This phase I trial tests the safety, best dose, and effectiveness of revumenib given as maintenance therapy after standard hematopoietic stem cell transplant (HSCT) in patients with acute lymphoblastic leukemia, acute myeloid leukemia, or mixed phenotype acute leukemia. Revumenib binds to a protein called menin, which prevents menin from interacting with another protein called MLL. This results in an inhibition of the proliferation of leukemic cells with certain genetic alterations. Revumenib may inhibit the survival, growth, transformation and proliferation of certain kinds of leukemia cells. It is approved for the treatment of patients with certain types of acute leukemia, but it is not approved for maintenance therapy (treatment that aims to prevent cancer from coming back) after HSCT.
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of revumenib monotherapy administered as maintenance therapy, orally post-HSCT, on continuous 28-day cycles for patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia (MPAL). II. To characterize the steady state pharmacokinetics of revumenib administered as post-HSCT maintenance in children with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia (MPAL). SECONDARY OBJECTIVES: I. To preliminarily estimate the 2-year relapse free survival of patients receiving revumenib as post-HSCT maintenance therapy at the MTD/RP2D, within the confines of a phase 1 study. II. To describe treatment related adverse events in patients with ALL, AML, or MPAL receiving revumenib post-HSCT as maintenance therapy up to 12 cycles. III. To estimate the proportion of patients with ALL, AML, or MPAL receiving revumenib post-HSCT as maintenance therapy who complete 12 cycles of maintenance therapy. IV. To estimate the proportion of patients with ALL, AML, or MPAL receiving revumenib post-HSCT as maintenance therapy who discontinue therapy due to treatment related adverse events. EXPLORATORY OBJECTIVES: I. To estimate the cumulative incidence of transplant-related mortality in patients with ALL, AML, or MPAL receiving revumenib post-HSCT as maintenance therapy for up to 12-cycles. II. To estimate the cumulative incidence of transplant-related relapse in patients with ALL, AML, or MPAL receiving revumenib post-HSCT as maintenance therapy for up to 12-cycles. III. To preliminarily estimate overall survival and disease-free survival in patients with ALL, AML, or MPAL receiving revumenib post-HSCT as maintenance therapy for up to 12-cycles, within the confines of a phase 1 study. IV. To estimate the cumulative incidence of acute and chronic graft versus host disease (GVHD) in patients with ALL, AML, or MPAL receiving revumenib post-HSCT as maintenance therapy for up to 12-cycles. OUTLINE: This is a dose-escalation study of revumenib followed by a dose-expansion study. Starting 42-100 days after HSCT, patients receive revumenib orally (PO) or via nasogastric (NG)- or gastric (G)-tube every 12 hours on days 1-28 of each cycle. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive optional intrathecal therapy (methotrexate intrathecally \[IT\] or cytarabine IT or methotrexate, hydrocortisone, and cytarabine IT) at the discretion of the physician on study. Patients also undergo bone marrow biopsy/aspiration and collection of blood samples throughout the trial. Patients may undergo echocardiography (ECHO) and radiologic assessment as clinically indicated. After completion of study treatment, patients are followed for up to 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Undergo collection of blood samples
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Given IT
Undergo ECHO
Given IT
Undergo radiologic assessment
Given PO or via NG- or G-tube
Given IT
Maximum tolerated dose (MTD)
Will use the Bayesian Optimal Interval (BOIN) design to estimate the MTD. The BOIN design with up to three pre-defined dose levels will estimate the MTD.
Time frame: During cycles 1 and 2 (cycle length = 28 days)
Recommended phase 2 dose (RP2D)
Will use the BOIN design to estimate the RP2D. The BOIN design with up to three pre-defined dose levels will estimate the RP2D.
Time frame: During cycles 1 and 2 (cycle length = 28 days)
Area under the concentration time curve of revumenib
Median and range of the area under the concentration time curve of revumenib determined by sampling on cycle 1 day 7 at time 0, 0.25, 0.5, 1, 2, 4, and 6 hours post dose by study part and dose level
Time frame: Up to day 7
Maximum concentration of the time curve of revumenib
Median and range of the maximum concentration of revumenib determined by sampling on cycle 1 day 7 at time 0, 0.25, 0.5, 1, 2, 4, and 6 hours post dose by study part and dose level
Time frame: Up to day 7
Half-life of revumenib
Median and range of the half-life of revumenib determined by sampling on cycle 1 day 7 at time 0, 0.25, 0.5, 1, 2, 4, and 6 hours post dose by study part and dose level
Time frame: Up to day 7
Clearance of revumenib
Median and range of the clearance of revumenib determined by sampling on cycle 1 day 7 at time 0, 0.25, 0.5, 1, 2, 4, and 6 hours post dose by study part and dose level
Time frame: Up to day 7
Relapse free survival
Median relapse-free survival time will be estimated with 95% confidence intervals. 12-month relapse-free rates will also be estimated with 95 confidence intervals.
Time frame: At 2 years
Incidence of treatment-related adverse events
Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.
Time frame: Up to 12 cycles (cycle length = 28 days)
Proportion of patients who complete 12 cycles of maintenance therapy
The percent of adverse event-evaluable patients who successfully complete 12-cycles of maintenance therapy with revumenib will be estimated with a 95% confidence interval. Evaluable patients who do not complete 12-cycles of maintenance therapy for any reason will be considered a failure, and those who complete 12-cycles will be considered a success.
Time frame: Up to 12 cycles (cycle length = 28 days)
Proportion of patients who discontinue therapy due to treatment-related adverse events
The percent of adverse event-evaluable patients without discontinuation-related adverse events will be estimated with a 95% confidence interval.
Time frame: Up to 12 cycles (cycle length = 28 days)
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