Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

A Phase 1 Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia

This is a research study to find out if adding a new study drug called revumenib to commonly used chemotherapy drugs is safe and if they have beneficial effects in treating patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that did not go into remission after treatment (refractory) or has come back after treatment (relapsed), and to determine the total dose of the 3-drug combination of revumenib, azacitidine and venetoclax that can be given safely in participants also taking an anti-fungal drug.

Primary Objective

• To determine the safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL.

Secondary Objectives

• Describe the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), and overall survival for patients treated with revumenib + azacitidine + venetoclax at the recommended phase 2 dose (RP2D).

Study Overview

• Status: Recruiting
• Conditions: Refractory Acute Myeloid Leukemia; Acute Leukemia of Ambiguous Lineage; Relapsed Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Revumenib; Drug: Venetoclax; Drug: Azacitidine; Drug: intrathecal (IT) chemotherapy; Drug: Cytarabine; Drug: Methotrexate

Detailed Description

Patients will receive revumenib + azacitidine + venetoclax in a dose-escalation fashion. The doses of revumenib and azacitidine will remain constant, while the duration of exposure to venetoclax will be escalated or de-escalated. Patients may continue to receive therapy if there is clinical benefit and no unacceptable toxicity.

Patients who achieve complete response (CR) or Complete remission with incomplete blood count recovery (CRi) and subsequently undergo hematopoietic cell transplant (HCT) may remain on study. Revumenib, with or without azacitidine and venetoclax, may be resumed after transplant if the patient is at least 60 days post-transplant, remains in CR or CRi, has engrafted, and does not have Grade ≥2 acute graft versus host disease (GVHD). In the absence of toxicity, revumenib may be continued for a maximum of 12 months.

Patients are followed for 30 days after completion of study treatment.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jeffrey E. Rubnitz, MD, PhD; Phone Number: 866-278-5833; Email: referralinfo@stjude.org

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Recruiting
      • St. Jude Children's Research Hospital
      • Contact: Jeffrey E. Rubnitz, MD, PhD; Phone Number: 866-278-5833; Email: referralinfo@stjude.org
      • Principal Investigator: Jeffrey E. Rubnitz, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria: Participants must have a diagnosis of AML or ALAL and meet the criteria below:

• Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, or relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission. Patients must have ≥5% blasts in the bone marrow as assessed by morphology or ≥1% blasts flow cytometry. However, if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with ≥5% blasts by morphology or ≥1% blasts flow cytometry in the blood.
• Presence of KMT2A rearrangement (KMT2Ar), NUP98 rearrangement (NUP98r), NPM1 mutation or fusion, PICALM::MLLT10, DEK::NUP214, UBTF-TD, KAT6A::CREBBP, or SET::NUP214
• Adequate organ function, defined as direct bilirubin ≤ 1.5 x institutional upper limit of normal unless attributed to leukemia, calculated creatinine clearance ≥60 mL/min/1.73 m^2, and left ventricular ejection fraction ≥ 40%
• QTcF < 480 msec (average of triplicate)
• Age ≥ 1 year and ≤ 30 years. The upper age limit may be defined by each institution, but may not exceed 30 years.
• Lansky ≥ 60 for patients who are < 16 years old and Karnofsky ≥ 60% for patients who are > 16 years old.
• At least 14 days or 5 half-lives (whichever is longer) must have elapsed since the completion of myelosuppressive therapy, with the exception of low-dose therapy used for cytoreduction according to institutional standards, such as hydroxyurea or low-dose cytarabine (up to 200 mg/m^2/day). In addition, all toxicities must have resolved to grade 1 or less.
• Patients must have a leukocyte count <25,000 cells/uL. Low-dose therapy, such as hydroxyurea or cytarabine as described above, to achieve this limit is acceptable.
• For patients who have received prior HCT, there can be no evidence of GVHD and greater than 60 days must have elapsed since the HCT, and patients should be off calcineurin inhibitors for at least 28 days prior to the start of protocol therapy. Physiologic prednisone for the treatment of adrenal insufficiency is acceptable..
• Patients must be taking posaconazole or voriconazole, which must be started at least 24 hours prior to the start of therapy.
• Patients of reproductive potential must agree to use effective contraception for the duration of study participation.
• Patients must be able to swallow tablets.

Patients who meet the criteria listed above are eligible for enrollment and treatment on the trial. However, patients in first relapse who are suitable for and willing to receive intensive remission induction therapy should be offered such therapy if deemed appropriate by the treating physician.

Exclusion Criteria:

• Patients who are pregnant or breastfeeding are not eligible.
• Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible.
• Patients with uncontrolled infection are not eligible. Patients with infections that are controlled on concurrent anti-microbial agents are eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: All Eligible Participants; All eligible patients receive the following intervention: Revumenib, Venetoclax, Azacitidine, Intrathecal chemotherapy

Drug: Revumenib; Given by mouth (capsule or liquid solution) or liquid solution by Nasogastric tube (NG) or Gastrostomy tube (G-tube); Other Names: SNDX-5613; Drug: Venetoclax; Given by mouth (tablet); Other Names: Venclextra®; Drug: Azacitidine; Given intravenously (IV) infusion; Other Names: 5-azacitidine; VIDAZA®; Drug: intrathecal (IT) chemotherapy; Given intrathecal (IT); Other Names: ITMHA; methotrexate/hydrocortisone/cytarabine; Drug: Cytarabine; Given intrathecal (IT) as part of intrathecal (IT) chemotherapy.; Other Names: Ara-C; Cytosar®; Drug: Methotrexate; Given intrathecal (IT) as part of intrathecal (IT) chemotherapy.; Other Names: MTX; Trexall®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The safety and tolerability of revumenib + azacitidine + venetoclax in pediatric patients with relapsed or refractory AML or ALAL	The primary endpoint is the recommended phase 2 dose (RP2D) of revumenib + azacitidine + venetoclax.	43 days from the start of therapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The rates of complete remission (CR)	CR is defined as bone marrow with < 5% blasts confirmed by flow cytometry, ANC ≥500/μL and platelets ≥50,000/μL without transfusions, and no evidence of extramedullary disease.	43 days from the start of therapy
The rates of complete remission with incomplete count recovery (CRi)	CRi is defined as bone marrow with <5% blasts confirmed by flow cytometry and ANC <500/μL or platelets <50,000/μL without transfusions	43 days from the start of therapy
The overall survival of patients treated at the RP2D.	Kaplan-Meier estimates with 95% confidence intervals will be used to describe overall survival.	1 year

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Syndax Pharmaceuticals
• Investigators: Principal Investigator: Jeffrey E. Rubnitz, MD, PhD, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: December 11, 2023
• First Submitted That Met QC Criteria: December 11, 2023
• First Posted (Actual): December 20, 2023

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Venetoclax; Azacitidine; Cytarabine; Methotrexate; Hydrocortisone
• Other Study ID Numbers: RAVAML; NCI-2023-10509 (Registry Identifier: NCI Clinical Trial Registration Program)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.
• IPD Sharing Time Frame: Data will be made available at the time of article publication.
• IPD Sharing Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No