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Venetoclax + Azacitidine vs. Induction Chemotherapy in AML
Recruiting
I'm InterestedTrial ID: NCT04801797
Purpose
This research is being done to assess the therapeutic activity of a promising combination
(azacitidine and venetoclax) versus conventional cytotoxic chemotherapy in induction-eligible
patients with acute myeloid leukemia.
This study involves the following:
- Venetoclax and azacitidine (investigational combination)
- Cytarabine and idarubicin or daunorubicin (per standard of care) or Liposomal
daunorubicin and cytarabine (per standard of care)
Official Title
A Phase 2 Randomized Study Comparing Venetoclax and Azacitidine to Induction Chemotherapy for Newly Diagnosed Fit Adults With Acute Myeloid Leukemia
Stanford Investigator(s)
Gabriel Mannis
Associate Professor of Medicine (Hematology)
Eligibility
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 with or
without treatment or; (2) as a product of previous exposure to a proven
leukemogenic chemotherapeutic agent
- Eligible for intensive induction chemotherapy, according to their treating physician
- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
- Left ventricular ejection fraction > 50% as measured by echocardiogram or 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).
- Adequate hepatic function per local laboratory reference ranges as follows:
- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0X ULN (unless
secondary to leukemia, in which case patient may be eligible after consideration
and approval by the Overall 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
childbearing 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. Women should use contraceptives for at least 30 days
following the last dose of venetoclax. 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 4 months after completion of therapy.
- 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) - see notes below.
- 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% VAF or less, below that
typically detectable on the companion diagnostics approved for use by the 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 a known diagnosis of 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/m2 daunorubicin
or equivalent (or >400 mg/m2 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 PI.
Individuals with the following cancers are eligible if diagnosed and 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 or history of congestive heart failure New York Heart Association (NYHA) class
3 or 4, or any known history of an LVEF <50%, as measured by MUGA scan or
echocardiogram. Prior to study entry, any 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.
- WBC > 25 x 109/L. Note: hydroxyurea is permitted to meet this criterion. If WBC cannot
be controlled to <25 x 109/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 hypersensitivity to
blood products
- Patients with clinically significant persistent electrolyte abnormalities such as
hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and
hypermagnesemia of Grade > 1 per NCI CTCAE, v5.0. 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 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 β-human
chorionic gonadotropin (β-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.
Intervention(s):
drug: Cytarabine
drug: Idarubicin
drug: Daunorubicin
drug: Liposomal daunorubicin and cytarabine
drug: Venetoclax
drug: Azacitidine
Recruiting
I'm InterestedContact Information
Stanford University
School of Medicine
300 Pasteur Drive
Stanford,
CA
94305
Kyle Cobarrubias
kcobarru@stanford.edu