Background:
More than 130 primary tumors of the central nervous system (CNS) have been identified. Most
affect less than 1,000 people in the United States each year. Because these tumors are so
rare, there are few proven therapies. This study will test whether the immunotherapy drug
nivolumab is an effective treatment for people with rare CNS tumors.
Objectives:
To learn if stimulating the immune system using the drug nivolumab can shrink tumors in
people with rare CNS (brain or spine) tumors or increase the time it takes for these tumors
to grow or spread.
Eligibility:
Adults whose rare CNS tumor has returned.
Design:
Participants will be screened:
- Heart and blood tests
- Physical and neurological exam
- Hepatitis tests
- Pregnancy test
- MRI. They will lay in a machine that takes pictures.
- Tumor tissue sample. This can be from a previous procedure.
At the start of the study, participants will have blood tests. They will answer questions
about their symptoms and their quality of life.
Participants will get nivolumab in a vein every 2 weeks for up to 64 weeks.
Participants will have monthly blood tests. Every other month they will have an MRI and a
neurologic function test. They will also answer questions about their quality of life.
Genetic tests will be done on participants' tumor tissue. Participants will be contacted if
any clinically important results are found.
After treatment ends, participants will be monitored for up to 5 years. They will have a
series of MRIs and neurological function tests. They will be asked to report any symptoms
they experience....
Background:
- There are more than 130 identified primary tumors of the central nervous system (CNS).
Most have an annual incidence of less than 1000 in the United States.
- Given the rarity of each of the tumors listed above, there is a paucity of proven
therapies. Most of these neoplasms are treated with maximum surgical resection followed
by treatment with external beam radiotherapy. With few exceptions (medulloblastoma,
adult ependymoma), there are no effective systemic regimens and even in chemotherapy
sensitive disease, most patients with recurrence eventually have no remaining salvage
treatments available.
- In the setting of this unmet need, we propose to create a basket protocol that will
evaluate the efficacy of the PD-1 inhibitor, nivolumab, in patients with refractory rare
central nervous system neoplasms.
- This study seeks to establish effective therapies at recurrence in patients with rare
CNS tumors. We hypothesize that this therapy will improve progression free survival
and/or objective responses.
- It will be important to determine whether any determined survival benefit is associated
with improvements in symptoms or does a worsening of symptoms offset the increase in
survival. Precedence exists for measuring non-therapeutic endpoints in oncology
research, and specifically in studies evaluating therapeutic benefit in patients with
CNS tumors. There have been efforts in neuro-oncology to evaluate secondary endpoints
using validated instruments as an additional indicator of benefit. The M.D. Anderson
Symptom Inventory-Brain Tumor Module (MDASI-BT) and Spine Tumor Module (MDASI-SP) allow
for the self-reporting of symptom severity and interference with daily activities for
patients with either brain or spinal cord tumors. The availability of validated
instruments provides an opportunity to prospectively assess the impact of treatment,
both positive and negative, on patients.
Objective:
Determine the efficacy of nivolumab in a variety of recurrent, refractory primary central
nervous system tumors as measured by disease control rate (confirmed CR/PR or durable SD for
at least 6 months).
Eligibility:
- Documented recurrent or progressive disease that corresponds to one of the tumors
eligible for testing.
- Age greater than or equal to 18 years of age.
- Karnofsky Performance greater than or equal to 70%.
- Tumor tissue available for review to confirm morphologic diagnosis
- Tumor tissue or slides available for molecular and immune profiling
Design:
- This is an open label phase II clinical trial. Patients will be treated with the immune
checkpoint inhibitor, nivolumab, at a standard dose of 240 mg intravenously every 2
weeks (+/- 3 days) for cycles 1 through 2, then doses of 480 mg every 4 weeks for a
total of 14 additional doses (cycles). A maximum of 18 treatments will be given (64
weeks).
- A cycle will be defined as 4 weeks and patients will undergo efficacy assessments using
MR imaging every 2 cycles. Toxicity assessments will occur before the initiation of each
cycle and patient outcomes measures (PROs) will be completed at the time of each
imaging study (every 2 cycles) but prior to the patient being informed of the imaging
results.
-After completion of the planned treatment course or if treatment was stopped because of
toxicity, patients will undergo imaging evaluations and PRO measurements every 8 weeks (or 2
months) for one year, then every 3 months for the next year, then every 4
months for the next year and then every 6 months while the patient remains on the protocol.
Patients off treatment because of disease progression will not undergo future imaging or PRO
assessments on this protocol.
- Bayesian Optimal Phase 2 design (BOP2), will be used to conduct this phase II trial in
patients with a variety of recurrent, refractory primary central nervous system tumors.
- The study will be comprised of 2 disease cohorts: heavily pretreated (defined as having
received 3 or more prior therapies due to relapse) and non-heavily pretreated (defined
as having received up to 2 prior therapies due to relapse). Each cohort will be
evaluated
independently for efficacy.
- INCLUSION CRITERIA:
1. Histopathologically proven diagnosis of Ependymoma, Medulloblastoma, Parenchymal
Pineal Region Tumors (Pineoblastoma, Pineocytoma, Pineal Tumor of Intermediate
Differentiation, Papillary Tumor of the Pineal Region), Choroid Plexus Tumors
(Carcinoma, Papilloma, Atypical Papilloma), Histone Mutated Gliomas, Gliomatosis
Cerebri, ATRT, Malignant/Atypical Meningioma, Gliosarcoma or Primary CNS Sarcoma,
Pleomorphic Xanthoastrocytoma (PXA) and Anaplastic Pleomorphic Xanthoastrocytoma
(APXA), and tumors formerly known as Primitive Neuro-Ectodermal Tumors (Embryonal
Tumor with Multilayered Rosettes, Medulloepithelioma, CNS Neuroblastoma, CNS
Ganglioneuroblastoma, CNSEmbryonal Tumor NOS) prior to registration as confirmed
by NCI Laboratory of Pathology.
2. The tumor tissue (e.g. block or 15 unstained slides) must be available to be sent
for immunophenotyping.
3. Patients must have progressive tumor growth after having received established
standard of care treatment for their disease. Patients will be enrolled into 2
different cohorts (cohort 1 or heavily pretreated; cohort 2 or not heavily
pretreated)
4. Age greater than or equal to 18;
5. Karnofsky performance status greater than or equal to 70 within 14 days prior to
Step 2 registration;
6. Adequate hematologic function based on CBC/differential within 14 days prior to
Step 2 registration defined as follows:
- Absolute neutrophil count greater than or equal to 1,500 cells/mm3;
- Platelet count greater than or equal to 100,000 cells/mm3
- Hemoglobin > 9.0 g/dl (may be transfused to achieve this level)
7. Adequate renal function within 14 days prior to Step 2 registration defined as
follows:
- BUN less than or equal to 30 mg/dl and
- Serum creatinine less than or equal to 1.7 mg/dl
8. Adequate hepatic function within 14 days prior to Step 2 registration defined as
follows:
- Total bilirubin (except patients with Gilbert s Syndrome, who are eligible
for the study but exempt from the total bilirubin eligibility criterion)
less than or equal to 2.0 mg/dl and
- ALT and AST less than or equal to 2.5x ULN
- No active or chronic hepatitis infection. HCV antibody (for Hepatitis C) and
Hepatitis B Surface antigen and Hepatitis B core antibody must be negative.
This has been routinely incorporated into immunotherapy trials with
checkpoint inhibitors because of concerns that the risk of treatment-induced
hepatic injury is increased in the setting of active viral hepatitis.
9. The patient must not be on a corticosteroid dose greater than physiologic
replacement dosing defined as 30 mg of cortisone per day or its equivalent.
10. The patient must provide study-specific informed consent prior to study entry. No
Durable Power of Attorney or Next of Kin can provide initial consent.
11. The effects of nivolumab on the developing human fetus are unknown. For this
reason, women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 5
months (30 days plus the time required for nivolumab to undergo five half-lives)
after the last dose of investigational drug.
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.
EXCLUSION CRITERIA:
1. Patients who are receiving any other investigational agents.
2. Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or
intracavitary or convectional enhanced delivery of therapy
3. Prior or concurrent malignancy unless its natural history or treatment does not have
the potential to interfere with the safety or efficacy assessment of the
investigational regimen
4. Severe, active co-morbidity defined as follows:
- Unstable angina within the last 6 months prior to Step 2 registration
- Transmural myocardial infarction within the last 6 months prior to Step 2
registration
- Evidence of recent myocardial infarction or ischemia by the findings of S-T
elevations of greater than or equal to 2 mm using the analysis of an EKG
performed within 14 days prior to Step 2 registration
- New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to Step 2 registration
- History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
within 6 months prior to Step 2 registration
- Serious and inadequately controlled cardiac arrhythmia
- Significant vascular disease (e.g., aortic aneurysm, history of aortic
dissection) or clinically significant peripheral vascular disease
- Evidence of bleeding diathesis or coagulopathy
- Serious or non-healing wound, ulcer, or bone fracture or history of abdominal
fistula, gastrointestinal perforation, intra-abdominal abscess major surgical
procedure, open biopsy, or significant traumatic injury within 28 days prior to
Step 2 registration, with the exception of the craniotomy for tumor resection.
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
- Known acquired immune deficiency syndrome (AIDS) based upon current CDC
definition; note, however, that HIV testing is not required for entry into this
protocol. The need to exclude patients with AIDS is based on the lack of
information regarding the safety of nivolumab in patients with active HIV
infection.
- Active connective tissue disorders, such as lupus or scleroderma, which in the
opinion of the treating physician may put the patient at high risk for
immunologic toxicity.
5. 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 or CIDP,
myasthenia gravis; systemic autoimmune disease such as 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.
--Of note, patients with vitiligo, endocrine deficiencies including thyroiditis
managed with replacement hormones including physiologic corticosteroids are eligible.
Patients with rheumatoid arthritis and other arthropathies, Sj(SqrRoot)(Delta)gren 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. However, patients with vitiligo, diabetes
mellitus, and Hashimoto thyroiditis on appropriate replacement therapy may be
enrolled.
6. Any other major medical illnesses or psychiatric impairments that in the
investigator's opinion will prevent administration or completion of protocol therapy.
7. Allergies and Adverse Drug Reaction: History of allergy to study drug components
8. Pregnancy or lactating females due to possible adverse effects on the developing fetus
or infant due to study drug. Women of childbearing potential must have a negative
serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to Step 2 registration.
9. History of severe hypersensitivity reaction to any monoclonal antibody.
