Neoplasms

Nervous System Diseases

All Conditions

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Archived CNS neoplasm specimens, in which primary diagnostic studies are complete, and for which there is excess tissue for analysis in the form of unstained slides or paraffin blocks

Terri S Armstrong, C.R.N.P.

Background:

The number of people who get tumors of the brain or central nervous system (CNS) is lower than other cancers. But these tumors cause a higher rate of serious effects and even death. Researchers want to test existing samples of tissue from these tumors to learn more about them. This may lead to better treatment.

Objective:

To study stored samples of CNS tumors to learn more about the tumors and explore new ways to diagnose them.

Eligibility:

The study will use tissue samples already collected at NIH from people with brain or CNS tumors.

Design:

The participants will have given their consent in a previous study.

Researchers will review the tissue samples and any data collected about them.

Researchers will do lab tests and scans on the samples.

All data will be kept secure.

BACKGROUND

* Central Nervous System (CNS) and brain tumors are a heterogeneous group of neoplasms. They can be broadly categorized to tumors of neuroepithelial tissue, meninges, hematopoietic system, germ cells, and sella.
* The Central Brain Tumor Registry of the United States reports an overall average annual age-adjusted incidence rate for the years 2006-2010 for primary brain and CNS tumors as 21.03 per 100,000. This leads to an estimated mortality of over 13,000 deaths per year. Although this number is small compared to other more common cancers, due to the location of CNS (brain and spinal cord) tumors, they are responsible for disproportionately high morbidity and mortality among cancer patients.
* Although much progress has been made on overall understanding of CNS tumors, not much is known about mechanisms responsible for intratumoral heterogeneity, disease relapse, progression into higher grades, and in vivo invasive mechanisms. This may involve new mutations, selection of specific clones of cells by either therapeutic pressure or as part of natural tumor evolution leading to progression, microenvironmental cues or combinations.
* This study will review the molecular pathological alterations of archived human CNS tumor specimens at initial presentation and at subsequent relapse. We will request archived brain tumor tissue samples from the NCI CCR Laboratory of Pathology at multiple time points to determine the expression of cellular proteins and surrogate markers involved in growth, proliferation, differentiation, invasion, and survival of brain tumor cells. Such information will be pooled with imaging data (MRI, PET, etc.) to identify potential surrogate markers of disease resistance.
* This study has the potential to uncover key molecular events underlying disease progression and thereby contribute to the understanding of CNS tumor pathogenesis without active patient intervention.

OBJECTIVES

-To study archived specimens of CNS tumors from the NCI CCR Laboratory of Pathology to explore potential new biomarkers for diagnosis and to better understand CNS tumor pathogenesis.

ELIGIBILITY

* Diagnosis of CNS neoplasm.
* Eligible cases include those in which primary diagnostic studies are complete, and for which there is excess tissue for analysis in the form of unstained slides or paraffin blocks archived in the NCI CCR Laboratory of Pathology as well as imaging stored in the NIH medical records system.
* We also request permission to extend this analysis, as may be relevant in the future, to surplus materials to be accrued under existing NCI protocols, upon completion of all superseding diagnostic tests and medical/scientific studies.

DESIGN

* We anticipate obtaining approximately 500 archived specimens in the NCI CCR Laboratory of Pathology from patients with CNS neoplasms to analyze parameters in order to better understand the biology and pathogenesis of disease.
* To identify potential specimens, medical records of patients seen in the Neuro-Oncology and Neurosurgery Clinics will be reviewed. Additional medical records will be reviewed in order to identify archived specimens and to obtain ancillary information such as result of imaging studies.
* Existing biomarker data will be analyzed in conjunction with review of histological features and clinical data existing in laboratory and imaging data to arrive at improved criteria for diagnosis, and to recognize newly identified, as yet undescribed, disease entities. New biomarkers, as they may become available, will be utilized to improve on current diagnostic methods for disease definition.
* Tissue may be collected from pathology to be processed for specific research question at a future time point. Time of processing may be contingent on accumulating sufficient number of specimens.

Biomarker Analysis of Central Nervous System Tumors

To study archived specimens of CNS tumors from the NCI CCR Laboratory of Pathology to explore potential new biomarkers for diagnosis and to better understand CNS tumor pathogenesis.

National Cancer Institute (NCI)

Antineoplastic Agents

All Drugs and Chemicals

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Three subjects will receive a single dose of 3 mg/kg dabrafenib on Day 1 and repeat dose will begin from Day 2, evenly divided in two daily doses. Once all 3 subjects have been fully evaluated for the first 28 days (including Day 15 PK) and no DLTs are observed, a next subject will be enrolled at the next higher dose levels (i.e., dose escalation to 3.75 mg/kg \[+1\] and may be further to 4.5 mg/kg \[+2\] and so on). If all 3 subjects have not been fully evaluated for the first 28 days or 1 DLT occurred, the fourth subject will be enrolled at the same dose level. If 2 or more DLTs are observed, the next subject will be enrolled at the next lower dose level (i.e., de-escalated to 2.25 mg/kg \[-1\] and may be further to 1.5 mg/kg \[-2\]). Similarly, the process is repeated for the fifth and sixth subjects in a cohort. All subjects will receive treatment till end of study.

Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Dabrafenib is available as 50 mg or 75 mg capsules and as oral suspension (10 mg/mL for subjects unable to swallow capsules). Dabrafenib (either formulation) will be administered orally as a single dose on Day 1 and twice daily from Day 2, based on weight at the appropriate study dose level.

Novartis Pharmaceuticals

This was a 2-part, Phase I/IIa, multi-center, open label, study in pediatric and adolescent patients with advanced BRAF V600 mutation-positive solid tumors. Part 1 was a dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). Part 2 was an expansion study to further evaluate the safety, tolerability, and clinical activity of dabrafenib in 4 tumor-specific pediatric populations. Patients participated in only either part 1 or part 2 of the study.

Part 1 was a dose escalation study in subjects with any BRAF V600 mutation-positive solid tumor, designed to optimize efficiency of enrollment, minimize the number of subjects being treated at potentially sub-efficacious dose levels, and incorporating the evolving pharmacokinetic, safety and efficacy data from the adult development program. Dose escalation part of the study was to determine the maximum tolerated dose (MTD) and recommend the dose for phase 2 studies (RP2D). An MTD has not been identified for dabrafenib in the adult population. This does not preclude the identification of an MTD in the pediatric population. Modified RSD was employed to determine the MTD. Part 1 used dual criteria of dose limiting toxicity (DLT) and observed dabrafenib exposures to make decisions to advance to the next dose level. Target exposure criteria based on adults treated at the approved adult dose of 300 mg (150 mg given BID) were observed in this study before meeting criteria for stopping dose escalation due to observations of DLTs, and served as the criteria for determining the RP2D for dabrafenib in pediatric subjects. Thus, MTD has not been established in pediatric population, similar to the previous dose finding efforts in adult subjects.

Part 2 was a tumor specific expansion study to further evaluate the safety/tolerability profile and to discover possible clinical efficacy of dabrafenib in 4 tumor-specific pediatric populations known to have BRAFV600 activation: high grade glioma (HGG), low grade glioma (LGG), Langerhans cell histiocytosis (LCH), miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other). The exposures for subjects dosed on the basis of weight were also evaluated by age categories.

A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects

Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects With Advanced BRAF V600-Mutation Positive Solid Tumors

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib was listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC(0-τ) and AUC(0-inf) of dabrafenib were to be listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Pre-dose (trough) concentration (C tau) was to be listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]).

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC\[0-t\]) dabrafenib metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were to be listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were to be listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. CL/F of dabrafenib was to be listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were listed and summarized using descriptive statistics.

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]).

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. T1/2 of dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) was listed and summarized using descriptive statistics.

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Event and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on total apparent clearance (CL/F) of dabrafenib estimated with the PopPK model is summarized in this record.

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on volume of distribution (V/F) of dabrafenib estimated with the PopPK model is summarized in this record.

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on absorption rate (ka) of dabrafenib estimated with a PopPK model is summarized in this record.

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on coefficients for significant covariates of dabrafenib estimated with a PopPK model is summarized in this record.

Any sign or symptom that occurs during the treatment period plus 28 days post-treatment.

Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.

Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)

Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)

Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)

Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)

Part 2 (Tumor Specific Expansion): Cohort 1 Low-Grade Gliomas (LGG)

Part 2 (Tumor Specific Expansion): Cohort 2 High-Grade Gliomas (HGG)

Part 2 (Tumor Specific Expansion): Cohort 3 Langerhans Cell Histiocytosis (LCH)

Part 2 (Tumor Specific Expansion): Cohort 4 Miscellaneous Tumors (Other)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Director

All deaths

On-treatment deaths

Adverse Events (AEs)

AEs suspected to be drug related

Serious Adverse Events (SAEs)

SAEs suspected to be drug related

Fatal SAEs

Fatal SAEs suspected to be drug related

AEs leading to discontinuation

AEs requiring dose interruptions

AEs requiring dose reductions

AEs requiring dose reductions or interruptions

Safety population. Deaths occurring more than 28 days after the last dose of study drug were not included in the on-treatment deaths. All deaths included on-treatment deaths and those occurring more than 28 days after the last dose of study drug.

Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)

Week 1 Day 1

Week 3 Day 15

All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg

All patients at recommended dose phase 2 (RP2D) of 5.25 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg

Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.

Maximum Concentration (Cmax) of Dabrafenib

Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.

Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-τ)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib

dabrafenib

hydroxy-dabrafenib

carboxy-dabrafenib

desmethyl-dabrafenib

Pharmacokinetic population. For each parameter, only participants with an evaluable PK sample collected were included in the analysis.

Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites

Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-t) PK parameters were collected/calculated.

The AUC(0-t) of Dabrafenib Metabolites

Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-tau) PK parameters were collected/calculated.

The AUC(0-tau) of Dabrafenib and Its Metabolites

Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable CL/F PK parameters were collected/calculated.

Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib

hydroxy-dabrafenib @ Week 1 Day 1

hydroxy-dabrafenib @ Week 3 Day 15

carboxy-dabrafenib @ Week 1 Day 1

carboxy-dabrafenib @ Week 3 Day 15

desmethyl-dabrafenib @ Week 1 Day 1

desmethyl-dabrafenib @ Week 3 Day 15

Pharmacokinetic population. For each parameter, only participants with an evaluable PK sample collected at each timepoint were included in the analysis.

Maximum Concentration (Cmax) of Dabrafenib Metabolites

dabrafenib @ Week 1 Day 1

dabrafenib @ Week 3 Day 15

Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites

Elimination Half Life (T½) of Dabrafenib and Its Metabolites

Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)

All LGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

All LGG Subjects at Recommended Phase 2 Dose (RP2D)

All LGG Subjects

Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects

All HGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

All HGG Subjects at Recommended Phase 2 Dose (RP2D)

All HGG Subjects

Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects

Participants in the study (all doses and all tumor types) with available pharmacokinetic data

Part 1 and Part 2 - All Participants With PK Data

All subjects who received at least one dose of dabrafenib in Part 1 and 2 and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.

Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model

Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model

All subjects who received at least one dose of dabrafenib in Part 1 and 2 and provided an evaluable PK profile. The covariate weight did not meet the pre-specified criteria to be considered a significant covariate on Ka based on the goodness-of-fit plots and the decrease of the objective function provided by the PopPK software (NONMEM). Therefore, effect of weight on Ka could not be calculated.

Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model

All subjects who received at least one dose of dabrafenib in Part 1 and 2 and provided an evaluable PK profile. The covariate weight did not meet the pre-specified criteria to be considered a significant covariate based on the goodness-of-fit plots and the decrease of the objective function provided by the PopPK software (NONMEM). Therefore, effect of weight on coefficients for significant covariates of dabrafenib could not be calculated.

Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model

Post-treatment deaths

On treatment deaths were collected from FPFT up to 28 days after study drug discontinuation, for a maximum duration of 360 weeks in Part I (treatment duration ranged from 5.6 to 356.0 weeks) and a maximum duration of 300 weeks in Part II (treatment duration ranged from 0.3 to 296.0 weeks).

Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 7 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.

Clinical database population; all treated patients.

All Collected Deaths in Parts I and II

Overall Study

Symptoms and General Pathology

Rare Diseases

Recurrence

Glioblastoma

Glioma

Disease Attributes

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Dermatologic Agents

Aminolevulinic Acid

Photosensitizing Agents

Fluorescent substance to help visualize and remove as much tumor as possible without harming healthy tissue.

20 mg/kg administered once 3-5 hours prior to surgery

5-ALA (Gliolan)

Costas Hadjipanayis, MD, PhD

The purpose of this study is to determine the safety and utility of 5-aminolevulinic acid (ALA) for identifying your tumor during surgery. 5-ALA is not FDA approved at this time. When the investigators remove the tumor from your brain, it is important that they remove all of the tumor and not remove parts of normal brain. Sometimes this can be difficult because the tumor can look like normal brain. In some brain tumors, 5-ALA can make the tumors glow red under blue light. This may make it easier for your doctor to take out all of the tumor from your brain. The purpose of this study is to:

* Make sure that 5-ALA helps the doctor remove more of the tumor.
* Make sure 5-ALA does not cause any side effects.

If you do not want to participate in this study, your doctor(s) will still do their best to remove all of the tumor in your brain. Whether or not you join this study will not change your treatment for your brain tumor.

More Complete Removal of Malignant Brain Tumors by Fluorescence-Guided Surgery

A Multicenter Phase II Study of 5-Aminolevulinic Acid (ALA) to Enhance Visualization and Resection of Newly Diagnosed or Recurrent Malignant Gliomas

NX PharmaGen

Constantinos Hadjipanayis

Professor and Chair, Neurosurgery

Gliosarcoma

Anti-Infective Agents

Flucytosine

The investigational drug in the amount of 1x10\^7, 3x10\^7cells per dose into the tumor or the tumor removal site using a syringe during surgery

Administration period: Single dose Route of administration: Intratumoral administration Dose: 1x10\^7, 3x10\^7cells/dose Summary: Administer the investigational drug in the amount of 1x107, 3x107cells per dose into the tumor or the tumor removal site using a syringe during surgery.

Concomitant drug: 5-Flucytosine (prodrug) Dose: 150mg/kg/day

Directions:

Administration period and directions: Administer 150m of 5-Flucytosine per kilogram of body weight every 6 hours for a total of 4 times a day (QID) for a duration of 7 days after surgery.

Route of administration: Oral administration

MSC11FCD

Kyunggi Cho, MD,PhD

This is a phase I trial evaluating the maximum tolerated dose, safety and efficiency of Mesenchymal stem cells into which the suicide gene, cytosine deaminase (CD), injected into the resection cavity of patients with recurrent glioblastoma.

Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients

Investigator-initiated and Open-labeled Clinical Trial for Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients

Assessment of the maximum tolerated dose based on the 3+3 method

* Blood concentrations of 5-FC and 5-FU(Day 1, Day 3, Day 7)
* MSC11FCD concentrations (MSCCD detection) (Day 0, 3months, 6months, 12months)

Evaluate the number of adverse event related to the treatment according to CTCAE V4.0 during the trial (including clinically significant changes in physical examination, radiographic images, safety lab tests, vital signs)

OS is defined as the time from the date of MSC injection to the date of death due to any cause.

The progress-free survival analysis shall be based on the RANO criteria.

Assess the treatment groups participating in this clinical trial based on the RANO criteria.

Compare and present the disease control rates by calculating the ratio of the number of subjects responding to treatment (complete response: CR, partial response: PR, stable disease: SD) among the treatment groups and control group assessed based on the RANO criteria.

Karnofsky performance status (KPS) assessment

Ajou University School of Medicine

CHA University

Professor

Topotecan

Topoisomerase I Inhibitors

Once a plastic catheter is placed, within 24 hours of placement, the catheter will be connected to a small pump at the bedside, and the convection-enhanced delivery of the Topotecan will begin. The Topotecan will be infused for 4 to 5 days after which time the catheters will simply be pulled out. Patients will be monitored with blood tests and MRI scans during the treatment and at different time periods during the following months.

microinfusion pumps to deliver chemotherapy directly into brain tumors

Convection-Enhanced Delivery

chemotherapeutic drug for the treatment of brain tumors

Jeffrey Bruce, MD

This study will evaluate the safety and efficacy of a chemotherapeutic drug (topotecan) as it is given directly into brain tumors by a delivery technique called convection-enhanced delivery. This drug has been used for different types of cancer, but in this study it will be given by an experimental delivery technique designed to maximize the amount of drug delivered to the brain tumor and minimize the side effects in other parts of the body.

This study will also evaluate advanced magnetic resonance (MR) imaging techniques.

The study will assess quality of life parameters throughout the follow-up period.

Clinical efficacy with chemotherapy has been discouraging for malignant brain tumors, mostly because of side effects and delivery limitations. Because they are locally invasive and rarely metastasize, malignant gliomas have features that make them uniquely amenable to new strategies of regional drug delivery. Intracerebral clysis (convection-enhanced delivery) is a novel drug delivery strategy that uses a microinfusion pump to establish a pressure gradient in the brain via implanted catheters. The pressure gradient produces convective forces that distribute a therapeutic agent throughout the tumor and surrounding brain tissue.

Non-invasive magnetic resonance imaging (MRI) methods of monitoring drug distribution and treatment response have been developed to maximize the clinical applications and minimize complications associated with treatment risks.

Study participants will be taken to the operating room to have 2 catheters surgically placed into their tumor and surrounding tumor bed. These catheters will then be connected to small infusion pumps which will slowly infuse topotecan continuously over 4-5 days. Patients will have daily MRI scans while in the hospital. Upon completion of the experimental treatment, patients will be discharged and will be followed up in the outpatient clinic.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Biomarker Analysis of Central Nervous System Tumors	NCT02692898	Central Nervous... Primary Brain N... Neoplasms, Brai... Cancer of the B... Brain Cancer		- 99 Years	National Institutes of Health Clinical Center (CC)
Biomarker Analysis of Central Nervous System Tumors	NCT02692898	Central Nervous... Primary Brain N... Neoplasms, Brai... Cancer of the B... Brain Cancer		- 99 Years	National Institutes of Health Clinical Center (CC)
A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects	NCT01677741	Neoplasms, Brai...	Dabrafenib	12 Months - 17 Years	Novartis
More Complete Removal of Malignant Brain Tumors by Fluorescence-Guided Surgery	NCT01445691	Benign Neoplasm... Brain Cancer Brain Neoplasms... Brain Neoplasms... Brain Tumor, Pr... Brain Tumor, Re... Brain Tumors Intracranial Ne... Neoplasms, Brai... Neoplasms, Intr... Primary Brain N... Primary Maligna... Primary Maligna... Gliomas Glioblastoma	5-ALA (Gliolan)	18 Years - 80 Years	Icahn School of Medicine at Mount Sinai
A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects	NCT01677741	Neoplasms, Brai...	Dabrafenib	12 Months - 17 Years	Novartis
Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients	NCT04657315	Glioblastoma Adult Gliosarco... Neoplasms, Brai... Neoplasms, Germ... Recurrent Gliob...	MSC11FCD	19 Years - 70 Years	CHA University
Safety Study of Intracerebral Topotecan for Recurrent Brain Tumors	NCT00308165	Brain Neoplasms...	Convection-Enha... Topotecan	1 Year -	Columbia University
Evaluation of Maximum Tolerated Dose, Safety and Efficiency of MSC11FCD Therapy to Recurrent Glioblastoma Patients	NCT04657315	Glioblastoma Adult Gliosarco... Neoplasms, Brai... Neoplasms, Germ... Recurrent Gliob...	MSC11FCD	19 Years - 70 Years	CHA University

Spots Global Cancer Trial Database for neoplasms, brain