Ruxolitinib and Duvelisib for the Treatment of Relapsed or Refractory T- or NK-Cell Lymphoma

Inclusion Criteria

• Pathologically-confirmed mature T-cell lymphomas at the enrolling institution. Permitted histologies include (for dose escalation and expansion): * Stage >= Ib primary cutaneous T-cell non-Hodgkin lymphoma (CTCL), which has relapsed or progressed after at least two systemic therapies. In order to ensure balanced enrollment for patients with systemic T-cell lymphoma and CTCL, a maximum of 15 CTCL patients will be enrolled in expansion cohort * Systemic anaplastic large cell lymphoma that has relapsed after therapy containing brentuximab vedotin * T-cell prolymphocytic leukemia (treatment naïve permitted)
• For the following histologies, patients are required to have received at least 1 prior therapy (dose escalation and expansion): * T-cell large granular lymphocytic leukemia * Aggressive NK-cell leukemia * Adult T-cell leukemia/lymphoma * Extranodal NK/T- cell lymphoma, nasal type * Enteropathy-associated T-cell lymphoma * Monomorphic epitheliotropic intestinal T-cell lymphoma * Hepatosplenic T cell lymphoma * Subcutaneous panniculitis-like T-cell lymphoma * Primary cutaneous anaplastic large cell lymphoma * Primary cutaneous gamma/delta T-cell lymphoma * Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma * Peripheral T-cell lymphoma, not otherwise specified * Angioimmunoblastic T cell lymphoma * Follicular T-cell lymphoma * Nodal peripheral T-cell lymphoma with T follicular helper phenotype
• Specific for T-PLL and TFH lymphoma expansion: histologies must be pathologically confirmed at the enrolling institutions * T-cell prolymphocytic leukemia (treatment naïve permitted) * T-follicular helper lymphomas (must have received at least 1 prior treatment)
• Age >= 18 years at time of enrollment
• Performance status, as assessed in the Eastern Cooperative Oncology Group (ECOG) grading system =< 2
• DOSE ESCALATION PHASE: Absolute neutrophil count >= 1.0 K/mcL (Note: growth factor is allowed)
• DOSE ESCALATION PHASE: Platelet count >= 80 K/ul or >= 50 K/ul if due to lymphoma
• DOSE ESCALATION PHASE: Creatinine ≤ 1.5 × upper limit of normal (ULN) OR measured calculated creatinine clearance ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutional ULN * Creatinine clearance should be calculated per institutional standard
• DOSE ESCALATION PHASE: Direct bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN if documented hepatic involvement with lymphoma, or =< 5 x ULN if history of Gilbert’s syndrome
• DOSE ESCALATION PHASE: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN; or =< 5 x ULN if due to lymphoma involvement
• DOSE EXPANSION PHASE AND T-PLL/TFH LYMPHOMA EXPANSION: Absolute neutrophil count >= 1.0 K/mcL or >= 0.5 K/mcL if due to lymphoma or >= 0.0 K/mcL if due to T-PLL or large granular lymphocytic leukemia (LGL) (Note: growth factor is allowed)
• DOSE EXPANSION PHASE AND T-PLL/TFH LYMPHOMA EXPANSION: Platelet count >= 80 K/ul or >= 50 K/ul if due to lymphoma
• DOSE EXPANSION PHASE AND T-PLL/TFH LYMPHOMA EXPANSION: Creatinine ≤ 1.5 × ULN OR measured or calculated creatinine clearance ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutional ULN * Creatinine clearance should be calculated per institutional standard
• DOSE EXPANSION PHASE AND T-PLL/TFH LYMPHOMA EXPANSION: Direct bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN if documented hepatic involvement with lymphoma, or =< 5 x ULN if history of Gilbert’s syndrome
• DOSE EXPANSION PHASE AND T-PLL/TFH LYMPHOMA EXPANSION: AST and ALT =< 3 x ULN; or =< 5 x ULN if due to lymphoma involvement
• Measurable disease, defined by at least one of the following: * Revised International Working Group Classification for systemic lymphoma * Atypical T lymphocytes quantifiable by flow cytometry or morphology in the peripheral blood or bone marrow * mSWAT (Modified Severity Weighted Assessment Tool) > 0
• Ability to swallow pills
• Women of reproductive potential must have a negative serum or urine beta human chorionic gonadotropin (beta hCG) pregnancy test within 14 days of initiating therapy. All women of reproductive potential and all sexually active male patients must agree to use adequate methods of birth control (e.g. latex condoms) throughout the study and for 3 months after the last dose of study drug * A woman of reproductive potential is a sexually-mature woman who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months) * The effects of duvelisib on conception, pregnancy, and lactation are unknown. Since duvelisib has not been evaluated in pregnant or nursing women, the treatment of pregnant women or women of childbearing potential who are not using a highly effective contraception is contraindicated

Exclusion Criteria

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
• Pregnant women. (Lactating women must agree not to breast feed while taking study medications)
• Prior allogeneic stem cell transplant within 6 months of starting treatment or patients with active graft versus host disease (GVHD) requiring immunosuppression. * Prior allogeneic stem cell transplant may be allowed after discussion with MSK principal investigator (PI) if no GVHD or immunosuppression is present at time of enrollment
• Prior use of duvelisib or ruxolitinib if either agent was discontinued due to toxicity
• Previous systemic anti-cancer therapy for TCL within 14 days of initiating study drug * Patients who have received localized radiation therapy (RT) as part of their immediate prior therapy may be allowed to enroll with shorter washout period after discussion with the MSK Principal Investigator ** Patients receiving treatment with single agent ruxolitinib or duvelisib may be allowed to enroll onto the study without a washout period * Systemic corticosteroids must be tapered to 20 mg/day or less prednisone (or equivalent) upon start of investigational treatment * Topical steroids for CTCL is permitted on study
• Ongoing use of immunosuppressant medications, including corticosteroids greater than 20 mg of prednisone or equivalent at the time of enrollment
• History of chronic liver disease, veno-occlusive disease, or current alcohol abuse
• Administration of a live vaccine within 6 weeks of first dose of study drug
• Prior surgery or gastrointestinal condition that may adversely affect drug absorption (e.g., gastric bypass surgery, gastrectomy)
• Patients with human immunodeficiency virus (HIV) infection if they meet either of the below criteria: * Detectable viral load * Undetectable viral load with CD4 count < 200 or not taking anti-retroviral medications
• Patients with chronic hepatitis B or C as defined by positive hepatitis B or C serology: * Subjects with a negative hepatitis B surface antigen (HBsAg) and a positive hepatitis B core antibody (HBcAb) require an undetectable/negative hepatitis B deoxyribonucleic acid (DNA) test (e.g., polymerase chain reaction [PCR] test) to be enrolled, and must receive hepatitis B prophylaxis until at least 6 months after completion of study drug(s)
• Subjects with active cytomegalovirus (CMV) (defined as positive CMV polymerase chain reaction [PCR] with clinical manifestations consistent with active CMV infection) and requiring therapy. Carriers will be monitored per institutional guidelines
• Unable or unwilling to receive prophylaxis against pneumocystis, herpes simplex virus, or herpes zoster
• Use of medications or consumption of foods that are strong inducers or inhibitors of CYP3A * Such agents must be discontinued at least 2 weeks prior to study intervention * Patients who (after enrollment) require use of a strong CYP3A4 inhibitor to treat a fungal/mold infection will require dose reductions
• Receipt of treatment for tuberculosis within 2 years prior to enrollment
• Receiving therapy for another primary malignancy (other than T-cell lymphoma). * Patients with more than one type of lymphoma may be enrolled after discussion with the MSK Principal Investigator * Early-stage cutaneous basal cell and squamous cell carcinomas are permissible * Adjuvant or maintenance therapy to reduce the risk of recurrence of other malignancy is potentially permissible after discussion with the MSK Principal Investigator
• Known central nervous system or meningeal involvement by TCL (in the absence of symptoms, investigation into central nervous system involvement is not required)
• Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition) or any important medical illness that would, in the Investigator’s judgment, increase the risk to the patient associated with his or her participation in the study