Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS

Sponsor

Ioannis Mantzaris (Other)

Overall Status

Recruiting

CT.gov ID

NCT05342584

Collaborator

(none)

Enrollment

Location

Arm

78.3

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase Ib 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 advanced myelodysplastic syndromes. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as daunorubicin, cytarabine 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes	Drug: Venetoclax Oral Tablet Drug: Daunorubicin Drug: Cytarabine	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To evaluate the safety and tolerability and to determine the dose-limiting toxicity and the maximum tolerated dose MTD of the combination of daunorubicin, cytarabine (7+3) + venetoclax for patients with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

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).
Evaluate ability of venetoclax with chemotherapy combination in eliminating leukemic stem cells (LSCs).

OUTLINE: This is a phase I, dose-escalation study of venetoclax in combination with intensive chemotherapy.

INDUCTION THERAPY: Patients receive venetoclax 400mg orally (PO) on days 1-8 or 1-11 or 1-14, daunorubicin IV over 15 minutes on days 2-4, cytarabine IV over 4 hours on days 2-8.

CONSOLIDATION THERAPY: Patients receive venetoclax PO on days 1-7, cytarabine IV over 2 hours every 12 hours on days 1,3 and 5. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

99 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 25, 2022

Anticipated Primary Completion Date :

Dec 1, 2028

Anticipated Study Completion Date :

Dec 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Venetoclax plus 7+3 see detailed description	Drug: Venetoclax Oral Tablet Given PO Drug: Daunorubicin Given IV Drug: Cytarabine Given IV

Arm

Intervention/Treatment

Experimental: Venetoclax plus 7+3

see detailed description

Drug: Venetoclax Oral Tablet

Given PO

Drug: Daunorubicin

Given IV

Drug: Cytarabine

Given IV

Outcome Measures

Primary Outcome Measures

Frequency and severity of adverse events (AEs) [Through study completion, up to 6 years]
To characterize the safety profile (incidence of AEs) and dose-limiting toxicities (DLTs) of Venetoclax in combination with Daunorubicin and Cytarabine
Maximum tolerated dose of Venetoclax in combination with Daunorubicin and Cytarabine [Through study completion, up to 6 years]
To determine a safe and tolerable dose of Venetoclax in combination with Daunorubicin and Cytarabine during induction
Maximum tolerated dose of Venetoclax in combination with high dose cytarabine [Through study completion, up to 6 years]
To determine a safe and tolerable dose of Venetoclax in combination high dose of Cytarabine during consolidation

Secondary Outcome Measures

Overall response rate (ORR) [Through study completion, up to 6 years]
Defined as complete response (CR) + CR with incomplete blood count recovery (CRi) + partial response (PR). Will be estimated along with the 95% credible interval.
Hematologic response rate [Through study completion, up to 6 years]
Will be estimated along with the 95% credible interval
Duration of response [From the date of initial response, assessed up to 6 years]
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. Will be calculated for all patients.
Overall survival [Through study completion, up to 6 years]
Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients.
Event-free survival [Through study completion, up to 6 years]
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.
Morphologic leukemia-free state [Through study completion, up to 6 years]
Will be estimated along with the 95% credible interval.

Other Outcome Measures

Rate of LSC eradication (exploratory objective) [Through study completion, up to 6 years]
The depth of remission will be evaluated with exploratory analyses of LSC MRD negativity by flow cytometry and single cell sequencing.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

New diagnosis of AML by WHO criteria. Patients with higher risk MDS (R-IPSS>3.5) and 10% blasts or more 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 (1 or 2 doses; up to 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).