PRIMARY OBJECTIVES:
I. To obtain preliminary data regarding the safety and tolerability of decitabine and
venetoclax in combination with nivolumab when given for frontline therapy in TP53 mutated
acute myeloid leukemia (AML) patients.
II. To obtain preliminary data regarding the rate of complete remission (CR), complete
remission with incomplete hematological recovery (CRh), and complete remission with
incomplete count recovery (CRi) in TP53 mutated AML who are treated with decitabine and
venetoclax in combination with nivolumab for frontline therapy.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To obtain preliminary data regarding
progression free survival (PFS) for TP53 mutated AML patients receiving combination therapy.
III. To obtain preliminary data regarding the overall survival (OS) for TP53 mutated patients
receiving this combination therapy.
IV. To obtain preliminary data regarding minimal residual disease through monitoring TP53
mutational burden prior and throughout treatment.
V. To obtain preliminary data regarding the frequency of graft versus host disease (GVHD)
including veno-occlusive disease (VOD) in patients who subsequently receive allogeneic
transplantation after this combination therapy.
OUTLINE:
INDUCTION: Patients receive nivolumab intravenously (IV) over 30 minutes on day 15 of cycle 1
and days 1 and 15 of subsequent cycles, decitabine IV over 60 minutes on days 1-10 of
induction cycle 1 (and cycles 2 and 3 if needed), and venetoclax orally (PO) once daily (QD)
on days 1-21. Treatment repeats every 28 days for up to 3 cycles in the absence of disease
progression or unacceptable toxicity.
MAINTENANCE: Patients who achieve a CR or CRi receive nivolumab IV over 30 minutes on days 1
and 15, decitabine IV over 60 minutes on days 1-5, and venetoclax PO QD on days 1-21. Cycles
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 3 years.
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed acute myeloid leukemia
(AML)
- Presence of TP53 mutation at diagnosis
- Newly diagnosed, untreated AML
- Patients who received prior hypomethylating therapy for a prior myelodysplastic
syndrome (MDS) diagnosis are allowed
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), (except for
patients with Gilbert's disease)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 x institutional ULN
- Glomerular filtration rate (GFR) > 40 mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- 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
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
- 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. A baseline troponin
should be within normal limits and baseline oxygen saturation should be greater than
or equal to 92%. A baseline electrocardiogram (ECG) should be normal, or with stable
changes if patient has chronic ECG changes
- Active infection is permitted if the infection is under control
- White blood count (WBC) must be =< 25,000 at time of day 1 of study treatment.
Cytoreduction with Hydrea and leukapheresis is allowed
- Risks from venetoclax and nivolumab to the developing human fetus cannot be ruled out.
For this reason and because decitabine is known to be teratogenic, women of
child-bearing 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. Contraception use should be continued 6 months after
the completion of all study treatments for women of child bearing potential. 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 7 months after
completion of decitabine, venetoclax, or nivolumab administration
- Ability to understand and the willingness to sign a written informed consent document.
Patients with impaired decision-making are allowed to participate as long as the
patient has a legally authorized representative (LAR) or caregiver
Exclusion Criteria:
- Patients with history of prior allogeneic transplantation. This is due to this being a
pilot study with a limited number of patients
- Patients with known autoimmune disease. Patients with active autoimmune disease or
history of autoimmune disease that might recur, which may affect vital organ function
or require immune suppressive treatment including systemic corticosteroids, 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, Sjogren'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 with hyperleukocytosis requiring immediate cytoreductive chemotherapy (WBC >=
100,000 with symptoms of leukostasis)
- Isolated extramedullary leukemia of central nervous system (CNS) involvement with
leukemia
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to decitabine, venetoclax, or nivolumab
- 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 fetal risk has been demonstrated
with decitabine 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 decitabine, breastfeeding should be discontinued if
the mother is treated with decitabine. These potential risks may also apply to other
agents used in this study
