Venetoclax and Azacitidine for the Management of Molecular Relapse/Progression in Adult NPM1-mutated Acute Myeloid Leukemia

March 1, 2022 updated by: Gruppo Italiano Malattie EMatologiche dell'Adulto

A Multicentric Phase 2 Study of Venetoclax and Azacitidine for the Management of Molecular Relapse/Progression in Adult NPM1-MUTATED Acute Myeloid Leukemia

This is a phase 2, non-randomized, interventional, open-label, multicenter trial evaluating the efficacy of VEN-AZA as a bridge-to-transplant therapy in chemotherapy-treated adult NPM1mut AML patients who experience molecular relapse or progression during treatment or follow-up. Subjects will receive cycles of venetoclax plus azacitidine. After each cycle, MRD will be evaluated and at any time of MRD-negativity, AlloSCT will be performed.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This is a phase 2, non-randomized, interventional, open-label, multicenter trial evaluating the efficacy of VEN-AZA as a bridge-to-transplant therapy in chemotherapy-treated adult NPM1mut AML patients who experience molecular relapse or progression during treatment or follow-up.

Subjects will receive venetoclax 400 mg orally QD on Days 1 - 28 plus azacitidine 75 mg/m2 SC or IV daily for 7 days. Cycle Length: 28 Days.

Subjects will continue treatment until subsequent alloSCT, documented morphological bone marrow and/or extramedullary disease progression, toxicity, withdrawal of consent, or the subject meets other protocol criteria for discontinuation (whichever occurs first).

After each cycle, MRD will be evaluated. AlloSCT is recommended at any time of MRD-negativity. After 6 cycles of treatment, regardless MRD status, patients will proceed to alloSCT.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
35

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Bologna, Italy
        • Recruiting
        • EMATOLOGIA- AOU Policlinico S.Orsola

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Subject must be ≥ 18 years of age
  2. Subject must have received previous diagnosis of NPM1mut AML with or without concomitant FLT3-TKD or FLT3-ITD
  3. At screening, subject must have confirmed NPM1 type A, B, or D mutant transcripts
  4. Subject must be eligible for alloSCT, according to transplant center policy
  5. Subject must have undergone at least two cycles of conventional anthracycline- and cytarabine-based chemotherapy, achieving first CR (CR1)

  6. Subject must be in morphological CR1 with bone marrow detectable minimal residual disease (MRD) positivity, defined as qRT-PCR NPM1 transcript ≥ 0.01/100 ABL1 copies and confirmed in two consecutive determinations performed at 2 to 4 weeks' distance

    1. Molecular progression is defined in patients with molecular persistence at low copy number as an increase of MRD copy number ≥ 1 log10 between 2 positive samples.
    2. Molecular relapse is defined in patients previously tested MRD negative as an increase in MRD copy number ≥ 1 log10 between 2 positive samples
  7. Subject must have a projected life expectancy of at least 12 weeks.
  8. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status < 2

  9. Subject must have adequate renal and hepatic function per local laboratory reference range as follows:

    • Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN
    • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
    • Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours' urine collection.
  10. Female subjects of childbearing potential must have negative results for pregnancy test at screening
  11. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from screening through 3 months after the end of treatment.
  12. Signed written informed consent according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

  1. Subject has acute promyelocytic leukemia (APL)
  2. Subject has known active CNS involvement with AML
  3. Subject has received previous treatment with venetoclax and/or hypomethylating agents
  4. Subject has undergone alloSCT for AML
  5. Subject has more than 5% of bone marrow blast cells at screening bone marrow aspirate
  6. Subject is known to be positive for HIV

  7. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

    1. Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
    2. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
  8. Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina;
  9. DLCO ≤ 65% or FEV1 ≤ 65%;
  10. Creatinine clearance < 30 ml/min

  11. Subject has a cardiovascular disability status of New York Heart Association Class > 2

    a. Class 2 is i. defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity ii. results in fatigue, palpitations, dyspnea, or anginal pain

  12. Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of induction therapy). Post-menopausal women must be amenorrhoic for at least 12 months to be considered of non-child bearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drugs.
  13. Patients unwilling or unable to comply with the protocol.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Venetoclax+azacitidine
subjects will receive treatment until alloSCT
Drug: Venetoclax+azacitidine
subjects will receive venetoclax 400 mg orally QD on Days 1 - 28 plus azacitidine 75 mg/m2 SC or IV daily for 7 days. Cycle Length - 28 Days. . Subjects will continue treatment until subsequent alloSCT.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Treatment efficacy in terms of relapse rate
Time Frame: at 6 months
Evaluation of treatment efficacy in terms of percentage of patients who do not experience overt relapse at 6 months or within stem cell transplant.
at 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Gruppo Italiano Malattie EMatologiche dell'Adulto

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 1, 2022

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2025

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 28, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 28, 2021

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 30, 2021

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 16, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 1, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • AML2521

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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