Phase II Trial of the Immune Checkpoint Inhibitor Nivolumab in Patients With Recurrent Select Rare CNS Cancers
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 136
- 试验地点
- 6
- 主要终点
- objective response
研究概览
简要总结
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:
Individuals will be screened:
- Heart and blood tests
- Physical and neurological exam
- Hepatitis tests
- Pregnancy test
- Magnetic resonance imaging (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.
Individuals will get nivolumab in a vein every 2 weeks for up to 64 weeks.
Individuals 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 individuals' tumor tissue. Individuals will be contacted if any clinically important results are found.
After treatment ends, individuals 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....
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
1/Experimental Therapy
Individuals 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
干预措施: Nivolumab (Drug)
结局指标
主要结局
objective response
时间窗: end of treatment
Rate of achieving a confirmed Complete Response/Partial Response (confirmed by imaging one month later)
progression free survival rate
时间窗: 6 months after end of treatment
Rate of durable Stable Disease lasting at least 6 months (PFS-6)
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
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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.
次要结局
- Overall Survival (OS)(Time from the study entry and after initiation of nivolumab to participants death, up to 5 years)
- 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))
- 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))
- 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.)
- 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.)
- 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))
- 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)
研究者
Jing Wu, M.D.
Principal Investigator
National Cancer Institute (NCI)