Pembrolizumab in Combination With Gemcitabine in People With Advanced Mycosis Fungoides or Sézary Syndrome

Inclusion Criteria:

• Confirmed mycosis fungoides/Sezary syndrome, disease stage IB (defined as patches,plaque, or papules that involve 10% of the skin surface viscera) or higher.

• Age ≥ 18 years.

• ECOG Performance Score between 0-1

• Receipt of at least one prior systemic therapy for MF/SS.

• Previous systemic anti-cancer therapy must have been discontinued at least 2 weeksprior to treatment. See section 6.2 Subject Exclusion Criteria for guidelinesregarding adjuvant and maintenance therapy for prior malignancy.

• Topical or systemic steroids (equivalent to ≤ 10 mg/day of prednisone) may beconsidered if dose has been constant and discontinuation may lead to rebound flarein disease, adrenal insufficiency, and/or unnecessary suffering.

• Prior therapy with gemcitabine allowed.

• Refer to Table 1 for laboratory inclusion criteria.

• The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial.

• A female participant is eligible to participate if she is not pregnant, notbreastfeeding, and at least one of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) as defined in Appendix C

• A WOCBP who agrees to follow the contraceptive guidance in Appendix C

• A male participant must agree to use a contraception as detailed in Appendix C ofthis protocol from screening and through 6 months after the last dose of gemcitabineor 120 days after the last dose of pembrolizumab (whichever is later) and refrainfrom donating sperm during this period.

Table 1: Laboratory Parameters for Inclusion Criteria

System : Laboratory Value

Hematological Absolute neutrophil count (ANC): ≥ 1500/μL Platelets: ≥ 100 000/μL Hemoglobin: ≥ 9.0 g/dL or ≥ 5.6 mmol/L^a

Renal Creatinine OR Measured or calculated^b creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤ 1.5 × ULN OR ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutional ULN

Hepatic Total bilirubin: ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT): ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases)

Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT): ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

• a: Criteria must be met without erythropoietin dependency and without packed redblood cell (pRBC) transfusion within last 2 weeks.

• b: Creatinine clearance (CrCl) should be calculated per institutional standard.

Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

Exclusion Criteria:

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to the firstdose of treatment (see Appendix C). If the urine test is positive or cannot beconfirmed 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 orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy

• ECOG Performance Score between 0-1

• Receipt of at least one prior systemic therapy for MF/SS.

• Previous systemic anti-cancer therapy must have been discontinued at least 2 weeks prior to treatment. See section 6.2 Subject Exclusion Criteria for guidelines regarding adjuvant and maintenance therapy for prior malignancy.

• Topical or systemic steroids (equivalent to ≤ 10 mg/day of prednisone) may be considered if dose has been constant and discontinuation may lead to rebound flare in disease, adrenal insufficiency, and/or unnecessary suffering.

• Prior therapy with gemcitabine allowed.

• Refer to Table 1 for laboratory inclusion criteria.

• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) as defined in Appendix C

• A WOCBP who agrees to follow the contraceptive guidance in Appendix C

• A male participant must agree to use a contraception as detailed in Appendix C of this protocol from screening and through 6 months after the last dose of gemcitabine or 120 days after the last dose of pembrolizumab (whichever is later) and refrain from donating sperm during this period. Table 1: Laboratory Parameters for Inclusion Criteria System : Laboratory Value Hematological Absolute neutrophil count (ANC): ≥ 1500/μL Platelets: ≥ 100 000/μL Hemoglobin: ≥ 9.0 g/dL or ≥ 5.6 mmol/L^a Renal Creatinine OR Measured or calculated^b creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤ 1.5 × ULN OR ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutional ULN Hepatic Total bilirubin: ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT): ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases) Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT): ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

• a: Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

• b: Creatinine clearance (CrCl) should be calculated per institutional standard. Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. Exclusion Criteria:

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to the first dose of treatment (see Appendix C). 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 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 the first dose of study drug.

• Has an active infection requiring systemic therapy.

• Has a known additional malignancy that is progressing or has required activetreatment within the past year. Participants with basal cell carcinoma of the skin,squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma,cervical cancer in situ) that have undergone potentially curative therapy are notexcluded.

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study intervention. A shorter timeframe down to 2 weeks may be acceptable if theinvestigator feels that this is in the best interests of the patient.

• Has received prior systemic anti-cancer therapy including investigational agents,phototherapy or radiotherapy within 4 weeks prior to the first dose of studyintervention excluding topical steroids. A shorter timeframe down to 2 weeks may beacceptable if the investigator feels that this is in the best interests of thepatient.

• Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.

• Has received a live vaccine within 30 days prior to the first dose of study drug.Examples of live vaccines include, but are not limited to, the following: measles,mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BacillusCalmette- Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (e.g., FluMist®) are live attenuated vaccines and are notallowed.

• Has active autoimmune disease that has required systemic treatment in the past year (i.e. with use of disease modifying agents, corticosteroids (exceeding 10 mg dailyof prednisone equivalent or immunosuppressive drugs). Replacement therapy (e.g.,thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal orpituitary insufficiency, etc.) is not considered a form of systemic treatment.

• Has known active CNS lymphoma. Participants with previously treated CNS lymphoma mayparticipate provided they are radiologically stable, i.e. without evidence ofprogression for at least 4 weeks by repeat imaging (note that the repeat imagingshould be performed during study screening), clinically stable and withoutrequirement of steroid treatment for at least 14 days prior to first dose of studyintervention.

• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of itsexcipients.

• Adjuvant or maintenance therapy to reduce the risk of recurrence of other malignancy (other than T-cell lymphoma) is permissible after discussion with the PrincipalInvestigator.

• Has a known history of Human Immunodeficiency Virus (HIV) infection.

• Has known active Hepatitis B (defined as Hepatitis B DNA detected by PCR) or knownactive Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.Patients with evidence of prior hepatitis B infection require prophylaxis withentecavir or equivalent.

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

• Has had an allogenic tissue/solid organ transplant.

• Has a known history of active TB (Bacillus Tuberculosis).

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

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

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 6 monthsafter the last dose of gemcitabine or 120 days after the last dose of pembrolizumab (whichever is later). See Appendix C for details regarding contraception.