Acute Myeloid Leukemia
Conditions
Keywords
AML, relapsed, refractory, checkpoint blockade, immune checkpoint inhibition
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).
Interventions
s.c. 75 mg/m2 BSA for 7 days
DRUGNivolumab
480 mg i.v.
DRUGRelatlimab
80-160mg i.v.
Sponsors
Ludwig-Maximilians - University of Munich
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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) |
| 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immunological changes | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | To study immunological changes in the peripheral blood and bone marrow in response to relatlimab + nivolumab + 5-azacytidine therapy, assessed by the frequency of T-cell (subsets), regulatory T cells, and immune checkpoint expression on blasts and T cells by flow cytometry and RNA Sequencing |
| Molecular changes | During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct | To study the methylation status of blast DNA in the peripheral blood and bone marrow in response to relatlimab + nivolumab + 5-azacytidine therapy |
Countries
Germany
Contacts
Primary ContactMarion Subklewe, MD
Backup ContactVeit Bücklein, MD
Outcome results
None listed