Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Optional and would only be performed Dose Level 1 is poorly tolerated

The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study and will not exceed a loading dose of 150 mg x 2 days and maintenance dose of 50 mg QD

ZE46-0134

Kate Dokukina, PhD, MD

Carolyn Grove, Prof

This is a clinical study aiming to assess pharmacokinetics, pharmacodynamics and preliminary efficacy of ZE46-0134 in patients with FLT3 mutated Relapsed or Refractory Acute Myeloid Leukemia

This is a Phase 1, open-label, multicenter, dose escalation, and dose optimization study to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of ZE46-0134 in adult patients with relapsed or refractory AML with FLT3-ITD and/or FLT3-TKD mutations. Patients with AML that are out-patients or hospitalized due to their AML can be enrolled in the study..

The study will be run in 2 parts: Part 1 will be dose escalation and determination of MTD, and Part 2 will be dose expansion.

In Part 1 of the study 3 to 6 eligible patients will be sequentially enrolled into each of 5 planned dose level cohorts. Patients will receive up to 24 cycles (28 days each) of study treatment. For patients that continued to derive benefit after 24 cycles of treatment, continuation of ZE46-0134 therapy will be considered.

In Part 2, the dose expansion phase will involve enrolling up to 30 patients across 2 dose cohorts (i.e., 15 patients per cohort). ZE46-0134 will be dosed as described for Part 1 of the study. The doses used in Part 2 of the study will be determined based on the data from Part 1 of the study.

Indication background information:

Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood cell cancers that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow (BM) and is the most commonly diagnosed adult leukemia with a median age at diagnosis is 68 years, with an overall survival (OS) rate of 29.8%. As patients age, there is a 10% decrease in 5-year OS for every additional decade of life, with a 5-year OS of 0.4% in patients age \>85 years1. Furthermore, remission rates and OS depend on a number of other factors, including cytogenetics, previous BM disorders, and comorbidities.

FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase (RTK) primarily expressed on immature hematopoietic progenitors and hematopoietic stem cells. FLT3 signaling is initiated when FLT3 ligand binds to FLT3, inducing the dimerization and activation of FLT3 via autophosphorylation. This then activates downstream signaling of phosphoinositide 3-kinase/protein kinase B (PI3K/PKB), mitogen-activated protein kinase (MAPK), and JAK2/STAT5 which leads to cell proliferation and suppression of apoptosis2.

FLT3 kinase is directly implicated in the pathogenesis of hematologic malignancies, particularly AML. FLT3 mutations are the most frequently identified mutations in AML patients. Activating mutations in FLT3, which are FLT3-internal tandom duplication (ITD) and FLT3 tyrosine kinase domain (TKD) mutations, account for 30% of all AML cases2. As a result of these mutations, the FLT3 receptor is continuously activated leading to the continuous activation of downstream signaling pathways, PI3K/AKT, MAPK, and signal transducer and activator of transcription (STAT5), resulting in increased cell proliferation and decreased apoptosis.

dose escalation and dose optimization study

Dose Escalation and Expansion Study to Evaluate the Safety, PK, PD and Efficacy of ZE46-0134 in Adults With FLT3 Mutated Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1, Open-label, Dose Escalation and Dose Expansion, Multicenter Clinical Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of ZE46-0134 in Adults With FLT3 Mutated Relapsed or Refractory Acute Myeloid Leukemia (AML)

The incidence of DLTs during Cycle 1 (i.e., C1D1 to C1D28) unless hematologic recovery in the absence of disease

Number of deaths, deemed related to the study drug by the Investigator

ZE46-0134 steady state plasma concentration

Minimum ZE46-0134 plasma concentration reached during a dosing interval

Area under the ZE46-0134 plasma concentration-time curve during a dosing interval

Eilean Therapeutics

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Daunorubicin

Midostaurin

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Protein Kinase Inhibitors

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

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

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

Revumenib

Kinase inhibitor, capsule taken orally per protocol.

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

Maximilian Stahl, MD

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)

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).

Revumenib in Combination With 7+3 + Midostaurin in AML

A Phase I Trial of Revumenib in Combination With 7+3 (7 Days of Cytarabine and 3 Days of Daunorubicin) + Midostaurin Induction Chemotherapy for the Frontline Treatment of NPM1 and FLT3 Mutated AML

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Detailed DLT consideration outline in protocol section 5.4.

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.

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.

CR rate is defined as the proportion of participants who achieve a CR as defined by the ELN 2022 response criteria after completion of induction chemotherapy.

CR rate is defined as the proportion of participants who achieve a CR as defined by the ELN 2022 response criteria after completion of consolidation chemotherapy.

Flow MRD rate is defined as the proportion of participants who achieve MRD negativity (MRD-) after completion of induction chemotherapy assessed by MRD sensitive flow cytometry.

Flow MRD rate is defined as the proportion of participants who achieve MRD negativity (MRD-) after completion of consolidation chemotherapy assessed by MRD sensitive flow cytometry.

Molecular MRD rate is defined as the proportion of participants who achieve MRD negativity (MRD-) after completion of induction chemotherapy as assessed by NPM1 MRD testing as well as FLT3 ITD MRD testing and duplex sequencing.

Molecular MRD rate is defined as the proportion of participants who achieve MRD negativity (MRD-) after completion of consolidation chemotherapy as assessed by NPM1 MRD testing as well as FLT3 ITD MRD testing and duplex sequencing.

RFS is defined as the length of time after the completion of a particular medical treatment during which a patient remains free of any signs or symptoms of disease relapse or recurrence based on Kaplan-Meier methodology.

OS1 is the probability estimated using the Kaplan-Meier method; OS is defined as the time from study entry to death, or censored at the date last known alive.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dose Escalation and Expansion Study to Evaluate the Safety, PK, PD and Efficacy of ZE46-0134 in Adults With FLT3 Mutated Relapsed or Refractory Acute Myeloid Leukemia	NCT06366789	AML With Gene M...	ZE46-0134	18 Years -	Eilean Therapeutics
Dose Escalation and Expansion Study to Evaluate the Safety, PK, PD and Efficacy of ZE46-0134 in Adults With FLT3 Mutated Relapsed or Refractory Acute Myeloid Leukemia	NCT06366789	AML With Gene M...	ZE46-0134	18 Years -	Eilean Therapeutics
Revumenib in Combination With 7+3 + Midostaurin in AML	NCT06313437	Acute Myeloid L... AML, Adult AML With Gene M... AML Leukemia	Revumenib Midostaurin Cytarabine Daunorubicin	18 Years - 75 Years	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for aml with gene mutations