Acute Myeloid LeukemiaPhase 1Venetoclax AMLNCT05342584
Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS
A Phase 1 study testing Venetoclax Oral Tablet, Daunorubicin and Cytarabine in people with Acute Myeloid Leukemia and Myelodysplastic Syndromes, run by Montefiore Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Acute Myeloid Leukemia, Myelodysplastic Syndromes
- What is being tested?
- Venetoclax Oral Tablet, Daunorubicin and Cytarabine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 99 participants
- Where
- 1 siteUnited States
- Study dates
- 25 May 2022to Dec 2028
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Montefiore Einstein Cancer Center and Children's Hospital at Montefiore (CHAM)
The Bronx, New York, 10467
Ioannis Mantzaris, MD, 718-920-4826, imantzar@montefiore.org
Amit K Verma, MD, 718-430-2205
About this study
Official title: Phase 1B Study of Venetoclax in Combination With Standard Intensive Chemotherapy With Daunorubicin Plus Cytarabine Followed by High-Dose Cytarabine in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia and Advanced Myelodysplastic Syndrome
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.
Read the detailed description
PRIMARY OBJECTIVE:
- To evaluate the safety and tolerability and determine the dose-limiting toxicity and the maximum tolerated dose (MTD) of the combination of daunorubicin \& cytarabine chemotherapy plus Venetoclax for patients with AML
SECONDARY OBJECTIVES:
- To assess efficacy by response per 2022 ELN and revised International Working Group (IWG) criteria.
II. To determine additional response parameters: CR/CRi and CR/CRh rates.
III. To determine time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR)
EXPLORATORY OBJECTIVES:
- To assess MRD eradication by targeted duplex sequencing
II. To assess rates of LSC eradication by means of MFC and single cell sequencing, as well as a novel assay that uses an extended leukemia-specific NGS panel for measuring MRD in cfDNA and BM ("high resolution MRD assay")
III. To comprehensively analyze the clonal architectural and transcriptomic shifts in residual LSC under therapy
IV. To determine the protein expression of BCL-2 family members and the reliance of leukemic cells on differing members of the BH3 family at the time of diagnosis and relapse and explore association of such observations with response to Venetoclax when combined with chemotherapy
Induction Phase
Dose Escalation Cohorts:
A minimum of 3 patients will be treated in each cohort (dose level) sequentially in a 3+3 design. Patients will receive the Venetoclax plus daunorubicin/cytarabine combination as shown below
Patients aged ≤ 60 years
Cohort 1A:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Cohort 2A:
Daunorubicin 90mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Cohort 3A:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-11
Cohort 4A:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-14
Note: No DLTs in induction phase have been observed and Cohort 3A has completed enrollment. However, the daunorubicin dose of 90mg/m2 will not be further studied due to recently reported results of no superiority over the dose of 60mg/m2.
Patients >60 years
Cohort 1B:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Cohort 2B:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-11
Cohort 3B:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-14
Expansion Cohort(s):
A maximum of 28 additional patients aged ≤ 60 years and 28 patients >60 years will be randomized (1:1) to the MTD the starting dose (assuming the MTD is not the starting dose), to further evaluate safety and efficacy of the study drug combination and identify the optimal phase 2 dose.
- Patients aged ≤ 60 years
Expansion Cohort 1A:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2-4 Cytarabine 100mg/m2 IV daily on Days 2-8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Expansion Cohort 2A:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2-4 Cytarabine 100mg/m2 IV daily on Days 2-8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-14
- Patients aged > 60 years
Expansion Cohort 1B:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2 to 4 Cytarabine 100mg/m2 IV daily on Days 2 to 8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Day 3 and until Day 8
Expansion Cohort 2B:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2 to 4 Cytarabine 100mg/m2 IV daily on Days 2 to 8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Day 3 and until Day 14
Consolidation Phase:
Patients who achieve CRc post induction will proceed to consolidation therapy with intermediate-dose cytarabine in combination with escalating doses of Venetoclax. The 3+3 algorithm will be applied for dose escalation/de-escalation of Venetoclax in combination with Cytarabine. As of February 2023, there have been 2/6 hematologic DLTs in consolidation cohort 1B, therefore Venetoclax was not given in combination with intermediate-dose cytarabine during the consolidation phase, in pts >60 yrs of age, during the dose-escalation phase of the study. In addition, dose escalation of Venetoclax during consolidation in the 60-year-old or younger age-group before RP2D of induction is determined will not be explored. All subjects ≤ 60yrs will be treated at the consolidation Cohort 1A dose.
In the expansion phase, Venetoclax, at the dose of 200mg daily, will be re-introduced in combination with chemotherapy, albeit at a shorter than a 7-day duration; the consolidation regimen for patients older than 60 years of age will consist of cytarabine at the dose of 0.5-1g/m2 every 12 hours on days 1, 3, 5 or days 1, 2, 3 (per ELN 2022 guidelines) plus Venetoclax 200mg for 5 days.
Patients ≤ 60 years
Consolidation cohort 1A:
Cytarabine 1-1.5g/m2 every 12 hours on Days 1, 3, 5 OR days 1, 2, 3; Venetoclax 200mg on Days 1-7
Patients >60 years
Consolidation cohort 1B:
Cytarabine 0.5-1g/m2 every 12 hours on days 1, 3, 5 OR days 1, 2, 3; Venetoclax 200mg on Days 1-5
A minimum of 3 patients will be treated in each cohort (dose level) sequentially in a 3+3 design. Additional 3 subjects may be backfilled to lower dose levels so that each cohort will reach a total of 6 subjects. Once the MTD is reached, a maximum of 28 additional patients will be randomized 1:1 to the MTD or a dose level below the MTD the starting dose (assuming the MTD is not the starting dose) for a total of up to 20 patients (6 from Part 1, 20 from Part 2) treated at each of those dose levels. A maximum of 52 patients (including backfill and expansion cohorts) 60 years or younger and 46 patients older than 60 years may be enrolled in this Phase 1b study.
Patients will receive 1-2 cycles of induction chemotherapy as described above. No dose adjustment of daunorubicin or cytarabine will be allowed during first induction, but may be required in second induction as described in the dose adjustment guidelines for renal insufficiency or liver dysfunction in the study protocol. Patients who do not achieve CR/CRi after a second induction will be taken off protocol and will be treated per treating physician's discretion. Patients who achieve CRc will proceed to consolidation therapy with intermediate-dose cytarabine in combination with escalating doses of Venetoclax (200-400mg) for up to four 28(-42)-day cycles, as described above (complete dose adjustment guidelines are outlined in the study protocol); consolidation with allogeneic transplantation off protocol is allowed per physician's discretion. The 3+3 algorithm will be applied for dose escalation/de-escalation of Venetoclax in combination with intermediate-dose cytarabine.
All participants should undergo response evaluations between Day 28 and Day 42 of first and/or second induction course. Unless there is clear evidence of progressive disease in the blood, bone marrow aspiration is required and bone marrow biopsy is strongly encouraged. In cases with hypocellular marrows (<10% cellularity), repeat bone marrow examinations should be considered when there is evidence of hematopoietic recovery. If multiple bone marrow examinations are performed, the last examination will be used to classify the patient's response. The final response will be determined no later than day 42 from the start of therapy.
- Conditions
- Acute Myeloid Leukemia, Myelodysplastic Syndromes
- Being tested
- Venetoclax Oral Tablet, Daunorubicin, Cytarabine
- Keywords
- AML, MDS, Venetoclax, Ven, 7+3, daunorubicin and cytarabine, daunorubicin, cytarabine
- Medical subject headings
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Venetoclax Oral TabletDrug
Given PO
DaunorubicinDrug
Given IV
CytarabineDrug
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Venetoclax plus 7+3 | Experimental | see detailed description Receives: Drug: Venetoclax Oral Tablet; Drug: Daunorubicin; Drug: Cytarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: During consolidation phase, up to 7 days
Secondary outcomes (6)
Overall response rate (ORR)
ORR is defined as the number/percentage of patients who achieve a complete response (CR), complete response with incomplete count recovery (CRi), or partial response (PR) to treatment. ORR will be summarized by the formula: complete response (CR) + CR with incomplete blood count recovery (CRi) + partial response (PR). The number/percentage of patients will be summarized along with the 95% credible interval.
Measured: Through study completion, up to 6 years
Hematologic response rate
Hematologic Response rate will be defined by the number/percentage of participants demonstrating improvement in hematologic parameters that do not meet criteria for Partial Response (PR) (i.e., transfusion independence and /or decline in incidence of febrile neutropenia and related hospitalizations) based on the 2022 ELN recommendations and revised IWG response criteria for AML. The number/percentage of patients will be summarized along with a 95% confidence interval.
Measured: Through study completion, up to 6 years
Duration of response (DoR)
DoR is defined as the number of days from the date of initial response (CRi or better) to the date of first documented disease progression/relapse or death, whichever occurs first. DoR will be calculated for all patients.
Measured: From the date of initial response, assessed up to 6 years
Overall survival (OS)
OS is defined as the duration of time from treatment initiation until a patient's death from any cause. OS will be estimated using Kaplan-Meier methods.
Measured: Through study completion, up to 6 years
Event-free survival (EFS)
EFS is 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. EFS will be calculated for all patients. In the event that neither disease progression nor death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, these endpoints will be censored at the date of last tumor assessment date. EFS will be estimated using Kaplan-Meier methods.
Measured: Through study completion, up to 6 years
Morphologic leukemia-free state (MLFS)
MLFS is the duration of time that patients maintain a state of remission based on specific bone marrow and blood criteria. For this study it will be defined as the patient having a morphologic leukemia-free state of CRMRD-, CRiMRD-, CRhMRD- without minimal residual disease. MLFS will be calculated using Kaplan-Meier methods along with the 95% confidence interval.
Measured: Through study completion, up to 6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Apr 2022
- Study start25 May 2022
- Primary completionDec 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- More trials run by Montefiore Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 99 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Montefiore Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- AbbVie, Dana-Farber Cancer Institute
- Responsible party
- Sponsor
- Investigators
- Ioannis Mantzaris, MD, Principal investigator, Montefiore Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05342584
- Sponsor's protocol ID
- 2021-13643
- Acronym
- Venetoclax AML
- Status last verified
- Jan 2026
- First submitted
- 19 Apr 2022
- Last updated
- 8 Jan 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 39919267
Study at a glance
From the registry record, last updated by the sponsor on 8 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1B Study of Venetoclax in Combination With Standard Intensive Chemotherapy With Daunorubicin Plus Cytarabine Followed by High-Dose Cytarabine in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia and Advanced Myelodysplastic Syndrome
- ClinicalTrials.gov ID
- NCT05342584
- Acronym / sponsor ID
- Venetoclax AML / 2021-13643
- Conditions
- Acute Myeloid Leukemia, Myelodysplastic Syndromes
- Keywords
- AML, MDS, Venetoclax, Ven, 7+3, daunorubicin and cytarabine, daunorubicin, cytarabine
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 99 participants (estimated)
- Lead sponsor
- Montefiore Medical CenterUniversity, hospital or other
- Collaborators
- AbbVie, Dana-Farber Cancer Institute
- Study start
- 25 May 2022 (actual)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 22 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVE:
- To evaluate the safety and tolerability and determine the dose-limiting toxicity and the maximum tolerated dose (MTD) of the combination of daunorubicin \& cytarabine chemotherapy plus Venetoclax for patients with AML
SECONDARY OBJECTIVES:
- To assess efficacy by response per 2022 ELN and revised International Working Group (IWG) criteria.
II. To determine additional response parameters: CR/CRi and CR/CRh rates.
III. To determine time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR)
EXPLORATORY OBJECTIVES:
- To assess MRD eradication by targeted duplex sequencing
II. To assess rates of LSC eradication by means of MFC and single cell sequencing, as well as a novel assay that uses an extended leukemia-specific NGS panel for measuring MRD in cfDNA and BM ("high resolution MRD assay")
III. To comprehensively analyze the clonal architectural and transcriptomic shifts in residual LSC under therapy
IV. To determine the protein expression of BCL-2 family members and the reliance of leukemic cells on differing members of the BH3 family at the time of diagnosis and relapse and explore association of such observations with response to Venetoclax when combined with chemotherapy
Induction Phase
Dose Escalation Cohorts:
A minimum of 3 patients will be treated in each cohort (dose level) sequentially in a 3+3 design. Patients will receive the Venetoclax plus daunorubicin/cytarabine combination as shown below
Patients aged ≤ 60 years
Cohort 1A:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Cohort 2A:
Daunorubicin 90mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Cohort 3A:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-11
Cohort 4A:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-14
Note: No DLTs in induction phase have been observed and Cohort 3A has completed enrollment. However, the daunorubicin dose of 90mg/m2 will not be further studied due to recently reported results of no superiority over the dose of 60mg/m2.
Patients >60 years
Cohort 1B:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Cohort 2B:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-11
Cohort 3B:
Daunorubicin 60mg/m2 IV daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-14
Expansion Cohort(s):
A maximum of 28 additional patients aged ≤ 60 years and 28 patients >60 years will be randomized (1:1) to the MTD the starting dose (assuming the MTD is not the starting dose), to further evaluate safety and efficacy of the study drug combination and identify the optimal phase 2 dose.
- Patients aged ≤ 60 years
Expansion Cohort 1A:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2-4 Cytarabine 100mg/m2 IV daily on Days 2-8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
Expansion Cohort 2A:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2-4 Cytarabine 100mg/m2 IV daily on Days 2-8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-14
- Patients aged > 60 years
Expansion Cohort 1B:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2 to 4 Cytarabine 100mg/m2 IV daily on Days 2 to 8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Day 3 and until Day 8
Expansion Cohort 2B:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2 to 4 Cytarabine 100mg/m2 IV daily on Days 2 to 8 Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Day 3 and until Day 14
Consolidation Phase:
Patients who achieve CRc post induction will proceed to consolidation therapy with intermediate-dose cytarabine in combination with escalating doses of Venetoclax. The 3+3 algorithm will be applied for dose escalation/de-escalation of Venetoclax in combination with Cytarabine. As of February 2023, there have been 2/6 hematologic DLTs in consolidation cohort 1B, therefore Venetoclax was not given in combination with intermediate-dose cytarabine during the consolidation phase, in pts >60 yrs of age, during the dose-escalation phase of the study. In addition, dose escalation of Venetoclax during consolidation in the 60-year-old or younger age-group before RP2D of induction is determined will not be explored. All subjects ≤ 60yrs will be treated at the consolidation Cohort 1A dose.
In the expansion phase, Venetoclax, at the dose of 200mg daily, will be re-introduced in combination with chemotherapy, albeit at a shorter than a 7-day duration; the consolidation regimen for patients older than 60 years of age will consist of cytarabine at the dose of 0.5-1g/m2 every 12 hours on days 1, 3, 5 or days 1, 2, 3 (per ELN 2022 guidelines) plus Venetoclax 200mg for 5 days.
Patients ≤ 60 years
Consolidation cohort 1A:
Cytarabine 1-1.5g/m2 every 12 hours on Days 1, 3, 5 OR days 1, 2, 3; Venetoclax 200mg on Days 1-7
Patients >60 years
Consolidation cohort 1B:
Cytarabine 0.5-1g/m2 every 12 hours on days 1, 3, 5 OR days 1, 2, 3; Venetoclax 200mg on Days 1-5
A minimum of 3 patients will be treated in each cohort (dose level) sequentially in a 3+3 design. Additional 3 subjects may be backfilled to lower dose levels so that each cohort will reach a total of 6 subjects. Once the MTD is reached, a maximum of 28 additional patients will be randomized 1:1 to the MTD or a dose level below the MTD the starting dose (assuming the MTD is not the starting dose) for a total of up to 20 patients (6 from Part 1, 20 from Part 2) treated at each of those dose levels. A maximum of 52 patients (including backfill and expansion cohorts) 60 years or younger and 46 patients older than 60 years may be enrolled in this Phase 1b study.
Patients will receive 1-2 cycles of induction chemotherapy as described above. No dose adjustment of daunorubicin or cytarabine will be allowed during first induction, but may be required in second induction as described in the dose adjustment guidelines for renal insufficiency or liver dysfunction in the study protocol. Patients who do not achieve CR/CRi after a second induction will be taken off protocol and will be treated per treating physician's discretion. Patients who achieve CRc will proceed to consolidation therapy with intermediate-dose cytarabine in combination with escalating doses of Venetoclax (200-400mg) for up to four 28(-42)-day cycles, as described above (complete dose adjustment guidelines are outlined in the study protocol); consolidation with allogeneic transplantation off protocol is allowed per physician's discretion. The 3+3 algorithm will be applied for dose escalation/de-escalation of Venetoclax in combination with intermediate-dose cytarabine.
All participants should undergo response evaluations between Day 28 and Day 42 of first and/or second induction course. Unless there is clear evidence of progressive disease in the blood, bone marrow aspiration is required and bone marrow biopsy is strongly encouraged. In cases with hypocellular marrows (<10% cellularity), repeat bone marrow examinations should be considered when there is evidence of hematopoietic recovery. If multiple bone marrow examinations are performed, the last examination will be used to classify the patient's response. The final response will be determined no later than day 42 from the start of therapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Venetoclax plus 7+3 | Experimental | Drug: Venetoclax Oral Tablet, Drug: Daunorubicin, Drug: Cytarabinesee detailed description |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Venetoclax Oral TabletGiven PO | Drug | Venetoclax plus 7+3 |
| DaunorubicinGiven IV | Drug | Venetoclax plus 7+3 |
| CytarabineGiven IV | Drug | Venetoclax plus 7+3 |
Primary outcome
Frequency and Severity of all Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Through study completion, up to 6 years
The number and percentage of patients with SAEs and AEs, including AEs leading to dose modifications or discontinuations, will be summarized.
Frequency and Severity of AEs and SAEs by Age Group
Time frame: Through study completion, up to 6 years
The number and percentage of patients with SAEs and AEs, including AEs leading to dose modifications or discontinuations, will be summarized by age group.
Frequency and Severity of AEs and SAEs by Dose Level
Time frame: Through study completion, up to 6 years
The number and percentage of patients with SAEs and AEs, including AEs leading to dose modifications or discontinuations, will be summarized by dose level.
Rate of Non-Hematologic Dose Limiting Toxicities (DLTs)
Time frame: Up to 28 days during induction and 1st consolidation cycle
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.
Rate of Hematologic Dose Limiting Toxicities (DLTs)
Time frame: Up to 42 days during induction and 1st consolidation cycle
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.
The Number/Percentage of Patients with Dose Modifications
Time frame: During the 3 days of chemotherapy administration
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.
Maximum tolerated dose of Venetoclax in combination with Daunorubicin and Cytarabine
Time frame: During induction phase, up to 14 days
To determine a safe and tolerable dose of Venetoclax in combination with Daunorubicin and Cytarabine during the induction phase.
Maximum tolerated dose of Venetoclax in combination with high dose Cytarabine
Time frame: During consolidation phase, up to 7 days
To determine a safe and tolerable dose of Venetoclax in combination high dose of Cytarabine during the consolidation phase.
6 secondary outcomes
Overall response rate (ORR)
Time frame: Through study completion, up to 6 years
Hematologic response rate
Time frame: Through study completion, up to 6 years
Duration of response (DoR)
Time frame: From the date of initial response, assessed up to 6 years
Overall survival (OS)
Time frame: Through study completion, up to 6 years
Event-free survival (EFS)
Time frame: Through study completion, up to 6 years
Morphologic leukemia-free state (MLFS)
Time frame: Through study completion, up to 6 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jan 2026.
- Results publication: PubMed 39919267Mantzaris 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Ioannis Mantzaris, MD principal investigator
Montefiore Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Venetoclax Oral Tablet, Daunorubicin and Cytarabine in people with Acute Myeloid Leukemia and Myelodysplastic Syndromes, run by Montefiore Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 8 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Ioannis Mantzaris, MD (718-920-4826, imantzar@montefiore.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Frequency and Severity of all Adverse Events (AEs) and Serious Adverse Events (SAEs) (time frame: Through study completion, up to 6 years). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05342584, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jan 2026.