Relation Between Venetoclax Plasma Concentration and Remission in Adults with Acute Myeloid Leukemia (PREDICLAX)

Official title

Study of the Association Between Residual Venetoclax Plasma Concentration and Composite Complete Remission in Adults with Newly Diagnosed Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy (PREDICLAX)

Overview

Background: In combination with hypomethylating drugs, venetoclax has recently changed the therapeutic management of patients with newly diagnosed acute myeloid leukemia (AML) for whom standard induction chemotherapy was not an option. Over and above the clinical benefits of this combination, the data show that more than half the patients did not show remission criteria, even after the first month's exposure to venetoclax. Hypothesis: To compare the mean residual venetoclax plasma concentrations obtained in patients who went into complete composite remission versus those who did not go into remission at the end of the first cycle of venetoclax + azacitidine treatment. Method: According to the French law, this is a multicenter, non-comparative, open-label, single-arm, interventional study with minimal risks and constraints. Selection, information and inclusion will concern adult patients (≥60 years) with a confirmed diagnosis of AML according to ELN 2022 guidelines. Included patients will be treated as standard care with a combination of venetoclax+azacitidine. This research protocol will not modify their usual care.

Interventions

• Biological Blood sampling for venetoclax drug dosage (venous puncture)
  8 blood samples for venetoclax and azole antifungal drugs identification and dosage will be taken by venous and capillary punctures throughout management of patients

Primary outcome measures

• Comparison of mean plasma residual concentration of venetoclax [Time frame: 1 month]

Secondary outcome measures (7)

• Study relationship between mean plasma residual concentration of venetoclax and remission occurrence [Time frame: 24 months]
• Study performance of mean venetoclax Cres [Time frame: 6 and 12 months]
• Study survival [Time frame: 24 months]
• Study early deaths [Time frame: 24 months]
• Study the variability of plasma venetoclax and antifungal concentrations over time [Time frame: 24 months]
• Study the impact of parameters in uni- and multivariate analyses. [Time frame: 24 months]
• Study adverse events of interest [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

• Subject must have a confirmed diagnosis of previously untreated AML (ELN 2022 criteria) within 28 days of the onset of symptoms. Only previous cytoreductive treatments (e.g. hydroxyurea) are authorized.
• Subject must be ineligible for standard cytarabine and anthracycline induction therapy according to the following criteria:

• Subject aged ≥ 75 years.
• OR subject aged between 60 and 74 with at least one of the following comorbidities:

• ECOG performance status: of 2 or 3.
• cardiac history: heart failure requiring treatment, left ventricular ejection fraction ≤ 50%, chronic stable angina.
• carbon monoxide diffusion capacity ≤ 65% or forced expiratory volume in one second ≤ 65%.
• creatinine clearance between 30 and 45 mL/min/m².
• liver damage (not related to AML) with total bilirubin between 1.5 and 3 × upper normal limit.
• any other comorbidity deemed by the physician to be incompatible with standard induction chemotherapy.
• Patients are eligible for the recommended standard treatment, i.e. a combination of venetoclax and a hypomethylating agent.
• Subjects must voluntarily sign and date an informed consent form authorized by the relevant authorities.
• The participation of the subject in another interventional study not interfering with the pathophysiological, pharmacological and clinical rationale of this protocol is possible.

Exclusion criteria

• blood leukocytes >25 G/L.
• Subject has already received anticancer treatment (drugs, surgery, radiotherapy) for AML, hematological malignancy or malignant cancer (within the last 2 years).
• Subjects with AML with central nervous system involvement or promyelocytic type (AML-M3).
• Subject to an uncontrolled intercurrent disease such as:

• infection (viral, bacterial or fungal) requiring treatment;
• symptomatic congestive heart failure;
• unstable angina pectoris
• cardiac arrhythmia
• psychiatric illness or drug addiction that would limit compliance with study requirements (risk of treatment non-adherence or low venous capital).
• Documented hypersensitivity to the drugs used to treat the subject.
• Subject has been exposed to potent CYP450 inducers or inhibitors (including grapefruit, Seville oranges) within 7 days prior to treatment initiation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

France · 1 center

• CHU de Caen — Caen

Identifiers

NCT: NCT06045819 · 2023-A01909-36

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗