An Open-Label Phase I/II Study of Relatlimab (BMS-986016) with Nivolumab (BMS-936558) in Combination with 5-Azacytidine for Relapsed/Refractory Acute Myeloid Leukemia and in Combination with 5-Azacytidine and Venetoclax for Newly Diagnosed, Previously Untreated Patients with Acute Myeloid Leukemia Negative for NPM1 and IDH 1/2 Mutations Who Are Ineligible for Intensive Chemotherapy (AARON)
试验速览
- 阶段
- 1/2 期
- 状态
- 尚未招募
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Lead-in phase I: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
研究概览
简要总结
Lead-in phase I: • To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of relatlimab in combination with nivolumab and 5-azacytidine in patients with relapsed/refractory (R/R) AML. • To determine the MTD and DLT of relatlimab in combination with nivolumab, 5-azacytidine and venetoclax in frontline non-fit AML patients
Expansion phase II: • To estimate the overall response rate (ORR) to treatment with relatlimab + nivolumab + 5-azacytidine in patients with R/R AML. • To estimate the ORR to treatment with relatlimab + nivolumab + 5-azacytidine + venetoclax in frontline non-fit AML patients
研究设计
- 研究类型
- Interventional clinical trial of medicinal product
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 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 CR, CRi, or CRp, or patients who have failed up to one prior salvage therapy.
- •At least 2 weeks OR at least 5 half-lives interval from prior treatment to time of initiation of study medication.
- •Written informed consent.
- •GvHD of grade ≤A on ≤10 mg prednisone without any additional immunosuppressive therapies (tacrolimus, ciclosporin, etc.).
- •Negative pregnancy test and adequate methods of contraception for females of childbearing potential, adequate methods of contraception for males.
- •Cohort 2 (frontline non-fit AML): Patients with previously untreated AML, negative for mutations in NPM1 and IDH 1/2 genes, who are ineligible for or decline standard induction therapy.
- •Patients not eligible for intensive induction chemotherapy and/or allogeneic stem cell transplant.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤
- •Age ≥18 years.
- •Total bilirubin ≤2 x upper limit of normal (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%.
排除标准
- •Acute promyelocytic leukemia (APL).
- •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.
- •Biphenotypic or bilineage leukemia.
- •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.
- •Known allergy or hypersensitivity to 5-azacytidine, nivolumab, relatlimab, or any of their components.
- •Known allergy or hypersensitivity to venetoclax, or any of its components, for patients in Cohort
- •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.
结局指标
主要结局
Lead-in phase I: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
Lead-in phase I: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.
Lead-in phase I: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine and venetoclax in frontline non-fit AML patients.
Lead-in phase I: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine and venetoclax in frontline non-fit AML patients.
Expansion phase II: ORR to treatment with relatlimab + nivolumab + 5- azacytidine in patients with R/R AML.
Expansion phase II: ORR to treatment with relatlimab + nivolumab + 5- azacytidine in patients with R/R AML.
Expansion phase II: ORR to treatment with relatlimab + nivolumab + 5- azacytidine + venetoclax in frontline non-fit AML patients.
Expansion phase II: ORR to treatment with relatlimab + nivolumab + 5- azacytidine + venetoclax in frontline non-fit AML patients.
次要结局
- % of grade I/II and grade III/IV toxicities for patients with R/R AML on therapy with relatlimab + nivolumab + 5- azacytidine.
- % of grade I/II and grade III/IV toxicities for frontline non-fit AML patients on therapy with relatlimab + nivolumab + 5- azacytidine + venetoclax.
- Number of patients with R/R AML who achieve a HI in platelets, hemoglobin, or ANC on therapy with relatlimab + nivolumab + 5-azacytidine.
- Number of patients with R/R AML who achieve ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine.
- Number of frontline non-fit AML patients who have an HI in platelets, hemoglobin, or ANC on therapy with relatlimab + nivolumab + 5-azacytidine + venetoclax.
- Number of frontline non-fit AML patients who have ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine + venetoclax.
- Duration of response, Disease-free survival (DFS), and Overall Survival (OS) of patients with R/R AML treated with relatlimab + nivolumab + 5-azacytidine.
- Duration of response, DFS, and OS in frontline non-fit AML patients treated with relatlimab + nivolumab + 5-azacytidine + venetoclax.
研究者
Prof. Dr. Marion Subklewe
Scientific
Klinikum der Universitaet Muenchen AöR