Venetoclax and Azacitidine in Treating Patients with Newly Diagnosed Acute Myeloid Leukemia
This phase I/II trial studies the side effects and best dose of venetoclax and how it works when given together with azacitidine in treating patients with newly diagnosed acute myeloid leukemia. Chemotherapy drugs, such as venetoclax, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and azacitidine may work better in treating patients with acute myeloid leukemia.
Inclusion Criteria
- Subject must have confirmation of non-acute promyelocytic leukemia (APL) and AML by World Health Organization (WHO) criteria
- Subject must have received no prior treatment for AML
- Without clinical signs of active central nervous system disease
- Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of =< 2
- Subject 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
- Aspartate aminotransferase (AST) =< 3.0 x upper limit of normal (ULN) * Unless considered due to leukemic organ involvement
- Alanine aminotransferase (ALT) =< 3.0 x ULN * Unless considered due to leukemic organ involvement
- Bilirubin =< 3.0 x ULN, unless due to Gilbert’s syndrome * Unless considered due to leukemic organ involvement
- Non-sterile male subjects must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug
- Female subjects who are pre-menopausal and have not had a hysterectomy or oophorectomy 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: * For at least 28 days before starting therapy * Throughout the entire duration of treatment * During dose interruptions * For at least 90 days after discontinuation of therapy (last dose of study drug)
- Subject is informed that consumption of the following fruits is prohibited 3 days prior to the initiation of study treatment and throughout participation: grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit
- Subject 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
- Subject must have adverse risk disease as defined by the European LeukemiaNet
Exclusion Criteria
- Subject has AML with monocytic features; this determination can be made by morphologic assessment, flow cytometry or immunohistochemical staining
- Subject has received disease modifying treatment for myelodysplastic syndrome (MDS) or AML. All-trans retinoic acid (ATRA) given for clinical suspicion of APL will not be exclusionary and no washout will be required in this scenario
- Subject is known to be positive for human immunodeficiency virus (HIV). HIV testing is not required
- Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to hepatitis B virus (HBV) (i.e., hepatitis B surface antigen [HBs Ag]-, anti-HBs+ and anti-hepatitis B core [HBc]–) may participate
- Subject has received within 7 days prior to the first dose of study drug: steroid therapy for anti-neoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers
- Subject 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: * New York Heart Association heart failure > class 2 * Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia
- Subject has a malabsorption syndrome or other condition that precludes enteral route of administration
- Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal)
- Subject has a history of other malignancies prior to study entry, with the exception of: * Adequately treated in situ carcinoma of the breast or cervix uteri * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin * Prostate cancer with no plans for therapy of any kind * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
- Subject has a white blood cell count > 25 × 10^9/L or absolute blast count of > 50 10^9/L. Hydroxyurea and leukapheresis are permitted, if clinically indicated
- Pregnant and breastfeeding females
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03573024.
PRIMARY OBJECTIVE:
I. To determine whether venetoclax with azacitidine has an acceptable response rate in newly diagnosed non-elderly adult (aged 18-59) acute myeloid leukemia (AML) patients.
SECONDARY OBJECTIVES:
I. To determine the safety and toxicity profile of venetoclax and azacitidine in newly diagnosed non-elderly adult AML patients.
II. To determine the remission duration of venetoclax with azacitidine in newly diagnosed non-elderly adult AML patients.
III. To determine the incidence of minimal residual disease negativity in newly diagnosed non-elderly adult AML patients who receive venetoclax and azacitidine.
IV. To determine the one-year event free survival (EFS) and overall survival (OS) of newly diagnosed non-elderly adult AML patients who receive venetoclax and azacitidine.
OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II.
INDUCTION: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7 or on days 1-5 and 8-9 and venetoclax orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity and cross over to maintenance.
CONSOLIDATION: Patients receive azacitidine SC or IV on days 1-7, or days 1-5 and 8-9 and venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity and cross over to maintenance.
MAINTENANCE: Patients who achieve complete remission(CR)/CR with incomplete blood count recovery (CRi)/ morphologic leukemia free state (MLFS) with minimal residual disease (MRD) negativity receive azacitidine SC or IV on days 1-5 and venetoclax PO QD on days 1-28. Patients who achieve CR/CRi/MLFS with MRD positivity receive azacitidine SC or IV on days 1-7 or on days 1-5 and 8-9 and venetoclax PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients undergo bone marrow aspirate and biopsy and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for 1 year, then annually for 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUCHealth University of Colorado Hospital
Principal InvestigatorDaniel A Pollyea
- Primary ID18-0709
- Secondary IDsNCI-2018-02119
- ClinicalTrials.gov IDNCT03573024