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

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 programmed cell death protein 1 (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 complete response (CR)/partial response (PR) or durable stable disease (SD) for at least 6 months).

Eligibility:

* Documented recurrent or progressive disease that corresponds to one of the tumors eligible for testing.
* Age >= 18 years of age.
* Karnofsky Performance >= 70%.
* Tumor tissue available for central review to confirm morphologic diagnosis
* Tumor tissue or slides must be 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.

• Nivolumab (Drug), also known as Opdivo: Individuals will receive nivolumab at standard dose of 240 mg intravenous (IV) every 2 weeks for cycles 1 through 2, then doses of 480 mg every 4 weeks for a total of 14 additional doses.
• EKG (Diagnostic test), also known as Electrocardiogram: Screening/baseline.
• MRI Brain and/or spine (Diagnostic test), also known as Magnetic resonance imaging brain and/or spine: Screening/baseline.
• Body CT Scan (Diagnostic test), also known as Body computed tomography: Screening/baseline.
• MDASI-BT (Other), also known as M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT): Screening/baseline. During active treatment and post therapy follow up.
• MDASI-SP (Other), also known as M.D. Anderson Symptom Inventory Spine Tumor (MDASI-SP): Screening/baseline. During active treatment and post therapy follow up.

Primary outcomes

• Disease Control Rate (Complete Response (CR) + Partial Response (PR) or Durable Stable Disease (SD) for 6 Months Measured in a Variety of Recurrent Refractory Primary Central Nervous System Tumors Reported With Standard Deviation [From cycle one Day 1 of the treatment through the end of treatment, up to 64 weeks]: Disease control rate (DCR) measured in a variety of recurrent refractory primary central nervous system tumors. DCR is defined as a confirmed CR/PR or durable stable disease (SD) for 6 months assessed by the Immunotherapy Response Assessment Neuro-Oncology (iRANO) criteria. Complete Response is complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. Partial Response is ≥ 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. Durable stable disease does not qualify for CR, PR or progression (>25% increase in the sum of the products of perpendicular diameters of enhancing lesions (over best response \[smallest tumor size\] or baseline if no decrease) on stable or increasing doses of corticosteroids. A single value was calculated (e.g. summed or averaged) by
• Disease Control Rate (Complete Response (CR) + Partial Response (PR) or Durable Stable Disease (SD) for 6 Months Measured in a Variety of Recurrent Refractory Primary Central Nervous System Tumors Reported With a 95% Confidence Interval [From cycle one Day 1 of the treatment through the end of the treatment, up to 64 weeks]: Disease control rate (DCR) measured in a variety of recurrent refractory primary central nervous system tumors. DCR is defined as a confirmed CR/PR or durable stable disease (SD) for 6 months assessed by the Immunotherapy Response Assessment Neuro-Oncology (iRANO) criteria. Complete Response is complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. Partial Response is ≥ 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. Durable stable disease does not qualify for CR, PR or progression (i.e., >25% increase in the sum of the products of perpendicular diameters of enhancing lesions (over best response \[smallest tumor size\] or baseline if no decrease) on stable or increasing doses of corticosteroids. A single value was calculated (e.g. summed or averaged) by
• Progression Free Survival (PFS) [From cycle one Day 1 of the treatment through the end of the treatment, up to 64 weeks]: PFS is defined as the date of on-study to the date of disease progression or death, estimated with the Kaplan-Meier method and reported with a 95% confidence interval. Response was assessed by the Immunotherapy Response Assessment Neuro-Oncology (iRANO) criteria and estimated using the Kaplan-Meier method. Progressive Disease is >25% increase in sum of the products of perpendicular diameters of enhancing lesions (over best response \[smallest tumor size\] or baseline if no decrease) on stable or increasing doses of corticosteroids.
• Progression Free Survival at 6 Months With 95% Confidence Interval [6 months after the initiation of treatment, up to 24 weeks]: PFS-6 is the rate of durable Stable Disease lasting at least 6 months defined from the day of study entry until imaging is confirmed to show disease progression reported with a 95% confidence interval based on the Brookmeyer-Crowley method. Response was assessed by the Immunotherapy Response Assessment Neuro-Oncology (iRANO) criteria and estimated using the Kaplan-Meier method. Progressive Disease is >25% increase in sum of the products of perpendicular diameters of enhancing lesions (over best response \[smallest tumor size\] or baseline if no decrease) on stable or increasing doses of corticosteroids.

Secondary outcomes

• Overall Survival (OS) [Time from the study entry and after initiation of nivolumab to participants death, up to 5 years]: OS is defined as the date of on-study to the date of death from any cause or last follow up, estimated with the Kaplan-Meier method and reported with a 95% confidence interval based on the Brookmeyer-Crowley method.
• Mean Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Module Reported With a 95% Confidence Interval, at Each Time Point [Baseline (Up to 14 days prior to treatment), and at time of imaging - cycle 2, 4, 6, 8, 10, and 12 (one cycle = 4 weeks)]: Symptom burden is composed of severity and interference as measured by the MD Anderson Symptom Inventory-Brain tumor (MDASI-BT) or MD Anderson Symptom Inventory-Spine Tumor. The MDASI-BT questionnaire contains 23 symptoms and 6 interference items. The MDASI-SP questionnaire contains 19 symptoms and 6 interference items. Symptom severity is the Mean of the 23 or 19 symptoms and ranges from 0 to 10. Symptom interference is the Mean of the 6 interference items and ranges from 0 to 10. Higher scores indicate worse symptoms or worse interference.
• Mean Symptom Burden Severity & Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) & MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Module Reported With Standard Deviation(SD) at Each Time Point [Baseline (up to 14 days prior to treatment), and at time of imaging - cycle 2, 4, 6, 8, 10, or 12 (one cycle = 4 weeks)]: Symptom burden is composed of severity and interference as measured by the MD Anderson Symptom Inventory-Brain tumor (MDASI-BT) or MD Anderson Symptom Inventory-Spine Tumor. The MDASI-BT questionnaire contains 23 symptoms and 6 interference items. The MDASI-SP questionnaire contains 19 symptoms and 6 interference items. Symptom severity is the Mean of the 23 or 19 symptoms and ranges from 0 to 10. Symptom interference is the Mean of the 6 interference items and ranges from 0 to 10. Higher scores indicate worse symptoms or worse interference.
• Mean Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Between Responders and Non-responders Reported With 95% Confidence Interval [Two possible timepoints dependent on response status. Non-responders: determined by whether disease progression occurred prior to or at cycle 6 or not. Responders: cycle 6. One cycle= 4 weeks/participants who did not have disease progression by cycle 6.]: Symptom burden is composed of severity and interference as measured by the MD Anderson Symptom Inventory-Brain tumor (MDASI-BT) or MD Anderson Symptom Inventory-Spine Tumor. The MDASI-BT questionnaire contains 23 symptoms and 6 interference items. The MDASI-SP questionnaire contains 19 symptoms and 6 interference items. Symptom severity is the Mean of the 23 or 19 symptoms and ranges from 0 to 10. Higher scores indicate. Symptom interference is the Mean of the 6 interference items and ranges from 0 to 10. Higher scores indicate worse symptoms or worse interference. Response status was determined by whether disease progression occurred prior to or at cycle 6 or not. Participants who had disease progression prior to or at cycle 6 were non-responders and participants who did not have disease progression by cycle 6 were responders. Relevant MDASI-BT \& MDASI-SP data are those that correspond to the cycle where response status was determined. It is a unique cycle for each participant.
• Mean Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Between Responders and Non-responders Reported With Standard Deviation [Two possible timepoints dependent on response status. Non-responders: determined by whether disease progression occurred prior to or at cycle 6 or not. Responders: cycle 6. One cycle= 4 weeks/participants who did not have disease progression by cycle 6.]: Symptom burden is composed of severity and interference as measured by the MD Anderson Symptom Inventory-Brain tumor (MDASI-BT) or MD Anderson Symptom Inventory-Spine Tumor. The MDASI-BT questionnaire contains 23 symptoms and 6 interference items. The MDASI-SP questionnaire contains 19 symptoms and 6 interference items. Symptom severity is the Mean of the 23 or 19 symptoms and ranges from 0 to 10. Higher scores indicate. Symptom interference is the Mean of the 6 interference items and ranges from 0 to 10. Higher scores indicate worse symptoms or worse interference. Response status was determined by whether disease progression occurred prior to or at cycle 6 or not. Participants who had disease progression prior to or at cycle 6 were non-responders and participants who did not have disease progression by cycle 6 were responders. Relevant MDASI-BT \& MDASI-SP data are those that correspond to the cycle where response status was determined. It is a unique cycle for each participant.
• Mean Change Scores in Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Module Between Baseline and Even-numbered Cycle [Between Baseline (up to 14 days prior to treatment) and at time of imaging - cycle 2, 4, 6, 8, 10, and 12 (one cycle = 4 weeks)]: Symptom burden is composed of severity and interference as measured by the MD Anderson Symptom Inventory-Brain tumor (MDASI-BT) or MD Anderson Symptom Inventory-Spine Tumor. The MDASI-BT questionnaire contains 23 symptoms and 6 interference items. The MDASI-SP questionnaire contains 19 symptoms and 6 interference items. Symptom severity is the Mean of the 23 or 19 symptoms and ranges from 0 to 10. Symptom interference is the Mean of the 6 interference items and ranges from 0 to 10. Higher scores indicate worse symptoms or worse interference. Mean change score is even-numbered cycle minus baseline. Hence, negative change scores indicate improvement.
• Number of Grades 1, 2, 3, 4, and/or 5 Treatment Related Serious and/or Non-serious Adverse Events and Type [Adverse Events were monitored/assessed from the first study intervention, Study Day 1 through 100 days after the study agent was last administered, up to 5 years]: Here is the number of Grade 1, 2, 3, 4, and/or 5 serious and/or non-serious adverse events and type assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.

Other outcomes

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). [Adverse Events were monitored/assessed from the first study intervention, Study Day 1 through 100 days after the study agent was last administered, up to 5 years]: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Sex: All, ages: 18 Years to 99 Years

* 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, Atypical Teratoid/Rhabdoid Tumor (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, Central Nervous System (CNS) Neuroblastoma, CNS Ganglioneuroblastoma, CNS Embryonal Tumor NOS; and tumor entities emerging from methylation profiling of CNS-PNETs: CNS neuroblastoma with Forkhead box protein R2 (FOXR2) activation, CNS Ewing sarcoma family tumor with CIC alteration, CNS high-grade neuroepithelial tumor with meningioma 1 (MN1) alterations, and CNS high-grade neuroepithelial tumor with BCOR alteration) prior to registration.

  *Individuals 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 National Cancer Institute (NCI) Laboratory of Pathology.
* Individuals must have progressive tumor growth after having received established standard of care and/or other experimental treatments for their newly diagnosed or recurrent disease. Individuals will be enrolled into 2 different cohorts (cohort 1 or heavily pretreated; cohort 2 or not heavily pretreated).
* Age >= 18
* Karnofsky performance status >= 70 within 14 days prior to Step 2 registration; Individuals with severe paraparesis/paraplegia who need minimal assistance for selfcare due to their motor deficit but are otherwise functionally independent will be considered eligible.
* Adequate hematologic function based on complete blood count (CBC)/differential within 14 days prior to Step 2 registration defined as follows:

  * Absolute neutrophil count >= 1,500 cells/mm\^3;
  * Platelet count >= 100,000 cells/mm\^3
  * 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:

  * Blood urea nitrogen (BUN) <= 30 mg/dl and
  * Serum creatinine <= 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)

* 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) <= 2.0 mg/dl and
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5x ULN
* No active or chronic hepatitis infection. Hepatitis C virus (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 individual must not be on a corticosteroid dose greater than physiologic replacement dosing defined as 30 mg of cortisone per day or its equivalent.
* The individual must provide study-specific informed consent prior to study entry. No Durable Power of Attorney or Next of Kin can provide initial consent.
* 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 individuals of childbearing potential (IOCBP) partners from exposure to an individual's seminal fluid, men that can father children will not be required to use contraceptive measures and/or a latex or other synthetic condom during sexual activity with an WOCBP partner.

EXCLUSION CRITERIA:

* Individuals who are receiving any other investigational agents.
* 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.
* 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.
* 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 >= 2 mm using the analysis of an electrocardiogram (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 Centers for Disease Control (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol. The need to exclude participants with acquired immunodeficiency syndrome (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.
* Individuals 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 individuals with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or chronic inflammatory demyelinating polyneuropathyI (CIDP), 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 individuals 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, individuals with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Participants 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. However, individuals with vitiligo, diabetes mellitus, and Hashimoto thyroiditis on appropriate replacement therapy may be enrolled.

* 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 women 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 human chorionic gonadotropin (HCG) within 24 hours prior to Step 2 registration.
* History of severe hypersensitivity reaction to any monoclonal antibody.
* Individuals unable to have magnetic resonance imaging (MRIs).

Participant flow

Outcome results

• Disease Control Rate (Complete Response (CR) + Partial Response (PR) or Durable Stable Disease (SD) for 6 Months Measured in a Variety of Recurrent Refractory Primary Central Nervous System Tumors Reported With Standard Deviation (Primary), Mean, Proportion of participants: Cohort 1- Heavily Pre-Treated 0.219 +/- 0.048; Cohort 2 - Non-Heavily Pre-Treated 0.379 +/- 0.09; Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Disease Control Rate (Complete Response (CR) + Partial Response (PR) or Durable Stable Disease (SD) for 6 Months Measured in a Variety of Recurrent Refractory Primary Central Nervous System Tumors Reported With a 95% Confidence Interval (Primary), Number, percentage of participants: Cohort 1- Heavily Pre-Treated 21.9 (13.1 to 33.1); Cohort 2 - Non-Heavily Pre-Treated 37.9 (20.7 to 57.7); Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Progression Free Survival (PFS) (Primary), Median, Days: Cohort 1- Heavily Pre-Treated 56.5 (55 to 111); Cohort 2 - Non-Heavily Pre-Treated 133 (110 to 223); Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Progression Free Survival at 6 Months With 95% Confidence Interval (Primary), Median, Percentage of participants: Cohort 1- Heavily Pre-Treated 21.9 (13.1 to 33.1); Cohort 2 - Non-Heavily Pre-Treated 37.9 (20.7 to 57.7); Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Overall Survival (OS) (Secondary), Median, years: Cohort 1- Heavily Pre-Treated 1.62 (1.05 to 3.42); Cohort 2 - Non-Heavily Pre-Treated 3.47 (2.15 to NA); Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Mean Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Module Reported With a 95% Confidence Interval, at Each Time Point (Secondary), Mean, score on a scale: Cohort 1- Heavily Pre-Treated: Symptom Severity 1.94 (1.53 to 2.34); Cohort 1- Heavily Pre-Treated: Symptom Interference 2.92 (2.31 to 3.54); Cohort 2 - Non-Heavily Pre-Treated: Symptom Severity 2.06 (1.145 to 2.68); Cohort 2 - Non-Heavily Pre-Treated: Symptom Interference 3.63 (2.51 to 4.75); Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Mean Symptom Burden Severity & Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) & MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Module Reported With Standard Deviation(SD) at Each Time Point (Secondary), Mean, score on a scale: Cohort 1- Heavily Pre-Treated: Symptom Severity 1.94 +/- 1.80; Cohort 1- Heavily Pre-Treated: Symptom Interference 2.92 +/- 2.72; Cohort 2 - Non-Heavily Pre-Treated: Symptom Severity 2.06 +/- 1.59; Cohort 2 - Non-Heavily Pre-Treated: Symptom Interference 3.63 +/- 2.91; Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Mean Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Between Responders and Non-responders Reported With 95% Confidence Interval (Secondary), Mean, score on a scale: Cohort 1- Heavily Pre-Treated: Responders 1.61 (0.86 to 2.36); Cohort 1- Heavily Pre-Treated: Non-Responders 2.19 (1.74 to 2.64); Cohort 2 - Non-Heavily Pre-Treated: Responders 1.08 (0.45 to 1.70); Cohort 2 - Non-Heavily Pre-Treated: Non-Responders 1.91 (1.22 to 2.61); Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles (p 0.18)
• Mean Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Between Responders and Non-responders Reported With Standard Deviation (Secondary), Mean, score on a scale: Cohort 1- Heavily Pre-Treated Responders 1.61 +/- 1.10; Cohort 1- Heavily Pre-Treated Non-Responders 2.19 +/- 1.74; Cohort 2 - Non-Heavily Pre-Treated Responders 1.08 +/- 0.96; Cohort 2 - Non-Heavily Pre-Treated Non-Responders 1.91 +/- 1.33; Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles (p 0.18)
• Mean Change Scores in Symptom Burden Severity and Interference Using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and MD Anderson Symptom Inventory-Spine Tumor (MDASI-SP) Module Between Baseline and Even-numbered Cycle (Secondary), Mean, score on a scale: Cohort 1- Heavily Pre-Treated: Symptom Severity 0.22 (-0.11 to 0.55); Cohort 1- Heavily Pre-Treated: Symptom Interference 0.07 (-0.51 to 0.64); Cohort 2 - Non-Heavily Pre-Treated: Symptom Severity -0.37 (-0.79 to 0.05); Cohort 2 - Non-Heavily Pre-Treated: Symptom Interference -1.14 (-2.28 to -0.01); Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles (p 0.36)
• Number of Grades 1, 2, 3, 4, and/or 5 Treatment Related Serious and/or Non-serious Adverse Events and Type (Secondary), Number, adverse events: Cohort 1- Heavily Pre-Treated: Grade 1 1; Cohort 1- Heavily Pre-Treated: Grade 2 3; Cohort 1- Heavily Pre-Treated: Grade 3 0; Cohort 1- Heavily Pre-Treated: Grade 4 0; Cohort 1- Heavily Pre-Treated: Grade 5 0; Cohort 2 - Non-Heavily Pre-Treated: Grade 1 2; Cohort 2 - Non-Heavily Pre-Treated: Grade 2 0; Cohort 2 - Non-Heavily Pre-Treated: Grade 3 0; Cohort 2 - Non-Heavily Pre-Treated: Grade 4 0; Cohort 2 - Non-Heavily Pre-Treated: Grade 5 0; Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles
• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). (Other pre specified), Count of participants, Participants: Cohort 1- Heavily Pre-Treated 76; Cohort 2 - Non-Heavily Pre-Treated 30; Participants Enrolled Who Were Not Treated OR Completed Treatment Cycles

Adverse events

Time frame: All-Cause Mortality was monitored/documented throughout the study and up to 5 years post treatment &/or until early termination of the study. Document adverse events from the first study intervention, Study Day 1 through 100 days after the study agent was last administered. Adverse events that are serious need to be recorded in 100 days. Beyond 100 days after the last intervention, only adverse events which are serious and related to the study intervention need to be recorded for up to 5 years.

Serious adverse events by term

7 more terms not shown.

Other adverse events by term

161 more terms not shown.

Limitations and caveats: 11 participating sites started/3completed:National Institutes of Health Clinical Center, Northwestern University, University of Texas MDAnderson Cancer Center. Sites contributed to data/closed early to enrollment due to poor accrual:University of Pittsburgh Medical Center, University of California San Diego, University of California Irvine, Orlando Health, Washington University in St. Louis, NorthShore University HealthSystem, The Ohio States University, and Medical University of South Carolina.

• 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. PMID 20425040
• 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. PMID 26545842
• 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. PMID 27525433
• Results publication: Collins RRJ, Florke Gee RR, Tozandehjani S, Bayat T, Hoyos Sanchez MC, Gutierrez JSS, Breznik B, Lee AK, Peters ST, Connelly JP, Pruett-Miller SM, Roussel MF, Rakheja D, Tillman HS, Potts PR, Fon Tacer K. Melanoma antigens in pediatric medulloblastoma contribute to tumor heterogeneity and species-specificity of group 3 tumors. Acta Neuropathol Commun. 2025 Jul 28;13(1):164. doi: 10.1186/s40478-025-02055-3. PMID 40721826

• Study Protocol and Statistical Analysis Plan (PDF, 2025-07-01)
• Informed Consent Form (PDF, 2025-03-13)

• Jing Wu, M.D., Principal investigator, National Cancer Institute (NCI)