Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers

STATUS

Recruiting
End date

Apr 21, 2027
participants needed

180
sponsor

National Cancer Institute (NCI)

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Updated on 3 September 2023

See if I qualify

platelet count

renal function

cancer

corticosteroids

absolute neutrophil count

meningioma

carcinoma

ependymoma

karnofsky performance status

investigational drug

MRI

gilbert's disease

experimental drug

neutrophil count

nivolumab

cortisone

gliosarcoma

sarcoma

medulloblastoma

central nervous system tumor

pineoblastoma

atypical meningioma

Summary

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....

Description

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 central review to confirm morphologic diagnosis
Tumor tissue or slides available for central 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 (+/- 3 days) 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 (and/or other imaging tests if applicable) 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) and non-heavily pretreated (defined as having received up to 2 prior therapies). Each cohort will be evaluated

independently for efficacy.

Details

Condition	Medulloblastoma, Ependymoma, Pineal Region Tumors, Choroid Plexus Tumors, Atypical/Malignant Meningioma
Treatment	Nivolumab
Clinical Study Identifier	NCT03173950
Sponsor	National Cancer Institute (NCI)
Last Modified on	3 September 2023

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	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, CNS Embryonal Tumor NOS; and tumor entities emerging from methylation profiling of CNS-PNETs: CNS neuroblastoma with FOXR2 activation, CNS Ewing sarcoma family tumor with CIC alteration, CNS highgrade neuroepithelial tumor with MN1 alterations, and CNS high-grade neuroepithelial tumor with BCOR alteration) prior to registration
	Patient with extra CNS metastases from meningioma will be eligible even if pathology review fails to demonstrate high grade features on available tumor samples
	The tumor tissue (e.g., block or 20 unstained slides) must be available to be sent for immunophenotyping by NCI Laboratory of Pathology
	Participants must have progressive tumor growth after having received established standard of care and/or other experimental treatments for their newly diagnosed or recurrent disease. Participants will be enrolled into 2 different cohorts (cohort 1 or heavily pretreated; cohort 2 or not heavily pretreated)
	Age >= 18
	Adequate hematologic function based on CBC/differential within 14 days prior to Step 2 registration defined as follows
	Karnofsky performance status >= 70 within 14 days prior to Step 2 registration; Participants with severe paraparesis/paraplegia who need minimal assistance for selfcare due to their motor deficit but are otherwise functionally independent will be considered eligible
	Absolute neutrophil count >= 1,500 cells/mm3
	Hemoglobin > 9.0 g/dl (may be transfused to achieve this level)
	Platelet count >= 100,000 cells/mm3
	Adequate renal function within 14 days prior to Step 2 registration defined as
	follows
	BUN <= 30 mg/dl and
	Adequate hepatic function within 14 days prior to Step 2 registration defined as
	Serum creatinine <= 1.7 mg/dl
	follows
	Note: If the serum creatinine is greater than 1.7 mg/dl, a 24-hour urine creatinine
	clearance will be obtained and if the result of this study is within normal limits _, the
	patient would be eligible to enroll onto study. (_ Normal Creatinine Clearance Range: Male
	- 130 ml/min; Female: 80 - 125 ml/min)
	replacement dosing defined as 30 mg of cortisone per day or its equivalent
	Total bilirubin (except patients with Gilbert s Syndrome, who are eligible for
	the study but exempt from the total bilirubin eligibility criterion) <= 2.0 mg/dl
	and
	ALT and AST <= 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
	The participant must not be on a corticosteroid dose greater than physiologic
	The participant must provide study-specific informed consent prior to study entry. No
	Durable Power of Attorney or Next of Kin can provide initial consent
	Participants must meet the below requirements regarding COVID-19 Status
	Participants must be fully vaccinated for coronavirus disease 2019 (COVID-19) and
	if applicable, up to date, as defined by the Center for Disease Control guidance
	for patients who are moderately or severely immunocompromised
	<https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html#an>
	chor_1630089774152 . Participants must have received required vaccination(s) and
	boosters (if applicable) by the time of Step 2 registration and be considered
	fully immunized (typically 2 weeks after final vaccination or booster) by the
	time of the initiation of treatment
	NOTE: Given the experimental nature of this treatment, participants on this trial will be
	considered moderately or severely immunocompromised for the purpose of COVID vaccination
	requirements
	Vaccinated participants must agree to follow current guidance to protect themselves
	from exposure to COVID-19, such as wearing masks, social distancing, and maintaining
	good hand hygiene even after vaccination
	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
	NOTE: Based on the evidence cited in Nivolumab IB ver. 20, given that nivolumab is not a
	dose of investigational drug
	genotoxic agent, and that relevant systemic concentrations sufficient to produce a risk of
	fetal toxicity are not expected in WOCBP partners from exposure to a male participant s
	seminal fluid, male study participants will not be required to use contraceptive measures
	and/or a latex or other synthetic condom during sexual activity with a WOCBP partner
Exclusion Criteria
	Severe, active co-morbidity defined as follows
	Unstable angina within the last 6 months prior to Step 2 registration
	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
	Serious and inadequately controlled cardiac arrhythmia
	registration
	Evidence of bleeding diathesis or coagulopathy
	New York Heart Association grade II or greater congestive heart failure requiring
	Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
	hospitalization within 12 months prior to Step 2 registration
	History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
	Chronic obstructive pulmonary disease exacerbation or other respiratory illness
	Prior use of an immunotherapy such as (but not limited to) a vaccine therapy
	Participants who are receiving any other investigational agents
	dendritic cell vaccine, other checkpoint inhibitors, or intracavitary or convectional
	enhanced delivery of chemotherapy
	Transmural myocardial infarction within the last 6 months prior to Step 2
	Evidence of recent myocardial infarction or ischemia by the findings of S-T
	elevations of >= 2 mm using the analysis of an EKG performed within 14 days prior
	to Step 2 registration
	diseases, scleroderma, inflammatory bowel disease (IBD), Crohn s, ulcerative colitis
	within 6 months prior to Step 2 registration, with the exception of pericavitary
	Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the
	ischemia due to tumor resection
	risk of recurrence or exacerbation of disease
	Significant vascular disease (e.g., aortic aneurysm, history of aortic
	dissection) or clinically significant peripheral vascular disease
	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
	registration
	Step 2 registration, with the exception of the craniotomy for tumor resection
	Any other major medical illnesses or psychiatric impairments that in the
	Acute bacterial or fungal infection requiring intravenous antibiotics at the time
	investigator's opinion will prevent administration or completion of protocol therapy
	of registration
	Allergies and Adverse Drug Reaction: History of allergy to study drug components
	Pregnancy or lactating females due to possible adverse effects on the developing fetus
	requiring hospitalization or precluding study therapy at the time of
	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
	hours prior to Step 2 registration
	Known acquired immune deficiency syndrome (AIDS) based upon current CDC
	History of severe hypersensitivity reaction to any monoclonal antibody
	definition; note, however, that HIV testing is not required for entry into this
	protocol. The need to exclude participants with AIDS is based on the lack of
	Participants with active autoimmune disease or history of autoimmune disease that
	information regarding the safety of nivolumab in patients with active HIV
	might recur, which may affect vital organ function or require immune suppressive
	infection
	treatment including systemic corticosteroids, should be excluded. These include but
	Active connective tissue disorders, such as lupus or scleroderma, which in the
	are not limited to participants with a history of immune related neurologic disease
	opinion of the treating physician may put the patient at high risk for
	multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or
	immunologic toxicity
	CIDP, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue
	hepatitis; and participants with a history of toxic epidermal necrolysis (TEN)
	Of note, participants with vitiligo, endocrine deficiencies including thyroiditis managed
	with replacement hormones including physiologic corticosteroids are eligible. Participants
	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
	Participants with contraindications to COVID-19 vaccination will not be eligible
	Participants unable to have MRIs

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Step 3 Enroll in the clinical study

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Step 4 Get your study results

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers