Venetoclax in Patients With MDS or AML in Relapse After AHSCT

A phase I-II study to assess venetoclax + azacitidine and donor lymphocyte infusion (DLI) in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in relapse after allohematopoietic stem cell transplantation (AHSCT).

Inclusion criteria

• Documented cytologic relapse of MDS according to FAB/WHO classification 2016 (including CMML with WBC < 13000/mm3) or AML, with WBC < 15000/mm3, after allo-SCT.

Relapse of MDS or AML is defined as :

• Return to pretreatment bone marrow blast percentage
• Decrement of at least 50% from maximum remission
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Patient must have adequate organ function:

• Serum creatinine < 2 mg/dL or calculated creatinine clearance ≥ 30 mL/min for patients with creatinine levels > 1.5 times Upper Limit of Normal
• Serum total bilirubin ≤ 2.5 times Upper Limit of Normal or direct bilirubin ≤ Upper Limit of Normal for patients with total bilirubin levels ≥ 2 mg/d
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 times Upper Limit of Normal
• Alkaline phosphatase ≤ 5 times Upper Limit of Normal (if > 2.5 times Upper Limit of Normal, then liver fraction should be ≤ 2.5 times Upper Limit of Normal).
• Patient not refractory to platelet transfusions.
• Female subject of childbearing potential must practice at least one protocol specified method of birth control, starting on Study Day 1 through at least 30 days after the last dose of venetoclax or 6 months after the last dose of azacitidine.

Not being of childbearing potential is defined as:

• Age > 55 years with no menses for 12 or more months without an alternative medical cause, or
• Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an Follicle Stimulating Hormone (FSH) level > 40 IU/L, or
• Permanent surgical sterility (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Female subjects of childbearing potential must have negative results for pregnancy test performed:

• At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
• Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results.

Female subjects who are not of childbearing potential at Screening do not require pregnancy testing.

• Male subjects sexually active with female partner(s) of childbearing potential, must agree from first dose of study drug(s) through at least 30 days after the last dose of venetoclax or 3 months after the last dose of azacitidine, whichever is later, to practice the protocol specified contraception.
• Patient is available for periodic blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.
• Patient has the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.
• Patient is able to swallow capsules.

Exclusion criteria

• Patient has active and uncontrolled infection.
• Patient has active acute or chronic Graft-versus-Host-Disease (GVHD).
• Patient receives more than 1mg/kg/day prednisolone.
• Patient has uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.
• Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug.
• Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy.
• Patient has clinically active hepatitis B or hepatitis C infection.
• Patient has a known allergy or hypersensitivity to any component of venetoclax or azacitidine.
• Patient with a "currently active" second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for > 2 years or are considered by their physician to be at less than 30% risk of relapse.
• Patient has received growth factors such as erythropoietin alfa (EPO) or granulocyte colony-stimulating factor (G-CSF) or has received non cytotoxic agents (including low dose oral chemotherapy) in the 30 days before inclusion. In case of previous cytotoxic treatment, an interval of 3 months is required.
• Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs.
• Patients with clinical evidence of Central Nervous System leukemia.
• Patient has a history of Gastrointestinal surgery or other procedures that might interfere with the absorption or swallowing of the study drugs.
• Subject has received strong or moderate CYP3A (Cytochrome P450, family 3, subfamily A) inhibitors within 3 days prior to the first dose of study drug.
• Patient is unable to take and/or tolerate oral medications on a continuous basis.
• Patient is pregnant or breastfeeding within the projected duration of the study.
• Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.
• Absence of social security.