Clinical trial NCT04913922: Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: AML
relapsed
refractory
checkpoint blockade
immune checkpoint inhibition
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
First posted: 2021-06-04
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct
measure: Dose-limiting toxicities (DLTs)
timeFrame: after completion of the first cycle in the fist 6-12 patients, approximately during the first 6-12 months of study conduct
measure: Objective response rate (ORR)
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
Secondary outcomes:
measure: Hematologic improvement
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
measure: Blast reduction
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
measure: Duration of response (DOR)
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
measure: Disease-free survival (DFS)
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
measure: Overall survival (OS)
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
Other outcomes:
measure: Immunological changes
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
measure: Molecular changes
timeFrame: During Phase II expansion phase, after completion of lead-in phase, approximately during months 7-48 of study conduct
Locations:
city: Munich
country: Germany
facility: University Hospital, LMU Munich
Study officials:
affiliation: Department of Medicine III, University of Munich
name: Marion Subklewe, MD
role: PRINCIPAL_INVESTIGATOR
References: