This phase II trial tests how well adding revumenib to usual treatment (blinatumomab) compared to usual treatment alone works in treating patients with B-cell acute lymphoblastic leukemia (B-ALL) or acute leukemia with ambiguous lineage (ALAL) with KMT2A-translocation. Revumenib binds to a protein called menin and keeps it from binding to another protein called KMT2A. This stops or slows the growth of leukemia cells with changes in the KMT2A gene. Blinatumomab binds to CD19, which is found on most B cells (a type of white blood cell) and some types of leukemia cells. It also binds to a protein called CD3, which is found on T cells (another type of white blood cell). This may help the immune system kill cancer cells. In addition to blinatumomab, usual treatment also includes dexamethasone, methotrexate, cyclophosphamide, cytarabine, mercaptopurine, calaspargase pegol, doxorubicin, thioguanine, daunorubicin, vincristine and leucovorin. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Methotrexate is in a class of medications called antimetabolites. It is also a type of antifolate. Methotrexate stops cells from using folic acid to make deoxyribonucleic acid (DNA) and may kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Chemotherapy drugs, such as cytarabine, mercaptopurine, calaspargase pegol, doxorubicin, thioguanine, and daunorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Leucovorin is also being studied in the treatment of cancer. It is a type of chemoprotective agent and a type of chemosensitizing agent. Adding revumenib to usual treatment with blinatumomab may be safe, tolerable and more effective than blinatumomab alone in lowering the amount of leukemia in patients with B-ALL or ALAL with the KMT2A translocation.
COHORT A: Participants must meet diagnostic criteria for either B-cell acute lymphoblastic leukemia (ALL) with KMT2A-translocation or acute leukemia with ambiguous lineage (ALAL) with KMT2A-translocation
COHORT A: Participants must have KMT2A-translocation documented locally by conventional cytogenetics, fluorescence in situ hybridization (FISH) or molecular studies such as next generation sequencing (NGS)
COHORT A: Participants must have achieved morphological first complete remission (CR1) after induction cycle (s) as defined bone marrow lymphoblasts < 5%
COHORT A: Participants must have either known trackable clone(s) by clonoSEQ that was identified at initial diagnosis, or a banked diagnostic sample, which can include clinical samples from the treating institution, available that can be used to identify trackable clone(s)
None
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo CSF and blood sample collection
Blinatumomab
Biological/VaccineGiven IV
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow biopsy and aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy and aspiration
Calaspargase Pegol
DrugGiven IV
Chest Radiography
Procedure/SurgeryUndergo chest x-ray
Computed Tomography
Procedure/SurgeryUndergo CT or PET/CT
Cyclophosphamide
DrugGiven IV
Cytarabine
DrugGiven IV or SC
Daunorubicin Hydrochloride
DrugGiven IV
Dexamethasone
DrugGiven PO or IV
Doxorubicin
DrugGiven IV
Echocardiography Test
Procedure/SurgeryUndergo ECHO
Leucovorin Calcium
DrugGiven PO or IV
Mercaptopurine
DrugGiven PO
Methotrexate
DrugGiven IT or IV
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Revumenib
DrugGiven PO
Thioguanine
DrugGiven PO
Vincristine
DrugGiven IV
Dose limiting toxicities (Safety run-in: Cohort A)
Will be evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 6.0. Will evaluate the proportion of participants with dose limiting toxicities and exact confidence intervals.
Measurable residual disease (MRD) negativity rate (Cohort A)
Difference in proportion of participants who achieve clonoSEQ MRD status between the two arms will be compared using a two-sample proportion test.
MRD-event-free survival (EFS) (Cohort A)
Will be compared using unstratified log-rank test.
Incidence of toxicities of interest (TOI) (Cohort B)
TOI rates will be reported with exact 90% confidence intervals.
Incidence of adverse events
Frequency and severity within each arm and across cycles of therapy will be assessed using NCI CTCAE v 6.0.
MRD negative complete remission (CR) rate (Cohort A)
Will be evaluated in participants with positive MRD before randomization.
EFS (Cohort A)
Will be estimated using the Kaplan-Meier method. Will be evaluated in participants with negative MRD before randomization.
MRD-EFS (Cohort A)
Will be estimated using the Kaplan-Meier method. Will be evaluated in participants with negative MRD before randomization.
Frequency of MEN1 mutations
Will be evaluated by quantitative polymerase chain reaction (PCR) and/or high sensitivity next generation sequencing.
Rate of KMT2A fusion reverse transcriptase (RT)-PCR MRD negativity within treatment arms (Cohort A)
KMT2A fusion RT-PCR MRD negativity (Cohort B)
Rate of IG/TR V(D)J MRD negative remission
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SWOG Cancer Research Network
Lead sponsor
National Cancer Institute (NCI)
Collaborator
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