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

Refractory Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06177067
• Other study ID #: RAVAML
• Secondary ID: NCI-2023-10509
• Status: Recruiting
• Phase: Phase 1
• Start date: April 19, 2024
• Est. completion date: July 2026

Study information

• Verified date: May 2024
• Source: St. Jude Children's Research Hospital
• Contact: Hiroto Inaba, MD, PhD
• Phone: 866-278-5833
• Email: referralinfo[@]stjude.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: July 2026
• Est. primary completion date: January 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 30 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Leukemia of Ambiguous Lineage
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Refractory Acute Myeloid Leukemia
• Relapsed Acute Myeloid Leukemia

Intervention

Drug:
• Revumenib
Given by mouth (capsule or liquid solution) or liquid solution by Nasogastric tube (NG) or Gastrostomy tube (G-tube)
• Venetoclax
Given by mouth (tablet)
• Azacitidine
Given intravenously (IV) infusion
• intrathecal (IT) chemotherapy
Given intrathecal (IT)
• Cytarabine
Given intrathecal (IT) as part of intrathecal (IT) chemotherapy.
• Methotrexate
Given intrathecal (IT) as part of intrathecal (IT) chemotherapy.

Locations

Country	Name	City	State
United States	St. Jude Children's Research Hospital	Memphis	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	Syndax Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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

External Links

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