Ritlecitinib in CTCL

INCLUSION CRITERIA:

• Age ≥ 18 years at time of enrollment

• CTCL >10% BSA involvement (stage IB-IVA by ISCL/EORTC staging criteria), previouslyconfirmed by histopathology

• CTCL subtypes eligible for this study include Mycosis fungoides and its subtypes, aswell as Sézary Syndrome.

• Failure of at least 2 skin-directed (ISCL/EORTC stage IB-IIA, i.e. early stagedisease) or systemic treatments (ISCL/EORTC stage IIB-IVA, i.e. late stage disease)due to progression or toxicity as assessed by the prescribing physician or by theprincipal investigator, or insufficient response to established skin-directed orsystemic treatments. i. Patients with documented CD30-positive CTCL must have previously received or beintolerant to brentuximab vedotin.

• Adequate hematological (Hb>9.0g/dl, absolute neutrophil count >1200/ul, platelets >75x10^9/L, absolute [non-malignant] lymphocyte count >800/ul), hepatic (AST and ALT <2x times upper limit of normal), and renal function (eGFR [CKD-EPI creatinineequation >50mL/min/1.73m2)

• ECOG ≤ 2 (Eastern Cooperative Oncology Group scoring system used to quantify generalwell-being and activities of daily life; scores range from 0 to 5 where 0 representsperfect health and 5 represents death.)

• Ability to take oral medication without crushing, dissolving or chewing tablets

• Ability to understand and the willingness to sign a written informed consent

• In the investigator's opinion, the patient has the ability to communicatesatisfactorily with the investigator and the study team, to participate fully in thestudy, and comply with all requirements

EXCLUSION CRITERIA:

• History of, or a concurrent, clinically significant illness, medical condition orlaboratory abnormality that, in the investigator's opinion, could affect the conductof the study

• Immunosuppressed by previous (within 4 weeks) or current systemic cytotoxictherapies, as evidenced by recurrent skin or systemic infections

• Pregnant or breast-feeding women

• Unwillingness or inability to use a contraception method during the time ofparticipation in the trial.

• Uncontrolled current illness, including, but not limited to the following: Ongoingor active infections requiring intravenous antimicrobials; symptomatic congestiveheart failure defined as NYHA class III or IV; unstable angina pectoris within 6months of study enrollment; history of myocardial infarction, stroke or intracranialhemorrhage within 6 months prior to enrollment; moderate to severe hepaticimpairment (Child-Pugh class B or C); psychiatric illness or social situations thatwould limit compliance with study requirements

• Previous or concurrent cancer that is distinct in primary site or histology formCTCL, except curatively treated basal or squamous cell carcinoma of the skin, andcuratively treated malignant melanoma stage 0-1A with a low risk ofrecurrence/metastasis as per assessment of the investigator, cervical carcinoma insitu, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis and T1)

• Known HIV infection

• Infected with Hepatitis B or Hepatitis C viruses

• Patients with history of either untreated or inadequately treated latent or activeTB infections/currently being treated for active TB.

• Recent (within 21 days before baseline) major surgery

• Patients who have history of single episode of disseminated HZ or disseminated HS orrecurrent (> 1 episode of) localized dermatomal HZ should be excluded.

• Less than 28 days have elapsed since last radiation therapy, phototherapy orchemotherapy treatment or patient has not recovered from all clinically significanttreatment-related toxicity as defined in discontinuation criteria.

• Less than 3 months have elapsed since last oral JAK inhibitors and/or less than 4weeks have elapsed since last topical JAK inhibitor.

• Glucocorticosteroids when used systemically; the use of nasal and inhaledglucocorticosteroids will be allowed PRN; the use of topical glucocorticosteroids (low to mid-potency) will only be allowed when given at a stable dose >4 weeks

• Prior treatment with other concomitant investigational agents

• Hypersensitivity or allergic reaction to compounds related to JAK inhibitors

• Treatment with medication that might interfere with blood levels or have a majorimpact on the clinical readout of the study drug, as per discretion of the studyinvestigator; best supportive care will be allowed at the discretion of theinvestigator (e.g. anti-emetics, skin care, pain medication, anti-thrombotic agents,herpes zoster prophylaxis)

• Any gastrointestinal or metabolic condition that could interfere with the absorptionof the oral medication

• Ongoing other MF-directed treatments (such as topical corticosteroids and topicalbexarotene) unless stable over a period of one month

• Active alcohol and/or drug abuse

• History of thrombosis/thromboembolic event, known coagulopathy

• Additional skin disease that might interfere with MF clinical assessments

• Patient has received a live attenuated vaccine ≤ 30 days prior to study screening

• Have hearing loss with progression over the previous 5 years, or sudden hearingloss, or middle or inner ear disease such as otitis media, cholesteatoma, Meniere'sdisease, labyrinthitis, or other auditory condition that is considered acute,fluctuating, or progressive.

• Patients who have received prohibited drugs that are CYP3A inducers within a 28 dayor 5 half-lives (whichever is longer) period prior to the first dose of studyintervention.

• Patients with ALCL or other forms of CTCL other than MF or Sézary Syndrome.