Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Eye Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Recurrence

Glioma

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Astrocytoma

Optic Nerve Glioma

Disease Attributes

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Nerve Sheath Neoplasms

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Peripheral Nervous System Diseases

Neuromuscular Diseases

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Optic Nerve Neoplasms

Cranial Nerve Diseases

Optic Nerve Diseases

Neurofibromatosis

Neurofibromatosis Type 1

Optic Pathway Glioma

Pilocytic Astrocytoma

Neuroepithelioma

Patients receive selumetinib PO BID on days 1-28. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience a sustained objective response from selumetinib on the phase I or phase II portions of the trial, and who have completed 2 years of treatment and stopped study drug may be enrolled on the re-treatment study after progression/recurrence. Patients in the re-treatment study may continue treatment indefinitely in the absence of disease progression or unacceptable toxicities. Patients undergo blood sample collection on study.

Biospecimen Collection

Selumetinib

Jason R Fangusaro

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) or recommend a Phase II dose of AZD6244 (selumetinib) in children with recurrent or refractory low-grade glioma. (Phase I, completed as of April 29, 2013) II. To describe the toxicity profile and define the dose limiting toxicity of AZD6244 in children with recurrent or refractory low-grade glioma. (Phase I) III. To study the safety of the maximum tolerated dose (MTD) or recommended a Phase II dose (RP2D) of AZD6244 as determined based on safety data from children \>= 12 years of age in children \< 12 years of age; if the MTD/RP2D of the older children is too toxic for the younger children, we will de-escalate to one dose level below and study the safety of that dose in the younger age cohort. (Phase I) IV. To assess the sustained response rate of AZD6244 administered at 25 mg/m\^2/dose twice daily (BID), in a single arm Phase II setting in patients assigned to strata based on neurofibromatosis (NF)-1 status and presence or absence of v-raf murine sarcoma viral oncogene homolog B (BRAF) aberrations, specifically BRAF V600E mutations and/or BRAF KIAA1549 fusion identified by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. (Phase II, completed as of January 4, 2021) V. To estimate the sustained response rate and prolonged disease stabilization rate (defined as lack of disease progression for \>= 12 courses) associated with AZD6244 in patients with recurrent and/or progressive low-grade gliomas who previously received treatment on PBTC-029 or PBTC-029B for a minimum of 12 courses, with at least stable disease or patients who had a sustained response but remained on treatment \< 12 courses. (Re-treatment Study, enrollment complete as of April 23, 2019)

SECONDARY OBJECTIVES:

I. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics administered on this schedule and to assess the influence of patient specific covariates (including concomitant drug therapy) on AZD6244 pharmacokinetics. (Phase I) II. To evaluate the feasibility of collecting pre-trial tumor samples and the feasibility of using in situ hybridization assay to identify BRAF aberrations in available tumor specimens. (Phase I) III. To determine if pre-trial tumor samples show the biochemical signature that indicates activation of the mitogen-activated protein kinase (MAPK) pathway. (Phase I) IV. To describe magnetic resonance imaging (MRI) characteristics of the tumors before and after treatment and to explore the diffusion changes in the tumors before and after treatment to determine if there is an early diffusion indicator of response. (Phase I) V. Within the constraints of a Phase I trial, to document antitumor activity of treatment with AZD6244, as measured by objective responses and progression-free survival (PFS). (Phase I) VI. To explore the pharmacogenetic polymorphisms in AZD6244 metabolizing enzymes and transporters and relate these polymorphisms to AZD6244 pharmacokinetics. (Phase I) VII. To estimate the PFS distributions associated with AZD6244 treatment separately in patients assigned to the six strata as well as for various other subsets e.g. histology and tumor grade across strata. (Phase II) VIII. To explore correlations between BRAF aberrations and treatment response and PFS in patients for whom relevant biology data are available. (Phase II) IX. To assess MAPK aberrations by a combination of whole-exome and ribonucleic acid (RNA) sequencing. (Phase II) X. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics administered on this schedule at the MTD/RP2D. (Phase II) XI. To determine progression-free survival following re-treatment with AZD6244 for progressive, recurrent low-grade gliomas and to evaluate the impact of variables such as previous response, interval treatment regimens, BRAF status and previous dose of AZD6244. (Re-treatment Study) XII. To evaluate the toxicity profile of re-treatment with AZD6244 and correlate with toxicities seen during initial treatment. (Re-treatment Study) XIII. To evaluate the toxicity profile of re-treatment with AZD6244 beyond 2 years for those patients who continue to show benefit from the drug, i.e. at least stable disease (SD). (Re-treatment Study)

OUTLINE: This is a phase I dose-escalation study (completed as of April 29, 2013) followed by a phase II study.

Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience a sustained objective response from selumetinib on the phase I or phase II portions of the trial, and who have completed 2 years of treatment and stopped study drug may be enrolled on the re-treatment study after progression/recurrence. Patients in the re-treatment study may continue treatment indefinitely in the absence of disease progression or unacceptable toxicities. Patient undergo blood sample collection on study.

After completion of study treatment, patients are followed up for 30 days.

Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma

A Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. In addition, the confirmed sustained objective response rate observed during treatment by cumulative incidence functions will be estimated. This provides not only an overall estimate of the response rate but also an estimate of the timing of responses as a function of number of months of treatment.

Exact confidence interval estimates will be provided.

Disease stabilization rates will be measured.

Plasma drug concentrations and pharmacokinetic parameters volume of the central compartment, elimination rate constant, half-life, apparent oral clearance, and area under the plasma concentration time curve.

Kaplan-Meier estimates of distributions of PFS all eligible subjects who received at least one dose of selumetinib will be provided separately for each stratum. It is unlikely that sufficient numbers of subjects will be followed until death to statistically support estimation of the survival distributions but survival estimation will also be considered.

Will be assessed by immunohistochemistry and fluorescence in situ hybridization, respectively. Frequency tables summarizing the presence and absence of BRAF aberrations in all patients from whom tissue is available will be provided. The association of presence/absence and type of BRAF aberrations versus PFS will be explored via Kaplan-Meier-plots. Log-rank tests and/or Cox regression models may also be used to assess statistical associations between BRAF and PFS provided more than 10 events are observed in a given strata to make such assessments meaningful.

Kaplan-Meier estimates of progression-free survival distributions for all eligible patients will be provided. Exact confidence interval estimates will be provided.

National Cancer Institute (NCI)

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Central Nervous System Neoplasms

Pinealoma

Brain Stem Neoplasms

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Infratentorial Neoplasms

Brain Neoplasms

Brain Diseases

Central Nervous System Diseases

Lymphosarcoma

Pineocytoma

Antineoplastic Agents

All Drugs and Chemicals

Entinostat

Histone Deacetylase Inhibitors

Enzyme Inhibitors

Patients receive entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Andrew Bukowinski

This phase I trial studies the side effects and best dose of entinostat in treating pediatric patients with solid tumors that have come back or have not responded to treatment. Entinostat may block some of the enzymes needed for cell division and it may help to kill tumor cells.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of entinostat administered as a single-agent, once weekly to children with recurrent or refractory solid tumors.

II. To define and describe the toxicities of entinostat administered as a single agent, once weekly to children with recurrent or refractory solid tumors.

III. To characterize the pharmacokinetics of entinostat in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of entinostat within the confines of a phase 1 study.

II. To assess change in histone H3 and H4 acetylation in peripheral blood mononuclear cells (PBMCs) as a marker of the biologic activity of entinostat.

OUTLINE: This is a dose escalation study.

Patients receive entinostat orally (PO) on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

A Phase 1 Study of Entinostat, an Oral Histone Deacetylase Inhibitor, in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors and Lymphoma

The MTD/RP2D will be defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity during cycle 1 of therapy among 6 toxicity-evaluable patients. The frequency of cycle 1 dose limiting toxicities will be summarized by dose level among patients in the dose escalation part of the study.

The frequency of patients with at least one Grade 3 or greater adverse event that are at least possibly attributable to entinostat during cycle 1 will be summarized by study part, dose level.

The median (min, max) Half-Life of entinostat stratified by study part and dose level. The half-life (t1/2) was calculated using the equation t1/2 = 0.693/λz, where the terminal elimination rate constant (λz) was determined from a least-squares regression of the log-transformed plasma concentration vs. time data for the last 3 - 4 time points.

The median (min, max) of the peak plasma concentration of entinostat stratified by study part, dose level. Time points were assessed at 0, 0.5, 1, 3, 6, 24, and 48-96 hours post-dose during cycle 1, day 1.

The median (min, max) of the total area under the plasma concentration curve of entinostat stratified by study part, dose level. Time points were assessed at 0, 0.5, 1, 3, 6, 24, and 48-96 hours post-dose during cycle 1, day 1.

The median (min, max) of the time to reach maximum plasma concentration of entinostat stratified by study part, dose level. Time points were assessed at 0, 0.5, 1, 3, 6, 24, and 48-96 hours post-dose during cycle 1, day 1.

Frequency of response to entinostat per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and/or assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, stratified by study part and dose

Median (IQR) change in H3 acetylation in peripheral blood mononuclear cells (PBMCs) versus baseline stratified by study part, dose level.

Median (IQR) change in H4 acetylation in PBMCs versus baseline stratified by study part, dose level.

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

Patients with recurrent or refractory solid tumors, including lymphoma and CSN tumors, treated once weekly with entinostat administered as a single-agent at 3 mg/m2

Stratum 1 With 3 mg/m²

Patients with recurrent or refractory solid tumors, including lymphoma and CSN tumors, treated once weekly with entinostat administered as a single-agent at 4 mg/m2

Stratum 1 With 4 mg/m²

Patients with recurrent or refractory solid tumors without bone marrow involvement, including lymphoma and CSN tumors, treated once weekly with entinostat administered as a single-agent at the RP2D (4 mg/m2)

PK Part With 4 mg/m²

Total

Patients must be ≥ than 12 months and ≤ 21 years of age at the time of study enrollment, and Karnofsky \>= 50% for patients \> 16 years of age and Lansky \>= 50 for patients =\< 16 years of age.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Results Reporting Coordinator

Patients with recurrent or refractory solid tumors, including lymphoma and CNS tumors, who receive entinostat on Days 1, 8, 15, and 22 of a 28-day cycle

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma	NCT01089101	Low Grade Gliom... Recurrent Child... Recurrent Neuro... Recurrent Visua... Refractory Neur... Refractory Visu...	Biospecimen Col... Selumetinib	3 Years - 21 Years	National Cancer Institute (NCI)
Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors	NCT02780804	Brain Stem Neop... Pineal Region N... Recurrent Lymph... Recurrent Malig... Recurrent Prima... Recurrent Visua... Refractory Lymp... Refractory Mali... Refractory Prim... Refractory Visu...	Entinostat Laboratory Biom... Pharmacological...	12 Months - 21 Years	National Cancer Institute (NCI)
Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors	NCT02780804	Brain Stem Neop... Pineal Region N... Recurrent Lymph... Recurrent Malig... Recurrent Prima... Recurrent Visua... Refractory Lymp... Refractory Mali... Refractory Prim... Refractory Visu...	Entinostat Laboratory Biom... Pharmacological...	12 Months - 21 Years	National Cancer Institute (NCI)
Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma	NCT01089101	Low Grade Gliom... Recurrent Child... Recurrent Neuro... Recurrent Visua... Refractory Neur... Refractory Visu...	Biospecimen Col... Selumetinib	3 Years - 21 Years	National Cancer Institute (NCI)
Entinostat in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors	NCT02780804	Brain Stem Neop... Pineal Region N... Recurrent Lymph... Recurrent Malig... Recurrent Prima... Recurrent Visua... Refractory Lymp... Refractory Mali... Refractory Prim... Refractory Visu...	Entinostat Laboratory Biom... Pharmacological...	12 Months - 21 Years	National Cancer Institute (NCI)
Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma	NCT01089101	Low Grade Gliom... Recurrent Child... Recurrent Neuro... Recurrent Visua... Refractory Neur... Refractory Visu...	Biospecimen Col... Selumetinib	3 Years - 21 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for refractory visual pathway glioma