Azacitidine and Abatacept in Relapsed or Refractory T-Cell Lymphoma

Background:

• Relapsed or refractory T-cell lymphoma is typically incurable with a median survival of less than 1 year. Angioimmunoblastic T-cell lymphoma (AITL) is the most commonly defined subtype of T-cell lymphoma and has a similarly poor prognosis.
• We have developed the first AITL cell lines that maintain immunophenotypic fidelity with AITL and used these cell lines to identify novel therapies for patients with AITL.
• We found that CD28 blockade with the Food and Drug Administration (FDA)-approved rheumatologic agent abatacept, which blocks CD28 signaling, impaired the proliferation of AITL cell lines, and that injection of abatacept into patient-derived xenograft (PDX) models of AITL significantly prolonged their survival. Based on this we conclude that targeting CD28 with abatacept in AITL is a promising, novel therapeutic approach that warrants clinical testing in people with relapsed/refractory (R/R) T-cell lymphoma.
• Abatacept can be combined with the deoxyribonucleic acid (DNA) methyltransferase inhibitor azacitidine, which has been shown to be preferentially active in patients with a TET2 mutation, the most common genetic abnormality in patients with AITL. We confirmed that azacitidine indeed inhibits AITL cell lines synergistically with abatacept.

Objectives:

• Arm 1: To estimate the maximum tolerated dose (MTD) of the combination of azacitidine and abatacept in relapsed or refractory T-cell lymphoma.
• Arm 2: To estimate the complete response rate (CRR) of the combination of azacitidine and abatacept.

Eligibility:

• Participants >= 18 years with relapsed or refractory T-cell lymphoma after initial systemic treatment.
• Adequate organ and marrow function.
• Eastern Cooperative Oncology Group (ECOG) performance status <= 2.

Design:

• This is a non-randomized, open-label, single-site phase I trial evaluating the combination of azacitidine and abatacept.
• Treatment will be delivered in cycles consistent of 28 days.
• During Cycle 0 abatacept will be administered intravenously on Days 1 and 15.
• During Cycles 1-6 abatacept administered on Day 1 will be combined with subcutaneous azacitidine delivered on Days 1-5 or Days 1-7.
• After Cycle 6 participants will be evaluated and participants who have a response will get additional 6 cycles of the monotherapy with azacitidine.

-INCLUSION CRITERIA

• Participants must have a histologically or cytologically confirmed T-cell lymphoma confirmed by the Laboratory of Pathology (LP), NCI. The one of the following T-cell lymphomas are included:

• Peripheral T-cell lymphoma not otherwise specified (PTCL, NOS)
• Angioimmunoblastic T-cell lymphoma (AITL)
• T-follicular helper (TFH) lymphoma
• Anaplastic large cell lymphoma (ALCL)
• Enteropathy-associated T-cell lymphoma (EATL)
• Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
• Adult T-cell leukemia/lymphoma (ATLL)
• Other T-cell lymphoma (TCL)
• Participants must have a disease that is relapsed or refractory after initial systemic treatment.
• Participants must have evaluable disease on screening imaging or by laboratory assessment.
• Age >= 18 years.
• ECOG performance status <= 2.
• Participants must have adequate organ and marrow function as defined below:

• Absolute neutrophil count (ANC) / >= 1,000 cells/mcL OR >= 500 cells/mcL if bone marrow involvement with lymphoma
• Platelets / >= 50,000 cells/mcL OR >= 25,000 cells/mcL if bone marrow involvement with lymphoma
• Hemoglobin / >= 8 g/dL (transfusions permitted)
• Renal function / Serum creatinine <= 2 mg/dL OR Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 as estimated by the Modification of Diet in Renal Disease (MDRD).

Note: there is no limit if involved by lymphoma.

If not on target, a 24-hour urine creatinine clearance can be used to directly measure creatinine clearance.

• Total bilirubin / <= 1.5 x upper limit of normal (ULN)
• Aspartate Aminotransferase (AST) / <= 3.0 x ULN
• Alanine Aminotransferase (ALT) / <= 3.0 x ULN
• Prothrombin time (PT) / <1.5 x ULN
• Activated partial thromboplastin time (aPTT) / <1.5 x ULN; < 5.0 x ULN if the aPTT is prolonged because of a positive Lupus Anticoagulant

International normalized ratio (INR) / <1.5 x ULN

• Participants, seropositive for human immunodeficiency virus (HIV), must have an undetectable HIV viral load.
• Participants, seropositive for hepatitis C virus (HCV) infection, must have been treated and have an undetectable HCV viral load.
• Participants who are hepatitis B core antibody (HBcAb) positive must have a hepatitis B virus (HBV) viral load result <100 IU/mL. Note: participants who are hepatitis B surface antigen (HBsAg) positive are excluded.
• Participants with detectable Epstein-Barr virus (EBV) or Cytomegalovirus (CMV) by polymerase chain reaction will be eligible provided they do not have end organ dysfunction from EBV or CMV infection.
• Participants with pulmonary disease such as chronic obstructive pulmonary disease and non-infectious liver disease who otherwise meet the requirements.
• Women of child-bearing potential (WOCBP) must agree to use effective methods of contraception (barrier, hormonal, surgical sterilization, abstinence) during the study treatment and for 6 months after the completion of the study treatment. Note: WOCBP is defined as any woman who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

Men able to father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) during the study treatment and for 3 months after the completion of the study treatment. These men must not freeze or donate sperm within the same period.

• Nursing participants must be willing to discontinue nursing from study treatment initiation through six (6) months after the last dose of the study drug(s).
• Ability of the participant to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Any second malignancy that requires current active systemic therapy.
• Latent tuberculosis (TB) infection.
• Active systemic bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring anti-infective treatment within 1 day prior to the study treatment initiation.
• Anti-cancer therapy within 2 weeks prior to the study treatment initiation. Note: systemic steroids are allowed if <= 100 mg/per day of prednisone (or equivalent) and were used for <= 7 days during 2 weeks before the study treatment initiation.
• Any investigational therapy within 2 weeks prior to the study treatment initiation.
• Known allergy or hypersensitivity to any of the study drugs.
• Pregnancy confirmed with beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test in WOCBP at screening.
• Active central nervous system involvement with lymphoma. Previously treated central nervous system involvement with lymphoma will be allowed if >3 months since end of treatment.
• Uncontrolled intercurrent illness, factors, evaluated by medical history, electrocardiogram (EKG), and physical exam that would potentially increase in risk of participant.