a newly obtained core or excisional biopsy of a tumor
lesion in appropriate low risk cutaneous lesions
- NOTE: if the tissue biopsy is deemed to be of increased risk for the patient, the
biopsy should not be performed and is optional
- NOTE: newly-obtained is defined as a specimen obtained up to 42 days prior to
registration where no anti-cancer therapy after the specimen was obtained and
registration
Exclusion Criteria:
- Any of the following:
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate
contraception
- NOTE: female subjects 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; subjects of childbearing potential are those
who have not been surgically sterilized or have not been free from menses
for > 1 year; male subjects should agree to use an adequate method of
contraception starting with the first dose of study therapy through 120 days
after the last dose of study therapy; abstain from heterosexual activity is
also acceptable method of contraception for males
- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm or used an investigational device =< 4 weeks from registration
- History of myocardial infarction =< 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
- Known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Prior anti-cancer monoclonal antibody (mAb) =< 4 weeks prior to registration or who
has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks prior to registration
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy =< 2 weeks
prior to registration or who has not recovered (i.e., =< grade 1 or at baseline) from
adverse events due to a previously administered agent
- Note: subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study
- Note: if subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy
- Known secondary malignancy that has progressed within the last 3 years or requires
active treatment; exceptions include basal cell carcinoma of the skin or squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in situ
cervical cancer
- Known central nervous system (CNS) metastases and/or carcinomatous meningitis
- 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 current pneumonitis
- Active infection requiring systemic therapy
- 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
- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial
- Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)
- Received a live vaccine =< 30 days prior to registration
- Note: seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed
