Venetoclax Plus Azacitidine Versus Intensive Chemotherapy for Fit Patients With Newly Diagnosed NPM1 Mutated AML

NCT05904106 | Recruiting Phase 2

• 1 other identifier: TUD-VINC01-080
• Study Type: interventional
• Target: 146
• Locations: 1 country
• Sites: 18

Brief Summary

This phase II clinical trial evaluates the efficacy and tolerability of the non-intensive treatment with venetoclax and the hypomethylating agent azacitidine as compared to the standard of care chemotherapy plus gemtuzumab ozogamicin in newly diagnosed NPM1 mutated AML patients fit for intensive chemotherapy.

Conditions

Acute Myeloid Leukemia

Keywords

AML; NPM1; venetoclax; azacitidine; Measurable Residual Disease

Outcome Measures

Primary Outcomes (1)

• modified event-free survival (mEFS)

  * Failure to achieve a CR/CRi/CRh after a maximum of two induction cycles in the control arm (SOC) or three induction cycles in the investigational arm (VEN+AZA), i.e. primary induction failure * Hematologic relapse after previous CR/CRi/CRh * Molecular failure, defined as either * Molecular progression, defined as confirmed ≥ 1 log10 increase of NPM1 MRD level in any two samples in a patient without prior MRD negativity or * Molecular relapse after previous MRD negativity, defined as confirmed ≥ 1 log10 between two consecutive positive samples in a patient who was previously tested as MRD negative * Death

  time interval from date of randomization until either primary treatment failure or hematologic relapse or molecular failure or death, whichever occurs first

Secondary Outcomes (8)

• Tolerability of treatment

  from FPFV until LPLV [4 years]

• Remission (CR/CRi/CRh) rate

  from FPFV until LPLV [4 years]

• molecular response rate

  from FPFV until LPLV [4 years]

• molecular persistence rate

  from FPFV until LPLV [4 years]

• Rate of CR/CRi/CRh with MRD negativity

  from FPFV until LPLV [4 years]

Study Arms (2)

Ven+Aza arm

EXPERIMENTAL

non-intensive treatment: venetoclax plus azacitidine

Drug: Venetoclax plus Azacitidine

SOC arm

ACTIVE COMPARATOR

standard of care treatment: intensive chemotherapy plus gemtuzumab ozogamicin

Drug: standard of care chemotherapy plus gemtuzumab ozogamicin

Interventions

Venetoclax plus Azacitidine DRUG

Induction cycle 1: 100 mg venetoclax p.o. on day 1; 200 mg venetoclax p.o. on day 2; 400 mg venetoclax p.o. on days 3-28; 75 mg/m\^2 azacitidine s.c. on days 1-7 Induction cycles 2-3: 400 mg venetoclax p.o. on days 1-28; 75 mg/m\^2 azacitidine s.c. on days 1-7 Postremission cycles 1-9: 400 mg venetoclax p.o. on days 1-28; 75 mg/m\^2 azacitidine s.c. on days 1-7

Ven+Aza arm

standard of care chemotherapy plus gemtuzumab ozogamicin DRUG

Induction cycle 1: 200 mg/m\^2 cytarabine cont inf i.v. on days 1-7; 60 mg/m\^2 daunorubicin i.v. on days 3-5; 3 mg/m\^2 (max 1 vial) gemtuzumab ozogamicin i.v. on days 1+4+7 Induction cycle 2 (patients not in remission, moderate or non-responders): 3000/1000 mg/m\^2 cytarabine i.v. BID on days 1-3; 10 mg/m\^2 mitoxantrone i.v. on days 3-5 Postremission cycles 1-3: 3000/1000 mg/m\^2 cytarabine i.v. BID on days 1-3

SOC arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A signed informed consent
• Newly diagnosed CD33-positive AML with NPM1 mutation according to WHO criteria
• Age 18-70 years
• Fit for intensive chemotherapy, defined by
• ECOG performance status of 0-2
• Adequate hepatic function: ALAT/ASAT/Bilirubin ≤ 2.5 x ULN unless considered due to leukemic organ involvement Note: Subjects with Gilbert's Syndrome may have a bilirubin \> 2.5 × ULN per discussion between the investigator and Coordinating investigator.
• Adequate renal function assessed by serum creatinine ≤ 1.5x ULN OR creatinine clearance (by Cockcroft Gault formula) ≥ 50 mL/min
• WBC \< 25 x 109/L (\<25,000/µL), prior hydroxyurea is permitted to meet this criterion
• Ability to understand and the willingness to sign a written informed consent.
• Male subjects must agree to refrain from unprotected sex and sperm donation from time point of signing the informed consent until 7 months after the last dose of study drug.
• Women of childbearing potential must have a negative serum or urine pregnancy test performed within 72 hours before first dose of study drug.

You may not qualify if:

• Activating FLT3 mutation
• Relapsed or refractory AML
• AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment
• Prior history of malignancy, other than MDS, unless the subject has been free of the disease for ≥ 1 year prior to start of study treatment (exceptions are basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system))
• Previous treatment with HMA or venetoclax
• Previous treatment for AML except hydroxyurea
• Cumulative previous exposure to anthracyclines of \> 200 mg/m\^2 doxorubicin equivalents
• CNS involvement or extramedullary disease only
• Known hypersensitivity to excipients of the preparation or any agent given in association with this study including venetoclax, azacitidine, cytarabine, daunorubicin, gemtuzumab-ozogamicin, or mitoxantrone
• Known positivity for human immunodeficiency virus (HIV) and History of active or chronic infectious hepatitis unless serology demonstrates clearance of infection (i.e.
• PCR undetectable viral load for hepatitis).
• Inability to swallow oral medications
• Any malabsorption condition
• Cardiovascular disability status of New York Heart Association (NYHA) Class ≥ 2; unstable coronary artery disease (MI more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Note: Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.

Sponsors & Collaborators

• Technische Universität Dresden: lead
• University Hospital Heidelberg: collaborator
• AbbVie: collaborator

Study Sites (18)

Universitätsklinikum Essen

Essen, North Rhine-Westphalia, 45147, Germany

RECRUITING

Universitätsklinikum Aachen

Aachen, 52074, Germany

RECRUITING

Universitätsklinikum Augsburg

Augsburg, 86156, Germany

RECRUITING

Klinikum Chemnitz gGmbH

Chemnitz, 09116, Germany

RECRUITING

Universiätsklinikum Köln

Cologne, 50937, Germany

NOT YET RECRUITING

Universitätsklinikum Dresden

Dresden, 01307, Germany

RECRUITING

Universitätsklinikum Erlangen

Erlangen, 91054, Germany

RECRUITING

Johann Wolfgang Goethe-Universität

Frankfurt am Main, 60590, Germany

RECRUITING

Universitätsklinikum Halle

Halle, 06120, Germany

RECRUITING

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

RECRUITING

Universitätsklinikum Schleswig-Holstein

Kiel, 24105, Germany

RECRUITING

Universitätsklinikum Leipzig

Leipzig, 04103, Germany

RECRUITING

Klinikum Mannheim gGmbH

Mannheim, 68167, Germany

RECRUITING

Philipps-Universität Marburg Fachbereich Medizin

Marburg, 35043, Germany

RECRUITING

Universitätsklinikum Münster

Münster, 48149, Germany

RECRUITING

Klinikum Nürnberg-Nord

Nuremberg, 90419, Germany

RECRUITING

Krankenhaus Barmherzige Brüder

Regensburg, 93049, Germany

RECRUITING

Robert-Bosch-Krankenhaus

Stuttgart, 70376, Germany

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasm, Residual

Interventions

venetoclax; Azacitidine; Gemtuzumab

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Calicheamicins; Aminoglycosides; Glycosides; Carbohydrates; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Christoph Röllig, Prof.

  Technische Universität Dresden, Medical Faculty Carl Gustav Carus

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Manja Reimann, Dr.

CONTACT

+49 351 458; vincent@ukdd.de

Frank Fiebig

CONTACT

+49 351 458; vincent@ukdd.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 25, 2023
• First Posted: June 15, 2023
• Study Start: April 7, 2024
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: December 2, 2024

Record last verified: 2024-11

Locations

DE (18)