A Phase 1b Study of Menin Inhibitor SNDX- 5613 in Combination With Daunorubicin and Cytarabine in Newly Diagnosed Patients With Acute Myeloid Leukemia and NPM1 Mutated/FLT3 Wildtype or MLL/KMT2A Rearranged or NUP98 Alterations Disease
Start Date
6/20/2024
Completion Date
12/31/2027
Summary
This phase Ib trial tests the safety, side effects, and best dose of SNDX-5613 when given in combination with the standard chemotherapy treatment (daunorubicin and cytarabine) in treating patients with newly diagnosed acute myeloid leukemia that has changes in the NPM1 gene or MLL/KMT2A gene. SNDX-5613 blocks signals passed from one molecule to another inside cancer cells that are needed for cancer cell survival. Drugs used in chemotherapy, such as daunorubicin and cytarabine, 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. Adding SNDX-5613 to the standard chemotherapy treatment may be able to shrink or stabilize the cancer for longer than the standard chemotherapy treatment alone.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) and safety of revumenib (SNDX-5613) combined with 7 + 3 induction in newly diagnosed, untreated patients with NPM1-mutated/FLT3-ITD wild type and NPM1-mutated/FLT3-TKD wild type, MLL(KMT2A)-rearranged, or NUP98 altered acute myeloid leukemia (AML) who are ≥ 18-75 years old who are candidates for intensive induction therapy. II. To determine the RP2D and safety of SNDX-5613 combined with one cycle of consolidation with high dose cytarabine in newly diagnosed patients with AML in complete response/complete response with incomplete platelet recovery (CR/CRp) (platelet recovery ≥ 75,000) after intensive induction therapy with 7+3 for NPM1-mutated/FLT3-ITD wild type and NPM1-mutated/FLT3-TKD wild type, MLL (KMT2A)-rearranged or NUP98 alterations who are ≥ 18-75 years old and are candidates for intensive therapy. III. To evaluate the effect of single-agent SNDX-5613 on AML cell cycle state across major differentiation states (stem/progenitor, mature blasts, etc.). SECONDARY OBJECTIVES: I. Evaluate the pharmacokinetics of SNDX-5613 and SNDX-5613 metabolites with this combination regimen and with or without antifungal agents. II. To determine the number of patients with CR/complete response with incomplete bone marrow recovery (CRi) out of the total number of patients treated at each dose level of this regimen. EXPLORATORY OBJECTIVES: I. Explore potential biomarker indicators of response and resistance in AML samples. II. To determine the measurable residual disease negative (MRD) response (CR/Cri) and its relation to CR/Cri status out of the total number of patients treated at each dose level of this regimen. III. Determine number of patients that undergo hematopoietic stem cell transplant (HSCT) out of the total number of patients treated at each dose level of this regimen. IV. Assess changes in OATP1B and CYP3A plasma biomarkers during treatment with SNDX-5613 with or without antifungal agents. V. Determine duration of response. OUTLINE: This is a phase Ib, dose-escalation study of revumenib followed by a dose-expansion study. INDUCTION: Patients receive revumenib orally (PO) every 12 hours (Q12h) on days 2-28, daunorubicin intravenously (IV) over 15 to 30 minutes on days 1-3, and cytarabine by continuous IV infusion (CIV) on days 1-7 in the absence of disease progression or unacceptable toxicity. Patients who achieve a response to Induction treatment continue to Consolidation treatment. Patients with persistent disease continue to Re-Induction treatment. Patients also undergo a transthoracic echocardiogram (ECHO) or multigated acquisition scan (MUGA) during screening, bone marrow aspiration and biopsy during screening and at the end of Induction, and collection of blood during screening, on days 2, 3, 15, and at the end of Induction. RE-INDUCTION: Patients receive revumenib PO Q12h on days 2-28, daunorubicin IV over 15 to 30 minutes on days 1-2, and cytarabine CIV on days 1-5 in the absence of disease progression or unacceptable toxicity. Patients also undergo a transthoracic ECHO or MUGA on day 1 and bone marrow aspiration and biopsy at the end of Re-Induction. Patients who achieve CR or CRp to Induction or Re-Induction treatment continue to Consolidation. CONSOLIDATION: Patients receive revumenib PO Q12h on days 2-28 and cytarabine over 3 hours every 12 hours on days 1-3 of each cycle. Cycles repeat every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy at the end of Consolidation, and collection of blood on days 2, 3, 15, and at the end of Consolidation. After completion of study treatment, patients are followed for up to 2 years or until death or relapse, whichever occurs first.
Eligibility Criteria
Age Range: 18 years to 75 years
Interventions
Biospecimen Collection
Bone Marrow Aspiration
Bone Marrow Biopsy
Cytarabine
Daunorubicin
Multigated Acquisition Scan
Revumenib
Transthoracic Echocardiography Test
Conditions
Locations
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California 92868
United States
University of California Davis Comprehensive Cancer Center
Sacramento, California 95817
United States
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida 33180
United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida 33146
United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida 33442
United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida 33136
United States
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida 33324
United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois 60637
United States
University of Kansas Clinical Research Center
Fairway, Kansas 66205
United States
University of Kansas Cancer Center
Kansas City, Kansas 66160
United States
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas 66211
United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas 66205
United States
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland 21201
United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina 27599
United States
Carolinas Medical Center/Levine Cancer Institute
Charlotte, North Carolina 28203
United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina 27157
United States
University of Cincinnati Cancer Center-UC Medical Center
Cincinnati, Ohio 45219
United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio 43210
United States
University of Cincinnati Cancer Center-West Chester
West Chester, Ohio 45069
United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma 73104
United States
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah 84112
United States
University of Virginia Cancer Center
Charlottesville, Virginia 22908
United States