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Kiran Naqvi

Olatoyosi M. Odenike

Alice S. Mims

Alice S Mims

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.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety of revumenib (SNDX-5613) combined with 7 + 3 induction in newly diagnosed, untreated, NPM1-mutated/FLT3-ITD wild type and NPM1-mutated/FLT3-TKD wild type or MLL(KMT2A)-rearranged, acute myeloid leukemia (AML) patients \>= 18-75 years old who are candidates for intensive induction therapy.

II. To determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and safety of SNDX-5613 combined with one cycle of consolidation with high dose cytarabine in newly diagnosed AML patients in complete response/complete response with incomplete count recovery (CR/Cri) after intensive induction therapy with 7+3 for NPM1-mutated/FLT3-ITD wild type and NPM1-mutated/FLT3-TKD wild type or MLL (KMT2A)-rearranged AML patients \>= 18-75 years old who are candidates for intensive therapy.

SECONDARY OBJECTIVES:

I. Evaluate the pharmacokinetics of SNDX-5613 with this combination regimen and characterize clinically relevant drug-drug interactions with antifungal agents.

II. To determine the number of patients with CR/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 who achieve a response to Re-Induction treatment continue to Consolidation. Patients also undergo a transthoracic ECHO or MUGA on day 1 and bone marrow aspiration and biopsy at the end of Re-Induction.

CONSOLIDATION: Patients receive revumenib PO Q12h on days 2-28 and cytarabine CIV on days 1-3 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 30 days or until death, whichever occurs first.

Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene

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 Disease.

"NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."

Will be determined for each patient using 2017 European LeukemiaNet criteria. The number of patients achieving response out of the total number of patients treated at a dose level will be described. Swimmer plots will be utilized to visually display how response improves/changes over time.

MRD negative status is defined as the following for each genomic subgroup: 1) NPM1mutated/FLT3 ITD and FLT3 TKD wildtype: negative NPM1 by polymerase chain reaction testing on bone marrow after cycle 1 of consolidation (or after induction if unable to receive consolidation) or 2) MLL (KMT2A) rearrangement: negative multi-parameter flow cytometry (flow cutoff 10-3) after induction chemotherapy. The number of patients with MRD negative status and the relationship to clinical response will be described at each time point of interest. Swimmer plots will be utilized to visually display how MRD status improves/changes over time.

Median survival will be estimated with 95% confidence interval using Kaplan-Meier method. Swimmer plots will be utilized to visually display how response improves/changes over time.

Median survival will be estimated with 95% confidence interval using Kaplan-Meier method. Swimmer plots will be utilized to capture milestone events including relapse of disease and death for each patient within a given dose level.

Will be described. Swimmer plots will be utilized to capture receipt of HSCT for each patient within a given dose level.

Assess changes in OATP1B and CYP3A plasma biomarkers during treatment with SNDX-5613 with or without antifungal agents.

MTD of induction will be determined based on isotonic regression. Specifically, the MTD is selected as the dose for which the isotonic estimate of the toxicity rate is closest to the targeted dose-limiting toxicity (DLT) (i.e., 25%) via Bayesian Optimal Interval ("BOIN") software (MD Anderson). 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.

MTD of induction will be determined based on isotonic regression. Specifically, the MTD is selected as the dose for which the isotonic estimate of the toxicity rate is closest to the targeted DLT (i.e., 25%) via "BOIN" software (MD Anderson). 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.

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.

The PK sampling is designed to enable estimation of individual PK parameters of SNDX-5613 using standard noncompartmental methods. The primary analysis will compare SNDX-5613 exposure (area under the curve from zero to infinity \[AUCinf\]) on day 2 (before strong antifungal agent administration starting on Day 4 after completion of anthracycline) and steady-state exposure (area under plasma concentration-time curve over dosing interval \[AUCtau\]) on day 15 (after administration of antifungal agent).

Will be calculated by the the number of patients achieving CR/CRi response out of the total number of patients treated on both the dose-escalation and expansion portions with 95% exact binomial confidence interveral.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene	NCT05886049	Acute Myeloid L... Acute Myeloid L...	Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Cytarabine Daunorubicin Multigated Acqu... Revumenib Transthoracic E...	18 Years - 75 Years	National Cancer Institute (NCI)
Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene	NCT05886049	Acute Myeloid L... Acute Myeloid L...	Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Cytarabine Daunorubicin Multigated Acqu... Revumenib Transthoracic E...	18 Years - 75 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for acute myeloid leukemia with npm1 mutation