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

The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphoid
neoplasms and account for 10-15% of all newly diagnosed cases of non-Hodgkin's lymphoma
(NHL). The current prevalence of PTCL in the United States is estimated to be approximately
9,500 patient. Treatment options for patients with relapsed/refractory (R/R) PTCL have been
limited. This study focuses on exploring rational combinations of these T-cell active agents
in an effort to develop novel treatment platforms.

Inclusion Criteria:

- Age >18 years at the time of signing the informed consent

- Patients must have histologically confirmed relapsed or refractory PTCL defined
according to the 2016 World Health Organization (WHO) classification criteria, with no
accepted curative options.

o Due to concerns for high risk of Epstein-Barr Virus (EBV) reactivation after
treatment with romidepsin, patients with the extranodal Natural killer (NK)/T-cell
lymphoma may only be allocated to treatment Arm D.

- Prior therapy: patients who have received at least one and no more than three previous
lines of therapy are eligible to be enrolled in this study

- Patients who are candidate for an autologous or allogeneic stem cell transplantation
(SCT) will be allowed to receive the study drugs as a "bridge" to transplantation if
candidates for transplant

- Measurable disease

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Patients must have adequate organ and marrow function as defined by:

- Aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2 x
institutional upper limit of normal (ULN); total bilirubin ≤ 1.5 x ULN (AST, ALT,
and total bilirubin ≤ 3 × 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/μL; platelet count > 75,000/μL;

- 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 or double-barrier method using
condoms or a diaphragm plus spermicide) during the treatment period and for at
least 1 month 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

- Be able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

- Prior Therapy:

- Exposure to any agent targeting PD-1, PD-L1 or cytotoxic T-lymphocyte-associated
protein (CTLA)-4.

- Previous therapy with pralatrexate, romidepsin, 5-azacitidine, or a combination
thereof.

- 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 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 (eg. intra-articular
injection); steroids as premedication for hypersensitivity reactions; systemic
corticosteroid at physiologic doses not to exceed 10mg/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 excipient.

- For patients who are treated with oral 5-azacitidine, any gastrointestinal disorder
that would interfere with the absorption, distribution, metabolism or excretion of the
study drug

- Uncontrolled inter-current illness.

- Significant cardiac disease (only for patients receiving romidepsin).

- Pregnancy or breast-feeding.

- Current malignancy or history of a prior malignancy.

- 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.

- Central nervous system involvement, including lymphomatous meningitis.

- Known active hepatitis A, B or C virus infection.

- Known HIV infection.

- History of primary immunodeficiency.

- Receipt 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.