PRIMARY OBJECTIVE:
I. To assess the percentage of patients with minimal residual disease (MRD) negative complete
remission (CR) (MRD-CR) as measured by flow cytometry at the end of first cycle of
consolidation therapy with chemotherapy + MK-3475 (pembrolizumab) and compare between the two
study arms.
SECONDARY OBJECTIVES:
I. Assess the rate of complete remission (CR)/complete remission with incomplete count
recovery (CRi) as defined per European LeukemiaNet 2017 response criteria at time of count
recovery after induction therapy with chemotherapy + MK-3475 (pembrolizumab) (Dohner et al.,
2017).
II. Rates of complete remission with partial recovery count (CRh) and hematologic improvement
(HI) to red blood cells and platelets.
III. Assess the rates of MRD negativity at day 14, MRD-negative CR at end of induction
therapy and MRD negative CR after last consolidation cycle.
IV. Assess event free survival (EFS), measured from randomization to failure to achieve
CR/CRi, relapse or death from any cause, and relapse free survival (RFS), calculated as the
time from first documentation of CR/CRi to either disease relapse or death from any cause.
V. Assess the 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),
defined as time from randomization to death from any cause.
VI. Assess safety endpoints including proportion of patients who develop severe toxicity as
defined in the protocol.
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. Correlate gut microbiome at baseline and changes in the microbiome with clinical
response, both in standard chemotherapy and immunotherapy/chemotherapy therapy settings.
VII. MRD assessment using duplex sequencing strategy for circulating cell-free tumor
deoxyribonucleic acid (DNA) and correlation with long-term outcomes.
OUTLINE: Patients are randomized to 1 of 2 arms.
INDUCTION PHASE:
ARM I: Patients receive cytarabine via continuous intravenous (IV) infusion on days 1-7 and
idarubicin hydrochloride IV over 15-30 minutes or daunorubicin hydrochloride IV over 15-30
minutes on days 1-3 of a 28-35 day cycle. Patients who have evidence of residual leukemia
receive cytarabine via continuous IV infusion over days 1-5 and idarubicin hydrochloride IV
over 15-30 minutes or daunorubicin hydrochloride IV over 15-30 minutes on days 1-2 for an
additional cycle in the absence of disease progression or unacceptable toxicity. Beginning
day 8, patients receive pembrolizumab IV over 25-40 minutes. Cycles repeat every 3 weeks in
the absence of disease progression or unacceptable toxicity. Patients who achieve a CR or a
CRi may undergo hematopoietic stem cell transplantation (HSCT) per physician discretion or
continue to consolidation therapy.
ARM II: Patients receive cytarabine via continuous IV infusion on days 1-7 and idarubicin
hydrochloride IV over 15-30 minutes or daunorubicin hydrochloride IV over 15-30 minutes on
days 1-3 of a 28-35 day cycle. Patients who have evidence of residual leukemia receive
cytarabine via continuous IV infusion over days 1-5 and idarubicin hydrochloride IV over
15-30 minutes or daunorubicin hydrochloride IV over 15-30 minutes on days 1-2 for an
additional cycle in the absence of disease progression or unacceptable toxicity. Patients who
achieve a CR or a CRi may undergo HSCT per physician discretion or continue to consolidation
therapy.
CONSOLIDATION THERAPY:
ARM I: Within 4 weeks of remission status documentation, patients receive high-dose
cytarabine (HiDAC) IV over 1-3 hours every 12 hours on days 1, 3, and 5 for a total of 6
doses and pembrolizumab IV over 25-40 minutes. Cycles with HiDAC repeat every 28-42 days and
cycles with pembrolizumab repeat every 3 weeks in the absence of disease progression or
unacceptable toxicity. Patients who remain in CR or CRi receive up to 3 additional cycles of
HiDAC and pembrolizumab in the absence of disease progression or unacceptable toxicity and
continue to maintenance therapy.
ARM II: Within 4 weeks of remission status documentation, patients receive HiDAC IV over 1-3
hours every 12 hours on days 1, 3, and 5 for a total of 6 doses in the absence of disease
progression or unacceptable toxicity. Patients who remain in CR or CRi receive up to 3
additional cycles of HiDAC in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY:
ARM I: Patients receive pembrolizumab IV over 25-40 minutes. Cycles repeat every 3 weeks for
up to 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 6
months for up to 5 years. Patients who undergo HSCT are also followed up at 100 days
post-transplant.
Inclusion Criteria:
- Newly diagnosed and pathologically-confirmed AML, confirmed by a bone marrow aspirate
and/or biopsy with >= 20% myeloid blasts. Secondary AML (myelodysplastic syndrome
[MDS]/AML, therapy-related [t]-AML) is also allowed. High risk MDS (EB2 with > 10%
blasts) is excluded, but AML arising from prior MDS is allowed. AML arising from
myeloproliferative neoplasms (MPN), MPN/MDS overlap (including chronic myelomonocytic
leukemia [CMML]) or other hematologic malignancy are NOT 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.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 and/or (Karnofsky >=
70%)
- The patient has to be eligible to receive intensive "7+3" induction chemotherapy as
judged by the treating physician
- Prior use of hypomethylating agents (HMA), lenalidomide, erythropoiesis-stimulating
agents (ESAs), and growth factors is allowed if used to treat prior MDS. AML must be
previously untreated
- Hydroxyurea/leukapheresis allowed for control of hyperleukocytosis but hydroxyurea
must be discontinued day prior to start of chemotherapy
- 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 (within 14 days prior to the first day of 7+3)
- 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 (within 14 days prior to the first day of 7+3)
- 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 (within 14 days prior to the
first day of 7+3)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants (within 14
days prior to the first day of 7+3)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants (within 14 days prior to the first day of 7+3)
- Patients with a known history of being 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
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association functional classification. To be
eligible for this trial, patients should be class 2B or better
- Female patients of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of 7+3 treatment. 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 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months). Female patients of
childbearing potential must be willing to use an adequate method of contraception for
the course of the study through 120 days after the last dose of study medication. Male
patients with female partners 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
- Treatment with a BCR-ABL tyrosine kinase inhibitor (TKI) for another indication (e.g.
a gastrointestinal stromal tumor [GIST]) is allowed in the study
Exclusion Criteria:
- Patients with a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin or squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in situ
cervical cancer. Prior treatment with the following are not allowed:
- Patient who have received anthracyclines for treatment of a prior, unrelated,
curatively-treated malignancy which would limit their ability to receive 7 + 3
chemotherapy treatment on study
- Anti-PD-1, anti-PD-L1, or anti-PD-L2, for a prior, unrelated, curatively-treated
malignancy, within last 3 months of enrollment in the study
- Anti-cancer monoclonal antibody (mAb) within 4 weeks, for a prior, unrelated,
curatively-treated malignancy, 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
- Experimental treatment within 4 weeks prior to study registration
- Patients who have had chemotherapy (except hydroxyurea and all trans retinoic acid
[ATRA] which are allowed but have to be stopped the day before induction therapy
starts), targeted small molecule therapy (aside from imatinib, dasatinib, or
nilotinib), or curative-intent radiotherapy within 4 weeks (6 weeks for nitrosoureas
or mitomycin C), for a prior curatively treated malignancy, prior to entering the
study
- Patients who have received prior anthracyclines not to exceed 150 mg/m^2 of
daunorubicin or equivalent for treatment of a prior, unrelated, curatively-treated
malignancy which would limit their ability to receive 7 + 3 chemotherapy treatment on
study
- Patients with a cardiac ejection fraction less than 50%
- 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)
- Patients who have FLT3-mutated AML
- Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have
not returned to baseline or 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 MK-3475 (pembrolizumab) or any of its excipients, or
other agents used in this study
- Current use of corticosteroids
- EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of
other steroid) used for treatment of non-hematologic medical condition (e.g.,
chronic adrenal insufficiency) is permitted
- Patients who received prior allogenic transplant
- Patients with a known history of hepatitis B (defined as hepatitis B surface antigen
[HBsAg] reactive) who are not on appropriate suppressive therapy
- 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 known active CNS disease and/or carcinomatous meningitis. Assessment of
the cerebral spinal 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 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
- Patients with a known history of non-infectious pneumonitis that required the use of
steroids or current pneumonitis
- Patients with active infection requiring systemic therapy
- Patients 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 MK-3475 (pembrolizumab) 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 MK-3475 (pembrolizumab), breastfeeding
should be discontinued if the mother is treated with MK-3475 (pembrolizumab). These
potential risks may also apply to other agents used in this study
- Patient who have 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
- 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
- Patients with clinically significant disseminated intravascular coagulation (DIC), as
assessed by treating physician, will be excluded from study
- Patients with no bone marrow involvement will be excluded (i.e., those with only
extramedullary disease)
- Patients with acute promyelocytic leukemia will be excluded
