Imiquimod and Pembrolizumab in Treating Patients With Stage IIIB-IV Melanoma

Study Overview
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Brief Summary
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This pilot trial studies the side effects and how well imiquimod and pembrolizumab work in treating patients with stage IIIB-IV melanoma. Imiquimod may stimulate the immune system. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving imiquimod and pembrolizumab may work better at treating melanoma.

Detailed Description
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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.

Official Title
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Pilot Study to Test the Safety and Efficacy of the Combination of Imiquimod and Pembrolizumab for the Treatment of Metastatic Melanoma

Conditions
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Metastatic Melanoma, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7

Intervention / Treatment
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* Drug: Imiquimod
* Other: Laboratory Biomarker Analysis
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pembrolizumab, imiquimod)<br>Patients receive pembrolizumab 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. | Drug: Imiquimod<br>* Applied cutaneously<br>* Other names: Zyclara;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | Will be estimated using the Kaplan-Meier method. | From registration to disease progression, assessed up to 2 years | 
| Incidence of adverse events graded using Common Terminology Criteria for Adverse Events version 4.0 | For each type of toxicity reported, the proportion of patients experiencing a severe level of that toxicity will be determined. | Up to 2 years | 
| Overall survival | Will be estimated using the Kaplan-Meier method. | From registration to death due to any cause, assessed up to 2 years | 
| Progression free survival | Will be estimated using the Kaplan-Meier method. | From registration to documentation of first disease progression or death due to any cause, assessed up to 2 years | 
| Tumor response rate defined as percentage of patients whose objective disease status meets the criteria for Response Evaluation Criteria in Solid Tumors (RECIST) criteria for partial or complete response on two consecutive disease evaluations | If there are no tumor responses documented among these 10 patients, then upper bound of a one-sided 95% confidence interval for the tumor response rate would be 25.9%. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarker changes during treatment | For each patient and each biomarker, a times-series plot of biomarker value will be constructed. These graphs will be visually examined for trends within and between the group of patients whose tumor responded to treatment and the group of patients whose tumor did not respond to treatment. Will include assessing total tumor RNA through RNA seq and PDL1 expression through the use of immunohistochemistry. | Baseline up to 12 weeks |