Azacitidine and Venetoclax in Treating Previously Untreated Elderly Participants with Acute Myeloid Leukemia
This phase II trial studies how well azacitidine and venetoclax work in treating elderly participants with acute myeloid leukemia that was not treated before. Drugs used in chemotherapy, such as azacitidine and venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving azacitidine and venetoclax may kill more cancer cells.
Inclusion Criteria
- Subject must have confirmation of non-acute promyelocytic leukemia (APL) AML by World Health Organization (WHO) criteria and be ineligible or unwilling to undergo treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidities or other factors
- Subject must have received no prior treatment for AML; hydroxyurea is not considered a treatment and is allowed
- Subject must be >= 60 years of age
- Subject must have a projected life expectancy of at least 12 weeks
- 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 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 must be either: * Postmenopausal; defined as age > 55 years with no menses for 12 or more months without an alternative medical cause OR * Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
- Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures
Exclusion Criteria
- Subject has received treatment with a hypomethylating agent and/or other chemotherapeutic agent either conventional or experimental for myelodysplastic syndrome (MDS) or AML
- Subject has acute promyelocytic leukemia
- Subject has known active central nervous system (CNS) involvement from AML
- 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 [HBsAg], hepatitis B surface antibody positive (anti-HBs+) and antibody to hepatitis B core antigen [anti-HBc–]) may participate
- Subject has received anticancer therapies including chemotherapy, radiotherapy or other investigational therapy, including targeted small molecule agents within 5 half-lives prior to first dose of study drug. All-trans-retinoic acid (ATRA) given for clinical suspicion of acute promyelocytic leukemia (APL) will not be exclusionary and no washout will be required in this scenario.
- Subject has received biologic agents (e.g. monoclonal antibodies) for anti-neoplastic intent within 30 days prior to first dose of study drug
- Subject has received the following within 7 days prior to the first dose of the study drug: * Steroid therapy for anti-neoplastic intent * Strong and moderate CYP3A inhibitors * Strong and moderate CYP3A inducers
- 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 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; note: hydroxyurea is permitted to meet this criteria
- Any subject who is a candidate for intensive induction therapy and agrees to receive this therapy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03466294.
PRIMARY OBJECTIVES:
I. To determine the response duration of “induction” therapy with azacitidine plus venetoclax followed by maintenance therapy with venetoclax alone for patients who achieve a minimal residual disease (MRD) negative response state.
SECONDARY OBJECTIVES:
I. To determine the rate of MRD negative composite responses (includes complete response [CR], complete remission with incomplete blood count recovery [Cri]/ C-reactive protein [CRp] and morphologic leukemia free state [MLFS]) with the “induction phase” of azacitidine and venetoclax.
II. To determine the median amount of time needed to achieve an MRD negative composite response.
III. To determine the one-year overall survival (OS) of older, newly diagnosed acute myeloid leukemia (AML) patients treated with “induction phase” of azacitidine with venetoclax followed by a maintenance phase of venetoclax alone.
IV. To assess the hematologic toxicity of “induction” venetoclax with azacitidine followed by maintenance venetoclax alone.
OUTLINE:
INDUCTION PHASE: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7 of each cycle, and venetoclax orally (PO) once daily (QD) on days 1-28 of each cycle. Patients who experience MRD negative status at the end of cycle 1 continue to Maintenance Phase. All other patients receive additional Induction Phase cycles every 28 days in the absence of disease progression, unacceptable toxicity, or MRD negative status.
MAINTENANCE PHASE: Patients receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days and for up to 1 year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUCHealth University of Colorado Hospital
Principal InvestigatorDaniel A Pollyea
- Primary ID17-7821
- Secondary IDsNCI-2018-00482
- ClinicalTrials.gov IDNCT03466294