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Central Nervous System Diseases

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Patients receive standard of care gadopentetate dimeglumine IV twice within 5 minutes or gadobenate dimeglumine IV twice within 5 minutes and then undergo DCE-MRI on day 1. Patients also receive gadobutrol IV twice within 5 minutes and then undergo DCE-MRI over approximately 30 minutes on day 3, 4, 5, 6, or 7.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Gadobenate Dimeglumine

Gadobutrol

Gadopentetate Dimeglumine

Meng Law

This pilot clinical trial compares gadobutrol with standard of care contrast agents, gadopentetate dimeglumine or gadobenate dimeglumine, before dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) in diagnosing patients with multiple sclerosis, grade II-IV glioma, or tumors that have spread to the brain. Gadobutrol is a type of contrast agent that may increase DCE-MRI sensitivity for the detection of tumors or other diseases of the central nervous system. It is not yet known whether gadobutrol is more effective than standard of care contrast agents before DCE-MRI in diagnosing patients with multiple sclerosis, grade II-IV glioma, or tumors that have spread to the brain.

PRIMARY OBJECTIVES:

I. To determine whether Gadavist® (gadobutrol) is consistent with Magnevist® (gadopentetate dimeglumine) or Multihance (gadobenate dimeglumine) in the preoperative grading of gliomas utilizing DCE MRI.

II. To determine whether Gadavist® is consistent with Magnevist® or Multihance in identifying the number of cerebral metastases from a primary cancer elsewhere in the body using T1-weighted post contrast MRI.

III. To determine if Gadavist® is consistent with Magnevist® or Multihance in identifying multiple sclerosis (MS) plaques using T1-weighted post contrast MRI.

IV. To determine if Gadavist® produces similar MR perfusion/permeability values of MS lesions as Magnevist® or Multihance.

V. Descriptive analysis to present the different rating patterns of Gadavist® versus Magnevist® or Multihance in differentiating therapeutic necrosis from recurrent tumor in gliomas utilizing DCE MRI.

OUTLINE:

Patients receive standard of care gadopentetate dimeglumine intravenously (IV) twice within 5 minutes or gadobenate dimeglumine IV twice within 5 minutes and then undergo DCE-MRI on day 1. Patients also receive gadobutrol IV twice within 5 minutes and then undergo DCE-MRI over approximately 30 minutes on day 3, 4, 5, 6, or 7.

After completion of study, patients are followed up at 7 days.

Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases

Dynamic Contrast Enhanced Steady State T1-Weighted Perfusion MRI (DCE MRI): Characterization of Intracranial Lesions

Weighted Kappa analysis will be used to examine the agreement of using Magnevist® or Multihance versus Gadavist® on glioma grading.

National Cancer Institute (NCI)

University of Southern California

Musculoskeletal Diseases

Ear, Nose, and Throat Diseases

Neurilemmoma

Craniopharyngioma

Adamantinoma

Neuroma, Acoustic

Glioma, Subependymal

Ameloblastoma

Neuroma

Neuroendocrine Tumors

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Cranial Nerve Diseases

Schwannoma

Acoustic Neuroma

Pilocytic Astrocytoma

Subependymal Giant Cell Astrocytoma

Subependymoma

Myxopapillary Ependymoma

Neuroendocrine Tumor

Antineoplastic Agents

Temozolomide

2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide

Gamma Secretase Inhibitors and Modulators

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

3-Dimensional Conformal Radiation Therapy

Gamma-Secretase Inhibitor RO4929097

Intensity-Modulated Radiation Therapy

Laboratory Biomarker Analysis

Pharmacological Study

Therapeutic Conventional Surgery

Antonio Omuro

This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) when given together with temozolomide and radiation therapy in treating patients with newly diagnosed malignant glioma. Enzyme inhibitors, such as gamma-secretase/Notch signalling pathway inhibitor RO4929097, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 together with temozolomide and radiation therapy may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose/recommended phase II dose of RO4929097 in combination with temozolomide and radiotherapy in patients with glioblastoma or malignant gliomas.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of RO4929097 when given in combination with temozolomide (correlative study C1).

II. To evaluate brain and tumor penetration of RO4929097 when given in recommended phase II single agent schedule and when given at the maximum tolerated dose (MTD) for the combination with radiotherapy and temozolomide (correlative study C2).

TERTIARY OBJECTIVES:

I. To evaluate pharmacodynamic effects of RO4929097 in the resected specimens, and comparison with specimens obtained from untreated patients.

II. Effects of RO4929097 on the cancer stem cell population (correlative study C4).

III. Effects of RO4929097 on angiogenesis (correlative study C5). IV. To evaluate the combined effects of RO4929097, radiation and temozolomide in explants established from patients' tumor specimens (correlative study C6).

V. To evaluate the effects of RO4929097 on magnetic resonance imaging (MRI) parameters (correlative study C7), including dynamic contrast enhanced (DCE) MRI perfusion, diffusion weighted imaging and volumetric analysis.

VI. Preliminary evaluation of efficacy of this treatment regimen: 6 month (6m) and median progression-free and overall survival, and response rates.

VII. To evaluate potential biomarkers of gamma-secretase and Notch inhibition activity (correlative study C8).

OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway inhibitor RO4929097. Patients are assigned to 1 of 2 treatment arms.

PRE-SURGERY TREATMENT: Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 orally (PO) once daily (QD) on days 1-7 of week 1 and day 1 of week 2.

SURGERY: Patients undergo surgery 2-3 hours after administration of gamma-secretase/Notch signalling pathway inhibitor RO4929097 on day 1 of week 2.

TREATMENT CONCURRENT WITH RADIOTHERAPY: Beginning 3-4 weeks after surgery, patients undergo conventional focal (intensity-modulated radiation therapy \[IMRT\] or 3-D conformal) radiotherapy 5 days a week for approximately 6 weeks. Patients also receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD for approximately 10 weeks beginning the day of radiotherapy and temozolomide PO QD for approximately 6 weeks beginning the day before radiotherapy.

ADJUVANT TREATMENT FOLLOWING RADIOTHERAPY: Approximately 4 weeks after completion of radiotherapy, patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-28 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months.

RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study

Analyses will include comparison of results before and after exposure to gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Wilcoxon rank sum test), as well as status of the Notch pathway and cancer stem cells in a control population of 20 untreated patients (Mann Whitney test).

The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.

Perfusion and diffusion-based MRI parameters including but not restricted to blood volume, mean and median apparent diffusion coefficient and structural volumes will be analyzed. Results will be summarized, and mean and median values at different time points will be tabulated. Changes in such parameters will be checked for statistical significance and correlated with the disease status.

Means and medians of all patients together will be calculated and tabulated for each time point, with depiction of standard deviations. A Wilcoxon test will be used to determine p value of changes in mean values of YKL-40 and hairy and enhancer of split 1, (Drosophila) (HES1), with a p value of less than 0.05 considered statistically significant.

Noncompartmental and/or compartmental methods will be used to calculate PK parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temozolomide from the plasma concentration-time data collected from each individual. Descriptive statistics (including number, mean and/or median, standard deviation, coefficient of variation, and range) for PK parameters will be tabulated by dose level.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases	NCT02967380	Adult Anaplasti... Adult Anaplasti... Adult Anaplasti... Adult Anaplasti... Adult Brain Ste... Adult Choroid P... Adult Diffuse A... Adult Ependymob... Adult Ependymom... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Adult Grade II ... Adult Medullobl... Adult Mixed Gli... Adult Oligodend... Adult Papillary... Adult Pineal Gl... Adult Pineoblas... Adult Primary M... Adult Supratent... Malignant Adult... Metastatic Mali... Multiple Sclero... Recurrent Adult...	Dynamic Contras... Gadobenate Dime... Gadobutrol Gadopentetate D...	18 Years -	University of Southern California
RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma	NCT01119599	Acoustic Schwan... Adult Anaplasti... Adult Anaplasti... Adult Anaplasti... Adult Brain Ste... Adult Choroid P... Adult Craniopha... Adult Diffuse A... Adult Ependymob... Adult Ependymom... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Adult Grade I M... Adult Grade II ... Adult Medullobl... Adult Mixed Gli... Adult Myxopapil... Adult Oligodend... Adult Papillary... Adult Pilocytic... Adult Pineal Gl... Adult Pineoblas... Adult Pineocyto... Adult Primary M... Adult Subependy... Adult Subependy... Adult Supratent... Malignant Adult...	3-Dimensional C... Gamma-Secretase... Intensity-Modul... Laboratory Biom... Pharmacological... Temozolomide Therapeutic Con...	19 Years -	National Cancer Institute (NCI)
Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases	NCT02967380	Adult Anaplasti... Adult Anaplasti... Adult Anaplasti... Adult Anaplasti... Adult Brain Ste... Adult Choroid P... Adult Diffuse A... Adult Ependymob... Adult Ependymom... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Adult Grade II ... Adult Medullobl... Adult Mixed Gli... Adult Oligodend... Adult Papillary... Adult Pineal Gl... Adult Pineoblas... Adult Primary M... Adult Supratent... Malignant Adult... Metastatic Mali... Multiple Sclero... Recurrent Adult...	Dynamic Contras... Gadobenate Dime... Gadobutrol Gadopentetate D...	18 Years -	University of Southern California

Spots Global Cancer Trial Database for adult primary melanocytic lesion of meninges