Pembrolizumab and Mogamulizumab in Advanced-stage, Relapsed/Refractory Cutaneous T-cell Lymphomas

Inclusion Criteria:

• Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately.

• Age ≥ 18 years at the time of consent.

• ECOG Performance Status of ≤ 1 within 7 days prior to Cycle 1 Day 1 treatment.

• Histological confirmation of cutaneous T-cell lymphoma (Mycosis Fungoides/SezarySyndrome) with Stage IIB-IVB disease (TNMB Classification).

• Measurable disease according to Modified Severity Weighted Assessment Tool (mSWAT)within 30 days prior to treatment.

• Patients must have measurable, unirradiated disease. Prior disease radiation, ifgreater than 7 days prior to C1D1, is acceptable (see protocol). However, patientmust have measurable disease that has not been radiated.

• Patients must have failed at least one prior line of systemic therapy. This includesECP. Prior cancer treatment must be completed at least 28 days prior to Cycle 1 Day 1(C1D1) and the subject must have recovered from all reversible acute toxic effectsof the regimen (other than alopecia) to ≤ grade 1 or baseline.

• Archival tissue is required and will be identified at screening and shipped prior toC1D1 (10-15 unstained slides; obtained within 90 days of registration). Subjectsthat do not have archival tissue will be required to undergo a skin biopsy.

• Systemic steroids at a dose less than the equivalent of 10 mg/day of prednisone andinhaled, nasal, and topical steroids are permitted. Adrenal replacement steroiddoses > 10 mg daily prednisone equivalent in the absence of active autoimmunedisease are permitted. Treatment with a short course of steroids (< 5 days) up to 7days prior to study registration is permitted.

• Demonstrate adequate organ function as defined below. All screening labs to beobtained within 28 days prior to Cycle 1 Day 1.

• Hematological

• Absolute Neutrophil Count (ANC) ≥ 500/µL

• Hemoglobin (Hgb) ≥ 8 g/dL

• Platelet Count ≥ 25 000/µL

• Renal ---Creatinine OR Measured or calculated creatinine clearance1 ≤ 1.5 × ULN OR ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutional ULN

• Hepatic

• Bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with totalbilirubin levels > 1.5 × ULN

• Aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for participants withliver metastases)

• Alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for participants withliver metastases)

• Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT)Activated Partial Thromboplastin Time (aPTT) ≤1.5 × ULN unless participant isreceiving anticoagulant therapy as long as PT or PTT is within therapeuticrange of intended use of anticoagulants

• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmedas negative, a serum pregnancy test will be required. See protocol for definition ofchildbearing potential.

• Females of childbearing potential must be willing to abstain from heterosexualintercourse or to use an effective method(s) of contraception as outlined inprotocol. Males must be willing to abstain from heterosexual intercourse or to usean effective method(s) of contraception as outlined in protocol.

• Subjects with CNS disease are eligible so long as they meet all other eligibilitycriteria.

• Patients must have a life expectancy of at least 6 months.

• As determined by the enrolling physician or protocol designee, ability of thesubject to understand and comply with study procedures for the entire length of thestudy.

Exclusion Criteria:

• Patients with a known history of Human Immunodeficiency Virus (HIV) infection areexcluded. NOTE: No HIV testing is required unless mandated by local healthauthority.

• Patients with concurrent active Hepatitis B (defined as HBsAg positive and/ordetectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive anddetectable HCV RNA) infection. NOTE: Hepatitis B and C screening tests are notrequired unless: (1) Known history of HBV and HCV infection or (2) As mandated bylocal health authority.

• Patients previously treated with checkpoint blockade, including pembrolizumab, ormogamulizumab, are excluded.

• Patients who have received disease radiation therapy within 7 days of C1D1.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to Cycle 1 Day 1. Systemic steroids ata dose less than the equivalent of 10 mg/day of prednisone and inhaled, nasal, andtopical steroids are permitted as detailed in protocol.

• Has active or prior autoimmune disease or inflammatory disorders that have requiredsystemic treatment in the past 2 years (i.e. with use of disease modifying agents,corticosteroids or immunosuppressive drugs) with teh exception of vitiligo oralopecia. Replacement therapy (eg., thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) isnot considered a form of systemic treatment and is allowed.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• Known additional malignancy that is progressing or has required active treatmentwithin the past 2 years. NOTE: patients with non-melanoma skin cancers and in situcancers that do not require systemic therapies are eligible.

• Active infection requiring systemic therapy.

• Prior allogeneic stem cell transplant or allogeneic cellular therapies, recentimmunosuppressive therapies (for any reason).

• Prior solid organ transplant.

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study).

• Has severe hypersensitivity (≥Grade 3) to pembrolizumab or mogamulizumab and/or anyof their excipients.

• Treatment with any investigational drug or investigation device within 30 days priorto registration.

• Has received a live vaccine or live-attenuated vaccine within 30 days before thefirst dose of study intervention. Administration of killed vaccines and mRNA orinactivated COVID-19 vaccine is allowed.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality or other circumstance that might confound the results of the study,interfere with the participant's participation for the full duration of the study,such that it is not in the best interest of the participant to participate, in theopinion of the treating investigator.