Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT04913922
- Lead Sponsor
- Ludwig-Maximilians - University of Munich
- Brief Summary
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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 30
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Combination therapy Azacitidine Injection 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 Combination therapy Nivolumab 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 Combination therapy Relatlimab 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
- Primary Outcome Measures
Name Time Method Objective response rate (ORR) 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) 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) 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.
- Secondary Outcome Measures
Name Time Method Blast reduction During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct To determine the number of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine who have a blast reduction (defined as ≥50% reduction in blast percentage compared to baseline blast percentage in bone marrow)
Duration of response (DOR) During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct To assess the duration of response (DOR) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine.
Overall survival (OS) During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct To assess the overall survival (OS) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine.
Hematologic improvement During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct To determine the number of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine who have a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC)
Disease-free survival (DFS) During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct To assess the disease-free survival (DFS) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine.
Trial Locations
- Locations (1)
University Hospital, LMU Munich
🇩🇪Munich, Germany