Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS

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

Overview

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:

I. 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:

I. 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:

I. 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.

A. 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

B. Patients aged \> 60 years

Expansion Cohort 1B:

Interventions

• Drug Venetoclax Oral Tablet
  Given PO
• Drug Daunorubicin
  Given IV
• Drug Cytarabine
  Given IV

Primary outcome measures

• Frequency and Severity of all Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time frame: Through study completion, up to 6 years]
• Frequency and Severity of AEs and SAEs by Age Group [Time frame: Through study completion, up to 6 years]
• Frequency and Severity of AEs and SAEs by Dose Level [Time frame: Through study completion, up to 6 years]
• Rate of Non-Hematologic Dose Limiting Toxicities (DLTs) [Time frame: Up to 28 days during induction and 1st consolidation cycle]
• Rate of Hematologic Dose Limiting Toxicities (DLTs) [Time frame: Up to 42 days during induction and 1st consolidation cycle]
• The Number/Percentage of Patients with Dose Modifications [Time frame: During the 3 days of chemotherapy administration]
• Maximum tolerated dose of Venetoclax in combination with Daunorubicin and Cytarabine [Time frame: During induction phase, up to 14 days]
• Maximum tolerated dose of Venetoclax in combination with high dose Cytarabine [Time frame: During consolidation phase, up to 7 days]

Secondary outcome measures (6)

• 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]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Montefiore Einstein Cancer Center and Children's Hospital at Montefiore (CHAM) — The Bronx

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: PMID 39919267

Identifiers

NCT: NCT05342584 · 2021-13643

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗