PRIMARY OBJECTIVES:
I. To evaluate the maximum tolerated combination and safety profile of multi-fraction
radiosurgery with concurrent nivolumab plus or minus ipilimumab for recurrent
radiation-relapsed high-grade meningioma. (Phase I) II. To evaluate the objective response
rate (ORR) of multi-fraction radiosurgery with concurrent nivolumab plus or minus ipilimumab
for recurrent radiation-relapsed high-grade meningioma. (Phase II)
SECONDARY OBJECTIVE:
I. To evaluate duration of overall response, progression-free survival (PFS) and overall
survival (OS) of recurrent radiation-relapsed high-grade meningioma patients treated with the
combination of multi-fraction radiosurgery and nivolumab plus or minus ipilimumab.
CORRELATIVE OBJECTIVES:
I. To analyze the immunophenotype changes of peripheral T-cells during the treatment with
multi-fraction radiosurgery in combination with nivolumab plus or minus ipilimumab.
II. To perform molecular profiling assays on pretreatment/baseline archival tumor, including,
but not limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA)
sequencing (RNAseq), in order to IIa. Identify potential predictive and prognostic biomarkers
(such as neoantigen signature or mutation burden) beyond any genomic alteration by which
treatment may be assigned.
IIb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based
assessment platforms.
III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
and future research; specimens will be annotated with key clinical data, including
presentation, diagnosis, staging, summary treatment, and if possible, outcome.
IV. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
Trials Network (ETCTN) Biorepository.
OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study.
Patients are randomized to 1 of 2 cohorts.
COHORT A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles
repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable
toxicity. Patients also undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5.
COHORT B: Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months)
and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90
minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence
of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic
radiosurgery on days 1, 3, and 5.
After completion of study treatment, patients are followed up for 100 days.
Inclusion Criteria:
- Patients must have histologically confirmed World Health Organization (WHO) grade
II-III meningioma which has relapsed after prior radiation therapy with radiologically
progressive or recurrent disease
- Patients must have measurable disease, defined as at least 1 lesion that can be
accurately measured in at least one dimension as >= 1 cm on brain magnetic resonance
imaging (MRI) but with the maximum dimension =< 5 cm OR gross tumor volume < 20 cm^3.
All the relapsed disease would need to be eligible to be treated with reirradiation
- Patients must have at least one prior surgery with available archival formalin-fixed
paraffin-embedded (FFPE) tumor blocks of the initial or recurrent meningioma. If there
are multiple tumor blocks from multiple surgeries, the most recent tumor block (and
ideally of the relapsed tumor after initial radiation therapy) should be submitted. If
a tumor block is not available, an alternative of 20-30 unstained slides may be
submitted instead. Annotation regarding whether the tumor block is before or after
initial radiation therapy should be provided
- Prior initial radiation therapy may include external beam radiation or radiosurgery,
or combination of both. However, the total dose of prior radiation exposure to the
site of recurrent tumor (for consideration of re-irradiation) cannot be more than 70
Gy. The duration since the previous radiation exposure to the site of reirradiation
need to be at least 6 months
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- 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)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN
- Serum creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 30
mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional normal
- The effects of nivolumab and/or ipilimumab on the developing human fetus are unknown.
For this reason and because radiation therapy is known to be teratogenic, women of
childbearing 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 5 months after the last dose of investigational drug. 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 7 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. 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 5 months 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 7 months 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 100 days
- 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
- Ability to understand and the willingness to sign a written informed consent document
or, if decision-making capacity is impaired, consent of a legally authorized
representative (e.g., spouse, adult child, live-in caretaker).
Exclusion Criteria:
- Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to entering the study
- Patients who have had radiation therapy (to the site of reirradiation) within 6 months
prior to entering the study
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1); however, alopecia, sensory neuropathy =<
grade 2, or other =< grade 2 not constituting a safety risk based on the
investigator's judgment are acceptable
- Patients who are receiving any other investigational agents
- Patients who have previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
co-stimulation or immune checkpoint pathways
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab and/or ipilimumab
- History of severe hypersensitivity reaction to any monoclonal antibody
- Current use of immunosuppressive medication (EXCEPT for the following: Intranasal,
inhaled, topical steroids, or local steroid injection [e.g. intra-articular
injection]; systemic corticosteroids at doses =< 4 mg/day of dexamethasone or
equivalent; steroids as premedication for hypersensitivity reactions [e.g. computed
tomography (CT) scan premedication])
- 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. However, patients with human immunodeficiency virus (HIV) on
stable therapy with minimal viral loads and patients with hepatitis B and hepatitis C
who have received treatment with minimal viral loads will be eligible
- Pregnant women are excluded from this study because radiation therapy is teratogenic
and that the effects of nivolumab and/or ipilimumab on the developing human fetus are
unknown. Because there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother with nivolumab and/or ipilimumab,
breastfeeding should be discontinued if the mother is treated with nivolumab and/or
ipilimumab
- 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)
- Prior organ transplantation including allogeneic stem cell transplantation
- Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric
conditions including recent (within the past year) or active suicidal ideation or
behavior, or laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study
- Live vaccination within 4 weeks of the first dose of nivolumab and while on trial is
prohibited except for administration of inactivated vaccines
