Azacitidine with low-dose venetoclax in acute myeloid leukemia

Trial details

Who runs it

Copenhagen University Hospital, Rigshospitalet

Trial code

NCT05431257EU 2023-510415-19-00

Record updated

24 June 2022

Original description

Multi-center phase II study of standard azacytidine treatment (AZA; D1-D7, 75mg/m2 qd) in combination with a short duration of "low-dose" venetoclax treatment (LD-VEN; D1-D14 before CR and D1-D7 after CR, 400mg qd) per 28 days cycle for elderly/unfit (arm 1) and relapsed/refractory (arm 2) patients with acute myeloid leukemia.Read full original descriptionShow less

Phase II Study of Azacitidine in Combination With Low Dose Intensity Venetoclax in Patients With Acute Myeloid Leukemia With Integration of Explorative Multi-omics and ex Vivo Drug Screening Data

Multi-center phase II study of standard azacytidine treatment (AZA; D1-D7, 75mg/m2 qd) in combination with a short duration of "low-dose" venetoclax treatment (LD-VEN; D1-D14 before CR and D1-D7 after CR, 400mg qd) per 28 days cycle for elderly/unfit (arm 1) and relapsed/refractory (arm 2) patients with acute myeloid leukemia.

AZA and LD-VEN treatment is combined with exploratory AML profiling using established platforms for OMICs analyses and ex vivo drug sensitivity and resistance testing. This will validate the feasibility of AML profiling in a clinical setting to predict responders and non-responders to AZA/LD-VEN therapy. The exploratory AML profiling program will also identify biomarkers as well as novel drugs and drug combinations applicable for treatment of AML patients in future clinical trial initiatives.

Inclusion: Written informed consent; Patients who present with one of the following (except acute promyelocytic leukemia); De novo or secondary AML unfit for standard induction therapy; Relapsed/refractory AML after at least 1 line of prior therapies; Written informed consent to participate in an exploratory research protocol including bio-banking, comprehensive AML profiling (genomics, transcriptomics, proteomics, etc.) and ex vivo drug sensitivity testing to assess venetoclax and other drug sensitivities; All patients are treated with azacitidine+venetoclax irrespective of the ex vivo screening results; ECOG Performance status ≤ 2 for patients ≥ 75 years of age OR ≤ 3 for patients ≥ 18 to 74 years of age; Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion; Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula; Adequate liver function as demonstrated by; alanine aminotransferase (ALT) ≤ 4.0 × ULN; bilirubin ≤ 1.5 × ULN; Specific inclusion criteria for elderly/unfit AML patients:; ≥ 70 years of age OR; ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the following criteria:; Clinically significant comorbidities, as reflected by at least 1 of the following criteria:; Left ventricular ejection fraction (LVEF) < 50%; Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected; Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected; Chronic stable angina or congestive heart failure controlled with medication; Alanine aminotransferase (ALT) 3.0-4.0 × ULN; Other contraindication(s) to anthracycline therapy (must be documented); Adverse risk genetics (ELN criteria) associated with poor outcome with standard chemotherapy; Patient declines intensive chemotherapy; Secondary AML after previous disease modifying treatment (i.e. HMA/induction chemotherapy and/or allogeneic stem cell transplantation) of clonal myeloid diseases such as MDS, MDS/MPN, or MPN; Specific inclusion criteria for relapsed AML patients:; ≥ 55 years of age with non-CBF AML relapse OR; ≥ 18 of age and meeting at least one of the following criteria:; Not candidate for intensive chemotherapy (see criterion 8); Relapse after chemotherapy, or monotherapy with HMA, or allogeneic stem cell transplantation. (note: patients with 4th or higher relapse are excluded); Patient declines intensive chemotherapy; Specific inclusion criteria for refractory AML patients:; Patients who fail to achieve a complete or partial remission after previous monotherapy with HMA or induction chemotherapy (at least 1 cycle of chemotherapy containing cytarabine or clofarabine, in combination with a topoisomerase II inhibitor (e.g. anthracycline or mitoxantrone).

Exclusion: Prior venetoclax treatment for myeloid malignancy; Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment); HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with antiviral medication with the definition hereof at the discretion of the investigator; Cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain; Evidence of clinically significant condition(s), which at the investigator's discretion would adversely affect the patient's participation in this study (including but not limited to):; Chronic respiratory disease that requires continuous oxygen use; Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal); Malabsorption syndrome or other condition that precludes enteral route of administration; Uncontrolled GVHD; Previous malignancies with the exception of previous malignancy treated successfully with curative intent and indolent/smoldering malignancies (defined at the investigator's discretion); Known hypersensitivity to venetoclax or azacitidine or excipients of any of the drugs; Fertile men or women of childbearing potential unless:; Surgically sterile or ≥ 2 years after the onset of menopause; Willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 3 months after the end of study treatment; Acute promyelocytic leukemia (APL); Patients with 4th or higher AML relapse; Leukemic cell content (blast percentage) in bone marrow/peripheral blood < 10 %; ECOG >3; AML patients with CNS involvement (note: cerebrospinal fluid or radiological investigations are not required without clinical suspicion).

ClinicalTrials.gov NCT05431257 · EU CTIS 2023-510415-19-00