| Eligibility |
Inclusion Criteria:
- Dose Escalation: Histologically confirmed relapsed or refractory B cell lymphoma
(non-Hodgkin lymphoma [NHL] or Hodgkin lymphoma [HL])
- Dose Expansion: Patients must have histologically confirmed relapsed or refractory
DLBCL
- Patients with DLBCL must have failed at least first line chemotherapy and must be
transplant ineligible (either secondary to performance status or lack of adequate
disease control or patient preference). Patients may be relapsed after autologous or
allogeneic stem cell transplant (SCT), or after chimeric antigen receptor (CAR)-T cell
therapy
- In dose escalation patients with HL or B cell NHL other than DLBCL must have relapsed
after at least 2 lines of therapy and have no other curative options left. HL patients
must be brentuximab vedotin refractory or intolerant. Patients with classic HL must
have had autologous stem cell transplantation (ASCT), be ineligible, or have refused
ASCT
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of nivolumab in combination with ASTX727 in patients < 18 years of age,
children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status =< 2 (Karnofsky
>= 70%)
- Leukocytes >= 1,500/mcL (unless documented bone marrow involvement in which case lower
values may be allowed)
- Absolute neutrophil count >= 1,000/mcL (unless documented bone marrow involvement in
which case lower values may be allowed)
- Platelets >= 75,000/mcL (unless documented bone marrow involvement in which case lower
values may be allowed)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using
the Cockcroft-Gault formula)
- Patients with a requirement for steroid treatment or other immunosuppressive
treatment: 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
- 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 treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS specific treatment is not required and is unlikely to be required during
the first cycle of therapy
- Patients with a prior malignancy that has completed treatment and or in remission for
at least 3 years, or non-melanoma skin cancer or in situ cancer are eligible for this
trial. Patients with concurrent malignancy or recent treatment for a concurrent
malignancy are not eligible
- Patients should be New York Heart Association Functional Classification of class 2B or
better
- The effects of nivolumab and ASTX727 on the developing human fetus are unknown. For
this reason and because DNMTi agents as well as other therapeutic agents used in this
trial are known to be teratogenic, women of child-bearing potential (WOCBP) and men
must agree to use highly effective contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation.
WOCBP should use a highly effective contraception method to avoid pregnancy during
treatment with ASTX727 and for at least 6 months after the last dose of
investigational drug and must agree not to donate eggs (ova, oocytes) for the purpose
of reproduction for the same time period. 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. An extension up to 72 hours prior to the start of study treatment is
permissible in situations where results cannot be obtained within the standard 24-hour
window. 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 who are
sexually active with WOCBP will be instructed to adhere to highly-effective
contraceptive measures of birth control and not to father a child while receiving
treatment and for a period of 3 months 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. Women will
be considered post-menopausal if they have been amenorrheic for 12 months without
an alternative medical cause. The following age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women = 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses > 1 year ago, had
chemotherapy-induced menopause with last menses > 1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
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 ASTX727 will be instructed to adhere to contraception for a period of 6
months after the last dose of investigational product. Men receiving ASTX727 and who are
sexually active with WOCBP will be instructed to adhere to contraception for a period of 3
months after the last dose of investigational product. WOCBP receiving nivolumab as a
single agent will be instructed to adhere to contraception for a period of 5 months after
the last dose. 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 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.
Participants with impaired decision-making capacity who have a legally-authorized
representative (LAR) and/or family member available will also be eligible
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (2 weeks for
Revlimid, 6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
Palliative (limited-field) radiation therapy is permitted, if all of the following
criteria are met:
- Repeat imaging demonstrates no new sites of bone metastases
- The lesion being considered for palliative radiation is not a target lesion
- 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 have had prior treatment with anti-PD-1/PD-L1 inhibitors or anti CTLA4
antibodies and were permanently discontinued from further treatment because of an
adverse event. All other prior therapies are permissible
- Patients who are receiving any other investigational agents
- Patients with known brain metastases or leptomeningeal metastases may be excluded
because of poor prognosis and concerns regarding progressive neurologic dysfunction
that would confound the evaluation of neurologic and other adverse events
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ASTX727 or nivolumab, including severe hypersensitivity reaction to any
monoclonal antibody
- Patients with uncontrolled intercurrent illness
- Patients with cognitive or other impairment that would prevent compliance with study
requirements
- Pregnant women are excluded from this study because ASTX727 is a DNMTi agent and
nivolumab is a PD-L1 inhibitor 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 ASTX727 and nivolumab, breastfeeding
should be discontinued if the mother is treated with ASTX727 and nivolumab
- 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 (GBS),
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 who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are
known risk factors for bowel perforation should be evaluated for the potential need
for additional treatment before coming on study
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