PRIMARY OBJECTIVE:
I. To compare overall survival (OS) of MLN4924 (pevonedistat) and azacitidine in combination
versus azacitidine alone.
SECONDARY OBJECTIVE:
I. To compare the overall response rate (ORR) and duration of response (DOR) of MLN4924
(pevonedistat) and azacitidine in combination versus azacitidine alone.
EXPLORATORY OBJECTIVES:
I. To compare the rate of early mortality, rate of allogeneic hematopoietic cell
transplantation (HCT) and time to response of patients treated with MLN4924 (pevonedistat)
and azacitidine versus azacitidine alone.
II. To determine whether nuclear erythroid 2-related factor 2 (NRF2) target gene expression
is a biomarker of MLN4924 (pevonedistat) activity and predictive of treatment response.
III. To correlate cytogenetic and molecular abnormalities and additional potential biomarkers
with treatment activity and response.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 3, and 5
and azacitidine IV over 10-40 minutes or subcutaneously (SC) on either days 1-7, or days 1-5
and 8-9, or days 1-6 and 8. Cycles repeat every 28 days in the absence of disease progression
or unacceptable toxicity.
ARM B: Patients receive azacitidine IV or SC as in Arm A. Cycles repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year, then
every 6 months thereafter.
Inclusion Criteria:
- Patients must have an established and confirmed diagnosis of AML by World Health
Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL).
- Patients must have relapsed or refractory AML, defined as:
- Relapsed: >= 5% bone marrow blasts by morphology, reappearance of minimal
residual disease (MRD) (> 0.1%) by flow cytometry, reappearance of peripheral
blood blasts, or development of extramedullary leukemia after one or more prior
lines of therapy. Consolidation regimens, including autologous and allogeneic
HCT, do not count as a separate prior line of therapy, (e.g., 7+3 followed by
cytarabine consolidation followed by allogeneic hematopoietic cell
transplantation (HCT) would be considered one prior line of therapy). Note, there
is no restriction on the prior number of relapses and prior treatment of relapsed
disease is allowed.
- Refractory: no complete response (CR) or complete response with incomplete bone
marrow recovery (CRi) after two courses of induction therapy (e.g. therapy with
the intent to induce remission). Patients 75 years or older, or patients of any
age with comorbidities that prevent the use of further intensive chemotherapy,
will be eligible if they did not experience CR or CRi after one course of
induction therapy.
- Patients must have Karnofsky >= 60%.
- Patients must have a white blood cell count (WBC) =< 25 x 10^9 cells/L. Hydroxyurea
and leukapheresis are permitted to satisfy this criterion.
- Total bilirubin =< institutional upper limit of normal (ULN) except in patients with
Gilbert's syndrome or post-transfusion hemolysis. Patients with Gilbert's syndrome or
post-transfusion hemolysis may enroll if direct bilirubin =< 1.5 x ULN of the direct
bilirubin.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN (unless resulting from liver infiltration with leukemia).
- Creatinine clearance >= 30 mL/min (If serum creatinine not =< institutional ULN).
- Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value.
- Human immunodeficiency virus (HIV)-infected patients will be eligible for this trial
if they are on effective antiretroviral regimens utilizing non-CYP-interacting agents,
they have an undetectable viral load, they have a CD4 count > 350 cells/mm^3, and they
have no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic
infections. If there is evidence of chronic hepatitis B virus (HBV) infection, HBV
viral load must be undetectable on suppressive therapy, if indicated. If there is
history of hepatitis C virus (HCV) infection, the patient must have been treated and
have undetectable HCV viral load.
- Patients must be willing to submit blood samples for the integrated biomarker.
- Female patients of childbearing potential (i.e. who are not postmenopausal for at
least 1 year before screening or are not surgically sterile) must have a negative
serum pregnancy test within 72 hours prior to the first study drug administration and
must agree to practice one highly effective method and one additional effective
(barrier) method of contraception, at the same time, from the time of signing the
informed consent through 4 months after the last dose of study drug, or agree to
practice true abstinence, when this is in line with the preferred and usual lifestyle
of the patient. Male patients, even if surgically sterilized, must agree to practice
effective barrier contraception during the entire study treatment period through 4
months after the last dose of study drug, or agree to practice true abstinence when
this is in line with the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods),
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
contraception.
- Patients may have had prior allogeneic HCT at least 3 months prior to randomization
but should not have evidence of active graft versus host disease or require systemic
immune suppression.
- Patients must be able to understand and be willing to sign a written informed consent
document.
- Patients with impaired decision-making capacity (IDMC) will be eligible if they have a
legal guardian or a close family member available to assist them.
Exclusion Criteria:
- Patients must not have had prior treatment with MLN4924 (pevonedistat), azacitidine,
or decitabine.
- Patients for whom, in the opinion of the treating physician, azacitidine alone is not
an appropriate treatment will be excluded.
- Patients must not have documented active central nervous system (CNS) involvement by
leukemia. Patients with known brain metastases should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events.
- Patients must not have received any other investigational or commercial agents or
therapies administered with the intention to treat their leukemia within 14 days or
five half-lives (whichever is shorter) of first receipt of study drug, with the
exception of hydroxyurea used to control WBCs.
- All non-hematologic adverse events (AEs) of prior chemotherapy, surgery, or
radiotherapy, except alopecia, must have resolved to National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) grade =< 2 prior to starting
therapy.
- Patients must not have a history of other malignancies, except:
- Any malignancy that was treated with curative intent, has no known active disease
present for >= 1 year before the first dose of study drug, and is felt to be at
low risk of recurrence by the treating physician;
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease;
- Adequately treated carcinoma in situ without evidence of disease;
- Low-risk prostate cancer after curative surgery.
- Patients must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to MLN4924 (pevonedistat), azacitidine, or
mannitol.
- Clinically significant metabolic enzyme inducers are not permitted during this study,
or within 14 days before the first dose of study drugs. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product.
- Patients must not have severe and/or uncontrolled medical conditions or other
conditions that, in the opinion of the investigator, could affect their participation
in the study.
- Pregnant women are ineligible because, as an Nedd8 activating enzyme (NAE) inhibitor,
MLN4924 (pevonedistat) has the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for AEs in nursing infants secondary to
treatment of the mother with MLN4924 (pevonedistat), breastfeeding must be
discontinued if the mother is treated with MLN4924 (pevonedistat). These potential
risks may also apply to azacitidine.
- Patients must not have had major surgery within 14 days before the first dose of any
study drug or be scheduled for surgery during the study period.
- Patients must not have uncontrolled coagulopathy or a bleeding disorder unless
directly attributable to their AML (e.g., disseminated intravascular coagulation).
- Patients must not have known hepatic cirrhosis or severe pre-existing hepatic
impairment.
- Patients must not have known cardiopulmonary disease defined as:
- Unstable angina;
- Congestive heart failure (New York Heart Association [NYHA] class III or IV;
- Myocardial infarction (MI) within 6 months prior to first dose. Patients who had
ischemic heart disease such as acute coronary syndrome (ACS), MI, and/or
revascularization more than 6 months before screening and who are without cardiac
symptoms or those with a prior non-ST elevation MI due to demand-supply mismatch
(NSTEM type II) may enroll;
- Symptomatic cardiomyopathy;
- Clinically significant arrhythmia:
- History of polymorphic ventricular fibrillation or torsade de pointes,
- Permanent atrial fibrillation, defined as continuous atrial fibrillation
lasting for >= 6 months;
- Persistent atrial fibrillation, defined as sustained atrial fibrillation
lasting > 7 days and/or requiring cardioversion in the 4 weeks before
screening;
- Grade 3 atrial fibrillation, defined as symptomatic and incompletely
controlled medically, or controlled with a device (e.g., pacemaker) or by
ablation;
- Patients with paroxysmal atrial fibrillation or < grade 3 atrial
fibrillation for period of at least 6 months are permitted to enroll
provided that their heart rate is controlled on a stable regimen;
- Moderate or severe pulmonary hypertension.
- Patients must not have uncontrolled high blood pressure that cannot be controlled by
standard therapies.
- Patients must not have any life-threatening illness unrelated to cancer.
- Patients must not have an active, uncontrolled infection or severe infectious disease,
(e.g. severe pneumonia, meningitis, or septicemia). Patients with an uncontrolled
infection must not be enrolled until they have received treatment and the infection is
under control.
- Patients must not have prolonged rate-corrected QT (QTc) interval >= 480 msec,
calculated according to institutional guidelines.
- Patients must not have left ventricular ejection fraction < 40% as assessed by a
transthoracic echocardiogram or radionuclide angiography within one month prior to
study entry.
- Patients must not have known moderate to severe chronic obstructive pulmonary disease,
interstitial lung disease, or pulmonary fibrosis.
- Female patients who intend to donate eggs (ova) during the course of this study or
within 4 months of receiving their last dose of study drugs are ineligible.
- Male patients who intend to donate sperm during the course of this study or within 4
months of receiving their last dose of study drugs are ineligible.
