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

Sponsor

Technische Universität Dresden (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05904106

Collaborator

University Hospital Heidelberg (Other), AbbVie (Industry)

146

Enrollment

Locations

Arms

Anticipated Duration (Months)

8.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Venetoclax plus Azacitidine Drug: standard of care chemotherapy plus gemtuzumab ozogamicin	Phase 2

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

146 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Venetoclax Plus Azacitidine Versus Standard Intensive Chemotherapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) and NPM1 Mutations Eligible for Intensive Treatment

Anticipated Study Start Date :

Aug 1, 2023

Anticipated Primary Completion Date :

Sep 1, 2028

Anticipated Study Completion Date :

Sep 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ven+Aza arm non-intensive treatment: venetoclax plus azacitidine	Drug: 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
Active Comparator: SOC arm standard of care treatment: intensive chemotherapy plus gemtuzumab ozogamicin	Drug: 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

Arm

Intervention/Treatment

Experimental: Ven+Aza arm

non-intensive treatment: venetoclax plus azacitidine

Drug: 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

Active Comparator: SOC arm

standard of care treatment: intensive chemotherapy plus gemtuzumab ozogamicin

Drug: 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

Outcome Measures

Primary Outcome Measures

modified event-free survival (mEFS) [time interval from date of randomization until either primary treatment failure or hematologic relapse or molecular failure or death, whichever occurs first]
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

Secondary Outcome Measures

Tolerability of treatment [from FPFV until LPLV [4 years]]
cumulative occurence of CTCAE grade 3 and grade 4 adverse events
Remission (CR/CRi/CRh) rate [from FPFV until LPLV [4 years]]
CR/CRi/CRh rate is defined as the proportion of patients, who achieved a CR or CRi or CRh during study participation.
molecular response rate [from FPFV until LPLV [4 years]]
Proportion of patients with absence of detectable NPM1 mutant transcripts or with detectable NPM1 mutant transcripts who do not meet any of the definitions of molceular failure during study participation.
molecular persistence rate [from FPFV until LPLV [4 years]]
Proportion of patients with detectable NPM1 mutant transcripts present after four cycles of treatment with less than a 4 log10 reduction from baseline.
Rate of CR/CRi/CRh with MRD negativity [from FPFV until LPLV [4 years]]
Proportion of patients, who achieved a CR or CRi or CRh with NPM1-mutant transcripts/ABL1 transcripts <0.01% during study participation.
early mortality [from FPFV until LPLV [4 years]]
Early mortality is defined as death from any reason within 14, 30 and 60 days from day 1 of induction treatment.
Relapse-free survival (RFS) [from FPFV until LPLV [4 years]]
Relapse-free survival is defined as the time interval from date of first CR/CRi/CRh until either morphologic or molecular relapse or death in remission.
Overall survival (OS) [from FPFV until LPLV [4 years]]
Overall survival is defined as time interval from date of randomization until death from any cause.
health-related quality of life (QoL) [from FPFV until LPLV [4 years]]
Health-related quality of life at screening and month 3, 6, 12, 18 and 24 is evaluated from the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) . This is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).
health-related quality of life (QoL) [from FPFV until LPLV [4 years]]
Health-related quality of life at screening and month 3, 6, 12, 18 and 24 is evaluated from the EuroQol five-dimensional questionnaire (EQ-5D-5L). EQ-5D-5L (see Appendix 6) is a standardized instrument for measuring generic health status. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and also asks patients to rate their overall health on a scale of 1-100.
cumulative health-care resource use [from FPFV until LPLV [4 years]]
Health-care resource is defined as total number of hospital admission days at 12 and 24 months from randomization.
cumulative health-care resource use [from FPFV until LPLV [4 years]]
Health-care resource is defined as total number of total blood product usage at 12 and 24 months from randomization.
cumulative health-care resource use [from FPFV until LPLV [4 years]]
Health-care resource is defined as total number of total number of days on intravenous antibiotics and on antifungal medication for therapeutic use at 12 and 24 months from randomization.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Chronic respiratory disease that requires continuous oxygen use
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
Simultaneous participation in another interventional clinical trial
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.
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.

History of clinically significant liver cirrhosis (e.g., Child-Pugh class B and C)
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universitätsklinikum Essen	Essen	NRW	Germany	45147
2	Universitätsklinikum Aachen	Aachen		Germany	52074
3	Universitätsklinikum Augsburg	Augsburg		Germany	86156
4	Klinikum Chemnitz gGmbH	Chemnitz		Germany	09116
5	Universitätsklinikum Dresden	Dresden		Germany	01307
6	Universitätsklinikum Erlangen	Erlangen		Germany	91054
7	Johann Wolfgang Goethe-Universität	Frankfurt am Main		Germany	60590
8	Universitätsklinikum Halle	Halle		Germany	06120
9	Universitätsklinikum Heidelberg	Heidelberg		Germany	69120
10	Universitätsklinikum Schleswig-Holstein	Kiel		Germany	24105
11	Universiätsklinikum Köln	Köln		Germany	50937
12	Universitätsklinikum Leipzig	Leipzig		Germany	04103
13	Klinikum Mannheim gGmbH	Mannheim		Germany	68167
14	Philipps-Universität Marburg Fachbereich Medizin	Marburg		Germany	35043
15	Universitätsklinikum Münster	Münster		Germany	48149
16	Klinikum Nürnberg-Nord	Nürnberg		Germany	90419
17	Krankenhaus Barmherzige Brüder	Regensburg		Germany	93049
18	Robert-Bosch-Krankenhaus	Stuttgart		Germany	70376