This is a research study to find out if adding a new study drug called revumenib to commonly used chemotherapy drugs is safe and if they have beneficial effects in treating patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that did not go into remission after treatment (refractory) or has come back after treatment (relapsed), and to determine the total dose of the 3-drug combination of revumenib, azacitidine and venetoclax that can be given safely in participants also taking an anti-fungal drug.
Primary Objective
* To determine the safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL.
Secondary Objectives
* Describe the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), and overall survival for patients treated with revumenib + azacitidine + venetoclax at the recommended phase 2 dose (RP2D).
Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy (one course for secondary AML), or relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission. Patients must have ≥5% blasts in the bone marrow as assessed by morphology or ≥1% blasts flow cytometry.
Presence of KMT2A rearrangement (KMT2Ar), NUP98 rearrangement (NUP98r), NPM1 mutation or fusion, PICALM::MLLT10, DEK::NUP214, UBTF-TD, KAT6A rearrangement (KAT6Ar), or SET::NUP214
Adequate organ function, defined as total bilirubin < 1.5 × institutional upper limit of normal for age or normal conjugated bilirubin (for patients with known Gilbert's syndrome, total bilirubin <3 × the ULN) unless attributed to leukemia, calculated creatinine clearance ≥60 mL/min/1.73 m², and left ventricular ejection fraction ≥ 40%
QTcF < 480 msec (average of triplicate)
Patients who are pregnant or breastfeeding are not eligible.
Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible.
Patients with uncontrolled infection are not eligible. Patients with infections that are controlled on concurrent anti-microbial agents are eligible.
Single group
Revumenib
DrugGiven by mouth (capsule or liquid solution) or liquid solution by Nasogastric tube (NG) or Gastrostomy tube (G-tube)
Venetoclax
DrugGiven by mouth (tablet) or by NG or G-tube
Azacitidine
DrugGiven intravenously (IV) infusion
intrathecal (IT) chemotherapy
DrugGiven intrathecal (IT)
Cytarabine
DrugGiven intrathecal (IT) as part of intrathecal (IT) chemotherapy.
Methotrexate
DrugGiven intrathecal (IT) as part of intrathecal (IT) chemotherapy.
The safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL
The primary endpoint is the recommended phase 2 dose (RP2D) of revumenib + azacitidine + venetoclax.
The rates of complete remission (CR)
CR is defined as bone marrow with \< 5% blasts confirmed by flow cytometry, ANC ≥500/μL and platelets ≥50,000/μL without transfusions, and no evidence of extramedullary disease.
The rates of complete remission with incomplete count recovery (CRi)
CRi is defined as bone marrow with \<5% blasts confirmed by flow cytometry and ANC \<500/μL or platelets \<50,000/μL without transfusions
The overall survival of patients treated at the RP2D.
Kaplan-Meier estimates with 95% confidence intervals will be used to describe overall survival.
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St. Jude Children's Research Hospital
Lead sponsor
Syndax Pharmaceuticals
Collaborator
