This is an open label phase Ib/IIa study of patients with relapsed/refractory B- and T-cell lymphomas who are treated with carfilzomib, lenalidomide and romidepsin.

Inclusion Criteria:

• Pathologically confirmed B- or T-cell lymphomas at the enrolling institution, including stage ≥ Ib CTCL, which has relapsed or progressed after at least one systemic therapy.
• Hodgkin lymphoma is allowed and will be classified as a B-cell lymphoma in the phase IIA portion.
• Age ≥ 18,
• Previous systemic anti-cancer therapy must have been discontinued at least 3 weeks prior to treatment and adverse effects must have resolved to ≤Grade 1 or baseline. In the phase IIa portion, in progressing subjects, a 2 week washout may be allowed after discussion with the MSK Principal Investigator.
• Previous radiation, hormonal therapy, and/or surgery must have been discontinued or completed at least 2 weeks prior to treatment in this study and adverse effects must have resolved. Lymph node or other diagnostic biopsies within 2 weeks are not considered exclusionary.
• ECOG ≤ 2
• Meet the following laboratory criteria:
• Absolute neutrophil count 1.0/mm³,
• Platelet count 80 K/μ (in the Phase II portion, if thrombocytopenia is due to bone marrow involvement platelet count must be 50 K/μL),
• Phase Ib subjects must have calculated creatinine clearance 50ml/min by Cockcroft-Gault formula, phase IIa subjects must have calculated creatinine clearance ≥ 40ml4/min by Cockcroft-Gault formula.
• Total bilirubin 1.5 x upper limit of normal (ULN); AST (SGOT) and ALT (SGPT) 3 x ULN
• Measurable disease for phase IIa portion only.
• Lymphoma (includes CTCL patients who are without evidence of the disease in the skin): CT or PET/CT by modified Cheson criteria with incorporation of PET.
• CTCL: mSWAT >0, or absolute Sezary count ≥ 1000 cells/μL.
• All study participants must be registered into the mandatory Revlimid REMS ® program, and be willing and able to comply with the requirements of the REMS ® program.
• Short course systemic corticosteroids for disease control, improvement of performance status or non-cancer indication (< 7 days) must have been discontinued at least 6 days prior to study treatment. Stable ongoing corticosteroid use (≥ 30 days) up to an equivalent dose of 15 mg of prednisone is permissible.
• Topical steroids that have been used for > 3 weeks may be continued (CTCL only).
• Women of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. See Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
• A female of reproductive potential is a sexually mature female 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).

Exclusion Criteria:

• Patients who have a standard curative option for their lymphoid malignancy at current state of disease are excluded. For eligibility on this trial, allogeneic stem cell transplantation is not to be considered a standard curative option.
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
• Pregnant females. (Lactating females must agree not to breast feed while taking carfilzomib, lenalidomide or romidepsin).
• Known hypersensitivity to thalidomide.
• The development of erythema multiforme if characterized by a desquamating rash while taking thalidomide or similar drugs.
• Prior use of lenalidomide if discontinued due to toxicity.
• Prior therapy with romidepsin if discontinued due to toxicity.
• Prior therapy with carfilzomib if discontinued due to toxicity.
• Prior therapy with a proteasome inhibitor if discontinued due to toxicity.
• Concurrent use of other anti-cancer agents or treatments.
• Known seropositive and requiring anti-viral therapy for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Concurrent malignancy requiring active therapy.
• Patients with more than one type of lymphoma may be enrolled after discussion with the MSK Principal Investigator.
• Known central nervous system or meningeal involvement (in the absence of symptoms investigation into central nervous system involvement is not required).
• The following known cardiac abnormalities:
• Congenital long QT syndrome.
• QTc/QTf interval ≥ 480 milliseconds; unless secondary to pacemaker or bundle branch block.
• Myocardial infarction within 6 months of cycle one, day one (C1D1). Subjects with a history of myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate.
• Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block.
• Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see Appendix B). In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present.
• An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present.
• Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions (see Appendix C) and/or ejection fraction <45% by, echocardiogram, or cardiac MRI.
• A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD).
• Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes.
• Uncontrolled hypertension, i.e., blood pressure (BP) of ≥170/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria.
• Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)
• Patients taking drugs that can cause significant QTc/QTf prolongation unless able to be switched to non-QTc/QTf prolonging medication or on a stable dose without significant QT prolongation (>470 msec).
• Concomitant use of significant CYP3A4 inhibitors unless able to be switched to a non-CYP3A4 inhibiting medication.
• Caution should be used when administering study drugs to patients taking medications significantly metabolized by these enzymes refer to (http://medicine.iupui.edu/clinpharm/ddis/clinical-table/ ) for clinically relevant medications. Particular attention should be paid to patients receiving warfarin. Patient should have coagulation parameters monitored regularly, and warfarin dose adjusted accordingly. If these drugs cannot be discontinued or replaced, enrollment may be allowed after discussion with MSK PI.