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

  • STATUS
    Recruiting
  • End date
    May 21, 2024
  • participants needed
    180
  • sponsor
    National Cancer Institute (NCI)
Updated on 16 June 2022
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 IdentifierNCT03173950
SponsorNational Cancer Institute (NCI)
Last Modified on16 June 2022

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 high-grade 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
Age greater than or equal to 18
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
Adequate hematologic function based on CBC/differential within 14 days prior to Step 2 registration defined as follows
Karnofsky performance status (Bullet) 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 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)
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
Adequate hepatic function within 14 days prior to Step 2 registration defined as
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
ALT and AST less than or equal to 2.5x ULN
normal limits _, the patient would be eligible to enroll onto study. (_ Normal
Creatinine Clearance Range: Male: 90 - 130 ml/min; Female: 80 - 125 ml/min)
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
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
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 patient must provide study-specific informed consent prior to study entry. No
Durable Power of Attorney or Next of Kin can provide initial consent
[2.1.1.10](telnet://2.1.1.10) Participants must meet the below requirements regarding COVID-19 Status
[2.1.1.10](telnet://2.1.1.10).1 Participants must be fully vaccinated for coronavirus disease 2019
(COVID-19) as defined by the Center for Disease Control guidance for patients who
are immunocompromised. Participants must have received required vaccination(s) by
the time of Step 2 registration and be considered fully immunized (typically 2
weeks after final vaccination) by the time of the initiation of treatment
[2.1.1.10](telnet://2.1.1.10).2 Participants must have a negative COVID-19 test within 72 hours of the
first dose of study drug. Patients who had documented COVID-19 infection within
days of treatment but are more than 20 days from infection do not need to be
tested and are eligible if they fulfill the eligibility requirement regarding
adequate vaccination
[2.1.1.10](telnet://2.1.1.10).3 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 dose of investigational drug
NOTE: Based on the evidence cited in Nivolumab IB ver. 20, given that nivolumab is not a
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

Patients who are receiving any other investigational agents
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
requiring hospitalization or precluding study therapy at the time of registration
Prior use of an immunotherapy such as (but not limited to) a vaccine therapy
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 registration
Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations
of (Bullet) 2 mm using the analysis of an EKG performed within 14 days prior to Step 2
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
managed with replacement hormones including physiologic corticosteroids are eligible
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 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
Any other major medical illnesses or psychiatric impairments that in the
investigator's opinion will prevent administration or completion of protocol therapy
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
Known acquired immune deficiency syndrome (AIDS) based upon current CDC definition
or infant due to study drug. Women of childbearing potential must have a negative
note, however, that HIV testing is not required for entry into this protocol. The need
serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
to exclude participants with AIDS is based on the lack of information regarding the
hours prior to Step 2 registration
safety of nivolumab in patients with active HIV infection
History of severe hypersensitivity reaction to any monoclonal antibody
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
Participants 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 participants 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
hepatitis; and participants with a history of toxic epidermal necrolysis (TEN)
-Of note, participants with vitiligo, endocrine deficiencies including thyroiditis
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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

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.

Learn more

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

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note