Addition of Hydroxyurea to Fludarabine, Cytarabine, Idarubicin and Venetoclax Salvage Therapy for Adults With Relapsed or Refractory Acute Myeloid Leukemia

FLAsH-IV-AML: A Phase I/II Multi-center Study to Assess the Tolerability and Efficacy of the Addition of Hydroxyurea to Salvage Treatment With Fludarabine, Ara-C, Idarubicin and Venetoclax for Adults With Relapsed or Refractory Acute Myeloid Leukemia

This study is evaluating a new treatment approach for adults with acute myeloid leukemia (AML) that has either returned after previous treatment or has not responded to treatment. Outcomes for these patients are often poor, and there is a need for more effective therapies.

The study is investigating whether adding hydroxyurea to a combination of established AML medicines (fludarabine, cytarabine, idarubicin, and venetoclax) is safe and tolerable and can improve treatment results. Laboratory studies suggest that hydroxyurea may help leukemia cells become more sensitive to treatment and may increase the effectiveness of chemotherapy.

The study is being conducted in two parts. In the first part, researchers will determine the safest and most appropriate dose of hydroxyurea when given together with the study treatment. In the second part, researchers will evaluate whether adding hydroxyurea improves treatment outcomes, including the length of time patients remain free from disease progression, relapse, or death.

The overall goal of the study is to determine whether adding hydroxyurea to standard treatment for relapsed or refractory AML is safe and may improve patient outcomes.

Inclusion Criteria:

1. A diagnosis of either:

   • Refractory AML defined as having > 10% bone marrow blasts after induction with one cycle of intensive chemotherapy or no CR after two cycles of chemotherapy.
   • Relapsed disease (including extramedullary disease) according to the 2022 ELN criteria (see appendix A).
   • MRD relapse defined as evidence of measurable (minimal) residual disease (MRD) at a level of ≥5%, as determined by either molecular assays or multiparameter flow cytometry.

2. Age 18 years or older.

3. ECOG Performance Status ≤ 2.

4. Adequate renal and hepatic functions as indicated by the following laboratory values:

   • Creatinine clearance ≥ 30 mL/min calculated by the Cockcroft Gault formula.
   • Serum bilirubin ≤ 3 x upper limit of normal (ULN), unless due to Gilbert's syndrome.
   • Alanine aminotransferase (ALAT) ≤ 5 x ULN.

5. Considered fit for intensive chemotherapy.

6. Male patients must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid fathering a child (while on therapy and for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control.

7. Male patient must not donate sperm starting at screening and throughout the study period and for 6 months after the final study drug administration.

8. Female patients of nonchildbearing potential must be postmenopausal (defined as at least 1 year without any menses), documented surgically sterile prior to screening.

9. Female patients of childbearing potential must agree to avoid pregnancy during the study and for 6 months after the final study drug administration and have a negative urine or serum pregnancy test at screening, and if heterosexually active, agree to consistently apply one highly effective method of birth control in combination to a barrier method for the duration of the study and for 6 months after the final study drug administration.

10. The subject has given their written consent to participate in the trial.

11. Patient is capable of giving informed consent.

Exclusion Criteria:

1. Acute promyelocytic leukemia.

2. WBC ≥30; pretreatment with HU to reduce the level of WBC <30 is allowed in part B/phase II of the trial.

3. TP53 double hit mutation / biallelic TP53 inactivation.

4. CNS leukemia.

5. Relapse within 3 months from the date of allo-HCT.

6. Uncontrolled infection.

7. ECOG Performance Status > 2.

8. Major organ failure precluding administration of planned chemotherapy

9. Cardiac dysfunction as defined by:

   • Myocardial infarction within the last 3 months of study entry, or
   • Reduced left ventricular function with an ejection fraction < 50% as measured by echocardiogram (will only be performed when clinically suspected) or
   • Unstable angina or
   • New York Heart Association (NYHA) grade III or IV congestive heart failure (see appendix C) or
   • Severe cardiac arrhythmias

10. Age 75 years or older.

11. Known intolerance to any of the chemotherapeutic drugs in the protocol.

12. Positive pregnancy test.

13. Lactating female or female of childbearing potential not using adequate contraception.

14. Known inherited bone marrow failure syndromes (e.g., Fanconi anemia, Dyskeratosis congenita and related telomeropathies (e.g., TERT, TERC, DKC1 mutations).

15. Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.