Trial Title:
Venetoclax Plus Azacitidine Versus Intensive Chemotherapy for Fit Patients With Newly Diagnosed NPM1 Mutated AML
NCT ID:
NCT05904106
Condition:
Acute Myeloid Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Azacitidine
Venetoclax
Gemtuzumab
Conditions: Keywords:
AML
NPM1
venetoclax
azacitidine
Measurable Residual Disease
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Venetoclax plus Azacitidine
Description:
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
Arm group label:
Ven+Aza arm
Intervention type:
Drug
Intervention name:
standard of care chemotherapy plus gemtuzumab ozogamicin
Description:
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
Arm group label:
SOC arm
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.
Detailed description:
AML is a heterogeneous disease of malignant early myeloid cells with a poor prognosis.
Currently the only potentially curative treatment for patients with AML is intensive
induction chemotherapy with 7 days of standard-dose cytarabine plus 3 days of an
anthracyclin (7+3) followed either by several courses of consolidation chemotherapy with
high-dose cytarabine or by allogeneic stem cell transplantation as standard of care
(SOC). Complete remission (CR) is achieved in 60-80% of younger patients (aged 16-60
years) and in around 50% of older patients aged ≥ 60 years by this induction
chemotherapy. However, this induction chemotherapy is toxic, due to prolonged
myelosuppression with resulting infectious complications and organ toxicity with severe
nausea, mucositis, colitis and cardiotoxicity. Each cycle of this intensive chemotherapy
usually results in prolonged hospitalization of the patients and requires extensive
supportive care with blood products and anti-infective agents. In addition, patients
treated with intensive induction chemotherapy are at increased risk for several serious
long-term side effects including cardiac and neurological sequelae, infertility and
secondary cancers. The high toxicity burden in general and cardiovascular toxicity
specifically consistently increase total costs in intensive induction and consolidation
chemotherapy. From this perspective there is a need for therapies with lower toxicity and
better efficacy.
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).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. A 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
- 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:
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 ≥ 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Universitätsklinikum Essen
Address:
City:
Essen
Zip:
45147
Country:
Germany
Investigator:
Last name:
Maher Hanoun, PD Dr.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Aachen
Address:
City:
Aachen
Zip:
52074
Country:
Germany
Investigator:
Last name:
Edgar Jost, Prof.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Augsburg
Address:
City:
Augsburg
Zip:
86156
Country:
Germany
Investigator:
Last name:
Christoph Schmid, Prof.
Email:
Principal Investigator
Facility:
Name:
Klinikum Chemnitz gGmbH
Address:
City:
Chemnitz
Zip:
09116
Country:
Germany
Investigator:
Last name:
Mathias Hänel, Prof.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Dresden
Address:
City:
Dresden
Zip:
01307
Country:
Germany
Investigator:
Last name:
Christoph Röllig, Prof.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Erlangen
Address:
City:
Erlangen
Zip:
91054
Country:
Germany
Investigator:
Last name:
Stefan Krause, Prof.
Email:
Principal Investigator
Facility:
Name:
Johann Wolfgang Goethe-Universität
Address:
City:
Frankfurt am Main
Zip:
60590
Country:
Germany
Investigator:
Last name:
Björn Steffen, Dr.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Halle
Address:
City:
Halle
Zip:
06120
Country:
Germany
Investigator:
Last name:
Christine Dierks, Prof.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Heidelberg
Address:
City:
Heidelberg
Zip:
69120
Country:
Germany
Investigator:
Last name:
Tim Sauer, Dr.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Schleswig-Holstein
Address:
City:
Kiel
Zip:
24105
Country:
Germany
Investigator:
Last name:
Lars Fransecky, Dr.
Email:
Principal Investigator
Facility:
Name:
Universiätsklinikum Köln
Address:
City:
Köln
Zip:
50937
Country:
Germany
Facility:
Name:
Universitätsklinikum Leipzig
Address:
City:
Leipzig
Zip:
04103
Country:
Germany
Investigator:
Last name:
Klaus Metzeler, Prof.
Email:
Principal Investigator
Facility:
Name:
Klinikum Mannheim gGmbH
Address:
City:
Mannheim
Zip:
68167
Country:
Germany
Investigator:
Last name:
Nadine Müller, Dr.
Email:
Principal Investigator
Facility:
Name:
Philipps-Universität Marburg Fachbereich Medizin
Address:
City:
Marburg
Zip:
35043
Country:
Germany
Investigator:
Last name:
Andreas Neubauer, Prof.
Email:
Principal Investigator
Facility:
Name:
Universitätsklinikum Münster
Address:
City:
Münster
Zip:
48149
Country:
Germany
Investigator:
Last name:
Christoph Schliemann, Prof.
Email:
Principal Investigator
Facility:
Name:
Klinikum Nürnberg-Nord
Address:
City:
Nürnberg
Zip:
90419
Country:
Germany
Investigator:
Last name:
Kerstin Schäfer-Eckart, Dr.
Email:
Principal Investigator
Facility:
Name:
Krankenhaus Barmherzige Brüder
Address:
City:
Regensburg
Zip:
93049
Country:
Germany
Investigator:
Last name:
Nadia Maguire
Email:
Principal Investigator
Facility:
Name:
Robert-Bosch-Krankenhaus
Address:
City:
Stuttgart
Zip:
70376
Country:
Germany
Investigator:
Last name:
Martin Kaufmann, Dr.
Email:
Principal Investigator
Start date:
August 2023
Completion date:
September 2028
Lead sponsor:
Agency:
Technische Universität Dresden
Agency class:
Other
Collaborator:
Agency:
University Hospital Heidelberg
Agency class:
Other
Collaborator:
Agency:
AbbVie
Agency class:
Industry
Source:
Technische Universität Dresden
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05904106
