PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of the combination of entinostat and nivolumab
with or without ipilimumab in patients with advanced solid tumors.
II. To determine the maximum tolerated dose (MTD) of the combination of entinostat and
nivolumab with ipilimumab in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To evaluate whether there is an increased expression of checkpoint inhibitors (programmed
death [PD]-1/programmed death ligand [PD-L]1) in tumor biopsies after 2-week treatment with
entinostat alone 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 MTD.
TERTIARY OBJECTIVES:
I. To explore changes in the number of myeloid derived suppressor cells (MDSCs) in
peripheral blood and in tumor biopsies pre- and post-therapy.
II. To explore expression of checkpoint inhibitors (PD-1/PD-L1) post-combination therapy and
to correlate with response.
III. To explore changes in other immune-related biomarkers (e.g., the ratio of effector T
cells [Teffs]: regulatory T cells [Tregs], inflammatory T cell signature, T cell receptor
[TCR] repertoire) in tumor biopsies or peripheral blood lymphocytes (PBL) pre- and
post-therapy.
IV. To measure tumor-specific mutations and mutant neo-antigens recognized by patient T
cells in tumor biopsies and to describe association with response.
V. To evaluate changes in frequency of T cells recognizing tumor-specific mutant
neo-antigens in peripheral blood lymphocytes (PBL) pre- and post-therapy.
VI. To evaluate changes in candidate gene expression, including the azacitidine (AZA) immune
genes (5-AZA immune gene set [AIM] genes) in malignant tissue, gene methylation silencing in
circulating deoxyribonucleic acid (DNA) and malignant tissue pre- and post-therapy.
VII. 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.
VIII. To conduct pharmacogenomic association analyses to assess the potential clinical
utility of cluster of differentiation (CD)86 gene polymorphisms as genetic determinants of
immune mediated adverse events.
OUTLINE: This is a phase I, 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 2-3 weeks, and ipilimumab IV over
90 minutes on day 1 and then every 3 weeks for 4 doses. Courses repeat every 21-28 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 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;
NOTE: all women of childbearing potential (WOCBP) MUST have a negative pregnancy test
within 72 hours before receiving ipilimumab
- Patients must have measurable disease per Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured
in at least one dimension (longest diameter to be recorded for non-nodal lesions and
short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm
(>= 15 mm for nodal lesions) with spiral computed tomography (CT) scan, magnetic
resonance imaging (MRI), or calipers by clinical exam; 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 oxygen
- Patient must have an accessible tumor lesion from which a 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
- Women of child-bearing potential (WOCPB) 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; men who are sexually
active with WOCBP must use any contraceptive method with a failure rate of less than
1% per year; men and WOCBP must agree to adhere to contraception for the duration of
study participation and for a period of 31 weeks after completion of agent
administration; 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; in addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
- 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
- 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, 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
- The following recent and concurrent systemic medications are excluded:
- Systemic corticosteroid (> 10 mg daily prednisone equivalents) or other
immunosuppressive medication use within 2 weeks prior to study drug
administration
- Concurrent administration of valproic acid
- 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; patients with a history of
hepatitis, inflammatory bowel disease, including ulcerative colitis and Crohn's
disease, are excluded from this study, as are patients with a history of symptomatic
disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma],
systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's
Granulomatosis]); central nervous system (CNS) or motor neuropathy considered of
autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis, multiple
sclerosis); patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with
known immune impairment who may be unable to respond to anti-CTLA 4 antibody should
also be excluded
- 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; NOTE: patients with previously treated brain
metastases must have stable neurologic status and 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; 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 virus ribonucleic acid
(HCV antibody) indicating acute or chronic infection are also ineligible (baseline
testing required)
- 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 the cervix; NOTE: if there is a
history of prior malignancy, they must not be receiving other specific treatment for
their cancer
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
