Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS

NCT05342584 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 2021-13643
• Study Type: interventional
• Target: 99
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1b, open-label study evaluating Venetoclax in combination with intensive induction and consolidation chemotherapy in previously untreated, adult patients with acute myeloid leukemia. In Part 1, the dose escalation phase, the safety and tolerability of the combination with Venetoclax at different doses and duration will inform the appropriate dose(s) and regimen(s) for Part 2. In Part 2, the dose expansion phase, a maximum of 28 additional patients will be randomized 1:1 to the MTD determined in Part 1 and the starting dose (assuming the MTD is not the starting dose), to further evaluate the safety and efficacy of the study drug combination.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes

Keywords

AML; MDS; Venetoclax; Ven; 7+3; daunorubicin and cytarabine; daunorubicin; cytarabine

Outcome Measures

Primary Outcomes (8)

• Frequency and Severity of all Adverse Events (AEs) and Serious Adverse Events (SAEs)

  The number and percentage of patients with SAEs and AEs, including AEs leading to dose modifications or discontinuations, will be summarized.

  Through study completion, up to 6 years

• Frequency and Severity of AEs and SAEs by Age Group

  The number and percentage of patients with SAEs and AEs, including AEs leading to dose modifications or discontinuations, will be summarized by age group.

  Through study completion, up to 6 years

• Frequency and Severity of AEs and SAEs by Dose Level

  The number and percentage of patients with SAEs and AEs, including AEs leading to dose modifications or discontinuations, will be summarized by dose level.

  Through study completion, up to 6 years

• Rate of Non-Hematologic Dose Limiting Toxicities (DLTs)

  The rate of non-hematologic DLTs will be monitored. Non-hematologic DLTs will be defined as any Grade 3 or higher non-hematologic events occurring during the first cycle (i.e., the first 28 days) that are at least possibly attributable to Venetoclax unless the event is clearly due to extraneous causes or disease progression, confirmed Hy's law case, with the exceptions outlined in Section 4.5.1 of the study protocol. The number/percentage of patients non-hematologic DLTs will be summarized. 90% Confidence Intervals will be estimated using the Clopper-Pearson method with all available data at the Maximum Tolerated Dose (MTD) and, if relevant, for the dose level below.

  Up to 28 days during induction and 1st consolidation cycle

• Rate of Hematologic Dose Limiting Toxicities (DLTs)

  The rate of hematologic DLTs will be monitored. Hematologic DLT is defined as Grade ≥ 3 neutropenia and/or thrombocytopenia with no greater than 5% marrow blasts lasting for 6 weeks or more after the start of a course unless the delay in count recovery is due to another identifiable factor, such as documented myelosuppressive infection. Anemia will not be considered for the definition of DLT. The number/percentage of patients with hematologic DLTs will be summarized. 90% Confidence Intervals will be estimated using the Clopper-Pearson method with all available data at the MTD and, if relevant, for the dose level below.

  Up to 42 days during induction and 1st consolidation cycle

• The Number/Percentage of Patients with Dose Modifications

  The number/percentage of patients with dose modifications, as prescribed in the protocol for the 400mg and 200mg dosage, will be summarized. It should be noted that the only relevant dose modifications apply to consolidation cycles with intermediate dose cytarabine and specifically the older group cohort.

  During the 3 days of chemotherapy administration

• Maximum tolerated dose of Venetoclax in combination with Daunorubicin and Cytarabine

  To determine a safe and tolerable dose of Venetoclax in combination with Daunorubicin and Cytarabine during the induction phase.

  During induction phase, up to 14 days

• Maximum tolerated dose of Venetoclax in combination with high dose Cytarabine

  To determine a safe and tolerable dose of Venetoclax in combination high dose of Cytarabine during the consolidation phase.

  During consolidation phase, up to 7 days

Secondary Outcomes (6)

• Overall response rate (ORR)

  Through study completion, up to 6 years

• Hematologic response rate

  Through study completion, up to 6 years

• Duration of response (DoR)

  From the date of initial response, assessed up to 6 years

• Overall survival (OS)

  Through study completion, up to 6 years

• Event-free survival (EFS)

  Through study completion, up to 6 years

Other Outcomes (1)

• Rate of LSC eradication (exploratory objective)

  Through study completion, up to 6 years

Study Arms (1)

Venetoclax plus 7+3

EXPERIMENTAL

see detailed description

Drug: Venetoclax Oral Tablet; Drug: Daunorubicin; Drug: Cytarabine

Interventions

Venetoclax Oral Tablet DRUG

Given PO

Venetoclax plus 7+3

Cytarabine DRUG

Given IV

Venetoclax plus 7+3

Daunorubicin DRUG

Given IV

Venetoclax plus 7+3

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• New diagnosis of AML by WHO criteria. Patients with higher risk MDS (R-IPSS\>3.5) and 10% blasts or more, or proliferative (WBC ≥ 13 x 10⁹/L) CMML-2 are also eligible at the discretion of the PI. Patients having received any prior hypomethylating agent with or without BCL2 inhibitor therapy for MDS/AML are also eligible at the discretion of the PI
• Patients ≥ 18 to ≤ 75 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
• Adequate renal function including creatinine clearance \> 30 mL/min based on the Cockcroft Gault equation.
• Adequate hepatic function including total bilirubin \< 1.5x ULN unless increase is due to Gilbert's disease or leukemic involvement, and AST and/or ALT \< 3x 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.

You may not qualify if:

• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (FAB class M3-AML)
• Subject has known active CNS involvement with AML
• Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF \<45% 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 uncontrolled 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 10⁹/L. (Note: Hydroxyurea and/or cytarabine (up to 2 g/m\^2 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. Appropriate method(s) of contraception include oral or injectable hormonal birth control, IUD, and double barrier methods (for example a condom in combination with a spermicide).

Sponsors & Collaborators

• Montefiore Medical Center: lead
• AbbVie: collaborator
• Dana-Farber Cancer Institute: collaborator

Study Sites (1)

Montefiore Einstein Cancer Center and Children's Hospital at Montefiore (CHAM)

The Bronx, New York, 10467, United States

RECRUITING

Related Publications (1)

• Mantzaris I, Goldfinger M, Uriel M, Shastri A, Shah N, Gritsman K, Kornblum NS, Shapiro L, Sica RA, Munoz A, Chambers N, Dhawan A, Verceles JA, Fehn K, Tirone B, Shah L, Clark S, Zhang C, Kim M, Cooper DL, Verma A, Konopleva M, Feldman EJ. Venetoclax plus daunorubicin and cytarabine for newly diagnosed acute myeloid leukemia: results of a phase 1b study. Blood. 2025 Apr 24;145(17):1870-1875. doi: 10.1182/blood.2024026700.

  PMID: 39919267 RESULT

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

venetoclax; Daunorubicin; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Ioannis Mantzaris, MD

  Montefiore Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ioannis Mantzaris, MD

CONTACT

718-920-4826; imantzar@montefiore.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 19, 2022
• First Posted: April 22, 2022
• Study Start: May 25, 2022
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: January 8, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)