Dysautonomia International

A Study of the Combination of Ivosidenib, Azacitidine, and Venetoclax Followed by Ivosidenib Alone in People With Acute Myeloid Leukemia

Purpose

The researchers are doing this study to find out whether a 3-drug combination of ivosidenib, azacitidine, and venetoclax followed by maintenance therapy with ivosidenib alone is an effective treatment approach for people with newly diagnosed acute myeloid leukemia (AML) that has an IDH mutation. Maintenance therapy is additional treatment given to help keep cancer from coming back after it has disappeared following the first course of treatment. The researchers will also look at the safety of the treatment approach and what kind of a time commitment it involves for participants.

Condition

Acute Myeloid Leukemia

Eligibility

Eligible Ages: Over 60 Years
Eligible Sex: All
Accepts Healthy Volunteers: No

Inclusion Criteria

Participant must be at least 60 years of age at the time of signing the informed consent form (ICF). - Participant is willing and able to adhere to the study visit schedule and other protocol requirements. - Participant has newly diagnosed AML as per World Health Organization 2022 or European leukemia Network 2022 guidelines. - Participant has IDH1-R132 mutation present prior to initiating Ivo/Aza/Ven confirmed by CLIA approved local testing via next-generation sequencing (NGS) and/or polymerase chain reaction (PCR). Other 2-HG producing IDH1 variants may be eligible after discussion with MSK principal investigator. 1. At MSK, this testing will utilize the MSK-REACT, a rapid multi-gene NGS panel used in all new AML diagnoses that is clinically validated by the Laboratory of Diagnostic Molecular Pathology pursuant to the requirements of CLIA'88 and approved by New York State. Other sites may use local CLIA-certified laboratories and validated clinical assays as per standard of care. 2. The patient's chart will be utilized for screening purposes - Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Participant must have a WBC count <25,000/μL at the time of initiation of study drug (leukapheresis may be performed and/or hydroxyurea may be administered to decrease the WBC count to <25,000/μL). - Participant has adequate organ function defined as: 1. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered due to leukemic organ involvement. 2. Serum total bilirubin < 3.0 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, leukemia organ involvement or Gilbert's syndrome. 3. Serum creatinine < 2 x ULN or creatinine clearance 30 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation.

Exclusion Criteria

Participant with acute promyelocytic leukemia - Participants who have previously received ivosidenib or venetoclax - Participant receiving any other investigational anti-cancer agents. Cytoreductive therapy such as hydroxyurea is permitted. - Participants with immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation - Participant has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment). - Participants who are planned for allogeneic stem cell transplantation based on the assessment of the treating clinician. - Participant has significant active cardiac disease within 6 months prior to start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke - Participant has active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). As per exclusion criteria 5, patients receiving appropriate treatment would only be excluded if there is no improvement. - Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. - Participant has QTc interval (i.e., Fridericia's correction [QTcF]) ≥ 450 ms (mean of triplicate ECG) or other factors that increase the risk of QT prolongation or ventricular arrhythmic events (e.g. family history of long QT interval syndrome). Participants with a QTcF over 450 ms due - Male or female participants not willing to comply with contraceptive requirements

Study Design

Phase: Phase 2
Study Type: Interventional
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a phase II, single-arm, multicenter clinical trial.
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
Experimental Ivosidenib, Azacitidine, and Venetoclax Followed by Ivosidenib Alone	Patients will be initially treated with 7 days of azacitidine (IV or SC per institutional preference, 14 days of venetoclax and 14 days of Ivosidenib daily, days 15 through 28 for cycle 1, then days 1 through 28 for each cycle thereafter).	Drug: Ivosidenib Ivosidenib ( days 15 through 28 for cycle 1, then days 1 through 28 for each cycle thereafter) Drug: Azacitidine Azacitidine (IV or SC per institutional preference, days 1 through 7) Drug: Venetoclax Venetoclax (days 1 through 14)

Recruiting Locations

Memoral Sloan Kettering at Basking Ridge (Limited Protocol Activities)
Basking Ridge 5095409, New Jersey 5101760 07920