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Ivosidenib, Azacitidine, and Venetoclax Followed by Ivosidenib Alone for the Treatment of Newly Diagnosed Acute Myeloid Leukemia
Trial Status: active
This phase II trial tests the effect of ivosidenib, azacitidine and venetoclax followed by maintenance therapy with ivosidenib alone in treating patients with newly diagnosed IDH1 mutated acute myeloid leukemia (AML). Maintenance therapy is additional treatment given to help keep cancer from coming back after the first course of treatment. Ivosidenib, an IDH1 inhibitor, blocks the protein made by the mutated IDH1 gene, which may help keep cancer cells from growing. Azacitidine stops cells from making DNA and may kill cancer cells. It is a type of antimetabolite. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Standard of care treatment includes ivosidenib, azacitidine, and venetoclax as 2-drug combinations (ivosidenib and azacitidine, azacitidine and venetoclax). Giving ivosidenib, azacitidine and venetoclax together, followed by maintenance therapy with ivosidenib alone, may be safe, tolerable, and/or effective in treating patients with newly diagnosed IDH1 mutated AML.
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 Clinical Laboratory Improvement Act (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 Memorial Sloan Kettering (MSK) principal investigator
* 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
* 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 white blood cell (WBC) count < 25,000/uL 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/uL)
Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x upper limit of normal (ULN), unless considered due to leukemic organ involvement
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
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). 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 corrected QT (QTc) interval (i.e., Fridericia’s correction [QTcF]) ≥ 450 ms (mean of triplicate electrocardiogram [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 to a bundle branch block or a pacemaker may participate in the study with approval of the MSK principal investigator
Male or female participants not willing to comply with contraceptive requirements
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07392242.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Kuo-Kai Chin
Phone: 646-608-3749
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Kuo-Kai Chin
Phone: 646-608-3749
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Kuo-Kai Chin
Phone: 646-608-3749
New York
Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Kuo-Kai Chin
Phone: 646-608-3749
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Kuo-Kai Chin
Phone: 646-608-3749
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Kuo-Kai Chin
Phone: 646-608-3749
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Kuo-Kai Chin
Phone: 646-608-3749
PRIMARY OBJECTIVE:
I. To estimate the event free survival in newly diagnosed patients with IDH1 mutated AML treated with ivosidenib (Ivo)/azacitidine (Aza)/venetoclax (Ven) followed by Ivo maintenance.
SECONDARY OBJECTIVES:
I. To estimate clinical efficacy by rates of complete remission (CR), composite CR (CRc) (CR/CR without recovery of counts [CRi]) and overall response rate (ORR) (CRc/morphologic leukemia-free state [MLFS]/partial remission [PR]).
II. To estimate time to first response and time to best response.
III. To estimate duration of response (DOR).
IV. To estimate overall survival.
V. To estimate measurable residual disease (MRD) clearance.
VI. To estimate rates of significant pancytopenia and febrile neutropenia.
VII. To estimate transfusion requirements.
VIII. To estimate time away from home.
EXPLORATORY OBJECTIVES:
I. To evaluate clonal evolution at screening, transition to ivosidenib maintenance, and at time of relapse.
II. To evaluate rates of IDH1 mutational clearance.
III. To evaluate development of IDH1 resistance mutations and IDH1 isoform switching (IDH1 to IDH2).
IV. To assess 2HG (2-hydroxyglutarate) levels at baseline and following treatment.
OUTLINE:
Patients receive azacitidine intravenously (IV) over 30 minutes or subcutaneously (SC) on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-14, and ivosidenib PO QD on days 15-28 of cycle 1 in the absence of disease progression or unacceptable toxicity. Patients whose disease improves during cycle 1 (CRc) proceed to Maintenance Therapy. Patients whose disease does not improve enough during cycle 1 receive azacitidine IV over 30 minutes or SC on days 1-7, venetoclax PO QD on days 1-14, and ivosidenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles (cycles 2-3) in the absence of disease progression or unacceptable toxicity. Patients whose disease improves during cycles 2-3 proceed to Maintenance Therapy.
MAINTENANCE THERAPY: Patients receive ivosidenib PO on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo bone marrow biopsy and aspiration at the end of treatment, as well as blood sample collection throughout the study.
After completion of study treatment, patients are followed monthly for up to 1 year, then every 3 months for up to 1 year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
