Ritlecitinib in CTCL

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate the effectiveness and safety of Ritlecitinib in skin and blood in persons with Cutaneous T-Cell Lymphoma (CTCL). CTCL is a rare type of cancer that starts in the white blood cells and eventually can result in rashes or tumors in the skin. This study includes a 24 week Treatment Period and a 24 week Follow-up Period. This study will involve physical examinations, visual assessments, laboratory tests, PET-CT scans, electrocardiograms, photographs of your skin, skin biopsies, and hearing tests.

Detailed Description
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After providing informed consent, patients will be assessed for study eligibility at the Screening visit (day -28 to day -1) which includes: assessment of inclusion/exclusion criteria; targeted physical examination (including vital signs); mSWAT scoring and disease staging; electrocardiogram (ECG); review of medical history and concomitant medications as well as prior medications/treatments; and serum pregnancy test (if applicable). Laboratory tests will be performed for Complete Blood Count (CBC) with differentials (basophils, eosinophils, lymphocytes, monocytes, neutrophils), serum chemistry including albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine, creatine kinase, potassium, sodium, total bilirubin, LDH, viral surveillance panel (EBV, CMV, HSV1, HSV2, and VZV), as well as hepatitis B surface antigen (HBsAg), HBcAb, hepatitis C antibody, and undergo testing for human immunodeficiency virus (HIV). Urinalysis will be performed. Patients will also undergo tuberculin purified protein derivative (PPD) or QuantiFERON TB-Gold test (QFT) testing. Patients will also undergo flow cytometric analyses and TCR rearrangement studies of peripheral blood to monitor potential CTCL blood involvement. CT scans with PET (positron emission tomography) scans will be performed within 4 weeks before baseline to help establish or confirm peripheral lymph node size and assign TNM classification, or at any time if internal involvement is suspected by the investigator. Patients who meet eligibility criteria (meeting all inclusion and no exclusion criteria) will undergo Baseline / Day 0 assessments. These assessments include vital signs and targeted physical examination, mSWAT scoring, clinical disease staging, questionnaires, clinical photography, urine pregnancy test (if applicable), and blood collection for chemistry, hematology, mechanistic studies, baseline for drug levels, blood DNA analysis, blood RNA analysis, and blood proteomic analysis. Two skin biopsies will be obtained (one from an involved area and one from an adjacent uninvolved area). Concomitant medications and any adverse events will be assessed. Patients will then receive the first oral dose (200mg) of ritlecitinib. Patients will continue to receive the study drug QD through Week 24. Patients will return for visits every 2-4 weeks to have the following performed: vital signs and targeted physical will be taken; concomitant medications and any adverse events will be assessed. Safety, laboratory, and clinical assessments, as well as questionnaires will be performed at specified clinic visits. A serum pregnancy test will be performed at Screening and urine pregnancy tests will be performed at Baseline and every 2-4 weeks prior to administration of the study drug, if applicable. Clinical photographs of the skin lesions will be taken at each visit. Skin biopsies will be performed on all patients at Baseline and Week 24 or Early Termination visit. At Baseline, biopsies will be obtained from involved and uninvolved areas of a CTCL lesion. At Week 24 or Early Termination visit, the biopsy will be performed in the vicinity of the involved area biopsied at Baseline. An optional biopsy will be performed at Week 12, within the same area that was biopsied at Baseline. At Baseline, serum will be obtained for DNA (1 PaxGene), RNA (2 PaxGene), and proteomic analysis (2 tubes serum). Studies of RNA and proteomic analysis will further be performed at Weeks 12, 24 and 48/early termination.

Official Title
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A Single-center, Single-arm, Open-label Phase IIA Clinical Trial to Investigate Efficacy and Safety of Ritlecitinib (PF-06651600) in Patients With Cutaneous T Cell Lymphomas

Conditions
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CTCL, Mycosis Fungoides, Sezary Syndrome

Intervention / Treatment
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* Drug: Ritlecitinib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age ≥ 18 years at time of enrollment CTCL >10% BSA involvement (stage IB-IVA by ISCL/EORTC staging criteria), previously confirmed by histopathology CTCL subtypes eligible for this study include Mycosis fungoides and its subtypes, as well as Sézary Syndrome. Failure of at least 2 skin-directed (ISCL/EORTC stage IB-IIA, i.e. early stage disease) 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 the principal investigator, or insufficient response to established skin-directed or systemic treatments. i. Patients with documented CD30-positive CTCL must have previously received or be intolerant 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 creatinine equation >50mL/min/1.73m2) ECOG ≤ 2 (Eastern Cooperative Oncology Group scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 5 where 0 represents perfect health and 5 represents death.) Vaccination of SARS-CoV-2 (either initial dosing or boosters) within 1 year prior to Day 1 visit 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 communicate satisfactorily with the investigator and the study team, to participate fully in the study, and comply with all requirements EXCLUSION CRITERIA: History of, or a concurrent, clinically significant illness, medical condition or laboratory abnormality that, in the investigator's opinion, could affect the conduct of the study Immunosuppressed by previous (5 x half-lives or 12 weeks, whichever is longer) or current systemic cytotoxic therapies, as evidenced by recurrent skin or systemic infections Pregnant or breast-feeding women Unwillingness or inability to use a contraception method during the time of participation in the trial Uncontrolled current illness, including, but not limited to the following: Ongoing or active infections requiring intravenous antimicrobials; symptomatic congestive heart failure defined as NYHA class III or IV; unstable angina pectoris within 6 months of study enrollment; history of myocardial infarction, stroke or intracranial hemorrhage within 6 months prior to enrollment; moderate to severe hepatic impairment (Child-Pugh class B or C); psychiatric illness or social situations that would limit compliance with study requirements Previous or concurrent cancer that is distinct in primary site or histology form CTCL, except curatively treated basal or squamous cell carcinoma of the skin, and curatively treated malignant melanoma stage 0-1A with a low risk of recurrence/metastasis as per assessment of the investigator, cervical carcinoma in situ, 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 active TB 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 or recurrent (> 1 episode of) localized dermatomal HZ should be excluded. Less than 28 days have elapsed since last radiation therapy, phototherapy or chemotherapy treatment or patient has not recovered from all clinically significant treatment-related toxicity as defined in discontinuation criteria. Less than 3 months have elapsed since last JAK inhibitors Glucocorticosteroids when used systemically; the use of nasal and inhaled glucocorticosteroids 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 major impact on the clinical readout of the study drug, as per discretion of the study investigator; best supportive care will be allowed at the discretion of the investigator (e.g. anti-emetics, skin care, pain medication, anti-thrombotic agents, herpes zoster prophylaxis) Any gastrointestinal or metabolic condition that could interfere with the absorption of the oral medication Ongoing other MF-directed treatments (such as topical corticosteroids and topical bexarotene) 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 hearing loss, or middle or inner ear disease such as otitis media, cholesteatoma, Meniere's disease, 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 day or 5 half-lives (whichever is longer) period prior to the first dose of study intervention. Patients with ALCL or other forms of CTCL other than MF or Sézary Syndrome.

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
Interventional Model Description: Open-Label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Open-Label Ritlecitinib | Drug: Ritlecitinib<br>* 200 mg QD for 8 weeks followed by 100 mg for 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Severity Weighted Assessment Tool (mSWAT) | Skin response was primarily classified based on an assessment using mSWAT, provided there was documented evidence of stable disease or better in lymph node/viscera.The mSWAT is a tool specifically developed to evaluate the extent of skin disease in CTCL. Responses in the skin based on SWAT are defined as: Complete Response (CR): no evidence of skin disease Partial Response (PR): ≥ 50% decrease of the modified SWAT score compared with baseline Stable Disease (SD): Neither CR, PR, or PD as compared with baseline, i.e. change from baseline is less than a 50% decrease but also less than a 25 % increase in the modified SWAT score Progressive Disease (PD): ≥ 25% increase in the modified SWAT score compared with baseline. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Modified Severity Weighted Assessment Tool (mSWAT) | Skin response was primarily classified based on an assessment using mSWAT, provided there was documented evidence of stable disease or better in lymph node/viscera.The mSWAT is a tool specifically developed to evaluate the extent of skin disease in CTCL. Responses in the skin based on SWAT are defined as: Complete Response (CR): no evidence of skin disease Partial Response (PR): ≥ 50% decrease of the modified SWAT score compared with baseline Stable Disease (SD): Neither CR, PR, or PD as compared with baseline, i.e. change from baseline is less than a 50% decrease but also less than a 25 % increase in the modified SWAT score Progressive Disease (PD): ≥ 25% increase in the modified SWAT score compared with baseline. | at each visit from week 2 to week 48 / EOS except for week 24 | 
| Treatment Emergent Adverse Events | Incidence and severity of treatment-emergent adverse events | up to Week 48 | 
| Number of Serious Adverse Events | Number of serious adverse events (SAE) leading to discontinuation | up to Week 48 | 
| Number of Adverse Events | Number of Adverse events (AE) leading to discontinuation | up to Week 48 | 
| Number of significant events of hypertension or hypotension measured per CTCAE 5.0 | Number of significant events of hypertension or hypotension, events starting at Grade 2 according to the CTCAE 5.0 | up to Week 48 | 
| Number of significant events of bradycardia or tachycardia measured per CTCAE 5.0 | Number of significant events of bradycardia or tachycardia, events starting at Grade 2 according to the CTCAE 5.0 | up to Week 48 | 
| Hematocrit | Hematocrit is a blood test that measures how much of a person's blood is made up of red blood cells. This measurement depends on the number of and size of the red blood cells. Normal results vary, but in general they are: Male: 40.7% to 50.3% Female: 36.1% to 44.3% | up to Week 48 | 
| Hemoglobin count | Hemoglobin is a protein in red blood cells that carries oxygen. The hemoglobin test measures how much hemoglobin is in the blood. Normal results for adults vary, but in general are: Male: 13.8 to 17.2 grams per deciliter (g/dL) or 138 to 172 grams per liter (g/L) Female: 12.1 to 15.1 g/dL or 121 to 151 g/L High hemoglobin level is most often caused by low oxygen levels in the blood (hypoxia), present over a long period of time. | up to Week 48 | 
| Platelet count | A platelet count is a lab test to measure how many platelets are in blood. Platelets are parts of the blood that help the blood clot. They are smaller than red or white blood cells. The normal number of platelets in the blood is 150,000 to 400,000 platelets per microliter (mcL) or 150 to 400 × 109/L. A low platelet count is below 150,000 (150 × 109/L). If a patients platelet count is below 50,000 (50 × 109/L), their risk for bleeding is higher. Even every day activities can cause bleeding. | up to Week 48 | 
| Red Blood Cells (RBC) count | An RBC count is a blood test that measures how many red blood cells (RBCs) a person has. RBCs contain hemoglobin, a protein which carries oxygen. How much oxygen the body tissues get depends on how many RBCs the person has and how well they work. Women usually have a lower RBC count than men, and the level of red blood cells tends to decrease with age. A normal RBC count would be around: men - 4.0 to 5.9 x 10*12/L women - 3.8 to 5.2 x 10*12/L | up to Week 48 | 
| White blood cell (WBC) count | A WBC count is a blood test to measure the number of white blood cells (WBCs) in the blood. WBCs are also called leukocytes. They help fight infections. The normal number of WBCs in the blood is 4,500 to 11,000 WBCs per microliter (4.5 to 11.0 × 109/L). A low number of WBCs is called leukopenia. A count less than 4,500 cells per microliter (4.5 × 109/L) is below normal. | up to Week 48 | 
| Basophils count | An absolute basophil count identifies how many basophils are present in a sample of your blood. The calculation for an absolute basophil count multiplies the percentage of basophils from a complete blood count by the total number of white blood cells from the same count. The results from this test identify whether or not your basophil count is too high, normal or too low. | up to Week 48 | 
| Eosinophils count | An absolute eosinophil count is a blood test that measures the number of one type of white blood cells called eosinophils. Normal eosinophil count is less than 500 cells per microliter (cells/mcL). A high number of eosinophils (eosinophilia) are often linked to a variety of disorders. | up to Week 48 | 
| B Lymphocytes count | Lymphocytes are formed in your bone marrow. There are various types of lymphocytes: B cells (B lymphocytes). These make antibodies. Antibodies can destroy foreign substances or tag them for attack. | up to Week 48 | 
| T cells count | T cells (T lymphocytes). These lymphocytes destroy any of your cells that have been taken over by viruses or cancers. | up to Week 48 | 
| Natural Killer count | Natural Killer: are able to destroy tumor cells without any prior activation. Normal lymphocyte ranges depend on your age. For adults, normal lymphocyte count is between 1,000 and 4,800 lymphocytes per microliter of blood. | up to Week 48 | 
| Monocytes count | A normal monocyte count is between 2% and 8% of the white blood cell count. This equals about 200 to 800 monocytes per microliter of blood in healthy adults. If the patients monocyte count is outside those ranges, they may be at risk of acquiring a monocyte-related condition. | up to Week 48 | 
| Neutrophils count | An absolute neutrophil count identifies how many neutrophils are in a sample of blood. The normal range of neutrophils in a healthy adult is between 2,500 and 7,000 neutrophils per microliter of blood. Any number above 7,000 or below 2,500 puts patients at risk of a neutrophil condition. | up to Week 48 | 
| Albumin | Albumin helps move many small molecules through the blood, including bilirubin, calcium, progesterone, and medicines. It plays an important role in keeping the fluid in the blood from leaking into the tissues. This test can help determine if patients have liver disease or kidney disease, or if their body is not absorbing enough protein. The normal range is 3.4 to 5.4 g/dL (34 to 54 g/L). | up to Week 48 | 
| Alkaline phosphatase | Alkaline phosphatase (ALP) is a protein found in all body tissues. Tissues with higher amounts of ALP include the liver, bile ducts, and bone. A blood test can be done to measure the level of ALP. The normal range is 20 to 130 U/L | up to Week 48 | 
| ALT (alanine aminotransferase) | An alanine transaminase (ALT) blood test measures the amount of ALT in your blood. ALT levels in the blood can increase when a liver is damaged. The normal range for alanine transaminase (ALT) are 4 to 36 U/L | up to Week 48 | 
| AST (aspartate aminotransferase) | The aspartate aminotransferase (AST) test is a blood test that checks for liver damage. AST is an enzyme your liver makes. Other organs, like the heart, kidneys, brain, and muscles, also make smaller amounts. AST is also called SGOT (serum glutamic-oxaloacetic transaminase). Normally, AST levels in your blood are low. When the liver is damaged, it puts more AST into the blood, and the levels rise. Normal ranges of AST: 8 to 33 U/L | up to Week 48 | 
| BUN (blood urea nitrogen) | The blood urea nitrogen (BUN) test reveals important information about how well the kidneys are working. A BUN test measures the amount of urea nitrogen that's in the blood. Normal ranges for BUN (blood urea nitrogen): 6 to 20 mg/dL (2.14 to 7.14 mmol/L) | up to Week 48 | 
| Calcium | Calcium is a mineral that makes up bones, as well as a salt that dissolves in the blood and regulates bodily function. The normal blood calcium level is a range: 8.5 to 10.2 mg/dL (2.13 to 2.55 mmol/L) | up to Week 48 | 
| Chloride | Chloride is a type of electrolyte. It works with other electrolytes such as potassium, sodium, and carbon dioxide (CO2). These substances help keep the proper balance of body fluids and maintain the body's acid-base balance. A typical normal range is 96 to 106 milliequivalents per liter (mEq/L) or 96 to 106 millimoles per liter (millimol/L). | up to Week 48 | 
| CO2 (carbon dioxide) | CO2 is carbon dioxide. This article discusses the laboratory test to measures the amount of carbon dioxide in the liquid part of the blood, called the serum. In the body, most of the CO2 is in the form of a substance called bicarbonate (HCO3-). Therefore, the CO2 blood test is really a measure of your blood bicarbonate level. The normal range is 23 to 29 milliequivalents per liter (mEq/L) or 23 to 29 millimoles per liter (mmol/L). | up to Week 48 | 
| Creatinine | The creatinine blood test measures the level of creatinine in the blood. This test is done to see how well the kidneys are working. Creatinine can also be measured with a urine test. A normal result is 0.7 to 1.3 mg/dL (61.9 to 114.9 µmol/L) for men and 0.6 to 1.1 mg/dL (53 to 97.2 µmol/L) for women. Women often have a lower creatinine level than men. This is because women often have less muscle mass than men. Creatinine level varies based on a person's size and muscle mass. | up to Week 48 | 
| Glucose | A blood sugar test measures the amount of a sugar called glucose in a sample of the blood. Glucose is a major source of energy for most cells of the body, including brain cells. Glucose is a building block for carbohydrates. Carbohydrates are found in fruit, cereal, bread, pasta, and rice. Carbohydrates are quickly turned into glucose in the body. This can raise the blood glucose level. Hormones made in the body help control blood glucose level. If you had a fasting blood glucose test, a level between 70 and 100 mg/dL (3.9 and 5.6 mmol/L) is considered normal. If you had a random blood glucose test, a normal result depends on when you last ate. Most of the time, the blood glucose level will be 125 mg/dL (6.9 mmol/L) or lower. | up to Week 48 | 
| Potassium | Potassium is an electrolyte (mineral). It is needed for cells to function properly. Potassium is gained through food. The kidneys remove excess potassium through the urinary system to keep a proper balance of the mineral in the body. Normal range is 3.7 to 5.2 mEq/L (3.7 to 5.2 mmol/L). | up to Week 48 | 
| Sodium | Sodium is a substance that the body needs to work properly. Sodium is found in most foods. The most common form of sodium is sodium chloride, which is table salt. The sodium blood test measures the concentration of sodium in the blood. Sodium can also be measured using a urine test. The normal range for blood sodium levels is 135 to 145 milliequivalents per liter (mEq/L). | up to Week 48 | 
| Total bilirubin | The bilirubin blood test measures the level of bilirubin in the blood. Bilirubin is a yellowish pigment found in bile, a fluid made by the liver. Bilirubin can also be measured with a urine test. It is normal to have some bilirubin in the blood. A normal level is: Total bilirubin: 0.1 to 1.2 mg/dL (1.71 to 20.5 µmol/L) | up to Week 48 | 
| Total protein | The total protein test measures the total amount of two classes of proteins found in the fluid portion of the blood. These are albumin and globulin. Albumin helps prevent fluid from leaking out of blood vessels. It also carries chemicals in your blood. Globulins are an important part of your immune system. The normal range is 6.0 to 8.3 grams per deciliter (g/dL) or 60 to 83 g/L. | up to Week 48 | 
| Change in Percentage of patients achieving 50% or greater improvement mSWAT score | Change in Percentage of patients achieving 50% or greater improvement in their mSWAT score (mSWAT50) at Week 48 compared to baseline. Skin response was primarily classified based on an assessment using mSWAT, provided there was documented evidence of stable disease or better in lymph node/viscera.The mSWAT is a tool specifically developed to evaluate the extent of skin disease in CTCL (Olsen et al 2007). Responses in the skin based on SWAT are defined as: Complete Response (CR): no evidence of skin disease Partial Response (PR): ≥ 50% decrease of the modified SWAT score compared with baseline Stable Disease (SD): Neither CR, PR, or PD as compared with baseline, i.e. change from baseline is less than a 50% decrease but also less than a 25 % increase in the modified SWAT score Progressive Disease (PD): ≥ 25% increase in the modified SWAT score compared with baseline. | Baseline and Week 48 | 
| Global Response Score | Percentage of patients achieving complete response (CR: 100% improvement), partial response (PR: 50% to 99% reduction from the baseline score), stable disease (SD: <25% increase to <50% clearance from baseline), and progressive disease (>25% worsening above the baseline score) in skin | up to Week 48 |