Testing the Effects of Novel Therapeutics for Newly Diagnosed, Untreated Patients With High-Risk Acute Myeloid Leukemia (A MyeloMATCH Treatment Trial)

Acute Myeloid Leukemia Clinical Trial

Official title:

A Randomized Phase II Study Comparing Cytarabine + Daunorubicin (7 + 3) to (Daunorubicin and Cytarabine) Liposome, Cytarabine + Daunorubicin + Venetoclax, and Azacitidine + Venetoclax in Patients Aged 59 or Younger With High-Risk (Adverse) Acute Myeloid Leukemia; A MYELOMATCH Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05554406
• Other study ID #: NCI-2022-07535
• Secondary ID: NCI-2022-07535MM
• Status: Recruiting
• Phase: Phase 2
• Start date: February 10, 2025
• Est. completion date: March 31, 2027

Study information

• Verified date: June 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II MyeloMATCH treatment trial tests whether the standard approach of cytarabine and daunorubicin in comparison to the following experimental regimens works to shrink cancer in patients with high risk acute myeloid leukemia (AML): 1) daunorubicin and cytarabine liposome alone; 2) cytarabine and daunorubicin with venetoclax; 3) azacitidine and venetoclax; 4) daunorubicin and cytarabine liposome and venetoclax. "High-risk" refers to traits that have been known to make the AML harder to treat. Cytarabine is in a class of medications called antimetabolites. It works by slowing or stopping the growth of cancer cells in the body. Daunorubicin is in a class of medications called anthracyclines. It also works by slowing or stopping the growth of cancer cells in the body. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. There is evidence that these newer experimental treatment regimens may work better in getting rid of more AML compared to the standard approach of cytarabine and daunorubicin.

Description:

PRIMARY OBJECTIVE:

I. To compare measurable residual disease (MRD) negative complete remission (CR) rates between each of the experimental regimens and cytarabine + daunorubicin (7+3).

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities with each of the regimens.

II. To estimate complete remission (CR) rates, complete remission with incomplete count recovery (CRi, with and without MRD) rates, event-free survival (EFS), time to relapse, relapse-free survival (RFS), and overall survival (OS) with each of the regimens.

III. To describe and compare MRD negative CR rates by genomic subgroups within and across randomized arms.

BAKING OBJECTIVE:

I. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 5 arms.

ARM I: Patients receive cytarabine intravenously (IV) continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM II: Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax orally (PO) on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM III: Patients receive azacitidine subcutaneously (SC) or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM IV: Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM V: Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

After completion of study treatment, patients follow up every month for first year, every 2 months for the second year, every 3 months for the third year and every 6 months to year 5.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 335
• Est. completion date: March 31, 2027
• Est. primary completion date: March 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 59 Years

Eligibility

Inclusion Criteria:

• STEP 1 REGISTRATION:

• Participants must have been registered to Master Screening and Re-Assessment Protocol, myeloMATCH MSRP, prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox, prior to registration to this study.

• Note: Pre-enrollment/diagnosis labs must have already been performed under the MSRP

• Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) per World Health Organization (WHO) criteria

• Participants must have high-risk (adverse) AML per European LeukemiaNet (ELN) 2017 criteria

• Participants with therapy-related AML (t-AML), or with AML evolving from an antecedent hematologic disorder (such as myeloproliferative neoplasm), or AML with myelodysplasia-related changes (AML-MRC) are eligible

• Acute promyelocytic leukemia is excluded

• Participants with favorable or intermediate risk disease are excluded

• Participants with FLT3 mutations (ITD or TKD) are excluded

• Participants with t(9;22) translocation are excluded

• A single dose of intrathecal chemotherapy is allowed prior to study entry

• Prior anthracycline therapy is allowed but must not exceed a cumulative lifetime dose of 200 mg/m^2 daunorubicin or equivalent. Prior hypomethylating agent (HMA) exposure is allowed, as long as not for AML diagnosis

• Participants must not have received or be currently receiving any prior therapy for acute myeloid leukemia. Hydroxyurea to control the white blood cells (WBC) is allowed prior to registration and initiation of protocol-defined therapy. All trans retinoic acid (ATRA) given until a diagnosis of acute promyelocytic leukemia is ruled out is also allowed.

• Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy

• Participants must be between 18 and 59 years of age

• Participants must have Zubrod performance status =< 3 as determined by a history and physical (H&P) completed within 14 days prior to registration

• Participants must have a complete medical history and physical exam within 7 days prior to registration

• Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications

• Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at time of registration and have undetectable HIV viral load within 6 months prior to registration

• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to registration and be on suppressive therapy, if indicated

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration

• The following tests must be performed within 14 days prior to registration to establish baseline values:

• Complete blood count (CBC)/differential/platelets

• Total bilirubin

• Lactate dehydrogenase (LDH)

• Albumin

• Glucose

• Fibrinogen

• Participants must have adequate kidney function as evidenced by creatinine clearance >= 30mL/min (by Cockcroft Gault) within 28 days prior to registration

• Participants must have adequate liver function as evidenced by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN), and total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert's disease) within 28 days prior to registration

• Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert's disease) within 28 days prior to registration

• Participants must have adequate cardiac function as determined by echocardiography or MUGA scan with an ejection fraction >= 50% within 28 days prior to registration

• Participants with a prior or concurrent malignancy whose natural history (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. No concurrent therapies for such malignancy are allowed with the exception of hormonal therapy

• Participants with known history of Wilson's disease or other known copper-metabolism disorder are excluded

• Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use 2 contraception methods. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods (e.g., hormonal contraceptives [examples include birth control pills, vaginal rings, or patches] associated with inhibition of ovulation for at least 1 month prior to taking study drug), "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. A barrier method should be used during this study along with hormonal contraceptives from initial study drug administration to 30 days after the last dose of study drug as drug-drug interaction with venetoclax is unknown

• Participants must have agreed to have specimens submitted for translational medicine (MRD) under the myeloMATCH MSRP and specimens must be submitted

• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic-Myeloproliferative Diseases
• Myeloproliferative Disorders

Intervention

Drug:
• Azacitidine
Given SC or IV

Procedure:
• Biospecimen Collection
Undergo collection of blood
• Bone Marrow Aspiration
Undergo bone marrow aspiration

Drug:
• Cytarabine
Given IV
• Daunorubicin Hydrochloride
Given IV

Procedure:
• Echocardiography
Undergo ECHO

Drug:
• Liposome-encapsulated Daunorubicin-Cytarabine
Given IV

Procedure:
• Multigated Acquisition Scan
Undergo MUGA

Drug:
• Venetoclax
Given PO

Locations

Country	Name	City	State
Puerto Rico	Centro Comprensivo de Cancer de UPR	San Juan
Puerto Rico	San Juan City Hospital	San Juan
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	OSF Saint Joseph Medical Center	Bloomington	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Minimal residual disease (MRD) response (Arm 1, 2, 4 and 5)	Will be analyzed using intent-to-treat (ITT) principles.	After induction (28 days) or re-induction (56 days)
Primary	Minimal residual disease (MRD) response (Arm 3)	Will be analyzed using intent-to-treat (ITT) principles.	After two cycles of therapy (56 days)
Secondary	Early mortality	Will be assessed by death due to any cause between experimental arms and the 7+3 arm will be reported for each arm every DSMC cycle. Fisher's exact will be used to compare observed rates. A one-sided p-value < 0.05 indicating increased early mortality rates in an experimental arm will be a threshold for termination of accrual to an arm due to increased early mortality.	On or before day 28
Secondary	Time to count recovery	Will be reported every DSMC cycle for the 7+3+venetoclax, (daunorubicin and cytarabine) liposome+venetoclax, and 7+3 arms. Median time to count recovery more than 7 days longer on either of the 7+3+venetoclax and (daunorubicin and cytarabine liposome+venetoclax arms compared to the 7+3 arm will be used a threshold to terminate accrual to an arm due to increased toxicity.	After cycle 1 and cycle 2
Secondary	Event-free survival (EFS)	Will be estimated using the Kaplan-Meier method.	From randomization to the first of: primary refractory disease; progressive disease; off protocol therapy without complete remission (CR) or CR with incomplete count recovery (CRi); relapse from CR or CRi, or death from any cause, assessed up to 5 years
Secondary	Relapse-free survival (RFS)	Defined for only patients achieving complete remission (CR), or CR with incomplete hematologic recovery (CRi). Will be estimated using the Kaplan-Meier method.	From the date of achievement of a remission until the date of relapse or death from any cause, assessed up to 5 years
Secondary	Overall survival (OS)	Will be estimated using the Kaplan-Meier method.	From day of randomization on study until death from any cause, assessed up to 5 years
Secondary	Time to relapse	Will be estimated with cumulative incidence curves with death without relapse analyzed a competing event. Response per 2017 European LeukemiaNet (ELN) guidelines will be tabulated and exact 95% confidence intervals will be calculated.	Up to 5 years
Secondary	MRD negative complete remission (MRDneg CR)	MRDneg CR rates will be tabulated by genomic subgroups within randomized arms and pooling arms. Rates across arms will be compared using Fisher's exact test. All p-values reported will be nominal.	Up to 5 years
Secondary	Incidence of adverse events	Will be analyzed using National Cancer Institute Common Terminology Criteria for Adverse Events version (v) 5.0	Up to 5 years