Venetoclax and Azacitidine for the Treatment of Fit Adults with Newly Diagnosed Acute Myeloid Leukemia
This phase II trial studies the effects of venetoclax and azacitidine in treating fit adults with newly diagnosed acute myeloid leukemia. Venetoclax may interact with BCL-S (a protein that initiates tumor growth, disease progression, and drug resistance) and inhibit BCL-S which can lead to cancer cell death. Azacitidine may cause cell death in rapidly dividing cells, which may lead to cancer cell death since cancer cells do not grow at a normal rate. Giving venetoclax and azacytidine and work better compared to chemotherapy in treating patients with newly diagnosed acute myeloid leukemia.
Inclusion Criteria
- Age >= 18 years
- Participants must have pathologically confirmed, newly diagnosed acute myeloid leukemia (AML), and characterized by 20% or more blasts in the peripheral blood or bone marrow. The AML may be either: * De Novo: AML in patients with no clinical history of prior myelodysplastic syndrome (MDS), myeloproliferative disorder, or exposure to potentially leukemogenic therapies or agents * Secondary AML (sAML): refers to an acute leukemic process (1) evolving from known prior myelodysplasia, myeloproliferative disorder or aplastic anemia, or (2) as a product of previous exposure to a proven leukemogenic chemotherapeutic agent
- Eligible for intensive induction chemotherapy, according to their treating physician
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Left ventricular ejection fraction > 50% as measured by echocardiogram or multigated acquisition scan (MUGA) scan
- Must not have received systemic prior antineoplastic therapy for treatment for the newly diagnosed AML, including radiation therapy, except hydroxyurea for the purposes of cytoreduction. Patients may also have received all-trans retinoic acid (ATRA) if there is an early suspicion of acute promyelocytic leukemia (APL, M3-AML), although if confirmed to have APL these patients will be excluded from the study
- Adequate renal function as defined by calculated creatinine clearance >= 30 mL/min (Cockcroft-Gault formula or measured by 24 hours urine collection)
- Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 X upper limit of normal (ULN) (unless secondary to leukemia, in which case patient may be eligible after consideration and approval by the overall principal investigator [PI])
- Total bilirubin =< 2.0 x ULN (unless bilirubin rise is known to be due to Gilbert’s syndrome or of non-hepatic origin)
- The effects of venetoclax on the developing human fetus are unknown. For this reason and because other chemotherapeutic agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Also, women should use contraceptives for at least 30 days following the last dose of venetoclax, at least 6 months following the last dose of azacitidine or liposomal daunorubicin and cytarabine and at least 6.5 months following the last dose of idarubicin (or daunorubicin) and cytarabine. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for at least 4 months following the last dose of venetoclax, at least 3 months following the last dose of azacitidine, at least 6 months following the last dose of liposomal daunorubicin and cytarabine, and at least 3.5 months following the last dose of idarubicin (or daunorubicin) and cytarabine
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Diagnosis of Acute promyelocytic leukemia (APL) or AML with favorable cytogenetics [t(8;21), inv(16), t(16;16)]
- Patients < 60 years old with NPM1-mutated AML
- Patients with FLT3-mutated AML (TKD or ITD) * Institutional FLT3 mutational assays can be used to assess for detection of the mutation * A patient with a FLT3 mutation detected at a level of 5% variant allele frequencies (VAF) or less, below that typically detectable on the companion diagnostics approved for use by the Food and Drug Administration (FDA) (http://www.fda.gov/CompanionDiagnostics), would be deemed eligible to enroll * A negative FLT3 mutation result using an outside laboratory assay that is equivalent or similar to that approved as a companion diagnostic by the FDA (http://www.fda.gov/CompanionDiagnostics) is sufficient to rule out FLT3 mutated disease * Patients with FLT3-TKD mutations not included on the companion diagnostics approved for use by the FDA (http://www.fda.gov/CompanionDiagnostics) may still be eligible to enroll after discussion and approval by the overall PI
- Patients with a known diagnosis of chronic myelogenous leukemia (CML) or known presence of BCR-Abl alteration
- Patients with acute leukemia with ambiguous lineage or mixed phenotype
- Patients that have received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment
- Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment
- Patients who have had prior systemic cytotoxic chemotherapy or radiotherapy for AML (excluding patients with therapy-related AML), except for hydroxyurea or 6-MP as noted. Empiric intrathecal chemotherapy during a diagnostic lumbar puncture is allowed, as long as CNS disease is not suspected
- Patients treated with prior hypomethylating therapy (such as azacitidine or decitabine)
- Patients who will exceed a lifetime anthracycline exposure of > 550 mg/m^2 daunorubicin or equivalent (or > 400 mg/m^2 daunorubicin or equivalent in the event of prior mediastinal radiation) if they receive the maximum potential exposure to anthracyclines per protocol (including both induction and consolidation cycles)
- Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with a history of other malignancies within 3 years and without any evidence of disease progression may be considered, but only after consideration and approval by the overall principal investigator (PI). Individuals with the following cancers are eligible if diagnosed and/or treated within the past 3 years: cervical cancer in situ, breast DCIS, and basal cell or squamous cell carcinoma of the skin
- Current clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukemic CNS involvement (no lumbar puncture required, clinical assessment per investigator’s judgment is sufficient)
- Prior bone marrow transplantation for a myeloid malignancy
- Participants who are receiving any other investigational agents within the prior 14 days
- Currently clinically active hepatitis C or hepatitis B infection, as suggested by serology or viral load
- Human immunodeficiency virus (HIV)-infected participants. Patients with detectable viral load on a stable anti-viral regimen may be eligible, after discussion with the study overall PI
- Current congestive heart failure New York Heart Association (NYHA) class 3 or 4, or an left ventricular ejection fraction (LVEF) < 50%, as measured by MUGA scan or echocardiogram). Prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
- Known hypersensitivity to the trial drugs or other contraindication to standard “7+3” induction chemotherapy
- White blood cell (WBC) > 25 x 10^9/L. Note: hydroxyurea is permitted to meet this criterion. If WBC cannot be controlled to < 25 x 10^9/L at the time of enrollment, the WBC management plan must be discussed and approved by the overall PI
- Patients who might refuse to receive blood products and/or have a generalized hypersensitivity to blood products
- Patients with clinically significant persistent electrolyte abnormalities such as hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and hypermagnesemia of grade > 1 per National Cancer Institute (NCI) CTCAE, version (v)5.0. Treatment for correction of above electrolyte imbalances is permitted during screening to meet eligibility
- Uncontrolled intercurrent illness including, but not limited to, clinically ongoing or active infection requiring intravenous antibiotics (IV antibiotics are allowed if infection is deemed to be controlled), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption or tolerance of the study drugs. Examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease
- Pregnant women are excluded from this study because venetoclax and azacitidine, along with standard induction chemotherapy, carries the potential for teratogenic or abortifacient effects. Because there is potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax as well as azacitidine, cytarabine, daunorubicin and idarubicin, breastfeeding should be avoided. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women
- Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up
- Patients who are otherwise felt unable to comply with the protocol, in the opinion of the investigator
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04801797.
PRIMARY OBJECTIVE:
I. To evaluate event free survival for patients treated with venetoclax and azacitidine compared to patients treated with either 7+3 regimen or liposomal daunorubicin and cytarabine.
SECONDARY OBJECTIVES:
I. To evaluate the safety and efficacy of venetoclax in combination with azacitidine compared to either 7+3 regimen or liposomal daunorubicin and cytarabine, as defined by:
Ia. Rate of remission.
Ib. Treatment-related toxicity, assessed using Common Terminology Criteria for Adverse Events (CTCAE) 5.
Ic. Rate of minimal residual disease (MRD) negativity (MRD burden < 0.1%), as centrally assessed by flow cytometry and next-generation sequencing, following 1-2 cycles of therapy.
Id. 30-day and 60-day mortality.
Ie. Overall survival (OS).
If. The proportion patients receiving stem cell transplantation (SCT) following induction.
Ig. Quality of life, mood, symptom burden, coping, and patients post-traumatic stress disorder.
Ih. Healthcare utilization: days alive and spent out of the hospital, number of hospital days, number of hospitalizations, emergency department (ED) visits, admission to the intensive care unit (ICU), days in the ICU, and overall cost of care, incidence of neutropenic fever or neutropenic infections.
Ii. 100-Day post-transplant mortality among patients that receive a SCT.
Ij. Incidence of grade 3 or greater acute graft versus host disease (GVHD).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I:
INDUCTION: Patients receive cytarabine intravenously (IV) continuously on days 1-7 and idarubicin (or daunorubicin) IV on days 1-3 for 1 cycle. Patients may also receive cytarabine IV on days 1-5 and idarubicin (or daunorubicin) IV on days 1-2 for 1 cycle. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with secondary acute myeloid leukemia (AML) or AML with myelodysplastic syndrome (MDS) related changes (AML-MRC) receive liposomal daunorubicin IV over 90 minutes and cytarabine IV over 90 minutes on days 1, 3, and 5 for 1 cycle. Patients may also receive liposomal daunorubicin IV over 90 minutes and cytarabine IV over 90 minutes on days 1 and 3 for 1 cycle. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: Patients younger than 60 years old receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. Patients 60 and older receive cytarabine IV over 3 hours every 12 hours on days 1-5. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with AML or AML-MRC receive liposomal daunorubicin IV over 90 minutes and cytarabine IV over 90 minutes on days 1 and 3. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive venetoclax orally (PO) once daily (QD) on days 1-28 and azacitidine IV over 60 minutes or subcutaneously (SC) on days 1-7. Treatment repeats every 28 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve response, receive venetoclax PO QD on days 1-28 and azacitidine IV over 60 minutes or SC on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not achieve response may be treated beyond 3 cycles if the treating physician believes there is a clinical benefit.
All patients undergo echocardiography or multigated acquisition scan (MUGA) at baseline and blood sample collection and bone marrow aspiration and biopsy throughout study.
After completion of study treatment, patients are followed up at 30 days, then every 3 months for 1 year followed by every 6 months for an additional 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorAmir Tahmasb Fathi
- Primary ID21-113
- Secondary IDsNCI-2021-05625
- ClinicalTrials.gov IDNCT04801797