Pembrolizumab in Treating Patients With Stage IB-IV Mycosis Fungoides

Study Overview
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Brief Summary
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This phase II trial studies how well pembrolizumab works in treating patients with stage IB-IV mycosis fungoides. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the antitumor activity of pembrolizumab in patients with advanced mycosis fungoides (MF) as initial systemic therapy. SECONDARY OBJECTIVES: I. To evaluate safety of pembrolizumab in this patient population. II. To evaluate response rates of pembrolizumab in this patient population. III. To determine the progression free survival, duration of response, time to response and overall survival of pembrolizumab in this patient population. CORRELATIVE OBJECTIVE: I. To characterize the histologic features of the anti-tumor response in patients with advanced MF before and after treatment with pembrolizumab. OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 cycles or until complete response in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 and 90 days, and then every 3 months for up to 1 year.

Official Title
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A Phase II, Open-Label, Single-Arm Trial Using KEYTRUDA (Pembrolizumab) as Initial Systemic Therapy in the Treatment of Advanced Mycosis Fungoides

Conditions
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Mycosis Fungoides, Sezary Syndrome, Stage IB Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage II Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IIA Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IIB Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage III Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IIIA Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IIIB Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IV Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IVA1 Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IVA2 Mycosis Fungoides and Sezary Syndrome AJCC v8, Stage IVB Mycosis Fungoides and Sezary Syndrome AJCC v8

Intervention / Treatment
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* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Histological confirmation of one of the following: Stage IIB-IV mycosis fungoides not previously treated with systemic therapy Stage IB/IIA mycosis fungoides with Modified Severity Weighted Assessment Tool (mSWAT) >= 20 with high risk morphologic features defined as thick plaque disease and/or follicular involvement who have failed one form of skin-directed therapy. Sezary syndrome patients not previously treated with systemic therapy. Measurable disease based on mSWAT and/or Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Note: Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to registration. Exception: Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Absolute neutrophil count (ANC) >= 1,500 /mcL (obtained =< 28 days prior to registration) Platelet count >= 100,000/mcL (obtained =< 28 days prior to registration) Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) 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 (obtained =< 28 days prior to registration) Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (obtained =< 28 days prior to registration) Albumin > 2.5 mg/dL (obtained =< 28 days prior to registration) Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 ml/min for subject with creatinine levels > 1.5 x institutional ULN (obtained =< 28 days prior to registration) Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 X ULN OR if patient is receiving anticoagulant therapy and PT/INR or PTT is within therapeutic range of intended use of coagulants (obtained =< 28 days prior to registration) Negative urine or serum pregnancy test done =< 28 days prior to registration and =< 72 hours prior to receiving the first dose of study medication, for women of childbearing potential only. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of the study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Male subjects of childbearing potential must agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of the study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Provide written informed consent. Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study). Willing to provide tissue samples for correlative research purposes. Exclusion Criteria: Any of the following because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Is currently participating and receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device =< 4 weeks prior to registration. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy =< 7 days prior to registration. Has a known history of active TB (Bacillus tuberculosis). Hypersensitivity to pembrolizumab or any of its excipients. Has had a 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 earlier. Has had 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. Has a known additional malignancy that is progressing or requires active treatment. Exceptions: basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Exceptions: subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging =< 4 weeks prior to registration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least =< 7 days prior to registration. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 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). Note: Replacement therapy (e.g., thyroxine, 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 pneumonitis. 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 screening visit through 120 days after the last dose of trial treatment. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Has 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). Has 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. Sezary syndrome patients with high blood burden requiring immediate cytoreduction.

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)<br>Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 cycles or until complete response in the absence of disease progression or unacceptable toxicity. | 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 |
| --- | --- | --- |
| Overall cutaneous response (cutaneous complete response [CR], cutaneous 90 response [CR90] or cutaneous partial response [PR]) | Will be assessed by the Modified Severity Weighted Assessment Tool (mSWAT). All calculated values will use the last-observation-carried forward for any participants who withdraw, are lost to follow up, or exit the study per protocol. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients will be analyzed using Mann-Whitney U for nonparametric data and the student t-test. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. | Up to 90 days after last dose | 
| Changes in mSWAT scores | Summary statistics will be calculated. Proportions of patients will be calculated and described using summary statistics. Proportions of interest are patients having CR, CR90 and PR; patients having stable subcutaneous disease; patients having progressive cutaneous disease; and patients having an overall systemic response rate. | Baseline and cycle 9 (each Cycle = 21 days) | 
| Progression free survival | The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. In addition, the progression-free survival rate at 5 years after registration will be reported. | Time from registration to relapse or death due to any cause, assessed up to 5 years | 
| Duration of response | The distribution of duration of complete response will be estimated using the method of Kaplan-Meier. | Up to 1 year | 
| Time to response | The distribution of survival time will be estimated using the method of Kaplan-Meier. | Time from registration to CR, CR90 or PR, assessed up to 1 year | 
| Overall survival | The distribution of survival time will be estimated using the method of Kaplan-Meier. In addition, the overall survival rate at 2 years after registration will be reported. | Time from registration to death due to any cause, assessed up to 2 years |