Testing Blinatumomab With or Without Revumenib in Patients With B-cell Acute Lymphoblastic Leukemia With a Genetic Change Requiring More Treatment

A Phase II Randomized Study of Blinatumomab With or Without Revumenib for Patients With KMT2A-Translocation B-Cell Acute Lymphoblastic Leukemia (ALL)/ Acute Leukemia With Ambiguous Lineage (ALAL) With Persistent Measurable Residual Disease (MRD)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: B Acute Lymphoblastic Leukemia; Acute Leukemia of Ambiguous Lineage; B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative; T Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Daunorubicin Hydrochloride; Drug: Cyclophosphamide; Drug: Mercaptopurine; Drug: Dexamethasone; Drug: Vincristine; Biological: Blinatumomab; Drug: Thioguanine; Drug: Doxorubicin; Procedure: Multigated Acquisition Scan; Procedure: Positron Emission Tomography; Drug: Leucovorin Calcium; Procedure: Chest Radiography; Procedure: Bone Marrow Biopsy; Drug: Methotrexate; Drug: Cytarabine; Procedure: Computed Tomography; Drug: Calaspargase Pegol; Procedure: Biospecimen Collection; Drug: Revumenib; Procedure: Bone Marrow Aspiration; Procedure: Echocardiography Test

Detailed Description

PRIMARY OBJECTIVES:

I. Among participants enrolled to the safety run-in cohort, to evaluate the safety of blinatumomab with revumenib in this participant population. (Cohort A: Children [≥ 1 year] and adults with CD19-positive [CD19+] KMT2Ar B-cell acute lymphoblastic leukemia [ALL]/ acute leukemia with ambiguous lineage [ALAL] in morphological first complete remission [CR1]) II. First primary randomized objective: Among participants with positive measurable residual disease (MRD) by clonoSEQ before randomization, to compare the rates of MRD negative complete remission (CR) by clonoSEQ after the completion of one cycle of blinatumomab versus one cycle of blinatumomab plus revumenib. (Cohort A: Children [≥ 1 year] and adults with CD19-positive [CD19+] KMT2Ar B-cell acute lymphoblastic leukemia [ALL]/ acute leukemia with ambiguous lineage [ALAL] in morphological first complete remission [CR1]) III. Secondary primary randomized objective (hierarchical tested): Among participants with positive MRD by clonoSEQ before randomization, if rates of MRD negative CR by clonoSEQ after completion of one cycle of therapy are improved with blinatumomab plus revumenib versus blinatumomab, to evaluate whether MRD-event-free survival is improved among patients randomized to blinatumomab plus revumenib versus blinatumomab. (Cohort A: Children [≥ 1 year] and adults with CD19-positive [CD19+] KMT2Ar B-cell acute lymphoblastic leukemia [ALL]/ acute leukemia with ambiguous lineage [ALAL] in morphological first complete remission [CR1]) IV. To describe and evaluate the feasibility of revumenib in combination with reduced intensity multiagent chemotherapy in this participant population. (Cohort B: Untreated newly diagnosed KMT2Ar B/T-ALL or ALAL in older adults [age ≥ 55 years])

SECONDARY OBJECTIVES:

I. Within each arm and cohort and across cycles of therapy, to estimate the frequency and severity of toxicities.

II. In Cohort A: Among participants with positive MRD by clonoSEQ before randomization, to estimate the rate of MRD negative CR by clonoSEQ after two cycles of blinatumomab or blinatumomab plus revumenib.

III. In Cohort A: Among participants with negative MRD by clonoSEQ before randomization, to estimate 6-month event-free survival and MRD-event-free survival in each arm.

IV. In Cohort A: Among participants with negative MRD by clonoSEQ before randomization, to estimate 6-month event-free survival in each arm.

V. In Cohort B: To estimate the post induction composite morphological CR (CR/CR with incomplete count recovery [CRi]) rate.

VI. To estimate proportion of participants MRD negative by multi-color flow cytometry after induction (Cohort B) and cycle 1 of blinatumomab (Cohorts A + B, including the safety cohort of Cohort A).

VII. Within each arm and cohort cohort (including the safety cohort of Cohort A): To estimate the rates of lineage switch and/or CD19-negative (CD19-) relapse.

VIII. Within each arm and cohort cohort (including the safety cohort of Cohort A): To estimate the rate of allogeneic hematopoietic stem cell transplantation (HSCT) in CR1.

IX. Within each arm and cohort cohort (including the safety cohort of Cohort A): To estimate event-free survival (EFS), MRD-EFS, relapse-free survival (RFS), progression-free survival (PFS), and MRD-PFS within each arm and cohort (including the safety cohort of Cohort A) and by age ≥ 1 year to < 18 years versus ≥ 18 years of age.

X. Within each arm and cohort cohort (including the safety cohort of Cohort A): To estimate time to MRD relapse by flow cytometry and/or clonoSEQ.

XI. Within each arm and cohort cohort (including the safety cohort of Cohort A): To estimate overall survival (OS).

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To estimate the frequency of MEN1 mutations by quantitative polymerase chain reaction (qPCR) and/or high sensitivity next generation sequencing (NGS) pre-induction (Cohort B), pre-randomization (Cohort A), after blinatumomab treatment (Cohorts A and B) and at the time of relapse (Cohorts A and B). (Primary) II. To estimate the rate of KMT2A fusion reverse transcriptase (RT)-PCR MRD negativity after the first and second cycle of blinatumomab therapy within treatment arms in Cohort A. (Secondary) III. To estimate the rate of KMT2A fusion RT-PCR MRD negativity after chemotherapy induction and blinatumomab post-induction therapy in Cohort B. (Secondary) V. To estimate the rate of immunoglobulin (IG)/T cell receptor (TR) variable (V) (diversity [D]) joining (J) next generation (NGS) MRD negative remission after first and second cycle of blinatumomab across treatment cohorts in Cohort A (among those with diagnosis specimens available) and after induction and blinatumomab (if administered) in Cohort B. (Secondary) V. To descriptively report changes in gene expression between diagnosis (in Cohort B, and as available in Cohort A) and relapse samples by ribonucleic acid (RNA) sequencing of registration and relapse samples. (Secondary)

OUTLINE: Patients 1 year of age or older with B-cell ALL or ALAL are assigned to Cohort A. Patients 55 and older with B-ALL, T-ALL or ALAL are assigned to Cohort B.

COHORT A: The first 6-12 eligible patients are assigned to Arm 1. Subsequent patients are randomized to Arm 1 or Arm 2.

ARM 1:

BLINATUMOMAB AND REVUMENIB CYCLE 1 (35 DAYS): Patients receive revumenib orally (PO) twice daily (BID) on days 4-28 of cycle 1, blinatumomab intravenously (IV) continuously on days 1-28 of cycle 1, dexamethasone PO or IV on days 1 and 8 (if indicated) of cycle 1, and methotrexate intrathecally (IT) on days 1 and 15 of cycle 1.

CONSOLIDATION PART 1 AND PART 2 (56 DAYS): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO once daily (QD) on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 or on days 1, 8, 29, and 43, vincristine IV on days 15, 22, 43, and 50 and calaspargase pegol IV over 1-2 hours on days 15 and 43 in the absence of disease progression or unacceptable toxicity.

BLINATUMOMAB AND REVUMENIB CYCLE 2 (35 DAYS): Patients receive revumenib PO BID on days 1-28 of cycle 2, blinatumomab IV continuously on days 1-28 of cycle 2, dexamethasone PO or IV on day 1 of cycle 2, and methotrexate IT on days 1 and 15 of cycle 2.

INTERIM MAINTENANCE 1 (63 DAYS): Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION PART 1 AND PART 2 (63 DAYS): Patients receive methotrexate IT on days 1, 29, and 36, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, 15, 43, and 50, doxorubicin IV over 3-15 minutes on days 1, 8, and 15, calaspargase pegol IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42 and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39 in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE 2 (56 DAYS): Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31 and calaspargase pegol IV over 1-2 hours on days 2 and 23 in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo chest x-ray and echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening and bone marrow biopsy and aspiration, cerebrospinal fluid (CSF) and blood sample collection, computed tomography (CT) or positron emission tomography (PET)/CT throughout the study.

ARM 2:

BLINATUMOMAB CYCLE 1 (35 DAYS): Patients blinatumomab IV continuously on days 1-28 of cycle 1, dexamethasone PO or IV on days 1 and 8 (if indicated) of cycle 1, and methotrexate IT on days 1 and 15 of cycle 1.

CONSOLIDATION PART 1 AND PART 2 (56 DAYS): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO QD on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 or on days 1, 8, 29, and 43, vincristine IV on days 15, 22, 43, and 50 and calaspargase pegol IV over 1-2 hours on days 15 and 43 in the absence of disease progression or unacceptable toxicity.

BLINATUMOMAB CYCLE 2 (35 DAYS): Patients receive blinatumomab IV continuously on days 1-28 of cycle 2, dexamethasone PO or IV on day 1 of cycle 2, and methotrexate IT on days 1 and 15 of cycle 2.

INTERIM MAINTENANCE 1 (63 DAYS): Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION PART 1 AND PART 2 (63 DAYS): Patients receive methotrexate IT on days 1, 29, and 36, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, 15, 43, and 50, doxorubicin IV over 3-15 minutes on days 1, 8, and 15, calaspargase pegol IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39 in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE 2 (56 DAYS): Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31 and calaspargase pegol IV over 1-2 hours on days 2 and 23 in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo chest x-ray and ECHO or MUGA at screening and bone marrow biopsy and aspiration, CSF and blood sample collection, CT or PET/CT throughout the study.

COHORT B:

INDUCTION (35 DAYS): Patients receive cytarabine IT on day 1 of cycle 1, vincristine IV on days 1, 8, 15, and 22 of cycle 1, dexamethasone PO or IV BID on days 1-7 and 15-21 or IV BID on days 1-7 of cycle 1, daunorubicin IV on days 1, 8, and 15 of cycle 1, methotrexate IT on days 8 and 29 or once weekly of cycle 1, and revumenib PO BID on days 8-28 of cycle 1.

POST-INDUCTION (84 DAYS): Patients with morphological CR after induction treatment may receive revumenib PO BID on days 4-28 of cycle 1 and on days 1-28 of cycle 2, blinatumomab IV continuously on days 1-28 of cycles 1 and 2 and methotrexate IT on days 1 and 15 of cycles 1 and 2. Cycles repeat every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo bone marrow biopsy and aspiration, CSF and blood sample collection, CT or PET/CT throughout the study.

After completion of study treatment, patients are followed every 3 months for the first 2 years, every 6 months for years 3-5 and then annually for up to 10 years after registration.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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)

  • Participants must not be known not to have trackable clones by clonoSEQ
  • Participants must not be known already to have MRD-negativity by clonoSEQ prior to enrollment
• COHORT A: Participants must have evidence of CD19 expression at any level in ALL or ALAL documented locally by flow cytometry or immunohistochemistry in bone marrow or peripheral blood at the time of initial diagnosis. Immunophenotyping of the blood or marrow lymphoblasts must be performed to determine lineage. Appropriate marker studies including CD19 (B cell) must be performed. If a bone marrow aspirate cannot be obtained despite an attempt (dry tap), appropriate Immunohistochemistry (IHC) testing, including CD19, must be performed on the bone marrow biopsy to determine lineage
• COHORT A: Participants must have Philadelphia-chromosome negative ALL or ALAL
• COHORT A: Participants must not have known lymphoid blast crisis arising from chronic myeloid leukemia (CML) or have received previous tyrosine kinase inhibitor (TKI) therapy for their chronic myeloid leukemia (CML)

• COHORT B: Participants must meet diagnostic criteria for either newly diagnosed with acute lymphoblastic leukemia (ALL) or acute leukemia with ambiguous lineage (ALAL)

  • Participants with either B or T-cell subtypes of ALL are permitted on Cohort B
  • 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 B: Participants must have Philadelphia-chromosome negative ALL or ALAL
• COHORT B: Participants must not have known lymphoid blast crisis arising from CML or have received previous TKI therapy for their chronic myeloid leukemia (CML)
• COHORT A: Participants ≥ 18 years may have received 1 to 3 cycles of induction/consolidation before entering the study. It is encouraged to enroll participants immediately after completing the first induction cycle if the patient achieves morphological CR. For pediatric patients < 18 years of age, enrollment must occur after induction therapy
• COHORT A: Participants must discontinue strong cytochrome P450 (CYP)3A4 inhibitors or strong or moderate inducers, except corticosteroids, within 14 days prior to registration

• COHORT A: Participants must have recovered from any prior major surgery adverse effects at least 14 days prior to registration, to the satisfaction of the local investigator

  • Note: Central venous access placement is not considered major surgery for the purposes of this protocol
• COHORT A: Participants must not be receiving any oral or intravenous systemic immunosuppressive therapy with the exception of induction/consolidation chemotherapy for the treatment of their current ALL or ALAL. Participants may receive up to 10 mg per day of prednisone or prednisone equivalent for adrenal insufficiency or other indications
• COHORT A: Participants must not have received a prior allogeneic hematopoietic stem cell transplant
• COHORT A: Participants must not have received prior blinatumomab, menin inhibitors, chimeric antigen receptor (CAR)-T therapy, or anti-CD19 antibodies

• COHORT B: Participants must not have received prior systemic therapy for ALL or ALAL, with the exception of hydroxyurea, steroid, retinoic acid, intrathecal chemotherapy, or induction chemotherapy as defined below

  • Participants who have been started on the study regimen backbone (i.e. induction therapy) before consenting and then are found to have the KMT2Ar and are eligible for the study, can be enrolled on the study as long as revumenib treatment can be started by day 8 of induction therapy
• COHORT B: Participants must discontinue strong CYP3A4 inhibitors or strong or moderate inducers, except corticosteroids, within 14 days prior to registration

• COHORT B: Participants must have recovered from any prior major surgery adverse effects at least 14 days prior to registration, to the satisfaction of the local investigator

  • Note: Central venous access placement is not considered major surgery for the purposes of this protocol
• COHORT B: Participants must not be receiving any systemic oral or intravenous immunosuppressive therapy with the exception of induction chemotherapy or corticosteroid for the treatment of their current ALL or ALAL
• COHORT B: Participants must not have received a prior allogeneic hematopoietic stem cell transplant
• COHORT A: Participant must be ≥ 1 years old at the time of registration. There is no upper age limit
• COHORT A: Participant must have Zubrod/Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or Lansky/Karnofsky performance status scores of 50-100
• COHORT A: Participants must have a complete medical history and physical exam within 28 days prior to registration
• COHORT A: Glomerular filtration rate (GFR) ≥ 50 ml/min/1.73 m^2 (within 14 days prior to registration)
• COHORT A: Absolute neutrophil count ≥ 1 x 10^3/uL (within 14 days prior to registration)
• COHORT A: Platelets ≥ 100 x 10^3/uL (within 14 days prior to registration)

• COHORT A: Direct bilirubin ≤ 2.0 mg/dL (34.2 micromoles/L) (within 14 days prior to registration)

  • Note: Participants with history of Gilbert's disease must have direct bilirubin ≤ 5 x institutional upper limit of normal (ULN)
• COHORT A: Alanine aminotransferase (ALT) ≤ 5 x institutional ULN (within 14 days prior to registration)
• COHORT A: Participants ≥ 18 years must have a calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 14 days prior to registration

• COHORT A: Adequate renal function for participants < 18 years of age is defined as:

  • A GFR ≥ 50 mL/min/1.73 m^2, as determined by one of the following methods:

    • Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m^2 "Bedside" Schwartz formula (2009)
    • Measured GFR ≥ 50 mL/min/1.73 m^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard)
• COHORT A: Participants must have adequate cardiac function. Participants must have cardiac ejection fraction ≥ 50% by MUGA or 2 dimensional (2-D) echocardiogram or shortening fraction (SF) ≥ 27% by echocardiogram within 90 days prior to registration. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
• COHORT A: Participants ≥ 18 years of age with a known history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration
• COHORT A: Participants ≥ 18 years of age with a known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated
• COHORT A: Participants ≥ 18 years of age with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated
• COHORT A: Participants must not have prolonged Fridericia's formula-corrected QT interval (QTcf) defined as > 450 msec on screening electrocardiogram (EKG) prior to registration
• COHORT A: Participants must not have relapsed or refractory disease in the bone marrow (≥ 5% blasts) or extramedullary sites involvement
• COHORT A: Participants must not have systemic fungal, bacterial, viral or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) as determined by the local investigator
• COHORT A: Participants must not have clinically significant autoimmune disease
• COHORT A: Participants must be able to take oral medications and comply with the oral regimen Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications. Administration via nasogastric/gastrostomy (NG/G)-tube is acceptable as long as oral solution is used

• COHORT A: Participants must not have uncontrolled intercurrent illness including, but not limited to:

  • Active central nervous system status 3 (CNS3) or CNS2 (CNS leukemia)

    • Note: Participants with CNS1 or who had prior CNS2 or CNS3 are eligible if this has cleared and have become CNS-1
  • Currently requiring supplemental oxygen (more than 2 liters per minute), mechanical ventilation, vasopressors
• COHORT A: Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen

• COHORT A: Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 24 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen

  • Note: Participants of childbearing potential must have a negative pregnancy test within 7 days prior to starting treatment
• COHORT B: Participant must be ≥ 55 years old at the time of registration
• COHORT B: Participant must have Zubrod/ECOG performance status of 0-2
• COHORT B: Participants must have a complete medical history and physical exam within 28 days prior to registration
• COHORT B: GFR ≥ 50 ml/min/1.73 m^2 (within 14 days prior to registration)

• COHORT B: Direct bilirubin ≤ 2.0 mg/dL (34.2 micromoles/L) (within 14 days prior to registration)

  • Note: Participants with history of Gilbert's disease or elevated bilirubin is related to underlying leukemia must have direct bilirubin ≤ 5 x institutional ULN
• COHORT B: ALT ≤ 5 x institutional ULN unless abnormal liver tests are related to underlying leukemia (within 14 days prior to registration)
• COHORT B: Participants must have a calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 14 days prior to registration
• COHORT B: Participants must have adequate cardiac function. Participants must have cardiac ejection fraction ≥ 50% by MUGA or 2-D echocardiogram within 28 days prior to registration. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
• COHORT B: Participants with a known history human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration
• COHORT B: Participants with a known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated
• COHORT B: Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated
• COHORT B: Participants must have a lumbar puncture to determine CNS involvement of ALL within 14 days prior to registration. Intrathecal cytarabine and/or methotrexate administered prior to study registration may count as the first dose of intrathecal therapy required as part of protocol therapy
• COHORT B: Participants must not have an active uncontrolled infection
• COHORT B: Participants must not have prolonged QTcf defined as > 450 msec participants on screening EKG prior to registration
• COHORT B: Participants must not have known clinical signs of bulk central nervous system involvement (CNS3c), such as facial palsy, brain/eye involvement or hypothalamic syndrome
• COHORT B: Participants must be able to take oral medications and comply with the oral regimen Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications. Administration via NG/G-tube is acceptable as long as oral solution is used
• COHORT B: Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen

• COHORT B: Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 24 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen

  • Note: Participants of childbearing potential must have a negative pregnancy test within 7 days prior to starting treatment
• ALL COHORTS: Participants must be offered the opportunity to participate in specimen collection submitted for translational medicine work. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System

• NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

  • Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
  • For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
  • This trial will use a slot reservation system to enroll the feasibility and safety run-in portions of the study for Cohort A and Cohort B. Patients planning to enroll at this portion of the study must first have a slot reserved in advance of the registration. All site staff will use OPEN to create a slot reservation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A, Arm 1 (revumenib and blinatumomab); See Detailed Description.	Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; B 518; B518; WR 138719; WR138719; Drug: Mercaptopurine; Given PO; Other Names: 6-MP; Purinethol; 3H-Purine-6-thiol; 6 MP; 6 Thiohypoxanthine; 6 Thiopurine; 6-Mercaptopurine; 6-Mercaptopurine Monohydrate; 6-Purinethiol; 6-Thiopurine; 6-Thioxopurine; 6H-Purine-6-thione, 1,7-dihydro- (9CI); 7-Mercapto-1,3,4,6-tetrazaindene; Alti-Mercaptopurine; Azathiopurine; Bw 57-323H; Flocofil; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptina; Mercaptopurinum; Mercapurin; Mern; NCI-C04886; Puri-Nethol; Purimethol; Purine, 6-mercapto-; Purine-6-thiol (8CI); Purine-6-thiol, monohydrate; Purinethiol; U-4748; WR-2785; Drug: Dexamethasone; Given PO or IV; Other Names: Decadron; Hemady; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycadron; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron DP; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone Intensol; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dxevo; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; TaperDex; Visumetazone; ZoDex; LenaDex; Drug: Vincristine; Given IV; Other Names: VCR; Leurocristine; Vincrystine; LCR; Biological: Blinatumomab; Given IV; Other Names: Blincyto; Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody; Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103; MEDI-538; MT-103; AMG 103; MT103; AMG103; MEDI538; AMG-103; MEDI 538; MT 103; Drug: Thioguanine; Given PO; Other Names: 6-TG; 2-Amino 6MP; 2-Amino-1,7-dihydro-6H-purine-6-thione; 2-Amino-6-mercaptopurine; 2-Amino-6-purinethiol; 2-Aminopurin-6-thiol; 2-Aminopurine-6(1H)-thione; 2-Aminopurine-6-thiol; 2-Aminopurine-6-thiol Hemihydrate; 2-Mercapto-6-aminopurine; 6-Amino-2-mercaptopurine; 6-Mercapto-2-aminopurine; 6-Mercaptoguanine; 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI); BW 5071; Lanvis; Tabloid; Thioguanine Hemihydrate; Thioguanine Hydrate; Tioguanin; Tioguanine; Wellcome U3B; WR-1141; X 27; Drug: Doxorubicin; Given IV; Other Names: Adriablastin; Hydroxydaunomycin; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; RNV Scan; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Leucovorin Calcium; Given PO or IV; Other Names: Wellcovorin; folinic acid; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Citrovorum Factor; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; Procedure: Chest Radiography; Undergo chest x-ray; Other Names: Chest X-ray; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy and aspiration; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Drug: Methotrexate; Given IT or IV; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Jylamvo; Drug: Cytarabine; Given IV or SC; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Calaspargase Pegol; Given IV; Other Names: Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl); Asparlas; EZN-2285; SC-PEG E. Coli L-Asparaginase; Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase; Calaspargase Pegol-mknl; Procedure: Biospecimen Collection; Undergo CSF and blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Drug: Revumenib; Given PO; Other Names: Menin-Mixed Lineage Leukemia Protein-Protein Interaction Inhibitor SNDX-5613; Menin-MLL Inhibitor SNDX-5613; Menin-MLL Interaction Inhibitor SNDX-5613; SNDX 5613; SNDX-5613; SNDX5613; Procedure: Bone Marrow Aspiration; Undergo bone marrow biopsy and aspiration; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC
Active Comparator: Cohort A, Arm 2 (blinatumomab); See Detailed Description.	Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; B 518; B518; WR 138719; WR138719; Drug: Mercaptopurine; Given PO; Other Names: 6-MP; Purinethol; 3H-Purine-6-thiol; 6 MP; 6 Thiohypoxanthine; 6 Thiopurine; 6-Mercaptopurine; 6-Mercaptopurine Monohydrate; 6-Purinethiol; 6-Thiopurine; 6-Thioxopurine; 6H-Purine-6-thione, 1,7-dihydro- (9CI); 7-Mercapto-1,3,4,6-tetrazaindene; Alti-Mercaptopurine; Azathiopurine; Bw 57-323H; Flocofil; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptina; Mercaptopurinum; Mercapurin; Mern; NCI-C04886; Puri-Nethol; Purimethol; Purine, 6-mercapto-; Purine-6-thiol (8CI); Purine-6-thiol, monohydrate; Purinethiol; U-4748; WR-2785; Drug: Dexamethasone; Given PO or IV; Other Names: Decadron; Hemady; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycadron; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron DP; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone Intensol; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dxevo; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; TaperDex; Visumetazone; ZoDex; LenaDex; Drug: Vincristine; Given IV; Other Names: VCR; Leurocristine; Vincrystine; LCR; Biological: Blinatumomab; Given IV; Other Names: Blincyto; Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody; Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103; MEDI-538; MT-103; AMG 103; MT103; AMG103; MEDI538; AMG-103; MEDI 538; MT 103; Drug: Thioguanine; Given PO; Other Names: 6-TG; 2-Amino 6MP; 2-Amino-1,7-dihydro-6H-purine-6-thione; 2-Amino-6-mercaptopurine; 2-Amino-6-purinethiol; 2-Aminopurin-6-thiol; 2-Aminopurine-6(1H)-thione; 2-Aminopurine-6-thiol; 2-Aminopurine-6-thiol Hemihydrate; 2-Mercapto-6-aminopurine; 6-Amino-2-mercaptopurine; 6-Mercapto-2-aminopurine; 6-Mercaptoguanine; 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI); BW 5071; Lanvis; Tabloid; Thioguanine Hemihydrate; Thioguanine Hydrate; Tioguanin; Tioguanine; Wellcome U3B; WR-1141; X 27; Drug: Doxorubicin; Given IV; Other Names: Adriablastin; Hydroxydaunomycin; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; RNV Scan; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Leucovorin Calcium; Given PO or IV; Other Names: Wellcovorin; folinic acid; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Citrovorum Factor; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; Procedure: Chest Radiography; Undergo chest x-ray; Other Names: Chest X-ray; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy and aspiration; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Drug: Methotrexate; Given IT or IV; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Jylamvo; Drug: Cytarabine; Given IV or SC; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Calaspargase Pegol; Given IV; Other Names: Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl); Asparlas; EZN-2285; SC-PEG E. Coli L-Asparaginase; Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase; Calaspargase Pegol-mknl; Procedure: Biospecimen Collection; Undergo CSF and blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Bone Marrow Aspiration; Undergo bone marrow biopsy and aspiration; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC
Experimental: Cohort B (revumenib and blinatumomab); See Detailed Description.	Drug: Daunorubicin Hydrochloride; Given IV; Other Names: Cerubidin; Cerubidine; Cloridrato de Daunorubicina; Daunoblastin; Daunoblastina; Daunoblastine; Daunomycin Hydrochloride; Daunomycin, hydrochloride; Daunorubicin.HCl; Daunorubicini Hydrochloridum; FI-6339; Ondena; RP-13057; Rubidomycin Hydrochloride; Rubilem; Drug: Dexamethasone; Given PO or IV; Other Names: Decadron; Hemady; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycadron; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron DP; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone Intensol; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dxevo; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; TaperDex; Visumetazone; ZoDex; LenaDex; Drug: Vincristine; Given IV; Other Names: VCR; Leurocristine; Vincrystine; LCR; Biological: Blinatumomab; Given IV; Other Names: Blincyto; Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody; Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103; MEDI-538; MT-103; AMG 103; MT103; AMG103; MEDI538; AMG-103; MEDI 538; MT 103; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy and aspiration; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Drug: Methotrexate; Given IT or IV; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Jylamvo; Drug: Cytarabine; Given IV or SC; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Biospecimen Collection; Undergo CSF and blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Drug: Revumenib; Given PO; Other Names: Menin-Mixed Lineage Leukemia Protein-Protein Interaction Inhibitor SNDX-5613; Menin-MLL Inhibitor SNDX-5613; Menin-MLL Interaction Inhibitor SNDX-5613; SNDX 5613; SNDX-5613; SNDX5613; Procedure: Bone Marrow Aspiration; Undergo bone marrow biopsy and aspiration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	During cycle 1 (cycle 1 length = 28 days)
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.	Up to 35 days after start of therapy
MRD-event-free survival (EFS) (Cohort A)	Will be compared using unstratified log-rank test.	From date of randomization and up to 10 years
Incidence of toxicities of interest (TOI) (Cohort B)	TOI rates will be reported with exact 90% confidence intervals.	Up to 30 days after last dose of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Frequency and severity within each arm and across cycles of therapy will be assessed using NCI CTCAE v 6.0.	Up to 30 days after last dose of study treatment
MRD negative complete remission (CR) rate (Cohort A)	Will be evaluated in participants with positive MRD before randomization.	Up to 70 days after start of therapy
EFS (Cohort A)	Will be estimated using the Kaplan-Meier method. Will be evaluated in participants with negative MRD before randomization.	At 6 months
MRD-EFS (Cohort A)	Will be estimated using the Kaplan-Meier method. Will be evaluated in participants with negative MRD before randomization.	At 6 months
Composite morphological CR rate (Cohort B)	Will be defined as CR/CR with incomplete count recovery (CRi).	Up to 35 days after start of therapy
Proportion of participants MRD negative (Cohorts A and B)	Will be evaluated using multi-color flow cytometry.	Up to 35 days after start of therapy
Rate of lineage switch and/or CD19-negative relapse (within each arm and cohort cohort)		Up to 10 years
Rate of allogeneic hematopoietic stem cell transplantation utilization (within each arm and cohort cohort)		Up to 10 years
EFS (within each arm and cohort cohort)	Will be reported within each arm and cohort and by age. Will be estimated using the Kaplan-Meier method.	From the date of trial registration/randomization until the first of death from any cause, relapse from remission, secondary malignancy, or completion of protocol therapy, assessed up to 10 years
MRD-EFS (within each arm and cohort cohort)	Will be reported within each arm and cohort and by age. Will be estimated using the Kaplan-Meier method.	From the date of trial registration/randomization until the first of death from any cause, relapse from remission, secondary malignancy, or completion of protocol therapy, assessed up to 10 years
Relapse-free survival (within each arm and cohort cohort)	Will be reported within each arm and cohort and by age. Will be estimated using the Kaplan-Meier method.	From date of trial registration until relapse from CR/CRi or death from any cause, assessed up to 10 years
Progression-free survival (PFS) (within each arm and cohort cohort)	Will be reported within each arm and cohort and by age. Will be estimated using the Kaplan-Meier method.	From the date of trial registration/randomization until the first of progression, death from any cause, relapse from morphologic remission, secondary malignancy, or completion of protocol therapy, assessed up to 10 years
MRD-PFS (within each arm and cohort cohort)	Will be reported within each arm and cohort and by age. Will be estimated using the Kaplan-Meier method.	From the date of trial registration/randomization until the first of progression, death from any cause, relapse from morphologic remission, secondary malignancy, or completion of protocol therapy, assessed up to 10 years
Time to MRD relapse (within each arm and cohort cohort)	Will be assessed using flow cytometry and/or clonoSEQ.	Up to 10 years
Overall survival (within each arm and cohort cohort)	Will be estimated using the Kaplan-Meier method.	From day of trial registration until death from any cause, assessed up to 10 years
Remission rate	Will be defined as CR/CRi/CR with partial hematological recovery) with and without MRD by flow. Will be estimated with 95% binomial confidence intervals.	Up to 10 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of MEN1 mutations	Will be evaluated by quantitative polymerase chain reaction (PCR) and/or high sensitivity next generation sequencing.	Up to 10 years after start of therapy
Rate of KMT2A fusion reverse transcriptase (RT)-PCR MRD negativity within treatment arms (Cohort A)		After the first and second cycle of blinatumomab (cycle length = 28 days)
KMT2A fusion RT-PCR MRD negativity (Cohort B)		Up to 90 days after start of therapy
Rate of IG/TR V(D)J MRD negative remission		Up to 35 days after start of therapy
Changes in gene expression between diagnosis (in Cohort B and as available in Cohort A) and relapse samples		Up to 10 years

Collaborators and Investigators

• Sponsor: SWOG Cancer Research Network
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ibrahim Aldoss, SWOG Cancer Research Network

Study record dates

Study Major Dates

• Study Start (Estimated): October 14, 2026
• Primary Completion (Estimated): April 16, 2031
• Study Completion (Estimated): April 16, 2032

Study Registration Dates

• First Submitted: May 22, 2026
• First Submitted That Met QC Criteria: June 3, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: June 1, 2026

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Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Infections; Virus Diseases; Neoplasms by Histologic Type; Hematologic Diseases; DNA Virus Infections; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Leukemia, Lymphoid; Leukemia; Epstein-Barr Virus Infections; Herpesviridae Infections; Tumor Virus Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hemic and Lymphatic Diseases; Burkitt Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Biphenotypic, Acute; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Nucleic Acids, Nucleotides, and Nucleosides; Cytodiagnosis; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Physical Phenomena; Alkaloids; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Hydrolases; Enzymes; Enzymes and Coenzymes; Indoles; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Benzene Derivatives; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Sulfonic Acids; Sulfur Acids; Spectrum Analysis; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Pregnadienetriols; Amidohydrolases; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Arabinonucleosides; Aminopterin; Anthracyclines; Naphthacenes; Aminoglycosides; Coenzymes; Electromagnetic Phenomena; Magnetic Phenomena; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Benzenesulfonates; Arylsulfonates; Arylsulfonic Acids; Sulfhydryl Compounds; Dexamethasone; Methotrexate; Cyclophosphamide; Cytarabine; Leucovorin; Doxorubicin; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Calcium Dobesilate; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; blinatumomab; dexamethasone 21-phosphate; X-Rays; N,N-dicyclohexyl-isoborneol-10-sulfonamide; calaspargase pegol; azathiopurine; merphos; auricularum; dexamethasone acetate; revumenib
• Other Study ID Numbers: S2507 (Other Identifier: CTEP); U10CA180888 (U.S. NIH Grant/Contract); NCI-2026-03381 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No