AZACITIDINE for Acute myeloid leukemia

Inclusion criteria

• {"criterion_text":"- A patient will be eligible for study participation if he/she meets the following criteria within 30 days prior to the first day of therapy (bone marrow biopsy can be performed 30 days prior to the first day of therapy). Historical records are permitted per investigator discretion.\n- Patients must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed screening procedures.\n- Patients must have confirmation of with acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) or MRD reappearance after frontline intensive chemotherapy (including at least one cycle of cytarabine and anthracycline), and prior to allogeneic hematopoietic cell transplantation (allo-HCT). a. In patients with NPM1 mutation, qRT-PCR of NPM1 will be the method used to establish a molecular failure, defined as failure to achieve molecular response after consolidation therapy (NPM1mut/ABL1·100 > 0.01) or MRD reappearance after molecular response. All cases of molecular failure must be confirmed with a second MRD assessment in 2 to 4 weeks. b. In patients with core-binding factor AML, qRT-BCR of RUNX1-RUNX1T1 and CBFb-MYH11 transcripts will be used. Patients failing to achieve a major MRD reduction after consolidation therapy (i.e., RUNX1-RUNX1T1/ABL1·100>0.1 or CBFb-MYH11/ABL1·100>0.1), a log increase in MRD between two positive samples or confirmed MRD CETLAM-LMA-AC-2024-01- Protocol Version - 1.0 17JUL2023 Page 14/103 VERDI reappearance after molecular response will be considered as molecular failures and could be included in the trial. c. In the remaining cases, an appropriate leukemia-associated immunophenotype (LAIP) measured by multiparameter flow cytometry will be used for MRD surveillance. A cutoff of 0.1% will be used to define MRD positivity.\n- Age ≥18 years.\n- Without clinical signs of active central nervous system disease.\n- Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2 or Karnosky performance status (KPS) equivalent (Appendix\n- Patients must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.\n- Patients must have adequate liver function as demonstrated by: a. aspartate aminotransferase (AST) ≤ 3.0 × upper limit normal (ULN) b. alanine aminotransferase (ALT) ≤ 3.0 × ULN c. bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome\n- Non-sterile male patients must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 3 months after the last dose of study drug. Male patients must agree to refrain from sperm donation from initial study drug administration until 3 months after the last dose of study drug.\n- WOCBP (Appendix 7) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting therapy; 2) throughout the entire duration of treatment; 3) during dose interruptions; and 4) for at least 6 months after discontinuation of therapy (last dose of study drug)."}

Exclusion criteria

• {"criterion_text":"- Patient has received other prior rescue treatment for MRD.\n- Patient has a history of other malignancies within the prior year to study entry, except for: a. Adequately treated in situ carcinoma of the breast or cervix uteri. b. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin. c. Prostate cancer with no plans for therapy of any kind. d. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.\n- Pregnant and breastfeeding females.\n- Patient is known to be positive for Human immunodeficiency virus (HIV). infection with the exception of those with an undetectable viral load under correct virological control throughout the study\n- Patient is known to be positive for hepatitis B (HBV) or C (HCV) infection with the exception of those with an undetectable viral load. CETLAM-LMA-AC-2024-01- Protocol Version - 1.0 17JUL2023 Page 15/103 VERDI Note: Hepatitis B or C testing is not required and patients with serologic evidence of prior vaccination to HBV (i.e., HBsAg-, anti-HBs+ and anti-HBc-) may participate.\n- El paciente tiene afectación activa conocida del sistema nervioso central (SNC) por leucemia mieloide aguda.\n- Patient has received within 7 days prior to the first dose of study drug: steroid therapy ≥ 20 mg/day (prednisone or equivalent) for antineoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers.\n- Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.\n- Patient has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to: a. New York Heart Association heart failure > class 2. b. Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.\n- Patient has a malabsorption syndrome or other condition that precludes the enteral route of administration.\n- Patient exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal)."}

Primary endpoints

• {"endpoint_text":"- Rate of MRD conversion after 2 to 4 courses of Ven/Aza treatment.","definition_or_measurement_approach":"MRD conversion assessed after 2–4 courses of venetoclax+azacitidine. MRD methods described in inclusion criteria: qRT‑PCR for NPM1 (molecular failure defined, e.g., NPM1mut/ABL1·100 > 0.01 with confirmation 2–4 weeks later), qRT‑BCR for RUNX1‑RUNX1T1 and CBFb‑MYH11, or multiparameter flow cytometry using an appropriate LAIP with a 0.1% cutoff for MRD positivity."}

Secondary endpoints

• {"endpoint_text":"- Duration of MRD response: The length of time from the first obtention of MRD clearance until MRD progression.","definition_or_measurement_approach":"Defined as time from first documented MRD clearance to MRD progression using the MRD assays described (qRT‑PCR, qRT‑BCR, or multiparameter flow cytometry LAIP with 0.1% cutoff)."}
• {"endpoint_text":"- Relapse risk after intervention: The length of time from the intervention for AML until confirmed hematological relapse.","definition_or_measurement_approach":"Defined as time from the intervention (Ven/Aza) to confirmed hematological relapse (hematologic criteria as per protocol; endpoint text specifies time to confirmed hematological relapse)."}

Spain

Earliest CTIS Part Ii Submission Date

19-07-2024

Latest Decision Or Authorization Date

21-07-2025

Processing Time Days

367

Number Of Sites

14

Number Of Participants

29

Primary sponsor

Full Name

Grupo Cooperativo De Estudio Y Tratamiento De Las Leucemias Agudas Y Mielodisplasias

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

Spain