An Open-Label Phase II Study of Relatlimab (BMS-986016) With Nivolumab (BMS-936558) in Combination With 5-Azacytidine for the Treatment of Patients With Refractory/Relapsed Acute Myeloid Leukemia and Newly Diagnosed Older Acute Myeloid Leukemia Patients
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Objective response rate (ORR)
研究概览
简要总结
The clinical trial will test the safety and tolerability of a combination therapy (azacitidine in combination with two checkpoint inhibitors, nivolumab [Anti-PD1] and relatlimab [Anti-LAG3]) in patients with relapsed/refractory Acute Myeloid Leukemia (AML) and patients ≥ 65 years with initial diagnosis of AML.
Primary objectives are:
- maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the combination therapy during the lead-in phase of the clinical trial (6-12 patients) and
- objective response rate (ORR) of the combination therapy in the phase II part of the study (up to 24 patients).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cohort 1 (R/R AML):
- •Patients with AML who have failed first line induction chemotherapy (consisting of a minimum of two intensive chemotherapy cycles, e.g. 7+3 or HAM) or patients with AML who have relapsed after achieving complete remission (CR), CRi, or CRp, or patients who have failed up to one prior salvage therapy
- •Cohort 2 (frontline older AML):
- •Patients aged ≥65 years with previously untreated AML who are unfit for or decline standard induction therapy.
- •General inclusion criteria:
- •Patients not eligible for intensive induction chemotherapy and/or allogeneic stem cell transplant.
- •Age ≥18 years
- •ECOG Performance Status ≤2
- •Adequate organ function:
- •Total bilirubin ≤2 x ULN (≤3 × ULN if due to leukemic involvement or Gilbert's syndrome) AST and ALT ≤2.5 × ULN (≤5.0 × ULN if due to leukemic involvement) Serum creatinine ≤2 × ULN or glomerular filtration rate (GFR) ≥50 mL/h
- •Adequate cardiac function: TTE with documented LVEF ≥50%
- •At least 2 weeks OR at least 5 half-lives interval from prior treatment to time of initiation of study medication
- •GvHD of grade ≤A on ≤10 mg prednisone without any additional immunosuppressive therapies (tacrolimus, ciclosporin, etc.)
- •Written informed consent
- •Negative pregnancy test and adequate methods of contraception for females of childbearing potential, adequate methods of contraception for males
排除标准
- •Acute promyelocytic leukemia (APL)
- •Biphenotypic or bilineage leukemia
- •Known allergy or hypersensitivity to 5-azacytidine, nivolumab, relatlimab, or any of their components
- •History of life-threatening toxicity related to prior immune therapy
- •Previous treatment with immunotherapeutic drugs targeting PD-1/PD-L1 in combination with 5-azacytidine
- •Previous treatment with LAG-3 targeted agents
- •Known history of severe interstitial lung disease or severe pneumonitis
- •Known history (active, known, or suspected) of any of the following autoimmune diseases:
- •inflammatory bowel disease rheumatoid arthritis systemic progressive sclerosis systemic lupus erythematosus autoimmune vasculitis
- •Active uncontrolled pneumonitis
- •Active uncontrolled infection
- •Symptomatic or poorly controlled CNS leukemia
- •Confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
- •Uncontrolled or significant cardiovascular disease
- •Troponin T (TnT) or I (TnI) > 2 × institutional ULN
- •Organ allografts
- •Allogeneic hematopoietic stem cell transplantation within the last 100 days before first study drug administration
- •Active GvHD > grade A
- •Known human immunodeficiency virus seropositivity
- •Known positivity for hepatitis B by surface antigen expression or active hepatitis C infection
- •Other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety
- •Patients unwilling or unable to comply with the protocol
- •Patients who are pregnant or breastfeeding
- •Prisoners and subjects who are compulsory detained
研究组 & 干预措施
Combination therapy
5-azacitidine 75 mg/m2 body surface area s.c. for 7 days nivolumab 480mg i.v. day 1 relatlimab 80-160mg i.v. day 1
repeat day 28
干预措施: Azacitidine Injection (Drug)
Combination therapy
5-azacitidine 75 mg/m2 body surface area s.c. for 7 days nivolumab 480mg i.v. day 1 relatlimab 80-160mg i.v. day 1
repeat day 28
干预措施: Nivolumab (Drug)
Combination therapy
5-azacitidine 75 mg/m2 body surface area s.c. for 7 days nivolumab 480mg i.v. day 1 relatlimab 80-160mg i.v. day 1
repeat day 28
干预措施: Relatlimab (Drug)
结局指标
主要结局
Objective response rate (ORR)
时间窗: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
To estimate the ORR to treatment with relatlimab + nivolumab + 5-azacytidine in patients with R/R AML and Patients ≥65 years with initial diagnosis of AML
Maximum tolerated dose (MTD)
时间窗: after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct
To determine the MTD of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
Dose-limiting toxicities (DLTs)
时间窗: after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct
To determine the DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
次要结局
- Blast reduction(During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct)
- Duration of response (DOR)(During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct)
- Overall survival (OS)(During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct)
- Hematologic improvement(During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct)
- Disease-free survival (DFS)(During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct)
研究者
Veit Bücklein, MD
Investigator
Ludwig-Maximilians - University of Munich