Azacitidine and Romidepsin for the Treatment of Relapse or Refractory Peripheral T-cell Lymphoma

Inclusion Criteria

• Patients must have histologically confirmed relapsed or refractory peripheral T-cell lymphoma as defined by 2016 World Health Organization (WHO) criteria, who have progressed following one line of prior systemic therapy
• Patients are required to have no more than 3 lines of prior therapy (with cytoreductive therapy [example (ex): ifosfamide, carboplatin and etoposide (ICE), dexamethasone, high-dose cytarabine and cisplatin (DHAP), etc.] followed by autologous stem cell transplant counting as one line of therapy). Patients are eligible if they have relapsed after prior autologous or allogeneic stem cell transplant
• Patients with anaplastic large cell lymphoma are required to have received brentuximab vedotin (BV) prior to study enrollment
• Measurable disease
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count (ANC) >= 1000/mm^3 (>= 1000/dL)
• Platelets >= 75,000/mm^3
• Serum creatinine < 2 x upper limit of normal (ULN) or creatinine clearance >= 50 mL/min/for patients with creatinine levels above ULN * Calculate creatinine clearance using the glomerular filtration rate (GFR) according to the Cockcroft and Gault equation, only if screening serum creatinine is > 1.5 mg/dL
• Bilirubin =< 1.5 x ULN (except in patients with Gilbert’s disease, where bilirubin to 4x ULN is allowed)
• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) =< 2 x ULN OR =<3 X ULN in presence of demonstrable liver involvement
• Serum potassium >= 3.8 mmol/L
• Serum magnesium >= 1.8 mg/dL
• Negative urine or serum pregnancy test for females of childbearing potential
• All females of childbearing potential and male subjects must agree to use an effective method of contraception
• Be willing and able to provide written consent or assent for the trial

Exclusion Criteria

• Diagnosis of patch/plaque stage mycosis fungoides
• Prior Therapy: Prior exposure to any hypomethylating agent or any histone deacetylase inhibitor (ex: romidepsin, chidamie, belinostat, or vorinostat); exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier
• Systemic steroids that have not been stabilized to the equivalent of =< 10 mg/day prednisone prior to the start of the study drugs
• No other concurrent investigational agents are allowed within 2 weeks of enrollment
• Known central nervous system metastases, including lymphomatous meningitis
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Nursing women
• Other active concurrent malignancy (except non-melanoma skin cancer, carcinoma in situ of the cervix, or carcinoma in situ of the breast [ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS)]). If there is a history of prior malignancy, the patient must be disease-free for >= 3 years. Patients whose lymphoma has transformed from a less aggressive histology remain eligible
• Patients known to be human immunodeficiency virus (HIV)-positive
• Patients with active hepatitis A, hepatitis B, or hepatitis C infection
• Concomitant use of CYP3A4 inhibitors
• History of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism, or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity
• Abnormal coagulation parameters (prothrombin time [PT] > 15 seconds, partial thromboplastin time [PTT] > 40 seconds, and/or international normalized ratio [INR] > 1.5) unless related to ongoing anticoagulation treatment required by the patient
• Known or suspected hypersensitivity to azacitidine (or any excipients in the formulation) or mannitol
• Any known cardiac abnormalities such as: * Congenital long QT syndrome * Corrected QT (QTc) interval >= 500 millisecond (using the Fridericia formula) * Patients taking drugs leading to significant QT prolongation * Myocardial infarction within 6 months of cycle 1 day 1 (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 electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min) * Symptomatic coronary artery disease (CAD), e.g., angina Canadian class II-IV. 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 and/or ejection fraction < 40% by multi-gated acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI) * A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest * Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes * Uncontrolled hypertension, i.e., blood pressure (BP) of >= 160/95; 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; or * Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)