This study aims to evaluate the effectiveness of new treatment combinations for patients with newly diagnosed Acute Myeloid Leukemia, which is a type of cancer that affects the blood and bone marrow. The research focuses on specific subtypes of this disease characterized by certain genetic changes, specifically NPM1 mutations or KMT2A rearrangements. These changes are specific alterations in the DNA of the cancer cells that influence how the disease behaves.
The research involves two different approaches to treatment. In the first approach, ziftomenib is used alongside a nonintensive therapy consisting of venetoclax and azacitidine. In the second approach, ziftomenib is combined with an intensive therapy known as 7+3, which includes cytarabine and daunorubicin hydrochloride. Some participants may receive a placebo instead of ziftomenib to allow for a comparison between the different treatment methods.
During the study, participants will receive their assigned medications through different methods, such as oral pills or intravenous administration, which is the delivery of medicine directly into a vein. The study will monitor how long patients live and the time until the disease begins to grow again. This process helps determine if adding the new drug to standard treatments improves the long-term outcomes for people with these specific genetic forms of leukemia.
Who Can Join the Study?
You must be at least 18 years old when signing the study agreement.
You must be able to understand the study requirements and give your informed consent, which means you agree to participate after being told all the details.
You must have a diagnosis of Acute Myeloid Leukemia (AML), a type of blood cancer, based on the 2022 medical standards.
Patients with therapy-related AML (leukemia caused by previous medical treatments) or secondary AML (leukemia that developed after having other blood disorders like myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN)) are allowed to join.
If you had MDS, you are eligible if you received only one type of previous treatment such as hypomethylating agents (HMA), lenalidomide, luspatercept, or imetelstat.
Your ECOG performance status, which is a scale used by doctors to measure how well you can perform daily activities, must be 0, 1, or 2. A score of 0 means you are fully active, while a score of 2 means you are capable of limited self-care and light work.
You must have adequate liver function, meaning your liver enzymes (AST and ALT) and bilirubin (a yellow substance found in blood) must be within specific safe levels.
You must have adequate kidney function, measured by creatinine clearance, which is a way to check how well your kidneys filter waste from your blood.
If you have other ongoing health problems, your doctor must believe you are expected to live longer than 2 years because of those conditions.
For the Nonintensive Therapy Study, you must have a documented NPM1-m mutation and be unable to receive intensive induction chemotherapy (a strong type of cancer treatment). This includes being 75 years or older, or having health issues like congestive heart failure, certain lung issues, or kidney problems.
For the Intensive Therapy Study, you must have a documented NPM1-m or KMT2A-r mutation, but you cannot have a partial tandem duplication (PTD).
For the Intensive Therapy Study, you must have a FLT3 wild-type status (meaning no mutation) or a very low level of a specific mutation called ITD, unless you are medically unable to take FLT3 targeted therapy (medicine designed to attack specific cancer cells).
For the Intensive Therapy Study, your heart health must be good, specifically having an ejection fraction (the percentage of blood leaving your heart each time it contracts) of more than 50%.
You must agree to follow strict contraception requirements (methods to prevent pregnancy) during the study and for 180 days after your last dose.
Male participants must not donate sperm and must use highly effective birth control and barrier methods, such as condoms, during sexual activity.
Female participants must not be pregnant or breastfeeding and must use highly effective birth control or meet specific medical criteria regarding childbearing potential.
Who Cannot Join the Study?
A diagnosis of acute promyelocytic leukemia (APL), which is a specific type of blood cancer, blast phase chronic myeloid leukemia, or isolated myeloid sarcoma (a tumor made of leukemia cells outside the bone marrow).
Having an uncontrolled illness, such as:
Symptomatic congestive heart failure (CHF), which is when the heart cannot pump blood effectively, causing symptoms like shortness of breath.
Unstable angina pectoris, which is chest pain that occurs unpredictably and is not relieved by rest.
Serious cardiac arrhythmia, which refers to an irregular heartbeat.
A myocardial infarction (heart attack) that left lasting heart problems within the last 6 months.
New York Heart Association Class III or IV heart failure, which represents severe heart failure that limits daily activities or occurs even at rest.
Severe uncontrolled ventricular arrhythmias (dangerous irregular heartbeats originating in the lower heart chambers) or signs of acute ischemia (lack of blood flow to the heart).
An abnormal QTcF interval on an electrocardiogram (ECG), which is a measurement of the time it takes for the heart muscle to recharge between beats.
An uncontrolled infection.
A known severe hypersensitivity (a serious allergic reaction) to the study drugs or any of their excipients (inactive ingredients used to make the medicine).
Being pregnant or breastfeeding.
A known history of the BCR-ABL mutation, which is a specific genetic change often found in certain blood cancers.
Having other active cancers, except for certain types of skin cancer that were removed or treated, or certain prostate or breast cancers being treated with adjuvant hormonal therapy (hormone treatment given to prevent cancer from returning).
Active central nervous system (CNS) involvement, which means the leukemia has spread to the brain or spinal cord.
Signs of leukostasis (a medical emergency where too many white blood cells make the blood too thick) or a white blood cell (WBC) count higher than 25×10^9/L.
Having received prior therapy for this type of leukemia, with specific exceptions for certain treatments used to lower white blood cell counts.
Having previously received ven+HMA therapy, isocitrate dehydrogenase 1 inhibitors (a specific type of targeted medicine), or intensive chemotherapy for myelodysplastic syndromes (MDS) (a group of disorders where blood cells do not mature properly).
Known uncontrolled HIV infection or active hepatitis B (HBV) or hepatitis C (HCV) infections. Patients with a history of these must have an undetectable viral load (meaning the amount of virus in the blood is too low to be measured).
Any other significant medical condition, such as a psychiatric illness (mental health condition) or laboratory abnormality (unusual test results), that the doctor believes would make it unsafe or difficult to participate in the study.
NPM1-mutated acute myeloid leukemia – This is a type of blood cancer characterized by the presence of a specific mutation in the NPM1 gene. It involves the uncontrolled production of abnormal white blood cells in the bone marrow. As the condition progresses, these immature cells build up and crowd out healthy blood cells. This disruption interferes with the normal production of red blood cells, white blood cells, and platelets.
KMT2A-rearranged acute myeloid leukemia – This is a form of blood cancer driven by a structural change in the KMT2A gene. This genetic rearrangement causes bone marrow cells to develop abnormally. The disease progresses as these defective cells multiply rapidly and accumulate in the bone marrow and bloodstream. This accumulation prevents the body from creating enough healthy blood components.
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