Venetoclax for Acute myeloid leukemia

Inclusion criteria

• {"criterion_text":"- Written informed consent."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Patients who present with one of the following (except acute promyelocytic leukemia) a. De novo or secondary AML unfit for standard induction therapy (see inclusion criterion 8). b. Relapsed/refractory AML1 (2022 ELN response criteria) after 1-3 lines of prior therapy (see inclusion criterion 9)."}
• {"criterion_text":"- Written informed consent to participate in an exploratory research protocol including biobanking, comprehensive AML profiling (genomics, transcriptomics, proteomics, etc.) and ex vivo drug sensitivity testing to assess venetoclax and other drug sensitivities. (Not applicable for patients enrolled in Sweden).a. All patients are treated with azacytidine + venetoclax irrespective of the ex vivo screening results."}
• {"criterion_text":"- ECOG Performance Status ≤ 2 for patients ≥ 75 years of age OR ≤ 3 for patients ≥ 18 to 74 years of age"}
• {"criterion_text":"- Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion."}
• {"criterion_text":"- Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula."}
• {"criterion_text":"- Adequate liver function as demonstrated by a. alanine aminotransferase (ALT) ≤ 4.0 × ULN. b. bilirubin ≤ 1.5 × ULN."}
• {"criterion_text":"- Specific inclusion criteria for elderly/unfit AML patients: a. ≥ 70 years of age OR b. ≥ 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: o Left ventricular ejection fraction (LVEF) < 50%. o Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected. o Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected. o Chronic stable angina or congestive heart failure controlled with medication. o Alanine aminotransferase (ALT) 3.0-4.0 × ULN.  Other contraindication(s) to anthracycline therapy (must be documented).  Adverse risk genetics (2022 ELN risk classification 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."}
• {"criterion_text":"- Specific inclusion criteria for relapsed AML patients: a. ≥ 55 years of age with non-CBF AML relapse OR b. ≥ 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."}

Exclusion criteria

• {"criterion_text":"- Acute promyelocytic leukemia (APL)."}
• {"criterion_text":"- Previous non-myeloid malignancies with the exception of previous malignancy treated successfully with curative intent or indolent/smoldering malignancies (defined at the investigator's discretion)."}
• {"criterion_text":"- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)."}
• {"criterion_text":"- Fertile men or women of childbearing potential unless: a. 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 3months after the end of study treatment."}
• {"criterion_text":"- Known hypersensitivity to venetoclax or azacitidine or excipients of any of the drugs."}
• {"criterion_text":"- Patients with 4th or higher AML relapse."}
• {"criterion_text":"- Blast percentage in peripheral blood < 10% (only applicable for patients in whom DSRT during screening is performed on blood)."}
• {"criterion_text":"- ECOG Performance Status >3 (see also inclusion criteria 4)."}
• {"criterion_text":"- Prior venetoclax treatment for myeloid malignancy."}
• {"criterion_text":"- AML patients with CNS involvement (note: cerebrospinal fluid or radiological investigations are not required without clinical suspicion)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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): a. Chronic respiratory disease that requires continuous oxygen use. b. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal). c. Malabsorption syndrome or other condition that precludes enteral route of administration. d. Uncontrolled GVHD."}

Primary endpoints

• {"endpoint_text":"- ORR (including CR/CRh/CRi/MLFS rate, composite CR/CRh/CRi rate, PR rate).","definition_or_measurement_approach":"Overall response rate (ORR) defined as CR + CRh + CRi + MLFS rate; composite CR/CRh/CRi rate and PR rate as specified in protocol/objectives."}

Secondary endpoints

• {"endpoint_text":"- Overall survival (OS), duration of response (DOR), progression free survival (PFS).","definition_or_measurement_approach":"Time-to-event endpoints measured as per standard definitions: OS, DOR, PFS (as stated in protocol)."}
• {"endpoint_text":"- Frequency and severity of adverse events (hematologic toxicities-AE grade 3+4, febrile neutropenia, days until neutrophil recovery ≥ 0.5 x 10E9/l and platelet recovery ≥ 50 x 10E9/l, severe AE grade 3+4).","definition_or_measurement_approach":"Safety assessed by frequency and severity of AEs using CTCAE grading including hematologic toxicities (grade 3+4), febrile neutropenia, time to neutrophil and platelet recovery as specified."}

Finland

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

31-03-2026

Processing Time Days

595

Number Of Sites

4

Number Of Participants

25

Norway

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

27-03-2026

Processing Time Days

591

Number Of Sites

4

Number Of Participants

26

Denmark

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

27-03-2026

Processing Time Days

591

Number Of Sites

4

Number Of Participants

70

Sweden

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

27-03-2026

Processing Time Days

591

Number Of Sites

4

Number Of Participants

26

Primary sponsor

Full Name

Rigshospitalet

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Denmark

Third parties

• {"country":"Denmark","full_name":"GCP-enheden ved Københavns Universitetshospital","duties_or_roles":"sponsorDuties code: 1","organisation_type":"Health care"}