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RecruitingInterventionalPhase 1

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

NCT ID: NCT05886049Sponsor: National Cancer Institute (NCI)Last updated: 2026-06-17

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.

Arms & interventions

  • ProcedureBiospecimen Collection

    Undergo collection of blood

  • ProcedureBone Marrow Aspiration

    Undergo bone marrow aspiration and biopsy

  • ProcedureBone Marrow Biopsy

    Undergo bone marrow aspiration and biopsy

  • DrugCytarabine

    Given IV

  • DrugDaunorubicin

    Given IV

  • ProcedureMultigated Acquisition Scan

    Undergo MUGA

  • DrugRevumenib

    Given PO

  • ProcedureTransthoracic Echocardiography Test

    Undergo transthoracic ECHO

Outcome measures

Primary

  • Recommended dose for expansion (RDE) for Induction

    Will be determined based on the totality of safety, tolerability, clinical activity, and pharmacokinetic (PK) data as appropriate. The tolerability of doses administered in cycles after the dose limiting toxicity (DLT) observation window should be taken into account in determination of the RDE. For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.

    Time frame: From day 1 to 42 of Induction or Re-Induction

  • RDE for Consolidation

    Will be determined based on the totality of safety, tolerability, clinical activity, and PK data as appropriate. The tolerability of doses administered in cycles after the DLT observation window should be taken into account in determination of the RDE.For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the CTCAE v5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.

    Time frame: From day 1 to 42 of Consolidation or until full count recovery with recovery to grade 1 toxicity from treatment, whichever comes first

  • Recommended phase 2 dose for expansion cohort

    RP2D of induction will be determined based on isotonic regression. Specifically, the RP2D that is selected is the dose for which the isotonic estimate of the toxicity rate is closest to the targeted DLT (i.e., 20%) via "BOIN" software \[MD Anderson\]) and will also factor in data such as PK/pharmacodynamic data to determine the biologically effective dose. For all patients who receive at least one dose of any of the study drug(s), adverse events will be documented and summarized by type, grade, severity, and attribution using the CTCAE v5.0 criteria. In addition, the number of treatment cycles received and reasons for going off treatment will be summarized to assess treatment tolerability.

    Time frame: From day 1 of Induction to day 42 of Consolidation or until full count recovery with recovery to grade 1 toxicity from treatment, whichever comes first

Secondary

  • Complete response/complete response with incomplete count recovery (CR/Cri) rate

    Time frame: At the end of cycle 1 of consolidation

  • Pharmacokinetics (PK) of revumenib (SNDX-5613)

    Time frame: Cycle 1, day 2 at pre-treatment, 0.5, 1.0, 2.0, 4.0, 8.0 hours (hr); Cycle 1 day 3 at 12 hr; cycle 1 day 15 at pre-treatment, 0.5, 1.0, 2.0, 4.0, and 8.0 hr

Eligibility criteria

Sex: AllAge: 18 Years to 75 YearsHealthy volunteers: No
Inclusion Criteria: * Dose escalation: Patients ages 18-75 years at time of diagnosis with NPM1-mutated/FLT3-ITD wildtype and NPM1-mutated/FLT3-TKD wildtype with high-risk features (adverse risk genetics per European LeukemiaNet \[ELN\] 2022 criteria, age ≥ 60 years, or secondary AML defined as either arising from a prior hematological malignancy or therapy-related), MLL (KMT2A) rearranged or NUP98 altered, untreated AML and who are candidates for intensive induction chemotherapy. Patients with CD33+ AML are eligible for this protocol. * Dose expansion: Patients ages 18-75 years at time of diagnosis with NPM1-mutated/FLT3-ITD wildtype and NPM1-mutated/FLT3-TKD wildtype (any patient-does not require high-risk features), MLL (KMT2A) rearranged, or NUP98 altered, untreated AML and who are candidates for intensive induction chemotherapy. Patients with CD33+ AML are eligible for this protocol * Because no dosing or adverse event data are currently available on the use of SNDX-5613 in combination with daunorubicin and cytarabine in patients \< 18 years of age, children are excluded from this study * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%). Patients over the age of 65 must have an ECOG performance status of 0-1 * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), except for patients with Gilbert's syndrome where required to be ≤ 3 x institutional ULN * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvate transaminase \[SGPT\]) =\< 3 x institutional upper limit of normal (ULN) * Glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 (via the Chronic Kidney Disease Epidemiology \[CKD-EPI\] glomerular filtration rate estimation) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better * Ejection fraction \>= 50% (or \>= 45% if no evidence of congestive heart failure \[CHF\] or other cardiac symptoms) by transthoracic echocardiogram (TTE) or multi-gated acquisition (MUGA) scan * White blood cells (WBC) must be \< 25 x 10\^9/L. Hydroxyurea and leukapheresis are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped within 24 hours of initiation of protocol therapy. Must not have had any signs of leukostasis requiring cytoreduction * Female patients of childbearing potential must agree to use 2 forms of contraception from screening visit until 120 days following the last dose of study treatment. Male patients of childbearing potential having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use 2 forms of contraception from screening visit until 180 days until the last dose of study treatment. They must also refrain from sperm donation from screening visit until 180 days following the last dose of study treatment * Patients must have previously untreated AML with no prior treatment other than hydroxyurea or intrathecal chemotherapy for central nervous system (CNS) prophylaxis/treatment. No chemotherapy for AML outside of hydroxyurea for treatment of leukostasis or all-trans retinoic acid (ATRA) for initially suspected acute promyelocytic leukemia (APL) (that is ruled out) is allowed * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants Exclusion Criteria: * History of allergic reactions attributed to compounds of similar chemical or biologic composition to SNDX-5613, daunorubicin or cytarabine * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous * Patient must not have received known strong or moderate CYP3A4 inhibitors, or strong CYP3A4 inducers (with the exception of antifungal prophylaxis with azoles) within 7 days of enrollment. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product * Pregnant women are excluded from this study because SNDX-5613 is a menin-KMT2A inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SNDX-5613, breastfeeding should be discontinued if the mother is treated with SNDX-5613. These potential risks may also apply to other agents used in this study * Isolated myeloid sarcoma (i.e., patients must have blood or marrow involvement with AML to enter the study) * Acute promyelocytic leukemia (French-American-British \[FAB\] M3) * Untreated, active central nervous system (CNS) involvement by AML. Patients are allowed to undergoing diagnostic lumbar puncture (LP) with intrathecal chemotherapy while on study * Uncontrolled symptomatic disseminated intravascular coagulopathy with active bleeding or signs of thrombosis * Patients with Fridericia's correction formula (QTcF) \>= 450 ms at screening; patients with right, left, or partial bundle branch blocks or a pacemaker who are asymptomatic are eligible regardless of QTC if cleared by cardiology for enrollment in the trial. Any factors that increase the risk of QTc prolongation or risk of arrhythmic event such as congenital long QT syndrome or family history of long QT syndrome * Patients who will exceed a lifetime anthracycline exposure of \> 550 mg/m\^2 daunorubicin or equivalent (or \> 400 mg/m\^2 daunorubicin or equivalent in the event of prior mediastinal radiation) if they receive the maximum potential exposure to anthracyclines per protocol (including both induction and reinduction cycles) * Patients with any gastrointestinal issue of the upper gastrointestinal (GI) tract that might affect oral drug absorption or ingestion (eg, gastric bypass, gastroparesis, etc) * Patients who have cirrhosis with a Child-Pugh score of B or C * Patients with Down Syndrome due to higher rates of chemotherapy-associated toxicities, and may have different pharmacokinetics, as well. Toxicities that occur at higher frequencies include cardiotoxicity, a known risk of SNDX-5613 treatment (i.e., QTcF prolongation) * Patients with myelodysplastic syndromes (MDS) treated with previous intensive induction regimens similar to 7+3

Study locations (22)

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868

Recruiting
Site Public Contact · Contact
Kiran Naqvi · Principal Investigator

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817

Suspended

UM Sylvester Comprehensive Cancer Center at Aventura

Aventura, Florida, 33180

Recruiting
Site Public Contact · Contact
Sangeetha Venugopal · Principal Investigator

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, 33146

Recruiting
Site Public Contact · Contact
Sangeetha Venugopal · Principal Investigator

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida, 33442

Recruiting
Site Public Contact · Contact
Sangeetha Venugopal · Principal Investigator

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, 33136

Recruiting
Site Public Contact · Contact
Sangeetha Venugopal · Principal Investigator

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation, Florida, 33324

Recruiting
Site Public Contact · Contact
Sangeetha Venugopal · Principal Investigator

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, 60637

Recruiting
Olatoyosi M. Odenike · Principal Investigator

University of Kansas Clinical Research Center

Fairway, Kansas, 66205

Recruiting
Site Public Contact · Contact
Jesus Gonzalez Lugo · Principal Investigator

University of Kansas Cancer Center

Kansas City, Kansas, 66160

Recruiting
Site Public Contact · Contact
Jesus Gonzalez Lugo · Principal Investigator

University of Kansas Hospital-Indian Creek Campus

Overland Park, Kansas, 66211

Recruiting
Site Public Contact · Contact
Jesus Gonzalez Lugo · Principal Investigator

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, 66205

Recruiting
Site Public Contact · Contact
Jesus Gonzalez Lugo · Principal Investigator

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201

Recruiting
Site Public Contact · Contact
Vu H. Duong · Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599

Recruiting
Site Public Contact · Contact
Joshua F. Zeidner · Principal Investigator

Carolinas Medical Center/Levine Cancer Institute

Charlotte, North Carolina, 28203

Recruiting
Site Public Contact · Contact
Brittany K. Ragon · Principal Investigator

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157

Recruiting
Site Public Contact · Contact
Matthew J. Wieduwilt · Principal Investigator

University of Cincinnati Cancer Center-UC Medical Center

Cincinnati, Ohio, 45219

Recruiting
Site Public Contact · Contact
Emily K. Curran · Principal Investigator

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210

Recruiting
Site Public Contact · Contact
Alice S. Mims · Principal Investigator

University of Cincinnati Cancer Center-West Chester

West Chester, Ohio, 45069

Recruiting
Site Public Contact · Contact
Emily K. Curran · Principal Investigator

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104

Recruiting
Site Public Contact · Contact
Mohamad Khawandanah · Principal Investigator

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112

Recruiting
Site Public Contact · Contact
Paul J. Shami · Principal Investigator

University of Virginia Cancer Center

Charlottesville, Virginia, 22908

Active Not Recruiting