Neoplasms

All Conditions

Nervous System Diseases

Musculoskeletal Diseases

Rare Diseases

Glioma

Brain Neoplasms

Meningioma

Ependymoma

Craniopharyngioma

Adamantinoma

Ameloblastoma

Central Nervous System Neoplasms

Nervous System Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Neoplasms, Vascular Tissue

Meningeal Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Bone Neoplasms

Bone Diseases

Neuroepithelioma

Stereotactic conformal radiotherapy (SCRT)

Conventional radiotherapy Patients in this arm will be treated with conventional radiotherapy techniques being used at the moment in the department. This involves patient being immobilised with a customised thermoplastic mask after which they will have a contrast enhanced planning CT scan. The radiation oncologist will draw the tumour on the appropriate CT slices and a margin of 1-2 cms grown for the planning target volume. Beam arrangement will be relatively simple and typically consist of 2-3 coplanar fields using 6 MV photons. Conventional planning optimisation will be carried out by the use of wedges, beam weightage and corner shields as appropriate. Radiotherapy doses, prescription and fractionation schedules will be identical to the SCRT arm

Stereotactic Conformal radiotherapy

Conventional radiotherapy

Rakesh Jalali, MD

Rajiv Sarin, MD FRCR

Brain tumours are the commonest solid tumours in children and the second most common neoplasms overall in this patient population. Radiotherapy plays an important part in the management in a majority of these tumours. While the cure rates of these tumours, especially the benign and low grade ones are quite encouraging, the treatment itself may lead to some late sequelae, which could have significant implications in the quality of life in these long-term survivors.

Stereotactic conformal radiotherapy (SCRT) is a modern high-precision radiotherapy technique, which reduces the volume of normal brain irradiated and has the capability to minimise the doses to critical structures. The present study is designed to prospectively estimate the incidence and severity of neuropsychological, cognitive and neuroendocrine dysfunction following radiotherapy delivered with conventional and stereotactic techniques and would be one of the most comprehensive studies providing very important longitudinal and reliable data regarding these sequelae. The study involving 200 patients would be to the best of our knowledge not only the largest ever study conducted so far but also the only randomised trial assessing these sequelae in patients receiving focal brain irradiation.

The study also examines whether the physical advantages of modern technological progress translate in clinical benefit. This could have significant implications in the radiotherapeutic management of children and young adults with brain tumours. The study is unique in design in terms of evaluating the efficacy of SCRT with respect to conventional radiotherapy in terms of long term tumour control and treatment related complications.

1.0 BACKGROUND AND RATIONALE

Brain tumours are the commonest solid tumours in children and with appropriate treatment, nearly half of them achieve long term cure. Radiotherapy is essential in the management of a majority of these tumours. Conventional radiotherapy alone or in combination with surgery and/or chemotherapy in tumours such as optic gliomas, hypothalamic gliomas, craniopharyngiomas, germ cell tumours, and other low grade tumours achieves excellent long term control rates ranging from 70 to 95%. However, while the tumour control has been effective, there have been concerns about treatment related morbidity.

which included cognitive dysfunction in 38%, motor deficit in 25%, visual impairment in 20%, hormonal dysfunction in 20% and psychological-emotional problems in 14% of the survivors.

It is difficult to ascertain from these reports the exact contribution of each of these factors and how they interact with each other. Radiotherapy is believed to be at least partly responsible although its exact role is yet to be quantified. Most of the evidence regarding post-radiotherapy neuropsychological and cognitive dysfunction is from retrospective studies involving whole brain radiotherapy.

Neuroendocrine dysfunction is well-documented late sequelae following treatment of patients with brain tumours. This could either be due to direct involvement of the pituitary hypothalamic axis (PHA) by the tumour or as a result of surgical or radiation injury to this region. For tumours not directly involving the PHA, the commonest cause of neuroendocrine dysfunction is cranial irradiation. PHA region unavoidably receives radiation with whole brain radiotherapy or if the tumour itself is arising from this region. For the treatment of tumours adjacent to PHA but not involving it, it may be frequently a part of radiotherapy planning target volume, which includes the gross tumour and a margin to account for any microscopic disease and possible daily set up inaccuracies and thus receive significant doses. The region may also sometimes come in the entry / exit path of radiation beams during treatment of tumours even away from this region. Radiation induced hormonal abnormalities are generally dose dependent and may develop many years after irradiation. To reduce the impact of endocrine dysfunctions on physical, mental and sexual development, it is important to detect and treat them timely. Early growth hormone replacement is the only way to minimise growth retardation caused by its deficiency but the treatment is expensive with significant financial implications, especially in our country. The annual cost of GH replacement is approximately Rs 200,000.00, which is prohibitive for the vast majority of the Indian parents as is the cost of LHRH analogues, which is useful to prevent early epiphyseal fusion and stunted growth in children with post radiation or tumour related precocious puberty.

1.4 Evolution of Stereotactic conformal radiotherapy (SCRT) Conventional radiotherapy techniques generally involve the use of 2-3 radiation beams covering the tumour and a margin of 1-3 cms for any subclinical disease and physical inaccuracies in the daily treatment delivery. The last decade has seen tremendous technological advances in radiotherapy planning and accurate treatment delivery. Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) techniques involve firm and accurate immobilisation with fixed or relocatable frames, high precision three-dimensional (3-D) target localisation with CT/CT-MRI fusion and focused radiation delivery. This is achieved either with a multiple source cobalt unit (gamma knife) or with multiple arcs using a modified conventional linear accelerator. Such conventional stereotactic irradiation techniques typically produce spherical high dose volumes and are therefore suitable only for small spherical lesions. A majority of the brain tumours considered for radiotherapy however are not spherical and frequently extend to adjacent structures. To treat large non-spherical volumes with conventional SRS requires the addition of multiple small spherical high dose volumes described as multiple isocentre treatment. The overlap of high dose spheres results in dose inhomogeneity, which has been associated with a higher incidence of radiation induced complications. It has been previously demonstrated that the optimum way of delivering high precision localised irradiation to larger non-spherical targets is with the use of multiple conformal fixed fields with individualised shielding of each radiation field conforming to the shape of the target. This principle of conformal therapy combined with the precision of stereotactic localisation and focused radiation delivery is described as stereotactic conformal radiotherapy (SCRT).

Traditionally, stereotactic irradiation has been delivered in a one session as single fraction radiosurgery. High doses of radiation given in one fraction are known to be associated with a high risk of radiation induced damage to normal tissue and this is particularly true for the central nervous system. Giving radiation in small individual doses allows the delivery of higher radiation doses without serious injury to the normal tissues, which is especially important for normal CNS structures. Single fraction SRS has been shown to be associated with considerable neurological toxicity to the optic apparatus the cranial nerves and normal brain. With the application of high precision relocatable non-invasive means of immobilisation, it has become possible to deliver stereotactic irradiation in a fractionated manner. The technique of SCRT combines the precision of focused radiation delivery and the radiobiological advantages of fractionation. It also ensures homogenous dose distribution within the irradiated volume further reducing the risk of damage.

The basic aim of high precision SCRT is to achieve a high dose differential between the tumour and the surrounding normal tissues. This allows for either an increase in the tumour dose to improve local control or for a potential decrease in radiation damage to the normal tissues. Further optimisation of the technique involving 3-4 conformal non-coplanar field arrangement has shown a significant dose reduction to the normal brain. Preliminary experience, mainly in adults has shown this technique to be feasible during the routine practice of a busy radiotherapy department. Early results in terms of local control are same as that with conventional radiotherapy, with an increased sparing of the surrounding normal brain and adjacent critical structures. While the experience is limited in young children, a few reports have suggested it to be feasible in this population also. The technique has the potential to minimise the dose to any critical site close to the tumour like pituitary-hypothalamic complex, cochlea, brain stem, optic apparatus and the mesial temporal lobes, which are believed to be the common sites of radiation injury leading to late morbidity.

NEED FOR THE PRESENT STUDY The finding of significant long-term effects in a large proportion of brain tumour survivors mandates the development of treatment strategies designed to minimise their impact on the quality of life. Although the precise role of radiotherapy in the causation of various post treatment sequelae is not established, it is generally believed to be at least partly responsible for these effects. There have been attempts to modify the management in terms of avoiding, delaying radiotherapy or reducing the total radiation dose to the tumour with a view to reduce its impact on the long-term toxicity. However, reduction of radiotherapy doses to the tumour has been shown to result in poorer local control rates. Also, a majority of the patients in whom the radiation is delayed eventually do require radiotherapy at later stages (37). There is also evidence that radiotherapy given upfront yields superior disease control than radiotherapy given at the time of tumour progression (38,39). In light of this data, there is therefore, an ever-increasing need to explore techniques of radiotherapy minimising the irradiation to the normal brain and critical structures without compromising radiotherapy doses essential for tumour control. SCRT is a modern high-precision radiotherapy technique, which reduces the volume of normal brain irradiated and has the capability to minimise the doses to critical structures.

The evidence of long term effects of focal irradiation so far is from retrospective studies and a few small prospective trials. There is therefore, a great need to evaluate this issue in a prospective manner in a large number of patients. The present study is designed to prospectively estimate the incidence and severity of neuropsychological, cognitive and neuroendocrine dysfunction following radiotherapy delivered with conventional and stereotactic techniques and would be one of the most comprehensive studies providing very important longitudinal and reliable data regarding these sequelae. The study involving 200 patients would be to the best of our knowledge not only the largest ever study conducted so far but also the only randomised trial assessing these sequelae in patients receiving focal brain irradiation.

The study also examines whether the physical advantages of modern technological progress translate in clinical benefit. This could have significant implications in the radiotherapeutic management of children and young adults with brain tumours. The study is unique in design in terms of evaluating the efficacy of SCRT with respect to conventional radiotherapy in terms of long term tumour control and treatment related complications.

If the present trial succeeds in reducing the incidence and severity of radiotherapy related sequelae by SCRT technique, it would undoubtedly result in a tremendous benefit to these patients. A possible reduction in the neuroendocrine sequelae not only will improve the quality of life of the patients but would also result in major financial saving. This is critical in patients living in the developing countries where the cost of endocrinological management in terms of hormonal assays and their replacement is largely prohibitive.

We have until Januray 2009 accrued 128 patients so far in the trial

SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors

Efficacy of Stereotactic Conformal Radiotherapy (SCRT) Compared to Conventional Radiotherapy in Minimising Late Sequelae in Children and Young Adults With Brain Tumours: a Randomised Clinical Trial

Terry Fox Foundation

Tata Memorial Hospital

Professor

Symptoms and General Pathology

Recurrence

Astrocytoma

Brain Diseases

Central Nervous System Diseases

Pharmaceutical Solutions

All Drugs and Chemicals

Immunotoxins

All subjects are enrolled onto this arm. All subjects will receive MR1-1.

Based on preclinical toxicity studies, the starting total drug dose will be 0.5μg (500ng) which represents 1/20th of the MTD in rats. The infusion flow rate will be fixed at 0.5 mL/h from each of two catheters. A total of 96 mLs of drug solution will be delivered over 96 hours. MR1-1KDEL dose escalation will be accomplished by increasing drug concentration allowing flow rate and infusion volume to remain unchanged. Drug dose will be doubled in successive cohorts so long as DLTs are not observed as follows: 25 ng/mL (2.4 μg)(starting dose); 50ng/mL (4.8μg); 100 ng/mL (9.6μg); 200ng/mL (19.2μg); 400 ng/mL (38.4μg); 800 ng/mL (76.8μg); and 1600 ng/mL (153.6μg).

MR1-1

Annick Desjardins, MD

Purpose of the study:

Primary Objective: Determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of MR1-1KDEL when delivered intracerebrally by convection-enhanced delivery (CED) in patients with supratentorial malignant brain tumors.

Secondary Objective: Document any radiographic responses associated with intracerebral CED of MR1-1KDEL.

Hypothesis: The investigators believe that MR1-1KDEL will be an effective anti-tumor agent for patients with supratentorial malignant brain tumors when delivered by CED.

Design \& procedures: This protocol is designed primarily to determine the MTD and DLT of a novel, tumor-specific immunotoxin, MR1-1KDEL. MR1-1KDEL will be delivered intracerebrally by CED using 2 intracerebral catheters with at least one catheter placed within the enhancing portion of the tumor. 124I-labeled albumin will be co-infused with gadolinium and PET and MRI images will be obtained at the conclusion of the infusion to monitor volume of drug distribution and leakage into the CSF space.

Based on preclinical toxicity studies, the starting total drug dose will be 0.5μg (500ng) which represents 1/20th of the MTD in rats. The infusion flow rate will be fixed at 0.5 mL/h from each of two to four catheters. A total of 144 mLs of drug solution will be delivered over 72 hours. MR1-1KDEL dose escalation will be accomplished by increasing drug concentration allowing flow rate and infusion volume to remain unchanged. Drug dose will be doubled in successive cohorts so long as DLTs are not observed as follows: 25 ng/mL (2.4 μg)(starting dose); 50ng/mL (4.8μg); 100 ng/mL (9.6μg); 200ng/mL (19.2μg); 400 ng/mL (38.4μg); 800 ng/mL (76.8μg); and 1600 ng/mL (153.6μg). At least 3 patients will be enrolled in each cohort. All patients in a given cohort will be observed for at least two weeks following infusion of the study drug before patients in the next cohort are treated. If no patients in a given cohort experience a DLT, the dose will be escalated in the next cohort. If 1 out of 3 patients in a given cohort experience DLT, 3 additional patients will be entered in that cohort. If 2 patients develop a DLT in any cohort of 3 or 6 patients, the previous dose will be declared the MTD. Patients will be followed at 1, 3, 6, 9, 12 month intervals for toxicity and adverse events, radiographic response, and survival. Patients will be off study when progressive disease is documented.

Risk/benefit assessment: This is an experimental study and unforeseeable or unexpected risks may be involved.

Study of Immunotoxin, MR1-1

Phase I Study of Immunotoxin, MR1-1

National Institute of Neurological Disorders and Stroke (NINDS)

Darell D. Bigner, MD, PhD

Director, The Preston Robert Tisch Brain Tumor Center at Duke

Diseases and Abnormalities at or Before Birth

Ear, Nose, and Throat Diseases

Skin and Connective Tissue Diseases

Neurilemmoma

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Neurofibromatosis 2

Nerve Sheath Neoplasms

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Peripheral Nervous System Diseases

Neuromuscular Diseases

Peripheral Nervous System Neoplasms

Neuroma

Neuroma, Acoustic

Neuroendocrine Tumors

Vestibulocochlear Nerve Diseases

Retrocochlear Diseases

Ear Diseases

Otorhinolaryngologic Diseases

Otorhinolaryngologic Neoplasms

Cranial Nerve Diseases

Schwannoma

Neurofibromatosis

Neurofibromatosis Type 1

Neurofibromatosis Type 2

Neuroendocrine Tumor

Antineoplastic Agents

Gastrointestinal Agents

Anti-Infective Agents

Everolimus

Lactitol

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age

Everolimus will be provided by Novartis. Everolimus is formulated as tablets for oral administration of 2.5 mg, 5 mg, 10 mg strength. Everolimus will be self-administered (by the patients themselves) or administered by the patient's parent or guardian (for minors). The investigator will instruct the patient to take the study drug exactly as specified in the protocol. Depending the age-based dosing schedule, everolimus should be administered orally once (or twice) daily, preferably in the morning (and evening), at the same time every day with our without food. Everolimus tablets should be swallowed whole with a glass of water. The tablets must not be chewed or crushed. In cases where tablets can not be swallowed, the tablets should be disintegrated in water just prior to being taken. Everolimus will be administered orally as per the age-based dosing schedule continuously from study day 1 until progression of disease or unacceptable toxicity.

Everolimus (RAD001) , Afinitor®

Matthias A Karajannis, MD, MS

This trial studies whether Everolimus is efficacious in treating neurofibromatosis 2.

Everolimus (RAD001) has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation and has obtained marketing authorization (Certican®) for prophylaxis of rejection in renal and cardiac transplantation in a number of countries, including the majority of the European Union. Everolimus has been in development for patients with various malignancies since 2002. Everolimus 2.5mg, 5mg and 10mg tablets were approved under the trade name Afinitor® for patients with advanced renal cell carcinoma (RCC) after failure of treatment with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU and several other countries and is undergoing registration in other regions worldwide. Afinitor® was also recently approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. Everolimus is being investigated as an anticancer agent based on its potential to act: 1. Directly on the tumor cells by inhibiting tumor cell growth and proliferation; and 2. Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity.

For pediatric cancer patients, safety of RAD001 has been established in a phase 1 trial and the recommended phase II dose is 5 mg/m2 once daily. This existing pediatric data allows for inclusion of children in this phase 2 trial, which is an important consideration since some NF2 patients with the most aggressive clinical course present at school age.

RAD001 was recently approved by the Food and Drug Administration (FDA) for the treatment of children and adults with subependymal giant cell astrocytoma (SEGA), a benign brain tumor associated with tuberous sclerosis (TS). Although surgical resection is effective at tumor reduction, serious complications may follow a radical resection, such as permanent deafness and facial nerve damage. Most importantly, the tumors often recur after surgery. Radiation therapy (RT) has been proposed as an alternative. However, its safety and efficacy in the NF2 population has not been established. A medical therapy option is desperately needed. This study is a single-center, 2-stage, phase II open-label study. All subjects will get RAD001 taken continuously until disease progression or unacceptable toxicity. The primary objective of this study is to look at the objective response rate to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Participation will consist of screening/baseline visit(s), Day 1, Weeks 1, 2, and 4; and up to 12 cycles and will include standard of care procedures such as medical history, vital signs, physical examinations, ECGs, MRIs, audiograms, and laboratory tests. Novartis will provide the RAD001 free of charge to eligible study subjects. The primary efficacy response for study purposes will be a greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors will constitute a complete response (CR).

Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2

To estimate the objective response rates to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Radiographic response for study purposes = greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors = complete response. MRI of the brain and spine will be performed every 3 months. If an objective response (15% reduction in tumor volume compared to baseline) is observed in any target tumor or stable disease, drug will be continued.

Defined as improvement in speech discrimination score (SDS), defined as an improvement in the score above the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment. Audiologic worsening: decrease in SDS score below the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment.

Patients with vestibular schwannomas will receive baseline audiograms within 28 days before enrollments and subsequent audiograms at the time of each MRI.

Novartis Pharmaceuticals

The Children's Tumor Foundation

NYU Langone Health

RAD001

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Matthias A. Karajannis

Radiographic Response

Audiologic Response

Change in Tumor Size From Baseline

Overall Study

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Pinealoma

Lymphosarcoma

Pineocytoma

Primary Central Nervous System Lymphoma

Katherine E Warren, M.D.

Background:

- An important new area of brain tumor research is the development of tumor and brain stem cell lines. Successful growth of these cell lines requires obtaining large volumes of fresh tumor and brain tissue, which is best accomplished by harvesting whole brains from recently deceased patients. These cell lines will help researchers understand how these tumors develop and will also help identify new targets for treatment. Researchers are interested in conducting a pilot study of planned inpatient hospice care with timely brain tumor tissue harvest at the time of death.

Objectives:

* To provide high-quality end of life inpatient hospice care for patients with untreatable brain tumors.
* To procure brain and tumor tissue shortly after time of death in order to derive viable tumor and neural stem cell lines for research purposes.

Eligibility:

* Individuals at least 18 years of age who have an untreatable primary brain or central nervous system tumor, are able to give informed consent (either their own or through a designated power of attorney), and have agreed to a Do Not Resuscitate order and Consent for Autopsy as part of the end-of-life care plan.
* HIV-positive individuals or those suspected of having infectious cerebritis are not eligible because of the potential for contamination of brain tissue.

Design:

* Participants will be enrolled in inpatient hospice admission to the National Institutes of Health Clinical Center either from home or from an outside hospital once a study investigator estimates an expected survival of less than 2 weeks.
* Participants will receive palliative care at the Clinical Center. Care will be tailored to each participant depending on the information provided in the individual's end-of-life care plan.
* Supportive medications such as antiseizure medications and pain relievers will be administered as appropriate.
* At the time of death, researchers will follow standard procedures for notifying next of kin and will collect brain tissue and tumor samples from the deceased.
* Following tissue collection, the deceased will be released for autopsy and funeral procedures.

BACKGROUND:

- Patients treated by the Neuro-Oncology Branch (NOB) for their brain tumors unfortunately and commonly succumb to their disease. They and their loved ones often seek a way of adding meaning and utility to their death by agreeing to donate brain tumor tissue for laboratory research that may serve the medical community, and ultimately other patients, through better understanding of these rare diseases. Important new avenues of brain tumor research includes the molecular characterization of tumor tissue, and the development of tumor and neural stem cell lines. Successful growth of these cell lines requires acquisition of large volumes of fresh tumor and brain tissue that can best be accomplished by harvesting whole brains from recently deceased patients. In an effort to provide high quality end of life care, with the additional intent of facilitating efficient donation of brain tumor tissue at the time of death, we are conducting a pilot study of planned inpatient hospice care incorporating timely brain tumor tissue procurement at the time of expiration.

OBJECTIVES:

* Provide high quality end of life inpatient hospice care for patients dying with untreatable brain tumors.
* Procure brain and tumor tissue shortly after time of death in order to derive viable tumor and neural stem cell lines for research purposes.

ELIGIBILITY:

- Adult patients with primary brain tumors.

DESIGN:

- This is a pilot study to assess feasibility of procuring viable brain and tumor tissue proximal to the time of death. Target accrual is 10 patients for brain harvest.

A Pilot Study of Inpatient Hospice With Procurement of Brain Tumor Tissue on Expiration for Research Purposes

National Cancer Institute (NCI)

Disease Progression

Anaplastic Ependymoma

Proteasome Inhibitors

Marizomib at days 1, 8, and 15 of each 28-day cycle

Data collection on pregnancy, birth and Health of Child

0.8mg/m(2) intravenous (IV) on days 1, 8, and 15 of each 28-day cycle, 24 cycles total.

Marizomib

Mark R Gilbert, M.D.

Background:

Ependymomas are rare tumors that arise from the ependyma. That is a tissue of the central nervous system. They can develop in the brain or the spine. They are usually treated with surgery, radiation, and/or chemotherapy. Researchers want to see if the new drug marizomib can help people with a certain kind of ependymoma.

Objective:

To see if marizomib stops tumor growth and prolongs the time that the tumor is controlled.

Eligibility:

Adults age 18 and older who have been diagnosed with ependymomas and have already been treated with standard therapies

Design:

Participants will be screened with the following tests or recent results from similar tests:

* Medical history
* Physical exam
* Neurological assessment
* Electrocardiogram (EKG) to evaluate the heart
* Review of symptoms and ability to perform normal activities
* Computed tomographic scan (CT) or magnetic resonance imaging (MRI) to produce an image of the brain or spine.
* Blood and urine tests
* Tests of tumor samples. Participants may have to have new tumor samples taken.

Participants will get the study drug in cycles. Each cycle is 4 weeks. Participants will have up to 24 cycles.

Participants will get the study drug through a small plastic tube in a vein on days 1, 8, and 15 of each cycle.

During each cycle, some screening tests will be repeated.

Participants will answer questions about their general well-being and functioning.

About 4 5 weeks after finishing the study drug, participants will have a follow-up visit. They will answer questions about their health, get a physical and a neurological exam, and have blood tests. They may have an MRI or CT scan.

...

Background:

* Ependymomas are rare primary brain tumors arising from radial glial stem cells. They comprise 5.2% of all pediatric primary brain tumors and 1.9% of all adult primary brain tumors.
* The standard therapy for newly diagnosed ependymoma is gross total resection followed by radiation therapy. For anaplastic ependymoma, recurrence rate is high with a median progression free survival (PFS) of 2.3 years.
* There are limited chemotherapy options for recurrent ependymomas, which have already been irradiated. Therefore, there is an unmet need to target novel pathways for treatment of ependymomas.
* About 70% of supratentorial ependymomas have a characteristic signature C11 orf95-V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA) fusion which drives tumorigenesis in ependymomas by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) transcription pathway.
* Marizomib is a second-generation irreversible proteasome inhibitor which penetrates across the blood-brain-barrier (BBB). It inhibits the activity of 20S proteasome in glioma cells, activates caspases, builds up reactive oxygen species and thus induces apoptosis. Marizomib blocks the NF-pathway by proteasome inhibition. Thus, it may have an additional targeted therapeutic effect in the RELA-fusion molecular subgroup of ependymomas.

Objective:

-To evaluate the efficacy of treatment with marizomib in RELA-fusion recurrent ependymoma and non RELA-fusion recurrent ependymoma as measured by progression-free survival at 6 months (PFS6).

Eligibility:

* Histologically proven intra-cranial or spinal ependymoma.
* Radiographic evidence of tumor progression
* Patients must be greater than or equal to 18 years old.

Patients must have had prior radiotherapy.

Design:

* This is a phase II study to determine the efficacy of marizomib in recurrent ependymoma.
* A novel 2-stage sequential design will be employed to conduct the trial for recurrent ependymoma.
* In the first stage, we will enroll 18 patients with RELA-fusion ependymoma and if 4 or more patients in Cohort 1 are progression free at 6 months, we will proceed to stage 2; otherwise, we will terminate the trial and conclude that marizomib is not effective.
* In the second stage, we will enroll 32 patients with non RELA-fusion ependymoma.
* Patients will be treated with marizomib in cycles consistent of 28 days until disease progression or a maximum of 24 cycles.

Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma

Phase II Clinical Trial of Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma

1. Biomedical Translational Research Information System (BTRIS): All IPD recorded in the medical record will be shared with intramural investigators upon request.
2. Database of Genotypes and Phenotypes (dbGaP): 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.

Here is the number of participants with serious and 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.

Progression was assessed by the Response assessment in neuro-oncology criteria (RANO) and is defined as a 25% increase in the sum of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline. Appearance of new lesions, or clear worsening of any evaluable disease. Failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

To determine the safety of marizomib in recurrent ependymoma patients and in a subset of patients with more than 2 prior chemotherapies (RELA-fusion Cohort 2 and non-RELA-fusion Cohort 4).

To estimate the efficacy of marizomib in recurrent ependymoma patients (RELA- fusion Cohort 2 and non RELA-fusion Cohort 4) with more than 2 prior chemotherapies as measured by progression free disease after 6 months. Progression was assessed by the Response Assessment in Neuro-oncology (RANO) criteria and is defined as a 25% increase in the sum of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline. Appearance of new lesions, or clear worsening of any evaluable disease. Failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Progression was assessed by the Response Assessment in Neuro-oncology criteria (RANO) and is defined as a 25% increase in the sum of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline. Appearance of new lesions, or clear worsening of any evaluable disease. Failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Changes in quality of life using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) instrument was used to determine symptom severity.To longitudinally evaluate participant reported outcome measures using self-reported symptom severity with daily activities using the MDASI-BT and/or MDASI-SP instrument.

To estimate the efficacy of marizomib in recurrent ependymoma patients (RELA- fusion Cohort 2 and non RELA-fusion Cohort 4) with more than 2 prior chemotherapies as measured by objective response. Complete Response is complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Partial Response is greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions.

Median amount of time subject survives 12 months after therapy

OS is defined as the time from treatment start date until date of death or date last known alive.

Changes in quality of life using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) instrument was used to determine symptom interference.To longitudinally evaluate participant reported outcome measures using self-reported symptom interference with daily activities using the MDASI-BT and/or MDASI-SP instrument.

Principal Investigator

Marizomib at days 1, 8, and 15 of each 28-day cycle

Marizomib: 0.8mg/m(2) intravenous (IV) on days 1, 8, and 15 of each 28-day cycle, 24 cycles total.

Participants with Intra-cranial or Spinal V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA)-fusion Ependymoma who have had none, 1 or 2 prior chemotherapies.

1/Cohort 1 - Participants With Ependymoma Who Had None, One or Two Prior Chemotherapies

Participants with intra-cranial or spinal RELA-fusion ependymoma who had more than two prior chemotherapies.

2/Cohort 2 - Participants With Ependymoma Who Had More Than Two Prior Chemotherapies

Total

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Dr. Mark Gilbert

Number of Participants That Are Progression-free at 6 Months Time Point After Initiation of Treatment

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Toxicities by Grade Using the Common CTCAE Version 5.0.

The one participant in Cohort 2 had progressive disease prior to 6 month mark and we did not enroll in Cohort 4 due to early study termination.

Number of Participants That Have Progressive Disease After 6 Months

Number of Participants With 12-month Progression-free Survival (PFS12)

This outcome measure was not done because we were unable to determine due to low accrual and few data timepoints for which meaningful data could be extracted.

Symptom Severity Using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) Instrument

We did not enroll to Cohort 4 due to early termination of the study.

Number of Participants Assessed Using the Response Assessment in Neuro-oncology Criteria (RANO) for Complete Response (CR) + Partial Response (PR)

This outcome measure was not done. We were unable to determine as participants were taken off study for early study termination prior to the 12 months post therapy timepoint.

Median Amount of Time Subject Survives 12 Months After Therapy

This outcome measure was not done. We were unable to determine for non RELA-fusion recurrent ependymoma patients since we did not enroll in those cohorts due to early study termination. And for the 4 participants with RELA-fusion recurrent ependymoma enrolled, the study was prematurely terminated pharmaceutical sponsor.

Overall Survival (OS) of RELAfusion and Non RELA-fusion Recurrent Ependymoma Patients Treated With Marizomib.

Symptom Interference Using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) Instrument

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors	NCT00517959	Low Grade Gliom... Craniopharyngio... Ependymomas Meningiomas	Stereotactic Co... Conventional ra...	3 Years - 25 Years	Tata Memorial Hospital
SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors	NCT00517959	Low Grade Gliom... Craniopharyngio... Ependymomas Meningiomas	Stereotactic Co... Conventional ra...	3 Years - 25 Years	Tata Memorial Hospital
Study of Immunotoxin, MR1-1	NCT01009866	Supratentorial ...	MR1-1	18 Years -	Duke University
Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2	NCT01419639	Neurofibromatos...	Everolimus (RAD...	3 Years -	NYU Langone Health
A Pilot Study of Inpatient Hospice With Procurement of Brain Tumor Tissue on Expiration for Research Purposes	NCT01251913	Ependymomas Gliomas PNET Pineal Tumors PCNSL (Primary ...		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
A Pilot Study of Inpatient Hospice With Procurement of Brain Tumor Tissue on Expiration for Research Purposes	NCT01251913	Ependymomas Gliomas PNET Pineal Tumors PCNSL (Primary ...		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Study of Immunotoxin, MR1-1	NCT01009866	Supratentorial ...	MR1-1	18 Years -	Duke University
Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma	NCT03727841	Anaplastic Epen... Ependymoma Ependymomas	Marizomib	-	National Institutes of Health Clinical Center (CC)
Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2	NCT01419639	Neurofibromatos...	Everolimus (RAD...	3 Years -	NYU Langone Health
Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2	NCT01419639	Neurofibromatos...	Everolimus (RAD...	3 Years -	NYU Langone Health

Spots Global Cancer Trial Database for ependymomas

Every month we try and update this database with for ependymomas cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for ependymomas

Every month we try and update this database with for ependymomas cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for ependymomas cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.