A Study of Enasidenib in People With T-Cell Lymphoma

Inclusion Criteria:

Screening Cohort (non-MSK patients only)

1. Age ≥18 years at time of consent

2. Has freely given written informed consent to participate in the study

Treatment Cohort:

1. Pathologically-confirmed AITL at the enrolling institution, with confirmed IDH2mutation (by MSK ddPCR). For R/R patients, disease must have relapsed or progressedafter at least one systemic therapy, diagnostic tumor samples have at least 5%tumor.

2. Age ≥18 years at time of enrollment

3. Previous systemic anti-cancer therapy for AITL must have been discontinued at least 2 weeks or 5 half-lives (whichever is longer) prior to treatment. i) See section 6.2 Subject Exclusion Criteria for guidelines regarding adjuvant andmaintenance therapy for prior malignancy. ii) Patients who have received localized RT as part of their immediate prior therapymay be allowed to enroll with shorter washout period after discussion with the MSKCCPrincipal Investigator iii) Systemic corticosteroids must be tapered to 25 mg/dayprednisone (or equivalent) upon start of investigational treatment iv) Topicalsteroids for treating cutaneous involvement of AITL is permitted

4. Performance status, as assessed in the ECOG grading system, ≤2

5. Laboratory criteria (use of GCSF and/or blood product transfusions to reacheligibility criteria must be discussed with the MSK PI on a case-by-case basis): i)Absolute neutrophil count ≥1.0 K/μL or ≥0.5 K/μL if due to lymphoma ii) Plateletcount ≥80 K/μl or ≥50 K/μl if due to lymphoma iii) Calculated creatinine clearance ≥30 mL/min by the Modification of Diet in Renal Disease (MDRD) glomerular filtrationrate iv) Total bilirubin ≤1.5x upper limit of normal (ULN) or ≤3x ULN if documentedhepatic involvement with lymphoma, or ≤5x ULN if history of Gilbert's syndrome; ASTand ALT ≤ 3x ULN; ≤ 5x ULN if due to lymphoma involvement

6. Measurable disease, defined by either of:

• Revised International Working Group Classification for systemic lymphoma(13)

• Atypical T lymphocytes quantifiable by flow cytometry or morphology in theperipheral blood or bone marrow

7. Women of reproductive potential* must have a negative serum or urine β humanchorionic gonadotropin (β-hCG) pregnancy test. All women of reproductive potentialmust agree to use adequate methods of birth control throughout the study and for 30days after the last dose of study drug. *A woman of reproductive potential is asexually mature woman who: has not undergone a hysterectomy or bilateraloophorectomy; or has not been naturally postmenopausal for at least 24 consecutivemonths (i.e., has had menses at any time in the preceding 24 consecutive months)

8. Women must agree to not breastfeed during the study period

9. Male subjects must agree to practice true abstinence from sexual intercourse or tothe use of highly effective contraceptive methods with non-pregnant female partnersof childbearing potential at screening and throughout the course of the study, andshould avoid conception with their partners during the course of the study and for 4months following the last study treatment

10. Subject is willing and able to adhere to the study visit schedule and other protocolrequirements

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness thatwould prevent the subject from signing the informed consent form.

2. On immunosuppressive therapy post-allogeneic stem cell transplantation at the timeof screening, or with clinically significant graft-versus-host disease (GVHD). Theuse of a stable dose of oral steroid post-HSCT and/or topical steroids for ongoingskin GVHD is permitted after discussion with the study PI

3. Subject has persistent, clinically significant non-hematologic toxicities grade >1or not to baseline level from prior therapies besides alopecia or neuropathy

4. Pregnant women

5. History of chronic liver disease, veno-occlusive disease, or alcohol abuse

6. Administration of a live vaccine within 6 weeks of first dose of study drug

7. Prior surgery or gastrointestinal condition that may adversely affect drugabsorption (e.g.,gastric bypass surgery, gastrectomy)

8. Patients with HIV infection with detectable viral load, CD4 count <200, or nottaking anti-retroviral medications

9. Patients with chronic hepatitis B or C as defined by positive hepatitis B or Cserology:

10. Subjects with a negative HBsAg and a positive HBcAb require anundetectable/negative hepatitis B DNA test (e.g., polymerase chain reaction [PCR] test) to be enrolled, and will require prophylactic antiviral treatmentaccording to institutional standards of care initiated prior to the first doseof study drug, and continued until approximately 18 months after completion ofstudy drug(s) if rituximab is utilized.

11. Patients who are hepatitis C antibody positive with negative PCR may enroll

12. Subjects with active CMV (defined as positive serum CMV PCR with clinicalmanifestations consistent with active CMV infection) and requiring therapy. Carriers (low-level positivity by PCR and without evidence of CMV disease) will be monitoredper institutional guidelines when such guidelines exist or individual physicianpractice in the absence of formal guidelines to ensure stability in the PCR levelover time and continued absence of CMV disease manifestations.

13. Receiving therapy for another primary malignancy (other than T-cell lymphoma).

14. Patients with more than one type of lymphoma may be enrolled after discussionwith the MSK Principal Investigator.

15. Early-stage cutaneous basal cell and squamous cell carcinomas are permissible

16. Adjuvant or maintenance therapy to reduce the risk of recurrence of othermalignancy is potentially permissible after discussion with the MSK PrincipalInvestigator.

17. Known central nervous system or meningeal involvement by AITL (in the absencesymptoms, investigation into central nervous system involvement is not required)

18. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvementdespite appropriate antibiotics, antiviral therapy, and/or other treatment)

19. Subject has significant active cardiac disease within 6 months prior to the start ofstudy treatment, including New York Heart Association (NYHA) class III or IVcongestive heart failure; acute coronary syndrome (ACS); and/or stroke; or leftventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gatedacquisition (MUGA) scan obtained within 28 days prior to the start of studytreatment.

20. Prior use of enasidenib

21. Subjects taking the following sensitive CYP substrate medications with narrowtherapeutic ranges are excluded from enrolment the study unless they can be safelyrotated to other medications within >4 half-lives prior to C1D1: warfarin andphenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline andtizanidine (CYP1A2).

22. Subjects taking the P-gp- and BCRP transporter-sensitive substrates digoxin androsuvastatin should be counseled with pharmacy input regarding drug-druginteractions.

23. Digoxin is acceptable with dose modification after consulting with a pharmacist

24. Patients taking rosuvastatin should be excluded from the study unless they cansafely be rotated to alternative medications within >4 half-lives prior toC1D1.

25. Caution should be exercised on patients on medications that are substrates forUGT1A1 (including but not limited to ezetimibe, raloxifene, and raltegravir). Suchpatients shall rotate to alternate therapies, or reduce doses of these medicationsin consultation with the prescribing provider and/or a consulting pharmacist. Closemonitoring for adverse events shall be pursued in these instances.