Induction and consolidation using fludarabine, cytarabine, idarubicin, and venetoclax for acute myeloid leukemia

A Phase II Randomized Clinical Trial of Venetoclax Combined With FLAG IDA Induction and Consolidation Compared to Standard of Care for Newly Diagnosed Patients With Acute Myeloid Leukemia

This trial tests whether adding venetoclax to induction and consolidation chemotherapy (fludarabine, cytarabine, and idarubicin) helps adults 18–65 with newly diagnosed acute myeloid leukemia or high-blast myelodysplastic syndrome achieve deeper remissions than standard cytarabine/daunorubicin therapy.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 102 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: OHSU Knight Cancer Institute (Academic / other)
• Drugs / interventions: chemotherapy, fludarabine
• Locations: 1 site (Portland, Oregon)
• Trial ID: NCT07228273 on ClinicalTrials.gov

What this trial studies

This Phase II interventional trial gives participants an induction and consolidation regimen that pairs fludarabine, cytarabine, idarubicin with the oral BCL-2 inhibitor venetoclax and compares outcomes to a standard cytarabine/daunorubicin induction with cytarabine consolidation. The primary endpoint is the rate of composite complete remission without measurable residual disease (CRc-MRD-) measured by multiparameter flow cytometry, with secondary endpoints including overall response, safety, survival, and transplant-related outcomes. The protocol includes serial bone marrow biopsies/aspirates and biospecimen collection to assess MRD depth and compare MRD detection methods. Participants who achieve remission may be referred for hematopoietic stem cell transplant, and post-transplant infection, GVHD, and relapse are tracked.

Who should consider this trial

Good fit: Adults aged 18 to 65 with newly diagnosed, previously untreated AML or MDS with ≥10% marrow blasts, ECOG 0–1, adequate organ function, ability to take oral medication, and willingness to consider HSCT are eligible.

Not a fit: Patients older than 65, those with poor performance status, significant organ dysfunction, prior AML treatment, or inability/unwillingness to undergo HSCT or take oral medications are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the regimen could produce deeper MRD-negative remissions that increase the chance of durable remission and improve outcomes after stem cell transplant.

How similar studies have performed: Early-phase studies combining venetoclax with intensive chemotherapy have shown promising remission and MRD-negative rates, but confirmatory randomized Phase III evidence is limited.

Eligibility criteria

Inclusion Criteria:

* Ability to comprehend the investigational nature of the study and provide written informed consent
* Age 18 to ≤ 65 years (yrs), at the time of consent
* All gender identities, races, or ethnicities are eligible
* Newly documented, previously untreated diagnosis of AML or myelodysplastic syndrome (MDS) with marrow blasts ≥ 10%, in agreement with 2022 European LeukemiaNet criteria (ELN22)

  * Leukapheresis and treatment with cytarabine or hydroxyurea prior to study initiation is permitted for cytoreduction in patients with proliferative disease. NOTE: Treatment with cytarabine is limited to up to 2 grams total at least 14 days prior to starting on protocol defined therapy
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Willingness to undergo hematopoietic stem cell transplant (HSCT)
* Ability to take medications by mouth or feeding tube
* Adequate hematologic and organ function
* Institutional standards, New York Heart Association (NYHA) criteria for cardiac function
* Calculated creatinine clearance (according to the Cockcroft-Gault equation) \> 40 mL/min
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 3 x upper limit of normal (ULN), unless considered due to leukemic involvement
* Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x ULN, unless considered due to leukemic involvement
* Total bilirubin ≤ 1.5 x ULN, unless due to Gilbert's disease or leukemic involvement
* Willing and able to

  * Adhere to study schedule of activities and lifestyle restrictions while on treatment;
  * Provide bone marrow (BM) aspirate and core biopsy samples; AND
  * Accept supportive and prophylactic care for hematologic toxicities, infection, and immediate sequelae, including transfusions
* Negative pregnancy test within 3 days of start of treatment for persons of childbearing potential (PCBP)
* Based on animal studies and the known pharmacology of the study drugs, PCBP and sperm-producing participants who are sexually active with a PCBP must comply with study requirements for contraception

  * PCBP (participants and PCBP partners of participants) must agree to use an approved contraception and to refrain from donating / cryopreserving ova from cycle (C) 1 day (D) 1 until 6 months following the last dose of study treatment
  * Participants who produce viable sperm and who have intercourse with PCBP must agree to use an approved contraception method and to refrain from donating sperm from C1D1 until 3 months following the last dose of study treatment

Exclusion Criteria:

* Documented t(15;17) (acute promyelocytic leukemia \[APL\]), and/or mutation(s) to FLT3 ITD or core binding factor (CBF). Point mutations within the tyrosine kinase domain (FLT3 TKD) are allowed
* Another active malignancy within the previous 5 years, except treated early stage carcinomas of the skin, or at the investigator's discretion
* Known, active central nervous system (CNS) involvement with AML
* Recent and significant medical interventions, such as major surgery within 28 days of start of treatment
* GVHD or autologous stem cell transplant within 100 days of start of treatment
* Currently receiving investigational therapy or chemotherapy within 28 days, or 5 half-lives, whichever is longer, with the exception of hydroxyurea or cytarabine for cytoreduction purposes
* Prior treatment with a BCL 2 inhibitor within 12 months prior to the start of treatment
* Use of strong or moderate CYP3A4 inducers or inhibitors or P-gp inhibitors within 2 days or 3 half-lives, whichever is longer, prior to start of treatment with venetoclax or at the discretion of the investigator if dose reductions, based on the interaction, have been specified
* History of allergic response to any of the interventional agents or any excipients in the formulations
* Inadequate organ function, including the following (or at the discretion of the investigator):

  * History of New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) \< 40% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
  * Unstable/uncontrolled angina pectoris, history of severe and/or uncontrolled ventricular arrhythmias, or history of myocardial infarction within the last 6 months
  * A white blood cell count (WBC) \> 25 x 10\^⁹/L
* Known dysphagia in the absence of a feeding tube, short-gut syndrome, or other conditions or causes that would affect the ingestion and/or gastrointestinal absorption of drugs administered orally
* Active hepatic disorder or documented positive hepatitis B or C virus (HBV/HCV, respectively) status, except in cases of undetectable HBV/HCV viral load for at least 3 months prior to the start of treatment. (Hepatitis B or C testing is not required for eligibility assessment.)
* Individuals with positive serology for human immunodeficiency virus (HIV) who are undergoing treatment with highly active antiretroviral therapy (HAART) (or another therapy that may interfere with metabolism of study agents) are not eligible. If the HIV infection is controlled with another medication type or if an acceptable alternative HIV treatment can be substituted for HAART, enrollment may proceed
* Uncontrolled infection. Participants with controlled infection must be afebrile and hemodynamically stable for at least 72 hours prior to start of treatment and must be amenable to alternate treatment if current treatment will interact with investigational regimen
* Psychiatric illness/social situations that would limit compliance with study requirements
* Unwillingness to stop breastfeeding. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding is not allowed throughout the study for 6 weeks after the last dose of study drug

Where this trial is running

Portland, Oregon

• OHSU Knight Cancer Institute — Portland, Oregon, United States (Recruiting)

Study contacts

• Principal investigator: Curtis A Lachowiez — OHSU Knight Cancer Institute

Conditions Acute Myeloid Leukemia; Myelodysplastic Syndrome