Venetoclax With Combination Chemotherapy in Treating Patients With Newly Diagnosed or Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive AML Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory AML

This phase Ib/II trial studies the best dose and side effects of venetoclax and how well it works when given with combination chemotherapy in treating patients with newly diagnosed acute myeloid leukemia or acute myeloid leukemia that has come back or does not respond to treatment. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine, cytarabine, filgrastim and idarubicin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with combination chemotherapy may work better in treating patients with acute myeloid leukemia.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; High Risk Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Cytarabine; Drug: Venetoclax; Drug: Fludarabine; Biological: Pegfilgrastim; Biological: Filgrastim; Drug: Idarubicin

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability and to determine the dose-limiting toxicity and the maximum tolerated dose MTD of the combination of fludarabine, cytarabine, filgrastim (GCSF), idarubicin (FLAG-IDA) + venetoclax for patients with acute myeloid leukemia (AML) (Phase 1b).

II. To determine the overall activity of this combination in patients newly diagnosed or relapsed/refractory (AML) (Phase 2).

SECONDARY OBJECTIVES:

I. Determine the preliminary assessment of efficacy by response to revised International Working Group (IWG) criteria and time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR).

II. Determine biomarkers that may be predictive of venetoclax activity.

OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.

INDUCTION THERAPY: Patients receive venetoclax orally (PO) on days 1-14, fludarabine intravenously (IV) over 30 minutes on days 2-6, cytarabine IV over 4 hours on days 2-6, idarubicin IV over 15-30 minutes on days 4 and 5, filgrastim subcutaneously (SC) on days 1-7, or pegfilgrastim SC after day 5. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY: Patients receive venetoclax PO on days 1-7, fludarabine IV over 30 minutes on days 2-4, cytarabine IV over 4 hours on days 2-4, filgrastim SC on days 1-7, or pegfilgrastim SC after days 3. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive idarubicin as in Induction Therapy during 1 cycle of Consolidation Therapy per the treating physician.

MAINTENANCE THERAPY: Patients receive venetoclax PO on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days.

• Study Type: Interventional
• Enrollment (Estimated): 116
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: DiNardo, MD; Phone Number: (713) 794-1141; Email: cdinardo@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: Courtney DiNardo; Phone Number: 713-794-1141; Email: cdinardo@mdanderson.org
      • Principal Investigator: Courtney DiNardo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of AML by World Health Organization (WHO) criteria. Patients with high risk myelodysplastic syndrome (MDS) as defined by the presence of >= 10% blasts are also eligible at the discretion of the principal investigator
• Patients older than 65 who are deemed fit to receive intensive chemotherapy by the treating physician will be eligible after discussion with the principal investigator (PI).
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault equation
• Total bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement
• Ability to understand and provide signed informed consent
• Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug
• Only patients who are relapsed, refractory, or intolerant of standard AML therapy will be eligible for Part 1 (minimum of 1 prior line of AML-directed therapy)

Exclusion Criteria:

• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
• Patients having received any prior BCL2 inhibitor therapy
• Subject has known active central nervous system (CNS) involvement with AML
• Patients with New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram or multi-gated acquisition (MUGA) scan
• Patients with a history of myocardial infarction within the last 6 months or unstable / uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
• Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
• Patients with known dysphagia, short-gut syndrome, or other conditions that would affect the ingestion or gastrointestinal absorption of drugs administered orally
• Subject has any other significant medical or psychiatric history that in the opinion of the investigator would adversely affect participation in this study
• Subject has a white blood cell count > 25 x 10{9}/L. (Note: hydroxyurea is permitted to meet this criterion)
• Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (a) appropriate method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (venetoclax, FLAG-IDA); See detailed description.

Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Biological: Pegfilgrastim; Given SC; Other Names: Filgrastim SD-01; filgrastim-SD/01; Fulphila; HSP-130; Jinyouli; Neulasta; Neulastim; Pegfilgrastim Biosimilar HSP-130; Pegfilgrastim Biosimilar Pegcyte; Pegfilgrastim-jmdb; SD-01; SD-01 sustained duration G-CSF; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Drug: Idarubicin; Given IV; Other Names: 4-Demethoxydaunomycin; 4-DMDR; 4-Demethoxydaunorubicin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	Defined as complete response (CR) + CR with incomplete blood count recovery (CRi) + partial response (PR). Will be estimated along with the 95% credible interval.	Up to 6 years
CR/CRi rate	Will be estimated along with the 95% credible interval.	Up to 6 years
Hematologic response	Will be estimated along with the 95% credible interval.	Up to 6 years
Duration of response	Defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first. Will be calculated for all patients.	From the date of initial response, assessed up to 6 years
Event-free survival	Defined as the number of days from the date of treatment initiation (i.e., course 1 day 1) to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first. Will be calculated for all patients. Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients.	From the date of treatment initiation, assessed up to 6 years
Overall survival	Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients.	Up to 6 years
Anti-tumor activity	Will be summarized graphically and with descriptive statistics.	Up to 6 years
Pharmacodynamic markers	Two samples t-test /Wilcoxon rank sum tests will be used to compare pharmacodynamics/pharmacokinetics (PD/PK) parameters between responder and non-responders, and logistic regression analysis will also be used to evaluate the association of PD/PK parameters with response.	Up to 6 years
Drug exposure levels	Will be summarized graphically and with descriptive statistics.	Up to 6 years
Overall incidence and severity of all adverse events	Graded using Common Toxicity Criteria version 4.0. Safety data will be summarized using frequency and percentage, by category and severity.	Up to 6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morphologic leukemia-free state	Will be estimated along with the 95% credible interval.	Up to 6 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory biomarkers	Will be summarized graphically and with descriptive statistics. Peripheral blood and bone marrow aspirate samples will be obtained at study specified time points. Biomarker assays may include, but are not limited to, BH3 profiling and characterization of BCL-2 and related proteins, and assessment of the depth of response and monitoring of disease recurrence by assessment of minimal residual disease (MRD) in the bone marrow.	Up to 6 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Courtney DiNardo, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• DiNardo CD, Jen WY, Takahashi K, Kadia TM, Loghavi S, Daver NG, Xiao L, Reville PK, Issa GC, Short NJ, Sasaki K, Wang SA, Mullin JK, Pierce S, Bradley C, Borthakur G, Maiti A, Alvarado Y, Pemmaraju N, Ferrajoli A, Swaminathan M, Ohanian M, Abbas HA, Hammond D, Burger J, Haddad F, Montalban-Bravo G, Chien K, Masarova L, Yilmaz M, Jain N, Andreeff M, Garcia-Manero G, Kornblau S, Ravandi F, Jabbour E, Konopleva MY, Kantarjian HM. Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia. Leukemia. 2025 Apr;39(4):854-863. doi: 10.1038/s41375-025-02531-8. Epub 2025 Feb 25. Erratum In: Leukemia. 2026 Jan;40(1):262. doi: 10.1038/s41375-025-02827-9.

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2017
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: July 10, 2017
• First Submitted That Met QC Criteria: July 10, 2017
• First Posted (Actual): July 11, 2017

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Intercellular Signaling Peptides and Proteins; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Daunorubicin; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Cytarabine; Idarubicin; fludarabine; venetoclax; Granulocyte Colony-Stimulating Factor; Filgrastim; pegfilgrastim
• Other Study ID Numbers: 2016-0979 (Other Identifier: M D Anderson Cancer Center); NCI-2018-01119 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No