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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04867928
Recruitment Status : Recruiting
First Posted : April 30, 2021
Last Update Posted : March 16, 2022
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Myeloid Leukemia, in Relapse NPM1 Mutation Drug: Venetoclax+azacitidine Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicentric Phase 2 Study of Venetoclax and Azacitidine for the Management of Molecular Relapse/Progression in Adult NPM1-MUTATED Acute Myeloid Leukemia
Actual Study Start Date : March 1, 2022
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2025


Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04867928


Contacts
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Contact: Paola Fazi 0670390526 p.fazi@gimema.it
Contact: Enrico Crea 0670390514 e.crea@gimema.it

Locations
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Italy
EMATOLOGIA- AOU Policlinico S.Orsola Recruiting
Bologna, Italy
Contact: Antonio Curti         
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT04867928    
Other Study ID Numbers: AML2521
First Posted: April 30, 2021    Key Record Dates
Last Update Posted: March 16, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Recurrence
Neoplasms by Histologic Type
Neoplasms
Disease Attributes
Pathologic Processes
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors