PRIMARY OBJECTIVE:
I. Assess the percentage of patients with minimal residual disease (MRD) negative complete
remission (CR) (MRD-CR) or complete remission with incomplete count recovery (MRD-CRi) with
azacitadine (AZA) + venetoclax (VEN) with pembrolizumab during the first 6 cycles and compare
to control arm.
SECONDARY OBJECTIVES:
I. Assess the investigator-assessed rates of CR/CRi/partial remission (PR)/morphological
leukemia free state (MLFS) as defined per the modified International Working Group (IWG) 2003
response criteria with AZA + VEN with pembrolizumab, as well as rates of MRD negative MLFS.
II. Rates of complete remission with partial count recovery (CRh) and hematologic improvement
(HI) to red blood cells and platelets.
III. Assess time to MRD negativity and duration of MRD negative state, event free survival
(EFS), relapse free survival (RFS), calculated as the time from initial treatment to either
disease relapse or death, duration of response (DOR, defined as the time from first CR/CRi to
the date of the first documented relapse or death, whichever occurs first) and overall
survival (OS).
IV. Assess the proportion of patients who develop severe toxicity.
EXPLORATORY OBJECTIVES:
I. MRD assessment by duplex sequencing (DS) and comparing DS and multiparameter flow
cytometry for MRD detection as an exploratory biomarker.
II. Assessment of immune-checkpoint expression and dynamic change of immune cell subsets in
response to the combination of checkpoint-inhibition and backbone combination in acute
myeloid leukemia (AML).
III. High-throughput sequencing of the T-cell receptor (TCR) Vb CDR3 regions on flow
cytometrically sorted t-cell subsets to assess the effect of immunotherapy on the diversity
of the t-cell repertoire and assess for correlation to clinical outcomes.
IV. Investigation of protein signatures and ribonucleic acid (RNA) signatures associated with
response and efficacy using O-link cytokine panel and RNA-sequencing (seq), respectively.
V. Determination of mutational load by whole exome sequencing to assess for correlation with
clinical outcomes, immune infiltrating profile, and T cell repertoire diversity and
clonality.
VI. Profiling of deoxyribonucleic acid (DNA) methylation patterns before and after treatment
to assess for correlation to response to treatment.
VII. Correlate gut microbiome at baseline and changes in the microbiome with clinical
response, both in standard chemotherapy and immunotherapy/chemotherapy therapy settings.
VIII. MRD assessment using duplex sequencing strategy for circulating cell-free tumor DNA and
correlation with long-term outcomes.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (AZA + VEN):
INDUCTION THERAPY PHASE: Patients receive azacitadine intravenously (IV) over 10-40 minutes
or subcutaneously (SC) on days 1-7 and venetoclax orally (PO) on days 1-28 of cycle 1 and
days 1-21 or 1-28 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in
the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY PHASE: Patients receive azacitadine IV over 10-40 minutes or SC on days
1-7 and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles.
Cycles repeat every 28 days for up to 3 years in the absence of disease progression or
unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or
have stable disease (SD) may continue treatment per physician discretion.
ARM II (AZA + VEN + PEMBROLIZUMAB):
INDUCTION THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of cycle
1 and every 3 weeks in cycle 2-6, azacitadine IV over 10-40 minutes or SC on days 1-7, and
venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles. Treatment
repeats every 28 days for up to 6 cycles in the absence of disease progression or
unacceptable toxicity.
MAINTENANCE THERAPY PHASE: Patients receive pembrolizumab IV over 30 minutes on day 8 of
cycle 1 and every 3 weeks in cycle 2-6, azacitadine IV over 10-40 minutes or SC on days 1-7,
and venetoclax PO on days 1-28 of cycle 1 and days 1-21 or 1-28 of subsequent cycles.
Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or
unacceptable toxicity. After completion of 24 cycles, patients who respond to treatment or
have SD may continue treatment with azacitadine and venetoclax per physician discretion.
After completion of study treatment, patients are followed up every 6 months for up to 3
years.
Inclusion Criteria:
- Newly diagnosed and pathologically-confirmed, previously untreated AML as defined by
World Health Organization (WHO) criteria. Secondary AML (myelodysplastic syndrome
[MDS]/AML, therapy related [t]-AML) is also allowed. High risk MDS (excess blasts
[EB]2 with > 10% blasts) is excluded, but AML arising from prior MDS is allowed. Note:
Patients must have evidence of bone marrow involvement on aspirate or biopsy. Patients
with only extramedullary disease and no bone marrow involvement will be excluded.
Every effort should be made to get an aspirate for central flow assessment at
screening and all subsequent required time points, but in cases were an aspirate
cannot be collected-including dry taps-the patient will not be excluded and
assessments will be performed on peripheral blood (PB) which should be collected at
every time that bone marrow (BM) is collected
- Patients who are ineligible for intensive chemotherapy according to treating
physician's assessment or who refuse intensive chemotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Prior use of lenalidomide, erythropoiesis-stimulating agents (ESAs), and growth
factors is allowed if used to treat prior MDS. AML must be previously untreated
- Hydroxyurea is allowed for hyperleukocytosis. White blood cell (WBC) count must be <
25 x 10^4/L to start on study therapy per venetoclax label. Hydroxyurea may be
administered up to one day prior to start of study treatment
- Intermediate-risk or poor risk AML as well as favorable risk by European LeukemiaNet
(ELN) with the exception of "good-risk" cytogenic profile (i.e. lack of the presence
of t(8;21), (inv[16] or t[16;16]), or t(15;17) by cytogenetics or fluorescence in situ
hybridization [FISH])
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
clearance (CrCl) >= 60 mL/min for patient with creatinine levels > 1.5 x institutional
ULN
- Creatinine clearance (CrCl) should be calculated per institutional standard
- Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total
bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
ULN OR =< 5 x ULN for patients with liver metastases
- Patients who are human immunodeficiency virus (HIV) positive may participate IF they
meet the following eligibility requirements:
- They must be stable on their anti-retroviral regimen, and they must be healthy
from an HIV perspective
- Patients must have an undetectable HIV viral load
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load. For patients with evidence of
chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on
suppressive therapy, if indicated
- Patients who have received major surgery must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy
- Female patients of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required. A female of childbearing potential is any woman, regardless of
sexual orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has
had menses at any time in the preceding 24 consecutive months). Female patients of
childbearing potential must be willing to use an adequate method of contraception as
for the course of the study through 120 days after the last dose of study medication.
Male patients of childbearing potential must agree to use an adequate method of
contraception, starting with the first dose of study therapy through 120 days after
the last dose of study therapy. NOTE: Abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the patient
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
Exclusion Criteria:
- Patients with core binding factor (CBF)-AML and acute promyelocytic leukemia (APL)
- Received a prior anti-cancer monoclonal antibodies (mAb) within 4 weeks prior to study
registration or have not recovered (recovery defined as baseline or =< grade 1) from
adverse events (AEs) due to agents administered more than 4 weeks earlier
- Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Patients who have had chemotherapy, targeted small molecule therapy (aside from
imatinib, dasatinib, or nilotinib, hydroxyurea, or all-trans retinoic acid [ATRA]), or
radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to
entering the study
- Left ventricular ejection fraction < 50% as determined by either echocardiogram or
multi-gated acquisition (MUGA)
- Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have
residual toxicities > grade 1) with the exception of =< grade 2 neuropathy and
alopecia
- NOTE: Participants must have recovered from all radiation-related toxicities, not
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout
is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central
nervous system (CNS) disease
- Patients currently participating and receiving study therapy or have participated in a
study of an investigational agent and received study therapy or used an
investigational device within 4 weeks of the first dose of treatment are ineligible
- History of hypersensitivity to pembrolizumab (MK-3475) or any of its excipients, or
other agents used in this study
- Current use of systemic corticosteroids or immunosuppressive agents
- EXCEPTION: Low doses of steroids (e.g., < 0.5 mg/kg/day, absolute maximum 40
mg/day of prednisone or equivalent dose of other steroid), inhaled
corticosteroids, or topical steroids are permitted
- Other active primary malignancy (other than non-melanomatous skin cancer or carcinoma
in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years
- NOTE: If there is a history of prior malignancy, they must not be receiving other
specific treatment (other than hormonal therapy for their cancer)
- Patient with known active CNS disease and/or carcinomatous meningitis. Assessment of
the cerebrospinal fluid (CSF) is not required to enroll in the study unless there is
clinical suspicion for CNS involvement. However, if CSF assessment is performed for
any reason, there should be no evidence of active leukemia in the CSF. Subjects with
previously treated brain metastases may participate provided they are stable (without
evidence of progression by imaging for at least four weeks prior to the first dose of
protocol treatment and any neurologic symptoms have returned to baseline), have no
evidence of new or enlarging brain metastases, and are not using steroids for at least
7 days prior to protocol treatment. This exception does not include carcinomatous
meningitis which is excluded regardless of clinical stability
- Patients who received prior allogenic transplant
- Patient with a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Patient with a diagnosis of immunodeficiency or receiving high dose systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of treatment
- Patient with active autoimmune disease except for patients with hypothyroidism and
vitiligo that has required systemic treatment in the past 2 years (i.e., with use of
disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment
- Patient with a known history of non-infectious pneumonitis that required the use of
steroids or current pneumonitis
- Patient with active uncontrolled infection
- Patient with a known history of active TB (Bacillus tuberculosis)
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because pembrolizumab (MK-3475) is
humanized antibody with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with pembrolizumab (MK-3475), breastfeeding
should be discontinued if the mother is treated with pembrolizumab (MK-3475). These
potential risks may also apply to other agents used in this study
- Patients with no bone marrow involvement (i.e., those with only extramedullary
disease)
- Patients who received prior hypomethylating agent (HMA) therapy for antecedent MDS
- Patients that received a live vaccine within 30 days of planned start of study therapy
- NOTE: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed
- Patients with active hemolytic anemia requiring immunosuppressive therapy or other
pharmacologic treatment. Patients who have a positive Coombs test but no evidence of
hemolysis are NOT excluded from participation
