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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
90
Undergo CSF and blood sample collection
Given IV
Undergo bone marrow biopsy and aspiration
Undergo bone marrow biopsy and aspiration
Given IV
Undergo chest x-ray
Undergo CT or PET/CT
Given IV
Given IV or SC
Given IV
Given PO or IV
Given IV
Undergo ECHO
Given PO or IV
Given PO
Given IT or IV
Undergo MUGA
Undergo PET/CT
Given PO
Given PO
Given 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.
Time frame: 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.
Time frame: Up to 35 days after start of therapy
MRD-event-free survival (EFS) (Cohort A)
Will be compared using unstratified log-rank test.
Time frame: 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.
Time frame: Up to 30 days after last dose of study treatment
Incidence of adverse events
Frequency and severity within each arm and across cycles of therapy will be assessed using NCI CTCAE v 6.0.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: At 6 months
Composite morphological CR rate (Cohort B)
Will be defined as CR/CR with incomplete count recovery (CRi).
Time frame: 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.
Time frame: Up to 35 days after start of therapy
Rate of lineage switch and/or CD19-negative relapse (within each arm and cohort cohort)
Time frame: Up to 10 years
Rate of allogeneic hematopoietic stem cell transplantation utilization (within each arm and cohort cohort)
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 10 years
Overall survival (within each arm and cohort cohort)
Will be estimated using the Kaplan-Meier method.
Time frame: 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.
Time frame: Up to 10 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.