PRIMARY OBJECTIVE:
I. To evaluate and compare the progression free survival rate after randomization in the two
treatment arms (nivolumab versus [vs.] observation).
SECONDARY OBJECTIVES:
I. To determine and compare the overall survival rates in the two arms. II. To determine and
compare the incidence of non-relapse mortality in the two arms.
III. To evaluate the toxicities of nivolumab as maintenance.
EXPLORATORY OBJECTIVES:
I. To analyze programmed cell death (PD)-ligand (L)1 expression on acute myeloid leukemia
(AML) cells from peripheral blood and/or bone marrow samples at diagnosis if available and at
the time of study enrollment.
II. To monitor AML minimal residual disease (MRD) by Wilms tumor 1 (WT1) polymerase chain
reaction (PCR) at enrollment and at subsequent defined time points in the nivolumab-treated
and control groups.
III. To perform an exploratory analysis on the frequencies, absolute numbers and subsets of T
cells (including regulatory T cells) in the nivolumab-treated and control groups with an
emphasis on activation markers.
IV. To perform deep sequencing of T cell receptor (TCR)-alpha and TCR-beta chains on
polyclonal T cells at baseline and at subsequent time points in the nivolumab and control
groups.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes once every 2 weeks.
Treatment repeats every 2 weeks for 46 cycles in the absence of disease progression or
unacceptable toxicity.
ARM II: Patients undergo standard of care clinical observation for up to 2 years. Upon
disease relapse, patients may cross-over to Arm I.
After completion of study treatment, patients are followed up periodically for 2 years, every
6 months for 1 year, and then yearly thereafter.
Inclusion Criteria:
- AML patients in first complete remission (CR) (CR1) or first complete remission with
incomplete blood count recovery (CRi) after induction and consolidation chemotherapy;
except young (< 60 years) AML patients in European LeukemiaNet favorable group; (Since
young AML patients in the European LeukemiaNet favorable group have excellent 2 year
progression free survival [PFS] at around 64%, further maintenance therapy might ot
provide additional benefit; thus the current trial will exclude young favorable group
AML patients), patients could receive any cycle consolidation or no consolidation per
the discretion by the treating physician
- Within 60 days after bone marrow biopsy confirmed remission after the patients recover
from their last course of chemotherapy, the goal will be to consent the eligible
patient prior to the remission confirmation bone marrow biopsy at the end of the
planned chemotherapy); ideally, the research samples will be collected during the bone
marrow biopsy, and the patient will be enrolled to the study within 2 weeks of the
bone marrow biopsy; if there is delay to enroll the patient after the bone marrow
biopsy and research sample collection, it is ok not to repeat bone marrow biopsy
within 4 weeks, after the last bone marrow biopsy, if there is no sign of disease
relapse; a repeat bone marrow biopsy should be done if the delay of enrollment is more
than 4 weeks after the last bone marrow biopsy; patients with confirmed remission
within 60 days after the last bone marrow biopsy, without research samples collection,
should have a repeat bone marrow biopsy conducted within two weeks prior to enrolling
on the study
- Patient is not a candidate for stem cell transplant due to advanced age or
co-morbidities; or the enrollee does not have donor available; or the enrollee
declines stem cell transplant due to personal belief; or stem cell transplant is not
standard of care based on the risk category of disease
- Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0 or 1
(Karnofsky >= 70%)
- Life expectancy of greater than 6 months
- Leukocytes >= 1,500/mcL
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 50,000/mcL or recovery to the baseline count
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x ULN
- Amylase and lipase =< 1.5 x ULN without any symptoms of pancreatitis
- Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using
the Cockcroft-Gault formula)
- The effects of nivolumab on the developing human fetus are unknown; for this reason,
women of child-bearing potential (WOCBP) 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; WOCBP should use an adequate method
to avoid pregnancy for 23 weeks after the last dose of investigational drug nivolumab;
women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of nivolumab; women must not be
breastfeeding; men who are sexually active with WOCBP must use any contraceptive
method with a failure rate of less than 1% per year; men receiving nivolumab and who
are sexually active with WOCBP will be instructed to adhere to contraception for a
period of 31 weeks after the last dose of investigational product; women who are not
of childbearing potential (i.e., who are postmenopausal or surgically sterile as well
as azoospermic men) do not require contraception
- Women of childbearing potential (WOCBP) is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes; in addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
- WOCBP receiving nivolumab will be instructed to adhere to contraception for a period
of 23 weeks after the last dose of investigational product; men receiving nivolumab
and who are sexually active with WOCBP will be instructed to adhere to contraception
for a period of 31 weeks after the last dose of investigational product; these
durations have been calculated using the upper limit of the half-life for nivolumab
(25 days) and are based on the protocol requirement that WOCBP use contraception for 5
half-lives plus 30 days and men who are sexually active with WOCBP use contraception
for 5 half-lives plus 90 days
- Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she (or the participating partner) should inform the
treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (AEs) due to agents administered more than 4 weeks
earlier
- Patients who are receiving any other investigational agents
- Patients should be excluded if they have had prior treatment with an anti-programmed
cell death protein 1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), anti-PD-L2,
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
pathways
- Patients with known central nervous system (CNS) involvement may be excluded because
of poor prognosis and concerns regarding progressive neurologic dysfunction that would
confound the evaluation of neurologic and other adverse events; however, if CNS
disease is cleared before the treatment with nivolumab, patients could be allowed if
no permanent CNS damage
- History of severe hypersensitivity reaction to any monoclonal antibody
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because nivolumab is an agent 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 nivolumab, breastfeeding should be discontinued if the mother is treated
with nivolumab
- Patients with known history of testing positive for human immunodeficiency virus (HIV)
or known acquired immunodeficiency syndrome (AIDS) might be enrolled if the viral load
by PCR is undetectable with/without active treatment and absolute lymphocyte count >=
350/ul
- Patients with a positive test for hepatitis B virus surface antigen (HBV sAg) or
hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute
or chronic infection might be enrolled if the viral load by PCR is undetectable
with/without active treatment
- Patients with active autoimmune disease or history of autoimmune disease that might
recur should be excluded; these include but are not limited to patients with a history
of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating)
neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease
such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma,
inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients
with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or
phospholipid syndrome should be excluded because of the risk of recurrence or
exacerbation of disease; patients with vitiligo, endocrine deficiencies including
thyroiditis managed with replacement hormones including physiologic corticosteroids
are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's
syndrome and psoriasis controlled with topical medication and patients with positive
serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be
evaluated for the presence of target organ involvement and potential need for systemic
treatment but should otherwise be eligible
- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event)
- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration; inhaled or
topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption); physiologic replacement doses of systemic
corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen) is permitted
- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis should be
evaluated for the potential need for additional treatment before coming on study
