Durvalumab in Different Combinations With Pralatrexate, Romidepsin and Oral 5-Azacitidine for Lymphoma

Exclusion Criteria

• •Prior Therapy (for patients with R/R PTCL)
• •1. Exposure to any agent targeting PD-1, PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
• •2. For three-drug combinations, the patient must not have been exposed to at least two of those drugs. For two drugs combinations patients must not have been exposed to any of those drugs. Patients will be enrolled in the first treatment Arm that satisfies this exclusion criterion, according to the following sequence: Arm A; Arm B; Arm C; Arm D.
• •3. Exposure to biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, or radiation therapy within 2 weeks prior to entering the study or lack of resolution of 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.
• •4. 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.
• •5. 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):
• •1. Congenital long QT syndrome;
• •2. corrected QT (QTc) interval ≥ 501 milliseconds;
• •3. Patients taking drugs leading to significant QT prolongation (See Appendix 3);
• •4. Myocardial infarction within 6 months of cycle 1, day 1. \[Subjects with a history of myocardial infarction between 6 and 12 months prior to cycle 1, day 1, who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event, may participate\];
• •5. Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min);
• •6. 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;
• •7. 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;
• •8. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions (see Appendix 5) and/or ejection fraction \< 40% by multitargeted acquisition (MUGA) scan or \< 50% by echocardiogram and/or magnetic resonance imaging (MRI);
• •9. 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);
• •10. Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes;