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

• Status: Not yet recruiting
• Trial end date: 2028-09-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Technische Universität Dresden
• Collaborators: AbbVie; University Hospital Heidelberg
• Treatments: Azacitidine; Gemtuzumab; Venetoclax

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.