Venetoclax plus azacitidine versus standard intensive chemotherapy for patients with newly diagnosed acute myeloid leukemia (AML) and NPM1 mutations eligible for intensive treatment (VINCENT)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Technische Universitaet Dresden

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

7 Apr 2024 → ongoing

Decision date (initial)

2024-10-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AbbVie Deutschland GmbH & Co. KG

External identifiers

EU CT number

2024-515267-59-00

EudraCT number

2021-003248-26

ClinicalTrials.gov

NCT05904106

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

To compare efficacy of azacitidine plus venetoclax with standard intensive therapy

Secondary objectives 6

1. Tolerability
2. Rate of morphologic & molecular complete remission
3. Minimal residual disease (MRD)
4. Molecular response & molecular persistence
5. Relapse-free survival, overall survival & early mortality
6. Health-care resource use & health-related quality of life

Conditions and MedDRA coding

Acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Signed informed consent
2. Newly diagnosed CD33-positive AML with NPM1 mutation according to WHO criteria
3. Age 18-70 years
4. Fit for intensive chemotherapy, defined by: 1. ECOG 0-2 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.) 3. Adequate renal function assessed by serum creatinine ≤ 1.5x ULN OR creatinine clearance (by Cockcroft Gault formula) ≥ 50 mL/min
5. WBC < 25 x 109/L (<25,000/µL) (Note: Prior hydroxyurea is permitted to meet this criterion.)
6. Ability to understand and the willingness to sign a written informed consent.
7. 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.
8. Women of childbearing potential must have a negative serum pregnancy test performed within 72 hours before first dose of study drug.

Exclusion criteria 13

1. Activating FLT3 mutation
2. Relapsed or refractory AML
3. AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment
4. Prior history of malignancy, other than MDS, unless the subject has been free of the disease for equal to or greater than 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))
5. Previous treatment with HMA or venetoclax
6. Previous treatment for AML except hydroxyurea
7. Cumulative previous exposure to anthracyclines of > 200 mg/m2 doxorubicin equivalents
8. CNS involvement or extramedullary disease only
9. 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
10. 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).
11. Inability to swallow oral medications
12. Any malabsorption condition
13. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Modified Event-free survival (mEFS)
2. Event is defined as: 1. Failure to achieve a CR/CRi/CRh after 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
3. Event is defined as: 2. Hematologic relapse after previous CR/CRi/CRh
4. Event is defined as: 3. Molecular failure, defined as either: 3.1 Molecular progression, defined as confirmed ≥ 1 log10 increase of NPM1 MRD level in any two samples in a patient without prior MRD negativity or 3.2 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
5. Event is defined as: 4. Death

Secondary endpoints 8

1. Cumulative occurrence of grade 3 and 4 adverse events (tolerability)
2. Rate of morphologic CR and CR/CRi/CRh with MRD negativity
3. MRD as detected by MFC and MRD kinetics in NPM1 real-time PCR
4. Rate of molecular response and molecular persistence
5. Relapse-free survival and overall survival
6. Early mortality (14 d, 30 d, 60 d from start of induction)
7. Change in Health-related quality of life (QoL)
8. Cumulative health-care resource use at 12 and 24 months

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Technische Universitaet Dresden

Sponsor organisation

Technische Universitaet Dresden

Address

Mommsenstrasse 11, Raecknitz/zschertnitz Raecknitz/zschertnitz

City

Dresden

Postcode

01069

Country

Germany

Scientific contact point

Organisation

Technische Universitaet Dresden

Contact name

Prof. Dr. med. Christoph Röllig

Public contact point

Organisation

Technische Universitaet Dresden

Contact name

Prof. Dr. med. Christoph Röllig

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications