Tulmimetostat (CPI-0209) in Patients With Mycosis Fungoides and Sézary Syndrome

Inclusion Criteria:

• Histologically or cytologically confirmed mycosis fungoides or Sézary syndrome,stages IB to IVB with measurable disease and/or detectable blood involvement basedon the Global Response Criteria for CTCL (Olsen et al., 2022).

• Received at least one prior line of systemic therapy.

• At least 18 years of age.

• ECOG performance status ≤ 2

• Adequate counts and organ function as defined below:

• ANC ≥ 0.7 x 109/L, without growth factor support (filgrastim or pegfilgrastim)for at least 14 days

• Platelets ≥ 75 x 109/L, without platelet transfusion for at least 14 days

• Hemoglobin ≥ 8.0 g/dL, with or without transfusion

• Serum total bilirubin ≤ 1.5 x IULN

• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

• Creatinine clearance > 30 mL/min by Cockcroft-Gault (using actual body weight)for patients with creatinine levels above institutional normal OR serumcreatinine ≤ 1.5 x ULN

• Patients with treated brain metastases are eligible if follow-up brain imaging afterCNS-directed therapy shows no evidence of progression.

• The effects of CPI-0209 on the developing human fetus are unknown. For this reason,women of childbearing potential and men must agree to use highly effective methodsof contraception for the duration of study participation and for 183 days after thelast dose of CPI-0209 for female patients and female partners of male patients, orfor 93 days after the last dose of CPI-0209 for male patients and male partners offemale patients. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informedconsent document.

Exclusion Criteria:

• Prior treatment with an EZH2 inhibitor.

• Patients with CNS lymmphoma.

• A history of other malignancy with the exception of malignancies for which alltreatment was completed at least 2 years before registration and the patient has noevidence of disease. Patients with a prior or concurrent malignancy whose naturalhistory or treatment does not have the potential to interfere with the safety orefficacy assessment of the investigational regimen are eligible for this trial.

• Those with local basal cell or squamous cell carcinoma of the skin, cervicalcarcinoma in situ, superficial bladder cancer, asymptomatic prostate cancerwithout known metastatic disease and with no requirement for therapy orrequiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to registration, asymptomatic breast cancer on adjuvant hormonaltherapy diagnosed more than 2 years ago, adequately treated Stage 1 or 2 cancercurrently in complete remission, or any other cancer that has been in completeremission for ≥ 3 years are eligible.

• Currently receiving any other investigational agents. Concomitant use of anothersystemic therapy for MF/SS. Patients must have the following minimum wash-out fromprevious treatments:

• At least 8 weeks for low-dose (12 Gy or less) total skin electron beam therapy (TSEBT)

• At least 4 weeks for systemic cytotoxic anticancer agents or fortumor-targeting monoclonal antibodies (mAbs), with the exception ofalemtuzumab, for which the washout is at least 16 weeks

• At least 2 weeks or 5 half-lives for systemic retinoids, interferons,vorinostat, romidepsin, and denileukin diftitox, or anticancer investigationalagents that are not defined as immunotherapy,

• At least 2 weeks for local radiation therapy

• At least 1 week for topical retinoids, nitrogen mustard, or imiquimod

• Taking concomitant medication(s) or food or beverage that are strong CYP3A inducersor inhibitors within 7 days prior to the first dose of study drug.

• History of allogeneic HCT within 90 days prior to the first dose of study drug.

• Clinically significant graft-versus-host disease (GVHD) or GVHD requiring systemicimmunosuppressive prophylaxis or treatment.

• Previous solid organ transplant.

• Clinically significant cardiovascular disease including:

• Myocardial infarction/stroke within 3 months prior to Day 1 of treatment

• Unstable angina within 3 months prior to Day 1 of treatment

• Congestive heart failure or cardiomyopathy with NYHA Class 3 or 4

• History of clinically significant ventricular arrhythmias (e.g. ventriculartachycardia, ventricular fibrillation, Torsades de pointes)

• Uncontrolled hypertension (as defined per institutional standards) despite 2concomitant antihypertensive therapies

• QT interval corrected by the Fridericia correction formula (QTcF) ≥ 480 msec attime of screening

• Major surgery within 4 weeks before starting study drug or not recovered from anyeffects of prior major surgery (uncomplicated central line placement or fine needleaspiration are not considered major surgery).

• Gastrointestinal disorders, i.e., ulcerative colitis, malabsorption syndrome,refractory nausea and vomiting, biliary shunt, significant bowel resection or anyother condition that may significantly interfere with absorption of the studymedication by the investigator's assessment.

• Uncontrolled active infection requiring IV antibiotic, antiviral, or antifungalmedications within 14 days before the first dose of study drug. Infections (e.g.,urinary tract infection) controlled on concurrent antimicrobial agents andantimicrobial prophylaxis per institutional guidelines are acceptable.

• Current known active or chronic infection with HIV, hepatitis B, or hepatitis C. Allpatients will require serologic testing to be performed within 6 months prior toC1D1.

• Patients with chronic HBV or HCV are defined as patients with positivehepatitis B serology: Patients with a negative HBsAg and a positive HBcAbrequire an undetectable/negative hepatitis B DNA test (e.g. polymerase chainreaction [PCR] test) to be enrolled, and will require prophylactic antiviraltreatment initiated prior to the first dose of study drug, and continued untilapproximately 6 to 12 months after completion of study drug(s).

• Patients should be excluded if they have a condition requiring systemic treatmentwith either corticosteroids (>10 mg daily prednisone equivalents) or otherimmunosuppressive medications within 7 days of study drug administration. Inhaled ortopical steroids, steroids for physiologic or adrenal replacement doses <10 mg dailyprednisone equivalents are permitted in the absence of active autoimmune disease.Patients are permitted to use topical, ocular, intra-articular, intranasal, andinhalational corticosteroids (with minimal systemic absorption) and use of theseagents does not require a washout period. A brief course of corticosteroids forprophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmuneconditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen)is permitted. Topical steroids for cutaneous manifestations of MF/SS will bepermitted as per below:

• Continued use of select concomitant topical steroids is permitted if thepatient has remained clinically stable for at least 4 weeks. Patients who areon low or moderate potency topical corticosteroids may participate if they areon a stable dose for at least 4 weeks before enrollment. Local injections ofcorticosteroids are acceptable; all corticosteroids will be reported asconcomitant medications. Patients prescribed prednisone 10 mg PO daily or less (or equivalent) will not be excluded.

• Ongoing treatment with other immunosuppressive agent including, but not limited to,methotrexate, azathioprine, anti-TNF agents, etc. with the exception of steroids.

• Clinically active or symptomatic chronic liver disease.

• Unstable or severe uncontrolled medical condition or any important medical orpsychiatric illness or abnormal laboratory finding that would, in the investigator'sjudgment, increase the risk to the patient associated with his/her participation inthis study.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativepregnancy test within 72 hours prior to first dose of study drug.