relatlimab with nivolumab and 5-azacytidine for the treatment of aml

Conditions: Acute Myeloid Leukemia

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

Keywords: aml relapsed refractory checkpoint blockade immune checkpoint inhibition