Durvalumab, Pralatrexate, Romidepsin, and Oral Azacitidine in Treating Patients with Peripheral T-Cell Lymphoma

Inclusion Criteria

• Patients must have histologically confirmed PTCL defined according to the 2016 World Health Organization (WHO) classification criteria
• Patients with previously untreated disease, relapsed or refractory disease are allowed irrespective of the number of lines of prior therapy
• Patients who are candidate for an autologous or allogeneic stem cell transplantation (SCT) are eligible
• Evaluable (phase 1) or measurable (phase 2) disease
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Aspartate aminotransferase (aspartate transaminase [AST]) and alanine aminotransferase (alanine transaminase [ALT]) levels =< 2 x institutional upper limit of normal (ULN) (AST, ALT, and total bilirubin =< 3 x ULN in subjects with documented Gilbert’s syndrome or hyperbilirubinemia clearly attributed to lymphoma involvement of the liver)
• Total bilirubin =< 1.5 x ULN (AST, ALT, and total bilirubin =< 3 x ULN in subjects with documented Gilbert’s syndrome or hyperbilirubinemia clearly attributed to lymphoma involvement of the liver)
• Creatinine levels < 2 mg/dL; or creatinine clearance > 40 mL/min
• Absolute neutrophil count (ANC) > 1,000/uL
• Platelet count > 75,000/uL
• Negative urine or serum pregnancy test for women of childbearing potential; all women of childbearing potential must agree to use an effective barrier method of contraception (either an intrauterine device [IUD] or double-barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 3 months after discontinuation of the study drugs; male subjects should use effective barrier method of contraception during the treatment period and for at least 3 months after discontinuation of the study drugs
• Ability to understand and the willingness to sign a written informed consent document
• Ability to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria

• Prior Therapy (for patients with R/R PTCL): * Exposure to any agent targeting PD-L1 * Patients must fulfill the following criteria regarding prior exposure to study drugs: in Arm A (azacitidine, romidepsin, durvalumab) no prior exposure to durvalumab, and no prior exposure to azacitidine (irrespectively to formulation) or romidepsin; in Arm B (pralatrexate, romidepsin, durvalumab) no prior exposure to durvalumab, and no prior exposure to pralatrexate or romidepsin; in Arm C (romidepsin, durvalumab) no prior exposure to durvalumab, and no prior exposure to romidepsin; in Arm D (5-oral azacytidine and durvalumab) no prior exposure to durvalumab and no prior exposure to azacitidine irrespectively of formulation * Lack of resolution of adverse events (AE) due to previously administered antineoplastic therapy to grade 1 or less according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 * Current or prior use of immunosuppressive medication within 14 days prior to first dose of durvalumab; the following are exceptions to this criterion: intranasal, inhaled, topical or local steroid injections (e.g. intra-articular injection); steroids as premedication for hypersensitivity reactions; systemic corticosteroid at physiologic doses not to exceed 10 mg/day of prednisone or equivalent for at least 5 days prior to the start of the study drugs * Prior allogeneic SCT
• History of, or suspected allergic reactions to durvalumab, pralatrexate, oral 5-azacitidine, or romidepsin or any of their excipients
• For patients who are treated with oral 5-azacitidine, any gastrointestinal disorder that would interfere with the absorption of the study drug
• Concomitant use of CYP3A4 inhibitors
• Uncontrolled intercurrent illness
• Any of the following cardiac abnormalities (only for patients receiving romidepsin): * Congenital long QT syndrome; * Corrected QT (QTc) interval >= 501 milliseconds; * Patients taking drugs leading to significant QT prolongation; * Myocardial infarction within 6 months of cycle 1, day 1; (Subjects with a history of myocardial infarction between 6 and 12 months prior to cycle 1, day 1, 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 definitions and/or ejection fraction < 40% by multitargeted 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 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 >= 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)
• Pregnancy or breast-feeding
• Active concurrent malignancy (except non-melanoma skin cancer, prostatic intraepithelial neoplasia, or carcinoma in situ of the cervix); patients whose lymphoma has transformed from a less aggressive histology remain eligible
• Receipt of solid organ transplant
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis, Crohn’s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener’s syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment; the following are exceptions to this criterion: subjects with vitiligo or alopecia; subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; or subjects with psoriasis not requiring systemic treatment; patients with autoimmune phenomena secondary to active lymphoma (e.g. autoimmune hemolytic anemia)
• Central nervous system (CNS) involvement, including lymphomatous meningitis
• Known active hepatitis A, B or C virus infection
• Known human immunodeficiency virus (HIV) infection
• History of primary immunodeficiency
• Administration of live attenuated vaccine within 30 days prior to study entry; enrolled patients should not receive live vaccine during the study and 30 days after the last dose of durvalumab