Venetoclax Plus Azacitidine Versus Intensive Chemotherapy for Fit Patients With Newly Diagnosed NPM1 Mutated AML
NCT ID: NCT05904106
Last Updated: 2024-12-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
RECRUITING
PHASE2
146 participants
INTERVENTIONAL
2024-04-07
2028-09-30
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
Due to the high risk of early mortality, older patients and those with severe pre-existing conditions are typically treated with non-intensive chemotherapy with either low-dose cytarabine (LDAC) or a hypomethylating agent (HMA) either azacitidine or decitabine.While these treatments offer at best modest efficacy with CR rates of only 10%-30% and median overall survival of 6-12 months, combinations with the B-cell lymphoma-2 inhibitor venetoclax have been shown to produce CR rates between 50-75% in patients not eligible for intensive chemotherapy. The best response of venetoclax-based regimens with response rates up to 93% and two-year overall survival of 75% has been found among others in the large group of AML patients with mutations in the NPM1 gene. Standard intensive treatment in NPM1 mutated AML patients without adverse risk features usually consisting of standard of care chemotherapy plus gemtuzumab ozogamicin (GO) induces CR rates around 85%, and leads to a 5-year overall survival of around 40% - 50%.The rate and durability of response to venetoclax-based combinations in single arm studies with NPM1 mutated AML patients compared favourably with outcomes from intensive chemotherapy. A retrospective analysis in elderly AML patients with NPM1 mutation found remission rates of 73% in the entire cohort and 96 % in patients \> 65 years. The venetoclax-based combination with the HMA azacitidine is generally well tolerated and has a better safety profile than intensive chemotherapy.
Based on these available clinical data it is postulated that non-intensive treatment with venetoclax plus azacitidine in NPM1 mutated fit AML patients may be equivalent or superior to the standard intensive treatment in terms of remission rates, relapse-free survival, treatment related mortality and health-related quality of life. This randomised controlled phase II trial (VINCENT) is to evaluate the efficacy and tolerability of the non-intensive treatment with venetolcax and azacitidine (Ven+Aza arm) in a wide age-range of newly diagnosed NPM1 mutated AML patients fit for intensive chemotherapy in comparison to standard of care chemotherapy plus GO (SOC arm).
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Ven+Aza arm
non-intensive treatment: venetoclax plus azacitidine
Venetoclax plus Azacitidine
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
SOC arm
standard of care treatment: intensive chemotherapy plus gemtuzumab ozogamicin
standard of care chemotherapy plus gemtuzumab ozogamicin
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
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Venetoclax plus Azacitidine
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
standard of care chemotherapy plus gemtuzumab ozogamicin
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
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
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
* 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
5. WBC \< 25 x 109/L (\<25,000/µL), 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 or urine pregnancy test performed within 72 hours before first dose of study drug.
Exclusion Criteria
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 ≥ 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/m\^2 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.
14. Chronic respiratory disease that requires continuous oxygen use
15. Substance abuse, medical, psychological, or social conditions that may interfere with the subject's cooperation with the requirements of the trial or evaluation of the study results
16. Simultaneous participation in another interventional clinical trial
17. Pregnant or breastfeeding women. Breastfeeding has to be discontinued before onset of and during treatment and should be discontinued for at least 3 months after end of treatment.
18. Patients who are unwilling to follow strictly highly effective contraception requirements including hormonal contraceptives with an Pearl Index \< 1% per year in combination with a barrier method from time point of signing the informed consent until 7 months after the last dose of study drug unless one of the following criteria is met:
* post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum FSH \> 40 U/ml)
* postoperative (6 weeks after bilateral ovarectomy with or without hysterectomy)
* medically confirmed ovarian failure
* vasectomy Note: At present, it is not known whether the effectiveness of hormonal contraceptives is reduced by venetoclax. For this reason, women must use a barrier method in addition to hormonal contraceptive methods.
19. History of clinically significant liver cirrhosis (e.g., Child-Pugh class B and C)
20. Live-virus vaccines given within 28 days prior to the initiation of study treatment Note: corona vaccines are not live-virus vaccines and are excluded from this criterion.
18 Years
70 Years
ALL
No
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
University Hospital Heidelberg
OTHER
AbbVie
INDUSTRY
Technische Universität Dresden
OTHER
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Christoph Röllig, Prof.
Role: PRINCIPAL_INVESTIGATOR
Technische Universität Dresden, Medical Faculty Carl Gustav Carus
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
Universitätsklinikum Essen
Essen, North Rhine-Westphalia, Germany
Universitätsklinikum Aachen
Aachen, , Germany
Universitätsklinikum Augsburg
Augsburg, , Germany
Klinikum Chemnitz gGmbH
Chemnitz, , Germany
Universiätsklinikum Köln
Cologne, , Germany
Universitätsklinikum Dresden
Dresden, , Germany
Universitätsklinikum Erlangen
Erlangen, , Germany
Johann Wolfgang Goethe-Universität
Frankfurt am Main, , Germany
Universitätsklinikum Halle
Halle, , Germany
Universitätsklinikum Heidelberg
Heidelberg, , Germany
Universitätsklinikum Schleswig-Holstein
Kiel, , Germany
Universitätsklinikum Leipzig
Leipzig, , Germany
Klinikum Mannheim gGmbH
Mannheim, , Germany
Philipps-Universität Marburg Fachbereich Medizin
Marburg, , Germany
Universitätsklinikum Münster
Münster, , Germany
Klinikum Nürnberg-Nord
Nuremberg, , Germany
Krankenhaus Barmherzige Brüder
Regensburg, , Germany
Robert-Bosch-Krankenhaus
Stuttgart, , Germany
Countries
Review the countries where the study has at least one active or historical site.
Central Contacts
Reach out to these primary contacts for questions about participation or study logistics.
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
TUD-VINC01-080
Identifier Type: -
Identifier Source: org_study_id