Revumenib in Combination With 7+3 + Midostaurin in AML

NCT06313437 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 24-021
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

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)

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (3)

• Number of Participants Experiencing Dose Limiting Toxicity (DLT)

  Detailed DLT consideration outline in protocol section 5.4.

  Up to 12 weeks

• Maximum Tolerated Dose (MTD)

  MTD is determined by the number of patients who experience a DLT. See previous primary outcome measure for the DLT definition. If 0 out of 3 participants experience DLT, next dose level will be proceeded. If \>=1 out of the group suffer DLT, dose escalation will be stopped and 3 additional participants will be entered at the next lowest dose level. If \<=1 out of 6 DLTs, this dose level is considered as MTD.

  Up to 12 weeks

• Recommended phase II dose (RP2D)

  The RP2D is determined by a combination of the MTD (see previous primary outcome measure), pharmacokinetics, pharmacodynamics and response rate to different doses of revumenib in combination with chemotherapy and the FLT3 inhibitor midostaurin.

  Up to 12 weeks

Secondary Outcomes (8)

• Complete Remission (CR) rate with induction chemotherapy

  Up to 8 weeks

• Complete Remission (CR) rate with consolidation chemotherapy

  Up to 12 weeks

• Flow Measurable Residual Disease Negative (MRD-) rate with induction chemotherapy

  Up to 8 weeks

• Flow Measurable Residual Disease Negative (MRD-) rate with consolidation chemotherapy

  Up to 12 weeks

• Molecular Measurable Residual Disease Negative (MRD-) rate with induction chemotherapy

  Up to 8 weeks

Study Arms (2)

Dose Escalation Revumenib

EXPERIMENTAL

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

Drug: Revumenib; Drug: Midostaurin; Drug: Cytarabine; Drug: Daunorubicin

Dose-Expansion Revumenib

EXPERIMENTAL

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

Drug: Revumenib; Drug: Midostaurin; Drug: Cytarabine; Drug: Daunorubicin

Interventions

Revumenib DRUG

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

Also known as: 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

Dose Escalation Revumenib; Dose-Expansion Revumenib

Midostaurin DRUG

Kinase inhibitor, capsule taken orally per protocol.

Also known as: Rydapt

Dose Escalation Revumenib; Dose-Expansion Revumenib

Cytarabine DRUG

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

Also known as: cytosine arabinoside (ara-C)

Dose Escalation Revumenib; Dose-Expansion Revumenib

Daunorubicin DRUG

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

Also known as: Daunomycin

Dose Escalation Revumenib; Dose-Expansion Revumenib

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• 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

You may not qualify if:

• 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;

Sponsors & Collaborators

• Syndax Pharmaceuticals: collaborator
• Richard Stone, MD: lead

Study Sites (2)

Yale Cancer Center

New Haven, Connecticut, 06150, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia

Interventions

revumenib; midostaurin; Cytarabine; Daunorubicin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Richard Stone, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Richard Stone, MD

CONTACT

617-632-5157; richard_stone@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: March 10, 2024
• First Posted: March 15, 2024
• Study Start: December 6, 2024
• Primary Completion (Estimated): March 2, 2027
• Study Completion (Estimated): March 2, 2028
• Last Updated: March 25, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)