Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Childhood Acute Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Childhood Mixed Phenotype Acute Leukemia, Mixed Phenotype Acute Leukemia
Conditions
Brief summary
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.
Detailed description
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.
Interventions
PROCEDUREBiospecimen Collection
Undergo collection of blood samples
PROCEDUREBone Marrow Aspiration
Undergo bone marrow aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
DRUGCytarabine
Given IT
PROCEDUREEchocardiography Test
Undergo ECHO
DRUGMethotrexate
Given IT
PROCEDURERadiologic Examination
Undergo radiologic assessment
DRUGRevumenib
Given PO or via NG- or G-tube
DRUGTherapeutic Hydrocortisone
Given IT
Sponsors
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Days to 22 Years
Healthy volunteers
No
Inclusion criteria
* STEP 0 PRE-TRANSPLANT INCLUSION CRITERIA: * Patients must be ≥ 30 days and \< 22 years of age * PLEASE NOTE: Eligibility criteria to enroll onto Step 1 for the treatment trial is \< 22 years of age at the time of Step 1 enrollment. Please plan accordingly to ensure that patients who are screened with Step 0 will be at an eligible age at the time of enrollment onto Step 1. Patients who are 21 at the time of screening who turn 22 at the time of enrollment onto Step 1 will not be eligible to enroll onto the study * Patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or mixed phenotype acute leukemia (MPAL) with a KMT2a rearrangement, NUP98 rearrangement, or NMP1 mutation confirmed in a College of American Pathologists (CAP)/Clinical Laboratory Improvement Act (CLIA) certified laboratory. Patients with a history of isolated or combined central nervous system (CNS) or extramedullary disease are eligible if they have no evidence of active CNS or extramedullary disease at the time of trial enrollment (Step 0) and treatment enrollment (Step 1). Eligible patients with histories of isolated or combined CNS or extramedullary disease at time of relapse are required to be in complete remission at time of transplant to be eligible for this study * AML and MPAL must be in morphologic complete remission confirmed by multiparameter flow (MDF) testing (with or without detectable minimal residual disease \[MRD\]). ALL must have bone marrow MRD \< 0.1% * Pre-HSCT bone marrow: * Assessment of disease status (complete response \[CR\] and minimal residual disease \[MRD\]) by multiparameter flow cytometry will be performed on bone marrow aspirate samples locally. Disease assessment will be required within 30 days prior to the start date of HSCT to determine CR (as part of the Step 0 screening criteria). Patients with CNS or extramedullary disease within 14 days prior to the start of the HSCT condition regimen are not eligible * Human immunodeficiency virus (HIV)-infected patients are eligible for this trial if the following criteria are met: * No history of HIV complications with the exception of CD4 count \< 200 cells/mm\^3 * No antiretroviral therapy with overlapping toxicity such as myelosuppression * CD4 count \> 500 cells/mm\^3 prior to the diagnosis of newly diagnosed, relapsed, refractory AML * HIV viral loads below the limit of detection within 6 months, as long as the patient is NOT receiving anti-retroviral agents that may interact with revumenib * No history of highly active antiretroviral therapy (HAART)-resistant HIV * Lansky/Karnofsky performance status ≥ 70% * Must be receiving an allogeneic hematopoietic stem cell transplant (all graft and donor types will be eligible) * Must be receiving myeloablative conditioning as defined by Center for International Blood and Marrow Transplant Research (CIBMTR) criteria * STEP 1 INCLUSION CRITERIA: * Patients must be ≥ 30 days and \< 22 years of age at the time of study enrollment to Step 0 and Step 1 * Post-HSCT bone marrow: * Assessment of disease status (CR and minimal residual disease \[MRD\]) by multiparameter flow cytometry will be performed on bone marrow aspirate samples locally. Disease assessment will be required within 30 days prior to enrollment onto Step 1 to confirm MRD negativity (as part of the Step 1 Enrollment eligibility criteria). Disease must be in complete remission with marrow minimal residual disease \< 0.05% for AML and \< 0.01% for ALL by MDF. Patients with CNS or extramedullary disease post-HSCT are not eligible * Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score * Patients must have recovered from the acute pre-transplant conditioning regimen related toxicities. If, after 42-100 days post-transplant, the eligibility criteria are met in criteria below the patient is considered to have recovered adequately * Pre-transplant exposure to revumenib will be allowed with the exception of patients who experienced a serious toxicity (CTCAE grade 4) attributed to revumenib (probably or definitely related) or those that experienced progression or relapse while receiving revumenib * For patients ≤ 17 years old estimated GFR (eGFR) ≥ 60 mL/min/1.73 m\^2 "Bedside" Schwartz formula OR for any age group a 24 hour urine creatinine clearance ≥ 60 mL/min/1.73 m2 OR a GFR ≥ 60 mL/min/1.73 m2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard) (must be performed within 7 days prior to enrollment) * For patients \> 17 years old the Cockroft-Gault equation should be utilized to calculate eGFR OR for any age group a 24 hour urine creatinine clearance ≥ 60 mL/min/1.73 m2 OR a GFR ≥ 60 mL/min/1.73 m2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard) (must be performed within 7 days prior to enrollment) * Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment) * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) ≤ 3 x upper limit of normal (ULN) (must be performed within 7 days prior to enrollment) * Aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) (must be performed within 7 days prior to enrollment) * Albumin ≥ 2 g/dL (must be performed within 7 days prior to enrollment) * Shortening fraction of \> 27% by echocardiogram, or ejection fraction of \> 50% by gated radionuclide study with no evidence of congestive heart failure * Ejection fraction of \> 50% by gated radionuclide study with no evidence of congestive heart failure * Corrected QT interval (QTc) \< 450 ms * No evidence of pulmonary disease and without need for continuous supplemental oxygen * Potassium \> 3.5mEq/L (supplementation allowed) (must be performed within 7 days prior to enrollment) * Magnesium ≥ 1.6mg/dL (supplementation allowed) (must be performed within 7 days prior to enrollment) * For patients with leukemia: platelet count ≥ 50,000 µL (without requirement for platelet transfusion within the last 7 days) (must be performed within 7 days prior to enrollment) * For patients with leukemia: hemoglobin ≥ 8.0 g/dL at baseline (may receive red blood cell \[RBC\] transfusions) (must be performed within 7 days prior to enrollment) * For patients with leukemia: absolute neutrophil count ≥ 1,000 µL with no myeloid growth factor support within the last 3 days (must be performed within 7 days prior to enrollment)
Exclusion criteria
* STEP 0 PRE-TRANSPLANT
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (MTD) | During cycles 1 and 2 (cycle length = 28 days) | 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. |
| Recommended phase 2 dose (RP2D) | During cycles 1 and 2 (cycle length = 28 days) | Will use the BOIN design to estimate the RP2D. The BOIN design with up to three pre-defined dose levels will estimate the RP2D. |
| Area under the concentration time curve of revumenib | Up to day 7 | 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 |
| Maximum concentration of the time curve of revumenib | Up to day 7 | 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 |
| Half-life of revumenib | Up to day 7 | 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 |
| Clearance of revumenib | Up to day 7 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse free survival | At 2 years | 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. |
| Incidence of treatment-related adverse events | Up to 12 cycles (cycle length = 28 days) | 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. |
| Proportion of patients who complete 12 cycles of maintenance therapy | Up to 12 cycles (cycle length = 28 days) | 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. |
| Proportion of patients who discontinue therapy due to treatment-related adverse events | Up to 12 cycles (cycle length = 28 days) | The percent of adverse event-evaluable patients without discontinuation-related adverse events will be estimated with a 95% confidence interval. |
Contacts
PRINCIPAL_INVESTIGATORBen K Watkins
Pediatric Early Phase Clinical Trial Network
Outcome results
None listed