This is an open-label, Phase 1/2a, dose-finding study with an initial phase 1 portion, articulated in four separate treatment arms, followed by a dedicated phase 2 for qualifying treatment Arm(s).
The primary objective of the Phase 1 portion is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of: Durvalumab, oral 5-azacitidine, and romidepsin (Arm A); durvalumab, pralatrexate, and romidepsin (Arm B); durvalumab and romidepsin (Arm C); or durvalumab and oral 5-azacitidine (Arm D), in patients with peripheral T-cell lymphoma (PTCL). The safety and toxicity profile of these combinations will be evaluated throughout the entire study.
If one or more of the combinations in Arms A, B, C, or D are found to be feasible and an MTD is established, the phase 2 portion of the study will be initiated for the combination(s) with the strongest efficacy signal provided acceptable toxicity.
Age >18 years at the time of signing the informed consent
Patients must have histologically confirmed newly diagnosed (ND) or Relapsed/Refractory Peripheral T-Cell Lymphoma (R/R PTCL) defined according to the 2016 World Health Organization (WHO) classification criteria.
Patients with R/R PTCL who have received at least one previous line 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.
Prior Therapy (for patients with R/R PTCL)
Exposure to any agent targeting PD-1, PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
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.
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.
Sequential
Durvalumab
DrugDurvalumab is an investigational human monoclonal antibody that works to inhibit (block) a protein called programmed cell death-1 ligand 1 (PD-L1). Durvalumab has not been approved by the FDA for the treatment of PTCL but has been given to patients other types of cancers. Given intravenously (through the vein). Starting dose: 1500 mg
Pralatrexate
DrugPralatrexate is an antimetabolite drug. Pralatrexate alone is FDA-approved for the treatment of PTCL. Given intravenously (through the vein). Starting dose: 25 mg/m2
Romidepsin
DrugRomidepsin is another type of chemotherapy known as histone deacetylase (HDAC) inhibitors. Romidepsin has not been approved for use in lymphoma other than Cutaneous T cell lymphoma (CTCL) by the FDA. Given intravenously (through the vein). Starting dose: 12 mg/m2
5-Azacitidine
DrugOral 5-azacitidine is used for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Azacitidine prevents the body from making DNA and RNA that cells need to grow. This stops the growth of cancer cells and causes them to die. Given by mouth (orally). Starting dose: 300 mg daily
Maximum Tolerated Dose (MTD)
The highest dose of study treatment that does not cause unacceptable side effects in patients with R/R PTCL in each study arm
Overall Response Rate (ORR)
ORR will be defined as the sum of complete response rate and partial response rate based on evaluation of best response in each patient.
Duration of Response (DoR)
Time from documentation of tumor response to disease progression
Progression Free Survival (PFS)
Time from study treatment until disease progression or death
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