Revumenib in Combination With 7+3 + Midostaurin in AML

NCT ID: NCT06313437

Last Updated: 2025-03-27

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-12-06
• Study Completion Date: 2027-03-02

Brief Summary

This research is being conducted to determine a safe and effective dose of revumenib that can be given in combination with standard induction (initial therapy to induce a remission) + FLT3 targeted therapy (midostaurin) and a single cycle of post-remission therapy + FLT3 targeted therapy (midostaurin) to participants with newly diagnosed Nucleophosmin (NPM1) and FMS-like tyrosine kinase 3 (FLT3) mutated Acute Myeloid Leukemia (AML).

The names of the study drugs involved in this study are:

• Revumenib (SNDX-5613) (a type of menin inhibitor)
• Midostaurin (a type of multi-kinase including FLT3 inhibitor)
• Cytarabine (a type of antineoplastic agent)
• Daunorubicin (a type of antineoplastic agent)

Detailed Description

This is a single arm open label phase I trial of the menin inhibitor, revumenib, in combination with cytarabine and daunorubicin (7+3) chemotherapy and the multikinase inhibitor midostaurin for the frontline treatment of Nucleophosmin (NPM1) and FMS-like tyrosine kinase 3 (FLT3) mutated Acute Myeloid Leukemia (AML).

Investigators are trying to determine the highest dose of revumenib that can be given safely in combination with these chemotherapy drugs. Treatment consists of 1-2 cycles of so-called "induction treatment" (initial chemotherapy to induce a remission of the leukemia). This "induction treatment" consists of revumenib + 7+3 (7 days of cytarabine + 3 days of daunorubicin) chemotherapy + midostaurin.

The U.S. Food and Drug Administration (FDA) has not approved the combination of revumenib, cytarabine, daunorubicin, and midostaurin as a treatment for AML.

The research study procedures include screening for eligibility, study treatment visits, blood and urine tests, bone marrow biopsies, and electrocardiograms (ECGs).

Participants will receive study treatment as long as there are no serious side effects and the disease does not progress.

The trial will include up to 12 participants in dose finding phase and 10 additional participants in the dose expansion phase for a total participant number of 22 participants.

Syndax Pharmaceuticals is supporting this research study by supply revumenib (SNDX-5613).

Conditions

Acute Myeloid Leukemia; AML, Adult; AML With Gene Mutations; AML; Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Escalation Revumenib

Standard 3+3 design for a recommended phase 2 dose of Revumenib per dose-limiting toxicity rules. Cycles are 28 days.

• Baseline
• Induction Cycle:

• Days 1-3: Predetermined dose of Daunorubicin 1x daily
• Days 1-7: Predetermined dose of Cytarabine
• Days 8-21: Predetermined dose of Midostaurin 2x daily
• Days 8-28: Predetermined dose of Revumenib 2x daily
• End of Induction visit
• Follow-up
• Reinduction Cycle: Therapy will be administered in the hospital

• Days 1-2: Predetermined dose of Daunorubicin 1x daily
• Days 1-5: Predetermined dose of Cytarabine
• Days 8-21: Predetermined dose of Midostaurin 2x daily
• Days 8-28: Predetermined dose of Revumenib 2x daily
• End of reinduction visit
• Follow-up
• Consolidation Cycle: Therapy will be administered in the hospital

• Days 1, 3, and 5: Predetermined dose of Cytarabine
• Days 8-21: Predetermined dose of Midostaurin 2x daily
• Days 8-28: Predetermined dose of Revumenib 2x daily
• End of consolidation visit
• Follow up

Group Type: EXPERIMENTAL

Revumenib

Intervention Type: DRUG

Menin inhibitor, 25 and 113 mg capsules, taken orally per protocol.

Midostaurin

Intervention Type: DRUG

Kinase inhibitor, capsule taken orally per protocol.

Cytarabine

Intervention Type: DRUG

Antineoplastic agent, via intravenous (into the vein) infusion per protocol.

Daunorubicin

Intervention Type: DRUG

Antineoplastic agent, via intravenous (into the vein) infusion per protocol.

Dose-Expansion Revumenib

Cycles are 28 days

• Baseline visit and assessments
• Induction Cycle:

• Days 1-3: Predetermined dose of Daunorubicin 1x daily
• Days 1-7: Predetermined dose of Cytarabine
• Days 8-21: Predetermined dose of Midostaurin 2x daily
• Days 8-28: Predetermined dose of Revumenib 2x daily
• End of Induction visit
• Follow-up
• Reinduction Cycle: Therapy will be administered in the hospital

• Days 1-2: Predetermined dose of Daunorubicin 1x daily
• Days 1-5: Predetermined dose of Cytarabine
• Days 8-21: Predetermined dose of Midostaurin 2x daily
• Days 8-28: Predetermined dose of Revumenib 2x daily
• End of Reinduction visit
• Follow-up
• Consolidation Cycle: Therapy will be administered in the hospital

• Days 1, 3, and 5: Predetermined dose of Cytarabine
• Days 8-21: Predetermined dose of Midostaurin 2x daily
• Days 8-28: Predetermined dose of Revumenib 2x daily
• End of Consolidation visit
• Follow up

Group Type: EXPERIMENTAL

Revumenib

Intervention Type: DRUG

Menin inhibitor, 25 and 113 mg capsules, taken orally per protocol.

Midostaurin

Intervention Type: DRUG

Kinase inhibitor, capsule taken orally per protocol.

Cytarabine

Intervention Type: DRUG

Antineoplastic agent, via intravenous (into the vein) infusion per protocol.

Daunorubicin

Intervention Type: DRUG

Antineoplastic agent, via intravenous (into the vein) infusion per protocol.

Interventions

Revumenib

Menin inhibitor, 25 and 113 mg capsules, taken orally per protocol.

Intervention Type: DRUG

Midostaurin

Kinase inhibitor, capsule taken orally per protocol.

Intervention Type: DRUG

Cytarabine

Antineoplastic agent, via intravenous (into the vein) infusion per protocol.

Intervention Type: DRUG

Daunorubicin

Antineoplastic agent, via intravenous (into the vein) infusion per protocol.

Intervention Type: DRUG

Other Intervention Names

SNDX-5613; Trans N-ethyl-2-((4-(7-((4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide; Rydapt; cytosine arabinoside (ara-C); Daunomycin

Eligibility Criteria

Inclusion Criteria

• Patients with AML who are newly diagnosed according to the WHO 2022 Classification and previously untreated except for hydroxyurea. ATRA pretreatment for suspected APL for less than 5 days is allowed. Eligible patients with AML arising from an antecedent hematologic disease (AHD) including MDS, may have been treated for their prior hematologic disease (except for allogenic transplant).
• Patients must be ≥ 18 and < 75 years old.
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.
• Presence of FLT3-ITD and/or TKD mutation(s) AND NPM1 mutation in bone marrow or peripheral blood
• Dose escalation phase only: Presence of any of the following adverse risk genetic characteristics:

• 2022 ELN adverse risk genetic features:

• t(6;9)(p23.3;q34.1)/DEK::NUP214
• t(v;11q23.3)/KMT2A-rearranged
• t(9;22)(q34.1;q11.2)/BCR::ABL1
• t(8;16)(p11.2;p13.3)/KAT6A::CREBBP
• inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1)
• t(3q26.2;v)/MECOM(EVI1)-rearranged
• -5 or del(5q); -7; -17/abn(17p)
• Complex karyotype, monosomal karyotype
• Mutations in either one of these genes: ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2
• Mutated TP53
• NPM1 + FLT3-ITD + DNMT3A mutation
• LVEF ≥ 50% by MUGA or ECHO at screening.
• Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min; determined by the Cockcroft Gault formula.
• Adequate liver function as demonstrated by:

• aspartate aminotransferase (AST) ≤ 2.5 × ULN*
• alanine aminotransferase (ALT) ≤ 2.5× ULN*
• total bilirubin ≤ 1.5 × ULN* * Unless considered due to leukemic organ involvement. Note: Subjects with Gilbert's Syndrome may have a total bilirubin > 1.5 × ULN per discussion with the Sponsor-Investigator
• Resolution of adverse reactions to prior drug therapy (such as hydroxyurea) to ≤ grade 1
• Eligible for intensive cytarabine/daunorubicin (7+3) chemotherapy based on the opinion of the treating physician.
• Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug.
• Females of childbearing potential (i.e., not postmenopausal for at least 1 year or not surgically sterile) must have negative results by a serum or urine pregnancy test performed within 7 days of day 1.
• Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)
• Consolidation should occur between 1-4 weeks following count recovery after induction and remission (must be confirmed by labs to document maximal response) is established. Subjects will receive medium intensity cytarabine -based consolidation in combination with midostaurin and revumenib if the following criteria are fulfilled.

• an induction response < 5% blasts in the bone marrow and ANC >1000 and PLT >75000 for whom documented path report is submitted.
• sufficiently fit (performance status <3)
• resolution of any adverse reactions to no greater than grade 1 severity

Exclusion Criteria

• Subject has acute promyelocytic leukemia, inversion (16), t(8;21) AML as described below. Contact Sponsor-Investigator with questions. Inversion 16 and t(8;21): CBF chromosomal abnormalities may be assessed by molecular (PCR), metaphase cytogenetics, or FISH.
• Subject has known active CNS involvement with AML.
• Subject has received a strong CYP3A4 inducer (APPENDIX C) within 7 days prior to the initiation of study treatment
• Strong CYP3A4 inhibitors (APPENDIX C) are contraindicated except strong CYP3A4 inhibitor antifungal azole medications (systemic itraconazole, ketoconazole, posaconazole, voriconazole). For strong CYP3A4 inhibitor antifungal azole medications, the starting dose of revumenib has to be adjusted (Table 1).
• QTc using Fridericia's correction [QTcF]) > 450 msec. Drugs that prolong QTc should be avoided if possible. A list of common QTc prolonging drugs and alternatives that are not QTc prolonging can be found in APPENDIX D.
• Subject has tested positive for HIV (due to potential drug-drug interaction between antiretroviral medications and Midostaurin/revumenib). Note: HIV testing is not required.
• Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV [i.e., HBs Ag-, and antiHBs+] are allowed.
• Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
• Subject has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
• Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
• Subject has chronic respiratory disease that requires continuous oxygen use.
• Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
• Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to uncontrolled systemic infection.
• Subject has a history of other malignancies prior to study entry, with the exception of:

• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
• Prior malignancies treated with (surgery+/- chemotherapy+/- radiation) that have remained disease free for at least two years after completion of therapy
• Subject treated with any form of chemotherapy, immunotherapy, or investigative agent within 1 month of enrollment.
• Patients who have had prior exposure to a menin inhibitor.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Syndax Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Richard Stone, MD

OTHER

Sponsor Role: lead

Responsible Party

Richard Stone, MD

Sponsor-Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Richard Stone, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Richard Stone, MD

Role: CONTACT

richard_stone@dfci.harvard.edu

617-632-5157

Facility Contacts

Richard Stone, MD

Role: primary

richard_stone@dfci.harvard.edu

617-632-5157

Richard Stone, MD

Role: primary

richard_stone@dfci.harvard.edu

617-632-5157

Other Identifiers

24-021

Identifier Type: -

Identifier Source: org_study_id