R/R AML
Conditions
Keywords
Hydroxyurea, FLAG-Ida, Venetoclax
Brief summary
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.
Interventions
DRUGHydroxycarbamid
Hydroxyurea 500-1000 mg administered 1 hour before each infusion of cytarabine.
Sponsors
Christer C Nilsson
Karolinska University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A non-randomized open label phase I/II multi-center study
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1-year EFS | From initiation of study treatment to the first occurrence of treatment failure, hematologic relapse after CR/CRi, or death from any cause, whichever occurs first, assessed up to 365 days. | Defined as event-free-survial from the time from initiation of study treatment to the first occurrence of treatment failure, hematologic relapse from CR/CRi, or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability: incidence and severity of treatment-emergent adverse events | From registration in the study until 60 days after the last dose of treatment. | Frequency, nature and severity of non-hematological toxicities, including potential ara-C or fludarabine related neurological or dermatological adverse events. |
| Overall survival (OS) | From initiation of study treatment through 2 years of follow-up. | Overall survival (OS), defined as the time from initiation of study treatment to death from any cause, with survival estimates reported at 1 and 2 years after initiation of study treatment. |
| 2-year event-free survival (EFS) | From initiation of study treatment through 2 years of follow-up. | Time from initiation of study treatment to the first occurrence of treatment failure, hematologic relapse after CR/CRi, or death from any cause, whichever occurs first. |
| Relapse-free survival (RFS) | From initiation of study treatment through 2 years of follow-up. | Overall survival (OS), defined as the time from initiation of study treatment to the date of death from any cause or hematologic relapse from CR/CRi, with survival estimates reported at 1 and 2 years after initiation of study treatment. |
| Cumulative incidence of hematologic relapse | From initiation of study treatment through 2 years of follow-up. | Cumulative incidence of hematologic relapse after achievement of CR/CRi, reported at 1 and 2 years. Death without prior relapse will be treated as a competing risk. |
| Response rate | At response assessment after Cycle 1 (between Day 25 and Day 35 from the start of Cycle 1). | Proportion of patients achieving complete remission (CR), complete remission with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR) and minimal residual disease (MRD) negativity. |
| Time to hematopoietic recovery | From the start of each treatment cycle until hematopoietic recovery. Treatment cycles are of variable duration, with no predefined cycle length; the subsequent cycle is initiated only after hematopoietic recovery. | Time to hematopoietic recovery (ANC 0.5 and 1.0 x 109/L; platelets 50 and 100 x 109/L) after each chemotherapy treatment cycle, defined as the time from the start of the cycle until recovery. |
| Rate of patients bridged to allo-HCT | From treatment initiation until allogeneic hematopoietic cell transplantation, relapse/progression, death, or 2 years of follow-up, whichever occurs first. | Proportion of patients undergoing allogeneic hematopoietic cell transplantation. |
| Early mortality (30-day and 60-day mortality) | 30 and 60 days after initiation of study treatment. | Proportion of patients who die from any cause within 30 and 60 days after initiation of study treatment. |
Countries
Sweden
Contacts
CONTACTChrister C Nilsson, Md PhD
PRINCIPAL_INVESTIGATORChrister C Nilsson, MD PhD
Karolinska University Hospital
Outcome results
None listed