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

• ClinicalTrials.gov Identifier: NCT03173950
• Recruitment Status: Recruiting
• First Posted: June 2, 2017
• Last Update Posted: May 23, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief 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....

Condition or disease	Intervention/treatment	Phase
Medulloblastoma; Ependymoma; Pineal Region Tumors; Choroid Plexus Tumors; Atypical/Malignant Meningioma	Drug: Nivolumab	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of the Immune Checkpoint Inhibitor Nivolumab in Patients With Recurrent Select Rare CNS Cancers
• Actual Study Start Date: July 13, 2017
• Estimated Primary Completion Date: April 21, 2026
• Estimated Study Completion Date: April 21, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1/Experimental Therapy; Patients will receive nivolumab at standard dose of 240 mg IV every 2 weeks for cycles 1 through 2, then doses of 480 mg every 4 weeks for a total of 14 additional doses	Drug: Nivolumab; Participants will receive nivolumab at standard dose of 240 mg IV every 2 weeks for cycles 1 through 2, then doses of 480 mg every 4 weeks for a total of 14 additional doses

Outcome Measures

Primary Outcome Measures :

1. objective response [ Time Frame: end of treatment ]
   Rate of achieving a confirmed Complete Response/Partial Response (confirmed by imaging one month later)
2. progression free survival rate [ Time Frame: 6 months after end of treatment ]
   Rate of durable Stable Disease lasting at least 6 months (PFS-6)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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, 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.
  2. The tumor tissue (e.g. block or 20 unstained slides) must be available to be sent for immunophenotyping.
  3. 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
  4. Age greater than or equal to 18;
  5. 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.

  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

     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: 90 - 130 ml/min; Female: 80 - 125 ml/min)

  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

  9. 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.

  1 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. The patient must provide study-specific informed consent prior to study entry.

  2 No Durable Power of Attorney or Next of Kin can provide initial consent.

  10. Participants must meet the below requirements regarding COVID-19 Status:

  1. 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#anchor_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.

  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 90 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.

  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.

  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.

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:

1. Patients who are receiving any other investigational agents.
2. 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.
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 (Bullet) 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, with the exception of pericavitary ischemia due to tumor resection.

   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 participants 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. 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 diseases, scleroderma, inflammatory bowel disease (IBD), Crohn s, ulcerative colitis, hepatitis; and participants 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, 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.

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.

10 Participants with contraindications to COVID-19 vaccination will not be eligible.

11 Participants unable to have MRIs.

Contacts and Locations

Contacts

Contact: NCI NOB Referral; (240) 760-6010; ncinobreferral@mail.nih.gov

Contact: Marta Penas-Prado, M.D.; (240) 858-3606; marta.penas-prado@nih.gov

Locations

United States, California

UC San Diego; Recruiting

La Jolla, California, United States, 92093-0603

Contact: David Piccioni 858-822-6346 dpiccioni@ucsd.edu

UC Irvine; Recruiting

Orange, California, United States, 92668

Contact: Daniela Bota 714-456-7214 dbota@uci.edu

United States, Florida

Orlando Health; Recruiting

Orlando, Florida, United States, 32806

Contact: Nicholas Avgeropoulos 407-303-2770 nicholas.avgeropoulos@orlandohealth.com

United States, Illinois

Northwestern University; Recruiting

Chicago, Illinois, United States, 60611

Contact: Priya Kumthekar 312-695-1300 priya.kumthekar@nm.org

NorthShore University Medical Center; Recruiting

Evanston, Illinois, United States, 60201

Contact: Janardan Khandekar 847-570-2507 jkhandekar@northshore.org

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: NIH Clinical Center Office of Patient Recruitment (OPR) 800-411-1222 ext TTY dial 711 ccopr@nih.gov

United States, Missouri

Washington University of St. Louis; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Milan Chheda 314-362-2877 rgkatumba@wustl.edu

United States, Ohio

Ohio State University; Recruiting

Columbus, Ohio, United States, 43210-1240

Contact: Pierre Giglio 614-293-4448 Pierre.Giglio@osumc.edu

United States, Pennsylvania

University of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15261

Contact: Megan Mantica 412-692-2600 manticam@upmc.edu

United States, South Carolina

Medical University of South Carolina; Recruiting

Charleston, South Carolina, United States, 29425

Contact: Scott Lindhorst 843-792-9563 lindhors@musc.edu

United States, Texas

UT MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030-4096

Contact: Carlos Kamiya-Matsouka 713-408-3538 ckamiya@mdanderson.org

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Marta Penas-Prado, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Gilbert MR, Ruda R, Soffietti R. Ependymomas in adults. Curr Neurol Neurosci Rep. 2010 May;10(3):240-7. doi: 10.1007/s11910-010-0109-3.

Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, Ellingson BM, Hashimoto N, Pollack IF, Brandes AA, Franceschi E, Herold-Mende C, Nayak L, Panigrahy A, Pope WB, Prins R, Sampson JH, Wen PY, Reardon DA. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015 Nov;16(15):e534-e542. doi: 10.1016/S1470-2045(15)00088-1.

Daud AI, Loo K, Pauli ML, Sanchez-Rodriguez R, Sandoval PM, Taravati K, Tsai K, Nosrati A, Nardo L, Alvarado MD, Algazi AP, Pampaloni MH, Lobach IV, Hwang J, Pierce RH, Gratz IK, Krummel MF, Rosenblum MD. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Invest. 2016 Sep 1;126(9):3447-52. doi: 10.1172/JCI87324. Epub 2016 Aug 15.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03173950
• Other Study ID Numbers: 170102; 17-C-0102
• First Posted: June 2, 2017
• Last Update Posted: May 23, 2023
• Last Verified: May 18, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Genomic data are made available via dbGaP through requests to the data custodians.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Immunotherapy; Anti-PD-1 Antibody; Brain Tumors; MDASI-BT; Spinal Cord Tumors

Additional relevant MeSH terms:

Neoplasms; Meningioma; Ependymoma; Medulloblastoma; Choroid Plexus Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors, Primitive; Cerebral Ventricle Neoplasms; Brain Neoplasms; Brain Diseases; Central Nervous System Diseases; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action