PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of the combination of entinostat and nivolumab
with or without ipilimumab in subjects with advanced solid tumors.
II. To determine the recommended phase II dose (RP2D) of the combination of entinostat and
nivolumab with ipilimumab in subjects with advanced solid tumors and to further confirm the
safety of the combination therapy in subjects with advanced HER2-negative breast cancer.
SECONDARY OBJECTIVES:
I. To evaluate whether treatment with entinostat alone or in combination with nivolumab and
ipilimumab results in an increase in the ratio of tumor antigen-specific effector T cells
(Teff) to regulatory T cell (Treg) in tumor biopsies compared to baseline.
II. To describe preliminary anti-tumor activity of entinostat and nivolumab in combination
with or without ipilimumab in patients with advanced solid tumors.
III. To assess preliminary anti-tumor activity in an expansion cohort of patients with
advanced breast cancer treated at the RP2D.
EXPLORATORY OBJECTIVES:
I. To explore changes in immune-related biomarkers (e.g., expression of checkpoint receptors
[PD-1/PD-L1], the number of myeloid derived suppressor cells [MDSCs], inflammatory T cell
signature, T cell receptor [TCR] repertoire) in tumor biopsies or peripheral blood
lymphocytes (PBL) pre- and post-therapy.
II. To correlate changes in immune-related biomarkers pre- and post-combination therapy with
response.
III. To measure tumor-specific mutations and mutant neo-antigens recognized by patient T
cells in tumor biopsies and to describe association with response.
IV. To evaluate changes in frequency of T cells recognizing tumor-specific mutant
neo-antigens in peripheral blood lymphocytes (PBL) pre- and post-therapy.
V. To evaluate changes in candidate gene expression, including the azacitidine (AZA) immune
genes (AIM genes) in malignant tissue, gene methylation silencing in circulating
deoxyribonucleic acid (DNA) and malignant tissue pre- and post-therapy.
VI. To correlate the pharmacodynamic outcomes (e.g., safety, efficacy, and changes in gene
methylation status) with the exposure of entinostat (i.e., pharmacokinetics) when
co-administered with nivolumab with or without ipilimumab.
VII. To conduct pharmacogenomic association analyses to assess the potential clinical utility
of CD86 gene polymorphisms as genetic determinants of immune mediated adverse events.
OUTLINE: This is a dose-escalation study.
Patients receive entinostat orally (PO) on days -14 and -7 and then weekly, nivolumab
intravenously (IV) over 60 minutes on day 1 and then every 2 weeks, and ipilimumab IV over 90
minutes on day 1 and then every 6 weeks for 4 doses. 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 until disease
progression and then every 6 months for up to 5 years.
Inclusion Criteria:
- Dose escalation: patients must have histologically or cytologically confirmed solid
tumor malignancy that is metastatic or unresectable and for whom either standard
curative or palliative measures do not exist or are no longer effective, or for whom
anti-PD-L1/cytotoxic T-lymphocyte antigen (CTLA)-4 is appropriate
- Dose expansion: patients must have histologically or cytologically confirmed invasive
adenocarcinoma of the breast (human epidermal growth factor receptor 2
[HER2]-negative) that is locally advanced/metastatic and has progressed despite
standard therapy; at least 1 prior chemotherapy regimen in the metastatic setting, and
two lines of hormonal therapy (administered in the adjuvant or metastatic setting) for
patients with hormone receptor-positive disease; NOTE: HER2-negativity will be defined
per American Society of Clinical Oncology (ASCO)-College of American Pathologists
(CAP) guidelines; patients whose tumors have HER2 immunohistochemistry (IHC) 3+, in
situ hybridization (ISH) >= 2.0, or average HER2 copy number >= 6.0 signals per cell
are not eligible
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >=
70%)
- Life expectancy of greater than 12 weeks
- Hemoglobin (HgB) >= 9.0 g/dL
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); an exception to
this may be allowed for participants with Gilbert's syndrome with documented approval
by the protocol chair
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN
- Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min
using the modified Cockcroft-Gault formula
- Negative (serum or urine) pregnancy test, for women of childbearing potential only
- Patients must have measurable or evaluable/non-measurable disease per Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1; patients with bone only disease are
not eligible due to difficulties in obtaining serial bone biopsies for correlative
analyses; NOTE: for patients with metastatic disease in the liver, tumor burden should
not be deemed significant (e.g., to no more than 30% of total liver volume as assessed
by local review/investigator)
- Adequate pulmonary function as assessed by oxygen saturation >= 90% when ambulating
and not requiring supplemental oxygen
- Patient must have an accessible non-bone tumor lesion from which serial core biopsy
specimen can be obtained; NOTE: if baseline biopsy is attempted and is unsuccessful
(e.g., patient intolerance, inadequate tissue), the patient will still be considered
eligible for the study; if core biopsy is not possible, other methods may be approved
in advance by the protocol chair/designee
- The effects of nivolumab, ipilimumab and entinostat on the developing human fetus are
unknown; for this reason and because other therapeutic agents used in this trial are
known to be teratogenic, 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
must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of human chorionic gonadotropin [HCG]) at baseline; women must not be
breastfeeding; women who are not of childbearing potential (i.e., who are
postmenopausal or surgically sterile as well as azoospermic men) do not require
contraception; NOTE: A 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
- Willingness to provide tissue and blood samples for mandatory translational research
- Willingness to return to the enrolling institution for follow-up
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy or other systemic therapy or radiotherapy, or those
who have not recovered from adverse events due to prior administered agents as
follows:
- Chemotherapy < 3 weeks prior to registration
- Hormone therapy < 2 weeks prior to registration
- Targeted therapy (other than below) < 2 weeks prior to registration (e.g.,
tyrosine kinase inhibitors)
- Trastuzumab < 6 weeks prior to registration
- Bevacizumab < 6 weeks prior to registration
- Nitrosoureas/mitomycin C < 6 weeks prior to registration
- Radiotherapy < 3 weeks prior to registration (NOTE: a previously irradiated
lesion may not be used as a target lesion unless there is evidence of
post-radiation progression)
- Surgery < 3 weeks prior to registration
- Other approved or investigational agents < 3 weeks prior to registration unless
otherwise noted by the protocol chair
- Patients who have received prior epigenetic (e.g., histone deacetylase [HDAC]
inhibitors such as entinostat, panobinostat, vorinostat, romidepsin or
demethylating agents such as 5-azacitidine or decitabine) immunomodulatory or
other checkpoint inhibitors should only be considered after discussion with the
protocol chair
- Those who have not recovered from acute adverse events to grade < 2 or baseline
due to agents administered, with exception of alopecia, unless approved by the
protocol chair
- Known sensitivity to or history of allergic reactions attributed to compounds of
similar chemical or biologic composition entinostat, nivolumab, or ipilimumab; history
of severe hypersensitivity reaction to any monoclonal antibody
- 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, autoimmune hepatitis, and patients with a history of toxic
epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should
be excluded; 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
- NOTE: 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)
- Subjects with interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity; NOTE: subjects
must have baseline oxygen/saturation level requirements as above
- Patients with active or untreated brain metastases or leptomeningeal metastases are
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; NOTE: Patients with previously treated brain
metastases must have stable neurologic status and magnetic resonance imaging (MRI)
imaging following local therapy (surgery or radiation) for at least 4 weeks, with no
requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day
prednisone equivalents) for at least 2 weeks prior to study drug administration
(stable low dose dexamethasone allowed at discretion of protocol chair)
- 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 in the judgment of the
investigator would limit compliance with study requirements
- Pregnant women are excluded from this study because the agents have 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,
breastfeeding should be discontinued
- Known human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible; patients who have a positive test for hepatitis
B virus surface antigen (HBV sAg) or hepatitis C antibody (HCV Ab)/ribonucleic acid
(RNA) (HCV RNA) indicating acute or chronic infection are also ineligible (baseline
testing required); these are because of the potential for pharmacokinetic interactions
with the study agents; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated
- 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 requiring concurrent administration of valproic acid are also excluded
- 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
- Another active malignancy =< 3 years prior to registration with the exception of
non-melanotic skin cancer or carcinoma-in-situ of any type; NOTE: if there is a
history of prior malignancy, they must not be receiving other specific treatment for
their cancer; any malignancy considered to be indolent and that has never required
therapy may allowed at the discretion of the protocol chair
