A Phase I Trial of Azacitidine and Abatacept in Relapsed or Refractory T-Cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Arm 2: To estimate the CRR of the combination of azacitidine and abatacept.
研究概览
简要总结
Background:
T-cell lymphoma is a blood cancer that affects immune system cells. People tend to survive less than 1 year if this disease does not respond to treatment (is refractory) or comes back after treatment (relapses). Azacitidine and abatacept are 2 drugs that are used to treat other diseases. Researchers want to know if these drugs, used together, can help people with T-cell lymphoma.
Objective:
To learn if azacitidine combined with abatacept can shrink tumors in people with T-cell lymphoma.
Eligibility:
People aged 18 years and older with T-cell lymphoma that either came back or did not respond to treatment.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have a test of their heart function. They will have imaging scans of their tumors. A sample of tumor tissue may be taken.
Azacitidine is injected under the skin of the thigh, abdomen, or upper arm. Abatacept is infused through a needle inserted into a vein in the arm.
Participants will receive the study drugs in 28-day cycles for up to 13 cycles. They will come to the clinic for each treatment. They will come to the clinic on day 1 and day 15 of the first cycle. After that, they will come to the clinic on the first 5 or 7 days of each cycle. Each clinic visit will take no more than 8 hours.
Imaging scans and other tests will be repeated during the study. Participants will have follow-up visits for up to 5 years after they stop taking the study drugs....
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 <=
- •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.
排除标准
- •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.
研究组 & 干预措施
Arm 1
Escalating/de-escalating doses of azacitidine + abatacept
干预措施: azacitidine (Drug)
Arm 1
Escalating/de-escalating doses of azacitidine + abatacept
干预措施: abatacept (Drug)
Arm 2
MTD of azacitidine + abatacept if less than 12 participants are enrolled in Arm 1
干预措施: azacitidine (Drug)
Arm 2
MTD of azacitidine + abatacept if less than 12 participants are enrolled in Arm 1
干预措施: abatacept (Drug)
结局指标
主要结局
Arm 2: To estimate the CRR of the combination of azacitidine and abatacept.
时间窗: Day 1 of Cycles 1, 4, 7, 10, EOT/PD visit, every 3 months for years 1-2, every 6 months for years 3-4, once a year for year 5.
Complete response rate (CRR) will be evaluated in Arm 2 in participants treated at MTD. CRR will be estimated along with a 95% confidence interval (CI).
Arm 1: To estimate the MTD of the combination of azacitidine and abatacept in relapsed or refractory T-cell lymphoma.
时间窗: 56 days (cycles 0-1)
MTD will be determined based on the DLT profile during the DLT window in Arm 1 56 days (cycles 0-1).
次要结局
- To determine the ORR defined as CR + PR to the combination of azacitidine and abatacept(Day 1 of every cycle then at the EOT/PD visit, every 3 months for years 1-2, every 6 months for years 3-4, then once a year until progression, initiation of another line of therapy, or 5 years since treatment initiation.)
- To determine the safety profile of a combination of azacitidine and abatacept in relapsed or refractory T-cell lymphoma(Day 1 through 30 days after the last study intervention was administered or before the initiation of a new anti-cancer treatment, whichever comes first.)