SNPMiner Trials by Shray Alag


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Report for Mutation K27M

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 15 clinical trials

Clinical Trials


1 A Phase 1 Study of AZD1775 (MK-1775) Concurrent With Local Radiation Therapy for the Treatment of Newly Diagnosed Children With Diffuse Intrinsic Pontine Gliomas

This phase I trial studies the side effects and the best dose of adavosertib when given together with local radiation therapy in treating children with newly diagnosed diffuse intrinsic pontine gliomas. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons, or other sources to kill tumor cells and shrink tumors. Giving adavosertib with local radiation therapy may work better than local radiation therapy alone in treating diffuse intrinsic pontine gliomas.

NCT01922076 Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Glioblastoma Gliosarcoma Drug: Adavosertib Other: Laboratory Biomarker Analysis Other: Pharmacological Study Radiation: Radiation Therapy
MeSH: Glioblastoma Glioma Astrocytoma Gliosarcoma
HPO: Astrocytoma Glioblastoma multiforme Glioma Subependymal giant-cell astrocytoma

Paired analysis methods will be used.. Inclusion Criteria: - Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible without histologic confirmation - Patients with brainstem tumors that do not meet these criteria or are not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma, gliosarcoma, diffuse midline glioma with histone H3 K27M mutation, or anaplastic mixed glioma; patients with pilocytic astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible - Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician - Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date - Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment - Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score - Patients must not have received any prior anti-cancer therapy such as chemotherapy, radiation therapy, immunotherapy or bone marrow transplant for the treatment of DIPG; prior dexamethasone and/or surgery are allowed - Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 - Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 --- K27M ---

congestive heart failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not eligible for this trial - Major surgical procedures =< 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy of the tumor) =< 7 days; no waiting period required following port-a-cath or other central venous access placement - Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible Inclusion Criteria: - Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible without histologic confirmation - Patients with brainstem tumors that do not meet these criteria or are not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma, gliosarcoma, diffuse midline glioma with histone H3 K27M mutation, or anaplastic mixed glioma; patients with pilocytic astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible - Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician - Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date - Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment - Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score - Patients must not have received any prior anti-cancer therapy such as chemotherapy, radiation therapy, immunotherapy or bone marrow transplant for the treatment of DIPG; prior dexamethasone and/or surgery are allowed - Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 - Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 --- K27M ---

congestive heart failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not eligible for this trial - Major surgical procedures =< 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy of the tumor) =< 7 days; no waiting period required following port-a-cath or other central venous access placement - Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Glioblastoma Gliosarcoma Glioblastoma Glioma Astrocytoma Gliosarcoma PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose and schedule of the adavosertib (Wee1 inhibitor AZD1775 [MK-1775]) administered concurrently with radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). --- K27M ---

Primary Outcomes

Description: MTD will be defined as the maximum dose at which fewer than one-third of patients experience a dose-limiting toxicity graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Measure: Maximum tolerated dose (MTD)

Time: Up to 42 days

Description: Adverse events will be graded using the NCI CTCAE version 4.0.

Measure: Incidence and grade of adverse events

Time: Up to 4 years

Other Outcomes

Description: A descriptive analysis of PK parameters of adavosertib will be performed to define systemic exposure and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

Measure: Pharmacokinetic (PK) parameters of adavosertib

Time: Pre-dose, 1, 2, 4, 6, 8, and 24 hours on day 1; pre-dose, 1, 2, 4, 6, and 8 hours on day 5; and pre-dose on day 8

Description: Disease response will be reported descriptively.

Measure: Response rate (partial response, complete response, or stable disease)

Time: Up to 4 years

Description: PFS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.

Measure: Progression-free survival (PFS)

Time: Up to 4 years

Description: OS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.

Measure: Overall survival (OS)

Time: Up to 4 years

Description: Will be assessed using flow cytometry. Paired analysis methods will be used.

Measure: Change in p-CDC2, p-HH3 and gamma-H2AX expression

Time: Baseline to day 8

2 Oral ONC201 in Recurrent Glioblastoma, H3 K27M-mutant Glioma, and Diffuse Midline Glioma

ONC201 is a new drug candidate that kills cancer cells but not normal cells in laboratory studies and has been previously evaluated in a phase I clinical trial in advanced cancer patients. This clinical trial will enroll patients with recurrent glioblastoma or recurrent WHO Grade IV gliomas with the H3 K27M mutation.

NCT02525692 Glioblastoma Diffuse Midline Glioma H3 K27M Glioma Thalamic Glioma Infratentorial Glioma Basal Ganglia Glioma Drug: ONC201
MeSH: Glioblastoma Glioma
HPO: Glioblastoma multiforme Glioma

Oral ONC201 in Recurrent Glioblastoma, H3 K27M-mutant Glioma, and Diffuse Midline Glioma. --- K27M ---

Oral ONC201 in Recurrent GBM, H3 K27M Glioma, and Midline Glioma ONC201 is a new drug candidate that kills cancer cells but not normal cells in laboratory studies and has been previously evaluated in a phase I clinical trial in advanced cancer patients. --- K27M ---

This clinical trial will enroll patients with recurrent glioblastoma or recurrent WHO Grade IV gliomas with the H3 K27M mutation. --- K27M ---

For Arm D: Must have a WHO Grade IV glioma as per above and tumor must harbor a histone H3 K27M mutation as evidenced by testing any tumor sample with an immunohistochemistry or DNA sequencing test. --- K27M ---

For Arm F: Must have a diffuse midline glioma, defined as a WHO Grade IV glioma involving the brainstem, thalamus or spinal cord, without the H3 K27M mutation or with unknown H3 mutation status. --- K27M ---

Glioblastoma Diffuse Midline Glioma H3 K27M Glioma Thalamic Glioma Infratentorial Glioma Basal Ganglia Glioma Glioblastoma Glioma null --- K27M ---

Primary Outcomes

Measure: Progression-free survival

Time: 6 months

3 A Phase I/II Study of Ribociclib, a CDK4/6 Inhibitor, Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)

In this research study the investigators want to learn more about the effects, both good and bad, when the study drug Ribociclib is given after radiation therapy. The investigators are asking people to be in this research study that have been newly diagnosed with a high grade glioma, and the tumor has been screened for the Rb1 protein, and have recently finished radiation therapy. Patients with a DIPG or a Bi-thalamic high grade glioma do not need to have tumor tissue screened for the Rb1 protein but do need to have finished radiation therapy. Tumor cells grow and divide quickly. In normal cells, there are proteins called cyclin-dependent kinases (CDK 4 and 6) that control cell division. Another protein Rb1 also controls cell division and works to stop cells from dividing so they do not become cancer cells. But in cancer, the CDK 4 and 6 proteins are out of control making the cells divide and grow quickly. The study drug, ribociclib stops the CDK 4 and 6 proteins. When the CDK 4 and 6 proteins are stopped, the normal Rb1 protein can now work to slow cell growth. For patients with HGG, to be in this study tumor tissue must have a normal Rb1 protein. The researchers think that if the study drug is given soon after radiation therapy, it may help improve the effect of the radiation in stopping the tumor from growing. The study drug, Ribociclib is considered investigational as it has not yet been approved by the United States Food and Drug Administration. The study drug has been tested in children and adults with cancer in prior research studies.

NCT02607124 High Grade Glioma Diffuse Intrinsic Pontine Glioma Bithalamic High Grade Glioma Drug: Ribociclib
MeSH: Glioma
HPO: Glioma

- Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to have + RB and be the following according to the 2016 World Health Organization classification of tumors of the central nervous system: an anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS), glioblastoma (IDH mutant, IDH wildtype or NOS), diffuse midline glioma, H3 K27M mutant or H3 K27M negative, diffuse astrocytoma (IDH mutant, IDH wildtype or NOS). --- K27M ---

- Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to have + RB and be the following according to the 2016 World Health Organization classification of tumors of the central nervous system: an anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS), glioblastoma (IDH mutant, IDH wildtype or NOS), diffuse midline glioma, H3 K27M mutant or H3 K27M negative, diffuse astrocytoma (IDH mutant, IDH wildtype or NOS). --- K27M --- --- K27M ---

Primary Outcomes

Description: Primary feasibility endpoint is the number of individual toxicities and incidence of significant delays

Measure: Number of adverse events

Time: 6 months

Measure: Number of patients alive at one year

Time: 1 year

Secondary Outcomes

Description: Progression free survival is defined as the time from initiation of treatment to the earliest date of failure (disease progression, death from any cause, or second malignancy) for patients who fail and to the last assessment date for patients who have not failed.

Measure: Time from initiation of treatment to the earliest date of failure - progression free survival

Time: 12 months

Description: The assessment of true vs. pseudo progression will be based on the tumor measurements from subsequent scans.

Measure: Number of patients with observed pseudoprogression

Time: 12 months

4 Phase 1 Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma (DIPG). Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stratum 1 treats patients with DIPG that has returned or gotten worse (progressed). Stratum 2 treats patients with DIPG that has not yet gotten worse. Currently, only Stratum 2 is enrolling patients.

NCT02717455 Glioma Drug: LBH589
MeSH: Glioma
HPO: Glioma

To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment.. Pharmacodynamics: Cell-free DNA - Blood and Urine (Optional). --- K27M ---

Based on the in vitro and in vivo activity of panobinostat in preclinical models using DIPG cell cultures and orthotopic xenograft model systems, and the potentially important role of histone deacetylases and histone 3 K27M mutations in relation to pontine malignancies, the investigators are conducting a Phase 1 study of panobinostat in children with recurrent/progressive DIPG. --- K27M ---

Primary Outcomes

Description: Adverse Events

Measure: To describe the toxicity profile and the dose-limiting toxicities of panobinostat in children with recurrent/progressive DIPG

Time: 26 courses (approximately 2 years)

Description: Dose Finding

Measure: To estimate the maximum-tolerated dose and/or the recommended-phase 2 dose of panobinostat in children with recurrent/progressive DIPG

Time: Course 1 (the first 4 weeks of treatment)

Description: Plasma Pharmacokinetics

Measure: To evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG

Time: Course 1, Day 1 and Day 3 sample collections

Description: Adverse Events

Measure: To describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with non-progressed DIPG treated with 3 times/week, every other week.

Time: 26 courses (approximately 2 years)

Description: Dose Finding

Measure: To estimate the maximum-tolerated dose and/or the recommended-phase 2 dose of panobinostat administered 3 times/week, every other week in children with non-progressed DIPG

Time: Course 1 (the first 4 weeks of treatment)

Description: Plasma Pharmacokinetics

Measure: To evaluate and characterize the plasma pharmacokinetics of panobinostat administered 3 times/week, every other week in children with non-progressed DIPG

Time: Course 1, Day 1 and Day 3 sample collections

Secondary Outcomes

Description: Evaluated Response per imaging or clinical progression

Measure: To describe the progression-free survival (PFS) and overall survival (OS) of children with recurrent or progressive DIPG who are treated with panobinostat

Time: 26 courses (approximately 2 years)

Description: Evaluated Response per imaging or clinical progression

Measure: To describe the progression-free survival (PFS) and overall survival (OS) of children with non-progressed DIPG who are treated with panobinostat

Time: 26 courses (approximately 2 years)

Description: Pharmacodynamics: Cell-free DNA - Blood and Urine (Optional)

Measure: To identify histone 3 K27M mutations in peripheral blood and urine, and evaluate changes with treatment.

Time: Day 1 of courses 1, 2, 4, 6, and 12

5 H3.3K27M Specific Peptide Vaccine Combined With Poly-ICLC for the Treatment of Newly Diagnosed HLA-A2+ H3.3K27M Positive Diffuse Intrinsic Pontine Glioma (DIPG) as Well as Other Newly Diagnosed HLA-A2+ H3.3K27M Positive Gliomas

This is a two cohort Phase I study within the Pacific Pediatric Neuro-Oncology Consortium (PNOC). This study will assess the safety of repeated administration of the H3.3K27M specific vaccine in HLA-A2+ children and young adults with H3.3K27M DIPGs and other gliomas.

NCT02960230 Diffuse Intrinsic Pontine Glioma Glioma Biological: K27M peptide
MeSH: Glioma
HPO: Glioma

Any eligible subject that receives at least one dose of the K27M/TT vaccine will be considered evaluable for clinical efficacy. --- K27M ---

Primary Outcomes

Description: Safety of the vaccine will be assessed by monitoring for adverse events (AEs), scheduled laboratory assessments, vital signs, & physical examinations for subjects who receive the vaccination. The severity of toxicities will be graded according to the NCI CTCAE v4.0. AEs & clinically significant lab abnormalities (meeting Grade 3, 4, or 5 criteria according to CTCAE) will be summarized by maximum intensity & relationship to study drug(s). Grade 1 & 2 AEs will be summarized if related to study therapy. Descriptive statistics will be utilized to display the data on toxicity seen.

Measure: Number of Participants with Adverse Events related to treatment

Time: 24 months

Description: OS12 will be the clinical efficacy primary endpoint. Any eligible subject that receives at least one dose of the K27M/TT vaccine will be considered evaluable for clinical efficacy. For subjects who are still alive at 12 months, OS12 will be censored at the last contact date. OS will be estimated using the Kaplan-Meier method.

Measure: Overall survival (OS) at 12 months (OS12)

Time: 36 months

Secondary Outcomes

Description: A subject will be considered to have responded, if at any of post-vaccine time point against H3.3K27M antigen, the number of spots is double that at baseline, and there are at least 10 spots/20,000 cells, and if the number of the post-vaccine spots is at least three times the standard-deviation of the pre-vaccine value. This definition provides some protection against false positive response. We will correlate response with OS data. We will plot the time course of the magnitude of response and model it using a mixed-effects model approach.

Measure: Induction of the H3.3K27M epitope-specific cytotoxic T lymphocyte (CTL) response in post vaccine peripheral mononuclear cells (PBMC) in HLA-A2+ children with DIPG and other gliomas

Time: 36 months

Other Outcomes

Description: In subjects with evidence of progression that will undergo tissue collection as part of their standard of care, the tumor tissue will be analyzed for H3.3K27M expression status and infiltration of H3.3K27M specific T cells.

Measure: Assess H3.3K27M expression status and infiltration of H3.3K27M specific T cells

Time: 36 months

Description: Archived tumor and normal DNA from each subject at time of initial diagnosis along with serial blood draw following therapy will be used for later studies to determine whether circulating tumor DNA (ctDNA) sequences in the subject's blood serve as biomarkers of tumor burden, response to therapy, or development of drug resistance.

Measure: Analyze circulating tumor DNA

Time: 36 months

6 International Diffuse Intrinsic Pontine Glioma (DIPG)/Diffuse Midline Glioma (DMG) Registry and Repository

Doctors and other medical scientists want learn about the biology of DIPG/DMG and to develop better ways to diagnose and treat patients with DIPG/DMG. To do this, they need more information about the characteristics of DIPG/DMG tumors. Therefore, they want to establish a central location for clinical information and tumor tissue collected from DIPG/DMG patients. The purposes of this study are: - To enroll patients diagnosed with DIPG/DMG in the International DIPG/DMG Registry and Repository. - To provide a central location for clinical information, scans, and tissue samples from patients with DIPG/DMG enrolled in the registry. - To collect tissue samples in order to study how DIPG/DMG works on the molecular level. Researchers may use the tissue samples to study molecules such as proteins and DNA. Proteins are needed for the body to function properly and DNA is the molecule that carries our genetic information. Other researchers will be able to use the stored samples in the future to learn more about DIPG/DMG. The information researchers get from the research studies will be kept in the registry along with the clinical information. - To help investigators around the world to work together to make more consistent diagnosis and better design of future research studies. We hope this will lead to better treatments for DIPG/DMG in the future.

NCT03101813 Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Diffuse Midline Glioma
MeSH: Glioma
HPO: Glioma

Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Diffuse Midline Glioma Glioma There are limited data regarding the biology of diffuse intrinsic pontine gliomas (DIPG) and diffuse midline gliomas (DMG). --- K27M ---

Primary Outcomes

Description: To implement a central repository for clinical, radiological, pathological and demographic data and specimens from patients with DIPG.

Measure: Identify the biological factors contributing to DIPG/DMG

Time: Through study completion, anticipated to be 25 years

Secondary Outcomes

Description: correlate registry data to a bioinformatics repository of molecular data on DIPG/DMG

Measure: Identify genetic and molecular signature of diffuse intrinsic pontine gliomas and diffuse midline gliomas.

Time: Through study completion, anticipated to be 25 years

Description: develop classification systems, uniform standards of diagnosis, assessment and response

Measure: Identify radiographic characteristics of DIPG/DMG

Time: Through study completion, anticipated to be 25 years

7 Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High Grade Gliomas

The objective of this expanded access program is to provide ONC201 to eligible patients with previously-treated glioma that exhibits the H3 K27M mutation and/or that is located in the midline region of the brain.

NCT03134131 Glioma Drug: ONC201
MeSH: Glioma
HPO: Glioma

Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High Grade Gliomas. --- K27M ---

Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High Grade Gliomas The objective of this expanded access program is to provide ONC201 to eligible patients with previously-treated glioma that exhibits the H3 K27M mutation and/or that is located in the midline region of the brain. --- K27M ---

Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High Grade Gliomas The objective of this expanded access program is to provide ONC201 to eligible patients with previously-treated glioma that exhibits the H3 K27M mutation and/or that is located in the midline region of the brain. --- K27M --- --- K27M ---

A glioma that is positive for the H3 K27M mutation (performed in a laboratory with CLIA certification); 2. A grade III or IV glioma involving the thalamus, hypothalamus, brainstem, cerebellum, midbrain, or spinal cord; 3. Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons. --- K27M ---


8 International Cooperative Phase III Trial of the HIT-HGG Study Group for the Treatment of High Grade Glioma, Diffuse Intrinsic Pontine Glioma, and Gliomatosis Cerebri in Children and Adolescents < 18 Years.(HIT-HGG-2013)

The HIT-HGG-2013 trial offers an innovative high-quality diagnostics and science program for children and adolescents >3 years, suffering from one of the following types of high grade gliomas: 1. glioblastoma WHO grade IV (GBM) 2. diffuse midlineglioma histone 3 K27M mutated WHO grade IV (DMG) 3. anaplastic astrocytoma WHO grade III (AA) 4. diffuse intrinsic pontine glioma (DIPG) 5. gliomatosis cerebri (GC) For 1.-3. diagnosis has to be confirmed by neuropathological survey, for 4. and 5. diagnosis has to be confirmed by neuroradiological survey. In addition to standard treatment (radiotherapy and temozolomide chemotherapy) the effects of two further drugs, which have been applied to millions of children and adolescents in other indications, will be compared to each other. The aim of the trial will be to investigate whether these drugs may increase the effects of radio- and chemotherapy, resulting in a better survival of the treated patients. One of these additional drugs will be valproic acid, traditionally used for treatment of seizure disorder. The other drug will be Chloroquin, a well-established drug for Malaria treatment. Recently, scientific studies provided evidence for anti-tumoral effects of both drugs: Valproat seems to be a so-called histondeacetylase inhibitor (HDAC inhibitor), controlling important genetic processes of tumor growth. Chloroquin is an autophagy inhibitor. It prevents the shutting-down of tumor cell metabolism, a strategy to ensure survival of the whole tumor by developing a resistance against radiation and antineoplastic agents. Studies in cell culture, animals and first clinical trials in adults as well provided evidence for efficacy of valproic acid and chloroquine in the treatment of glioblastoma. Due to this we hope children and adolescents suffering from GBM, DMG, AA, DIPG und GC will benefit from the treatment, too. As common for clinical trials, the treatment of the patients will be settled in a randomized manner to ensure impartiality of the investigators. One aim of the HIT-HGG-2013 trial will be to compare the effects of Valproat and Chloroquin to each other. Additionally, the results will be compared with data of the HIT-HGG-2007 trial (children and adolescents with same diseases, only treated with simultaneous temozolomide radiochemotherapy).

NCT03243461 Glioblastoma WHO Grade IV Diffuse Midline Glioma Histone 3 K27M WHO Grade IV Anaplastic Astrocytoma WHO Grade III Diffuse Intrinsic Pontine Glioma Gliomatosis Cerebri Drug: Temozolomide + Valproic Acid Drug: Temozolomide + Chloroquine
MeSH: Glioblastoma Glioma Astrocytoma Neoplasms, Neuroepithelial
HPO: Astrocytoma Glioblastoma multiforme Glioma Neuroepithelial neoplasm Subependymal giant-cell astrocytoma

International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013) The HIT-HGG-2013 trial offers an innovative high-quality diagnostics and science program for children and adolescents >3 years, suffering from one of the following types of high grade gliomas: 1. glioblastoma WHO grade IV (GBM) 2. diffuse midlineglioma histone 3 K27M mutated WHO grade IV (DMG) 3. anaplastic astrocytoma WHO grade III (AA) 4. diffuse intrinsic pontine glioma (DIPG) 5. gliomatosis cerebri (GC) For 1.-3. --- K27M ---

immune deficiency syndrome; known tumour predisposition syndromes which do not affect adequate performance of the trial represent no exclusion criterion a priori - Known HIV positivity - Severe manifest hepatic disease including hepatic porphyria as well as personal or family history of severe hepatic dysfunction, especially drug-related - Severe pancreatic disease - Severe hepatic disease - Lethal hepatic dysfunction in a sibling during valproic acid treatment - Known urea cycle defect - Severe coagulation disorders (in regards to thrombopenia see prerequisite for blood cell count before starting treatment) - Retinopathy and restricted visual fields (Exception: Brain tumour-related changes of visual fields) - Glucose-6-phosphate dehydrogenase deficiency (favism) - Myasthenia gravis - Known porphyria - Valproic acid as antiepileptc drug for any pre-existing epilepsy - Chloroquine or hydroxycloroquine as pre-existing and ongoing medication for malaria, lupus erythematodes, or any other medical reason Glioblastoma WHO Grade IV Diffuse Midline Glioma Histone 3 K27M WHO Grade IV Anaplastic Astrocytoma WHO Grade III Diffuse Intrinsic Pontine Glioma Gliomatosis Cerebri Glioblastoma Glioma Astrocytoma Neoplasms, Neuroepithelial Indication: First-line treatment of high grade gliomas, diffuse intrinsic pontine glioma, and gliomatosis cerebri in paediatric patients < 18 years of age. --- K27M ---

Primary Outcomes

Description: To confirm that the Event-Free Survival (EFS) in patients ≥ 3 years of age with paed HGG WHO grade IV, anaplastic astrocytoma WHO grade III (AAIII), DIPG, and gliomatosis cerebri differs for children treated with additional VPA compared to children treated with additional CQ.

Measure: Comparison of effects of valproine acid and chloroquine.

Time: 4.8 years

Description: To confirm that the Event-Free Survival (EFS) in patients ≥ 3 years of age with paed HGG WHO grade IV, anaplastic astrocytoma WHO grade III (AAIII), DIPG, and gliomatosis cerebri differs for children treated with additional VPA compared to children in the historical HIT-HGG-2007 study sample.

Measure: Comparison of effects of valproine acid with respect to historical control group.

Time: 4.8 years

Description: To confirm that the Event-Free Survival (EFS) in patients ≥ 3 years of age with paed HGG WHO grade IV, anaplastic astrocytoma WHO grade III, DIPG, and gliomatosis cerebri differs for children treated with additional CQ compared to children in the historical HIT-HGG- 2007 study sample.

Measure: Comparison of effects of chloroquine with respect to historical control group.

Time: 4.8 years

9 A Phase II, Open-label Study of ONC201 in Adults With Recurrent High-grade Glioma

The primary objective of this phase II trial is to determine the efficacy and safety of ONC201, an oral small molecule imipridone DRD2 antagonist, in adult subjects with recurrent high-grade glioma. This study will test the research hypothesis that histone H3 K27M mutation sensitizes to oral administration of ONC201 in gliomas.

NCT03295396 Glioma Drug: ONC201
MeSH: Glioma
HPO: Glioma

ONC201 in Adults With Recurrent H3 K27M-mutant Glioma The primary objective of this phase II trial is to determine the efficacy and safety of ONC201, an oral small molecule imipridone DRD2 antagonist, in adult subjects with recurrent high-grade glioma. --- K27M ---

This study will test the research hypothesis that histone H3 K27M mutation sensitizes to oral administration of ONC201 in gliomas. --- K27M ---

Inclusion Criteria: 1. Histologically confirmed diagnosis of high-grade glioma (HGG) in any tumor sample and presence of histone H3 K27M mutation detected in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory by immunohistochemistry or DNA sequencing test on any glioma tumor sample. --- K27M ---

Primary Outcomes

Description: Best overall response rate by RANO

Measure: Overall response rate

Time: Through study completion, an average of 1 year

10 ONC201 in Newly Diagnosed Diffuse Intrinsic Pontine Glioma and Recurrent/Refractory Pediatric H3 K27M Gliomas

This is a multicenter, open-label, five arm, dose escalation, phase I study of oral ONC201 in pediatric patients with newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and recurrent/refractory H3 K27M gliomas. Arm A will define the RP2D for single agent ONC201 in pediatric patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. This will allow for recurrent patients and also patients who have not yet recurred, but have completed radiation and will inevitably recur based on prior clinical experience and the literature. Arm B will define the RP2D for ONC201 in combination with radiation in pediatric patients with newly diagnosed DIPG. Arm C will determine intratumoral drug concentrations and biomarker expression in pediatric patients with midline gliomas. Arm D will determine H3 K27M DNA levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. Arm E will determine the RP2D for single agent ONC201 administered as a liquid formulation in Ora-Sweet to patients with DIPG and/or H3 K27M glioma. All patients must be 2-12 weeks from completion of first-line radiation.

NCT03416530 Diffuse Intrinsic Pontine Glioma Glioma, Malignant Drug: ONC201
MeSH: Glioma
HPO: Glioma

ONC201 in Newly Diagnosed Diffuse Intrinsic Pontine Glioma and Recurrent/Refractory Pediatric H3 K27M Gliomas. --- K27M ---

ONC201 in Pediatric H3 K27M Gliomas This is a multicenter, open-label, five arm, dose escalation, phase I study of oral ONC201 in pediatric patients with newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and recurrent/refractory H3 K27M gliomas. --- K27M ---

ONC201 in Pediatric H3 K27M Gliomas This is a multicenter, open-label, five arm, dose escalation, phase I study of oral ONC201 in pediatric patients with newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and recurrent/refractory H3 K27M gliomas. --- K27M --- --- K27M ---

Arm A will define the RP2D for single agent ONC201 in pediatric patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. --- K27M ---

Arm D will determine H3 K27M DNA levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. --- K27M ---

Arm D will determine H3 K27M DNA levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. --- K27M --- --- K27M ---

Arm E will determine the RP2D for single agent ONC201 administered as a liquid formulation in Ora-Sweet to patients with DIPG and/or H3 K27M glioma. --- K27M ---

3. Arm A: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. --- K27M ---

Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available. --- K27M ---

Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available. --- K27M ---

Arm D: Pediatric patients with recurrent glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory), have completed at least one line of prior therapy, must be willing to undergo serial lumbar puncture to obtain cerebrospinal fluid (CSF), and must be scheduled to undergo sedated MRIs. --- K27M ---

Arm E: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) or have diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. --- K27M ---

Arm F: - Histologically confirmed diagnosis of high-grade glioma in any tumor sample with a known histone H3 K27M mutation identified by IHC or DNA sequencing test performed in a CLIA setting. --- K27M ---

Archival tumor specimen: Subjects in all arms must submit at least 5 unstained slides from a tumor specimen that harbors H3 K27M mutation if archival tissue is available. --- K27M ---

For subjects in Arms A, B or E, if no archival tumor tissue is available, or if H3 K27M status of tumor is unknown, then subjects must agree to submit a post-mortem biopsy specimen. --- K27M ---

Subjects in Arm C do not require prior tumor biopsy or confirmation of the presence of the H3 K27M mutation. --- K27M ---

Subjects in Arm D must have confirmation of the presence of the H3 K27M mutation in any glioma sample prior to enrollment. --- K27M ---

Subjects in Arm F must submit at least 5 unstained slides from a tumor specimen that harbors H3 K27M mutation. --- K27M ---

NOTE: The H3 K27M mutation is often reported as H3 K28M in gene sequencing assays. --- K27M ---

Primary Outcomes

Description: Determination of recommended Phase 2 dose (RP2D) as a single agent or in combination with radiation

Measure: RP2D

Time: 28 days

11 A Phase 2 Study of Veliparib (ABT-888) and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients With Newly Diagnosed High-Grade Glioma (HGG) Without H3 K27M or BRAFV600 Mutations

This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. 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. Giving veliparib, radiation therapy, and temozolomide may work better in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations compared to radiation therapy and temozolomide alone.

NCT03581292 Anaplastic Astrocytoma Glioblastoma Malignant Glioma Radiation: Radiation Therapy Drug: Temozolomide Drug: Veliparib
MeSH: Glioblastoma Glioma Astrocytoma
HPO: Astrocytoma Glioblastoma multiforme Glioma Subependymal giant-cell astrocytoma

A Phase 2 Study of Veliparib (ABT-888) and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients With Newly Diagnosed High-Grade Glioma (HGG) Without H3 K27M or BRAFV600 Mutations. --- K27M ---

Veliparib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600 Mutations This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations. --- K27M ---

Veliparib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Malignant Glioma Without H3 K27M or BRAFV600 Mutations This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations. --- K27M --- --- K27M ---

Giving veliparib, radiation therapy, and temozolomide may work better in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations compared to radiation therapy and temozolomide alone. --- K27M ---

For analyses exploring associations of a large number of potential markers with clinical outcome, will utilize false discovery rate approaches in order to control family-wise error rate.. Inclusion Criteria: - Stratum 1 (IDH wild-type): Patients must be >= 3 years of age and =< 21 years of age at the time of enrollment - Stratum 2 (IDH mutant): Patients must be >= 3 years of age and =< 25 years of age at the time of enrollment - Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1: - Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma - Negative results for H3 K27M by immunohistochemistry (IHC) - Negative results for BRAFV600 mutation by next-generation sequencing (NGS) - Patients must have histological verification of diagnosis. --- K27M ---

If lumbar CSF cytology is positive, the patient is considered to have M+ disease and is ineligible - Note: False positive cytology can occur within 10 days of surgery - Patients with gliomatosis cerebri type 1 or 2 - Patients who are not able to receive protocol specified radiation therapy - Patients must not be currently receiving other anti-cancer agents - Patients with known constitutional mismatch repair deficiency syndrome (CMMR-D)/biallelic mismatch repair deficiency (bMMRD) - Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies - Lactating females are not eligible unless they have agreed not to breastfeed their infants - Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained - Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 6 months after the last dose of protocol-specified chemotherapy Inclusion Criteria: - Stratum 1 (IDH wild-type): Patients must be >= 3 years of age and =< 21 years of age at the time of enrollment - Stratum 2 (IDH mutant): Patients must be >= 3 years of age and =< 25 years of age at the time of enrollment - Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1: - Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma - Negative results for H3 K27M by immunohistochemistry (IHC) - Negative results for BRAFV600 mutation by next-generation sequencing (NGS) - Patients must have histological verification of diagnosis. --- K27M ---

If lumbar CSF cytology is positive, the patient is considered to have M+ disease and is ineligible - Note: False positive cytology can occur within 10 days of surgery - Patients with gliomatosis cerebri type 1 or 2 - Patients who are not able to receive protocol specified radiation therapy - Patients must not be currently receiving other anti-cancer agents - Patients with known constitutional mismatch repair deficiency syndrome (CMMR-D)/biallelic mismatch repair deficiency (bMMRD) - Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies - Lactating females are not eligible unless they have agreed not to breastfeed their infants - Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained - Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 6 months after the last dose of protocol-specified chemotherapy Anaplastic Astrocytoma Glioblastoma Malignant Glioma Glioblastoma Glioma Astrocytoma PRIMARY OBJECTIVES: I. To determine whether veliparib (ABT-888), when added to radiotherapy (RT) and temozolomide, is efficacious for the treatment of patients with newly-diagnosed high-grade glioma (HGG) whose tumors' molecular profile are wild-type for H3 K27M, BRAF, and IDH1/2. --- K27M ---

To determine whether veliparib (ABT-888), when added to RT and temozolomide, is efficacious for the treatment of patients with newly-diagnosed HGG whose tumors' molecular profile are wild-type for H3 K27M and BRAF and harbor an IDH1/2 mutation. --- K27M ---

Primary Outcomes

Description: Analysis will be based on a 2-sample, 1 sided logrank test. For each stratum will also consider Cox models that incorporate known prognostic factors as feasible including resection status (gross total resection [GTR] versus [vs.] < GTR) and tumor grade (grade 3 vs. 4), spinal primaries vs. others, etc. to ensure that these variables do not have undue influence on the overall outcome. For patients with measurable disease at baseline, will also report the objective response rate.

Measure: Event free survival (EFS)

Time: Up to 5.5 years

Secondary Outcomes

Measure: Objective response

Time: Up to 5.5 years

Measure: Overall survival (OS)

Time: Up to 5.5 years

Other Outcomes

Description: Will provide a frequency table summarizing the number of patients with each aberration/alteration detected in germline and/or tumor samples. For longitudinal plasma samples used to assess circulating tumor deoxyribonucleic acid, will summarize the percentage of patients with samples as well as display/summarize any changes in molecular markers. When feasible we will explore the association of these aberrations with EFS/OS and objective response rates via Cox models and fisher exact tests, respectively. Will also explore associations between genetic variants and clinical/demographic variables including age, resection status, histology, etc. For analyses exploring associations of a large number of potential markers with clinical outcome, will utilize false discovery rate approaches in order to control family-wise error rate.

Measure: Biomarker analysis

Time: Up to 5.5 years

12 A Phase 2 Study of Panobinostat in Combination With Everolimus for Children and Young Adults With Gliomas Harboring H3.3 or H3.1 K27M Mutation

This phase 2 trial will evaluate the activity of Panobinostat in combination with Everolimus for children with gliomas harboring H3.1 or H3.3K27M mutation, including newly diagnosed high-grade glioma or DIPG (diffuse intrinsic pontine glioma) after radiation (stratum A) and recurrent/progressive glioma (grade II-IV, including DIPG) (stratum B).

NCT03632317 Glioma Diffuse Intrinsic Pontine Glioma Drug: Panobinostat Drug: Everolimus
MeSH: Glioma
HPO: Glioma

A Phase 2 Study of Panobinostat in Combination With Everolimus for Children and Young Adults With Gliomas Harboring H3.3 or H3.1 K27M Mutation. --- K27M ---

- H3K27M mutation: Participants must have a mutation in H3.3 K27M or H3.1 K27M as identified by tumor (FFPE or fresh, diagnosis or relapse tissue, but relapse tissue preferred) sequencing, or by CLIA-certified immunohistochemistry staining positive for H3K27M, as defined by review by U of M neuro-pathology. --- K27M ---

- H3K27M mutation: Participants must have a mutation in H3.3 K27M or H3.1 K27M as identified by tumor (FFPE or fresh, diagnosis or relapse tissue, but relapse tissue preferred) sequencing, or by CLIA-certified immunohistochemistry staining positive for H3K27M, as defined by review by U of M neuro-pathology. --- K27M --- --- K27M ---

Primary Outcomes

Description: Median PFS at 1 year for stratum A will be measured. Progression is defined as > 25% increase in the size of the tumor or appearance of new lesions.

Measure: Median Progression Free Survival (PFS) at 1 Year

Time: 1year

Description: Median PFS at 1 year for stratum A will be measured. Progression is defined as > 25% increase in the size of the tumor or appearance of new lesions.

Measure: Median Progression Free Survival (PFS) at 2 Years

Time: 2years

Description: The proportion of patients alive at 1 year for stratum A.

Measure: Overall Survival at 1Year

Time: 1year

Description: The proportion of patients alive at 2 years for stratum A.

Measure: Overall Survival at 2Years

Time: 2years

Description: Overall Response Rate (ORR) After Two Cycles of Panobinostat + Everolimus for stratum B. Overall response is defined as a partial or complete response. Partial response is defined as a ≥50% decrease in size of tumor in comparison to baseline measurements. Complete response is defined as the disappearance of all abnormal signal. This includes return to normal size of the brainstem for brainstem lesions.

Measure: Overall Response Rate (ORR) After Two Cycles of Panobinostat + Everolimus

Time: 84 Days

13 Phase I Study of GDC-0084, a Brain-Penetrant PI3 Kinase/mTOR Inhibitor, in Pediatric Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Diffuse Midline Gliomas After Radiation Therapy

Pediatric high-grade gliomas are highly aggressive and treatment options are limited. The purpose of this first-in-pediatrics study is to examine the safety, tolerability, and pharmacokinetics of GDC-0084 and to estimate its maximum tolerated dose (MTD) when administered to pediatric patients with diffuse intrinsic pontine glioma (DIPG) or other diffuse midline H3 K27M-mutant gliomas after they have received radiation therapy (RT). GDC-0084 is a brain-penetrant inhibitor of a growth-promoting cell signaling pathway that is dysregulated in the majority of diffuse midline glioma tumor cells. This study is also designed to enable a preliminary assessment of the antitumor activity of single- agent GDC-0084, in the hope of enabling rational combination therapy with systemic therapy and/or radiation therapy (RT) in this patient population, which is in desperate need of therapeutic advances. Primary Objectives 1. To estimate the maximum tolerated dose (MTD) and/or the recommended phase 2 dosage (RP2D) of GDC-0084 in pediatric patients with newly diagnosed diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG) 2. To define and describe the toxicities associated with administering GDC-0084 after radiation therapy (RT) in a pediatric population 3. To characterize the pharmacokinetics of GDC-0084 in a pediatric population Secondary Objectives 1. To estimate the rate and duration of radiographic response in patients with newly diagnosed DIPG or other diffuse midline glioma treated with RT followed by GDC-0084 2. To estimate the progression-free survival (PFS) and overall survival (OS) distributions for patients with newly diagnosed DIPG or other diffuse midline glioma treated with RT followed by GDC-0084

NCT03696355 Brain and Central Nervous System Tumors Drug: GDC-0084 Radiation: radiation therapy
MeSH: Glioma Nervous System Neoplasms Central Nervous System Neoplasms
HPO: Glioma Neoplasm of the central nervous system Neoplasm of the nervous system

The purpose of this first-in-pediatrics study is to examine the safety, tolerability, and pharmacokinetics of GDC-0084 and to estimate its maximum tolerated dose (MTD) when administered to pediatric patients with diffuse intrinsic pontine glioma (DIPG) or other diffuse midline H3 K27M-mutant gliomas after they have received radiation therapy (RT). --- K27M ---

- Biopsied typical DIPG: WHO grade II diffuse astrocytoma (IDH WT or IDH NOS), WHO grade III anaplastic astrocytoma (IDH WT or IDH NOS), WHO grade IV glioblastoma (IDH WT or IDH NOS), or diffuse midline glioma, H3 K27M mutant. --- K27M ---

Subjects with a typical DIPG who undergo a biopsy may be eligible for the study if the tumor does not harbor the H3 K27M mutation, yet eligibility is restricted to diffuse astrocytoma, anaplastic astrocytoma or glioblastoma, IDH WT or IDH NOS, tumors. --- K27M ---

- Atypical brainstem glioma: diffuse midline glioma, H3 K27M mutant. --- K27M ---

- Non-brainstem midline glioma, defined as tumors with an epicenter within midline structures, including the thalamus, spinal cord, and cerebellum: diffuse midline glioma, H3 K27M mutant. --- K27M ---

Primary Outcomes

Description: The MTD is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days).

Measure: Estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of GDC-0084 after standard-of-care radiation therapy (RT)

Time: 1 month after start of GDC-0084 treatment

Description: Adverse event data will be summarized in tables by dose level.

Measure: Incidence of adverse events at least possibly associated with GDC-0084 after RT by stratum

Time: Up to 2 years after start of GDC-0084 treatment

Description: GDC-0084 area under the curve (AUC0-∞) is estimated based on course 1 day 1 (C1D1) PK samples, and AUC0-24 based on course 1 day 28 (C1D28) PK samples.

Measure: Pharmacokinetics of GDC-0084 by stratum

Time: GDC-0084 treatment course 1 days 1 and 28

Secondary Outcomes

Description: The best overall response is the best response recorded between the start of GDC-0084 treatment and the earliest of initiation of alternative therapy or disease progression/recurrence. Best responses include complete response (CR), partial response (PR), and stable disease (SD). The best response is unknown if the patient does not qualify for a best response of progressive disease and if all objective statuses after the first determination and before progression are unknown.

Measure: Rate of best overall response by stratum

Time: Up to 1 year after completion of GDC-0084 treatment

Description: The duration of best overall response is measured from the time the measurement criteria are met for CR, PR, or SD (whichever is recorded first) until the first day on which recurrent or progressive disease is objectively documented.

Measure: Duration of best overall response by stratum

Time: Up to 1 year after completion of GDC-0084 treatment

Description: Progression-free survival (PFS) is defined from the time of diagnosis until disease progression or until death from any cause for patients who experience an event and until the date of last follow-up for those who are alive and progression free at the time of analysis. PFS is estimated by Kaplan-Meier approach and median PFS is reported.

Measure: Progression-free survival for patients treated with GDC-0084 after RT

Time: Up to 3 years from diagnosis

Description: Overall survival (OS) is defined from the time of diagnosis until death from any cause for patients who experience an event and until the date of last follow-up for those who are alive at the time of analysis. OS is estimated by Kaplan-Meier approach and median OS is reported.

Measure: Overall survival for patients treated with GDC-0084 after RT

Time: Up to 3 years from diagnosis

14 A Phase 2 Study of Dabrafenib (NSC# 763760) With Trametinib (NSC# 763093) After Local Irradiation in Newly-Diagnosed BRAF V600-Mutant High-Grade Glioma (HGG)

This phase II trial studies how well the combination of dabrafenib and trametinib works after radiation therapy in children and young adults with high grade glioma who have a genetic change called BRAF V600 mutation. Radiation therapy uses high energy rays to kill tumor cells and reduce the size of tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their growth. Giving dabrafenib with trametinib after radiation therapy may work better than treatments used in the past in patients with newly-diagnosed BRAF V600-mutant high-grade glioma.

NCT03919071 Anaplastic Astrocytoma Anaplastic Ganglioglioma Anaplastic Pleomorphic Xanthoastrocytoma Glioblastoma Malignant Glioma WHO Grade III Glioma Drug: Dabrafenib Drug: Dabrafenib Mesylate Radiation: Radiation Therapy Drug: Trametinib Drug: Trametinib Dimethyl Sulfoxide
MeSH: Glioblastoma Glioma Astrocytoma Ganglioglioma
HPO: Astrocytoma Glioblastoma multiforme Glioma Subependymal giant-cell astrocytoma

- Patients must be >= 3 years and =< 21 years of age at the time of enrollment - Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1 - Newly diagnosed high-grade glioma with BRAFV600-mutation - Negative results for H3 K27M by immunohistochemistry (IHC) - Histologically confirmed high-grade glioma (World Health Organization [WHO] grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS) - Patients must have had histologic verification of a high-grade glioma diagnosis. --- K27M ---

Anaplastic Astrocytoma Anaplastic Ganglioglioma Anaplastic Pleomorphic Xanthoastrocytoma Glioblastoma Malignant Glioma WHO Grade III Glioma Glioblastoma Glioma Astrocytoma Ganglioglioma PRIMARY OBJECTIVE: I. To estimate the event-free survival (EFS) distribution for newly-diagnosed patients with BRAFV600-mutant high-grade glioma (HGG) without H3 K27M mutations excluding anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic ganglioglioma (aGG) treated with radiation therapy followed by a maintenance combination of dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) and to compare this EFS to contemporary historical controls. --- K27M ---

SECONDARY OBJECTIVES: I. To describe the overall survival (OS) distribution for newly-diagnosed patients with BRAFV600-mutant HGG without H3 K27M mutations excluding aPXA and aGG treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib. --- K27M ---

To describe the EFS and overall survival (OS) distribution for newly-diagnosed patients with BRAFV600E-mutant aPXA and aGG without H3 K27M mutations treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib. --- K27M ---

Primary Outcomes

Description: The EFS curve for the new treatment cohort (Stratum 1) will be estimated by Kaplan Meier estimates. A 2-sample, 1 sided log-rank test will be used to test whether the EFS distribution is better in new treatment compared with historical control. Calculation of the EFS will be based on the site determination as central review will be performed retrospectively.

Measure: Event-free survival (EFS) for stratum 1

Time: From the date of diagnosis until disease progression date, secondary malignant neoplasm occurrence date, death date of any cause, or last follow-up, assessed up to 5 years

Secondary Outcomes

Description: The OS curve for the new treatment cohort (Stratum 1) will be estimated by Kaplan Meier estimates. A 2-sample, 1 sided log-rank test will be used to test whether the OS distribution is better in new treatment compared with historical control. For Stratum 2, Kaplan Meier estimates will be provided for OS distribution.

Measure: Overall survival (OS) for stratum 1 and stratum 2

Time: From the date of diagnosis until death date of any cause or last follow up date, assessed up to 5 years

Description: For Stratum 2, Kaplan Meier estimates will be provided for EFS distribution .

Measure: Event-free survival (EFS) for stratum 2

Time: Follow up date, assessed up to 5 years

Description: Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Grade 3 and higher toxicities observed by cycle will be listed for each stratum separately. The grade 3 and higher toxicities observed by cycle and by system organ class for the eligible patients will also be listed for each stratum separately. Toxicity data will be reported separately for the radiation therapy phase versus the maintenance therapy phase for clarity of attribution. Toxicity monitoring will include toxicities such as grade 2 or higher pyrexia, uveitis, retinal vein occlusion, retinal pigment epithelial detachment, and decreased left ventricular ejection fraction.

Measure: Incidence of adverse events

Time: Up to 5 years

15 Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR) T Cells (GD2.BB.z.iCasp9-CAR T Cells) for Diffuse Intrinsic Pontine Gliomas (DIPG) and Spinal Diffuse Midline Glioma (DMG)

The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.

NCT04196413 Glioma of Spinal Cord Glioma of Brainstem Drug: GD2 CAR T cells Drug: Fludarabine Drug: Cyclophosphamide
MeSH: Glioma
HPO: Glioma

The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.. Maximum tolerated dose (MTD)/RP2D of GD2.BB.z.iCasp9-CAR T cells with H3K27M DIPG or spinal H3 K27M-mutant DMG. --- K27M ---

Primary Outcomes

Description: The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.

Measure: Rate of successful manufacture of GD2.BB.z.iCasp9-CAR T cells using a retroviral vector in the Miltenyi CliniMACS Prodigy system

Time: 14 days after apheris

Description: Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2.BB.z.iCasp9-CAR T cells, will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at each dose level tested in subjects with H3K27M-mutant DIPG and spinal H3K27M-mutant DMG following standard upfront radiation therapy.

Measure: Maximum tolerated dose (MTD)/RP2D of GD2.BB.z.iCasp9-CAR T cells with H3K27M DIPG or spinal H3 K27M-mutant DMG

Time: 28 days after infusion

Secondary Outcomes

Description: OS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of death from any cause

Measure: Overall Survival (OS)

Time: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.

Description: PFS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of radiographic progression or death from any cause.

Measure: Progression-Free Survival (PFS)

Time: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.

Description: PPS is measured for each subject with DIPG as OS minus PFS, and for each patient with recorded progression as OS minus Time to Progression (TTP)

Measure: Post-progression survival (PPS)

Time: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.

Description: Radiographic Response will be evaluated using tumor response criteria: Complete Response (CR): disappearance on MR of all evaluable tumor and mass effect; stable or improving neurologic examination. If CSF was positive, it must be negative. Partial Response (PR): ≥ to 50% reduction in tumor size; stable or improving neurologic examination. Stable Disease (SD): at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither PR nor PD Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression; OR a > 25% increase in the bi-dimensional measurement, OR the appearance of a new tumor lesion.

Measure: Radiographic Response Rate

Time: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.

Description: Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2.BB.z.iCasp9-CAR T cells within 72 hours

Measure: Measure resolution of toxicity

Time: 72 hours of administration of AP1903


HPO Nodes


Glioma
Genes 50
TSC2 GLI3 BRCA2 TSC1 LRP5 MLH1 PMS2 APC IDH1 MSH6 POT1 TSC2 CDKN2A NF2 MSH3 MSH6 APC NF1 EPCAM TSC1 TGFBR2 SEMA4A IDH1 IDH2 FAN1 APC MSH3 BMPR1A KRAS MLH1 MSH2 C11ORF95 PMS2 MLH3 PIK3CA NBN RELA SETBP1 IFNG RPS20 NF1 PMS1 CHEK2 APC TP53 MSH2 NBN ERBB2 APC NF2
Glioblastoma multiforme
Genes 23
FAN1 APC BMPR1A KRAS BRCA2 RPS20 MLH1 MSH2 MSH6 EPCAM PMS2 MLH1 MLH3 PMS2 PMS1 MSH6 TP53 MSH2 TGFBR2 PIK3CA SEMA4A ERBB2 IDH1
Astrocytoma
Genes 27
TSC2 APC MSH3 BRCA2 MLH1 TSC1 PMS2 APC IDH1 MSH6 POT1 TSC2 CDKN2A NF2 IFNG MSH3 APC TSC1 NF1 APC TP53 MSH2 ERBB2 IDH1 APC IDH2 NF2
Neoplasm of the central nervous system
Genes 193
NRAS GLI3 PDE6D SUFU SUFU SUFU APC KIF7 GNAS RERE NTHL1 PTEN MSH3 PHOX2B PIK3CA NF2 SLC25A11 SDHD SIX6 TUBB ASCL1 BMPR1A IDH2 FAN1 NF1 TMEM216 ASCL1 GDNF MSH3 KEAP1 DICER1 DICER1 CCM2 PTCH2 PTPN11 NBN RELA IFNG GLI3 MDH2 SMARCB1 SMARCE1 EDN3 TP53 MSH2 ERBB2 PDGFB TUBB NF2 NUTM1 BRCA2 PHOX2B TSC1 PTEN POT1 OFD1 SMARCB1 NF2 PTCH2 TSC1 PTEN MAX RET TP53 PDGFB RAF1 SMARCB1 TCTN3 BRAF BMPR1A NOTCH3 FAM149B1 FH MLH3 SUFU PIK3CA TMEM127 MYO1H ALX1 WT1 PTEN SETBP1 SDHA MAPRE2 FGFR1 DLST FLI1 NF1 PMS1 SDHB CHEK2 PALB2 SKI NBN FAT4 APC ZSWIM6 NF2 TSC2 BDNF AKT1 AKT1 SDHC NTHL1 SMARCB1 LRP5 MLH1 PMS2 IDH1 RET SDHAF2 LMNA MSH6 PRDM16 TSC2 NF2 EPHB2 WDPCP PHOX2B SMARCA4 CDKN2A SDHB MSH6 APC KIF1B MN1 BAP1 IDH1 PDGFRB VHL GABRD CTNNB1 RUNX1 GDNF KRIT1 KRAS BRD4 KIAA0753 MSH2 LZTR1 WRN SDHC VHL PIK3CA SDHD OFD1 RPS20 PHOX2B PTCH1 ARMC5 TP53 APC AKT1 CCND1 GPC4 VHL POLE CCBE1 EWSR1 CPLANE1 OCRL BRCA2 NF1 EPCAM KLLN EDN3 SEC23B KIF1B TGFBR2 SEMA4A POLD1 PIK3CA ALX3 APC ADAMTS3 RET GLI3 PDCD10 MLH1 SOX2 C11ORF95 PMS2 GPC3 WRN PTEN ALX3 SDHB PHOX2B KCNAB2 PTEN CPLANE1 RB1 PTCH1
Neoplasm of the nervous system
Genes 259
SDHC NSD1 SDHC SETD2 NRAS GLI3 PDE6D SUFU SUFU SUFU APC KIF7 GNAS RERE NTHL1 PTEN MSH3 PHOX2B PIK3CA NF2 SLC25A11 SDHD SIX6 TUBB SDHB ASCL1 BMPR1A IDH2 FAN1 NF1 TMEM216 SDHD ASCL1 GDNF MSH3 CDKN2B KEAP1 DICER1 DICER1 CCM2 CDKN2A PTCH2 ALK PTPN11 DLST CDKN2C SLC25A11 RET NBN RELA CHEK2 IFNG GLI3 RET PRKAR1A MDH2 SMARCB1 SMARCE1 EDN3 TP53 MSH2 ERBB2 PDGFB TUBB SDHB NF2 NUTM1 BRCA2 MEN1 PHOX2B MDM2 TSC1 PTEN POT1 SDHC OFD1 MAX SMARCB1 NF2 NF1 L2HGDH PTCH2 MEN1 TSC1 RET SDHD PTEN MAX RET TP53 HACE1 PDGFB RAF1 SMARCB1 TCTN3 BRAF BMPR1A NOTCH3 FAM149B1 FH MLH3 SUFU PIK3CA MYCN TMEM127 MYO1H ALX1 WT1 PTEN SETBP1 SDHC SDHA MAPRE2 MEN1 LMNA FGFR1 DLST FLI1 NF1 PMS1 SDHB CHEK2 PALB2 SKI NBN FAT4 APC ZSWIM6 NF2 TSC2 SPRED1 BDNF AKT1 AKT1 SDHC NTHL1 SMARCB1 LRP5 MLH1 DNMT3A PMS2 IDH1 RET SDHAF2 LMNA MSH6 PRDM16 TSC2 NF2 EPHB2 SDHD WDPCP PHOX2B SMARCA4 CDKN2A STAT6 SDHB MSH6 APC KIF1B MN1 PHOX2B BAP1 IDH1 PDGFRB VHL GABRD CTNNB1 RUNX1 GDNF KRIT1 KRAS BRD4 RNF43 KIAA0753 SDHB MSH2 LZTR1 WRN SDHC PRKAR1A VHL PIK3CA SDHD OFD1 CDKN1A RPS20 PHOX2B PTCH1 SDHB ALK ARMC5 TP53 APC KARS1 AKT1 CCND1 LIN28B GPC4 VHL ATRX POLE DAXX CCBE1 EWSR1 LMO1 KIT NAB2 CPLANE1 CDKN1B OCRL BRCA2 SDHD GCGR CDKN1B SDHD NF1 TMEM127 EPCAM KLLN EDN3 SEC23B KIF1B TGFBR2 SEMA4A POLD1 PIK3CA ALX3 APC SDHAF2 ADAMTS3 RET HRAS GLI3 PDCD10 MLH1 SOX2 C11ORF95 PMS2 GPC3 WRN PTEN GDNF ALX3 SDHB PHOX2B KCNAB2 PTEN MAFA KIF1B CPLANE1 VHL TP53 TOP2A SDHA CDKN1B RB1 PTCH1 APC2
Neuroepithelial neoplasm
Genes 92
TUBB TSC2 RB1 GPC4 BDNF NUTM1 GLI3 BRCA2 PHOX2B TSC1 LRP5 MLH1 PMS2 APC IDH1 RET MSH6 POT1 PRDM16 TSC2 PHOX2B CDKN2A RERE NF2 MSH3 SDHB MSH6 PHOX2B APC NF1 EPCAM TSC1 KIF1B EDN3 TUBB TGFBR2 SEMA4A ASCL1 IDH1 IDH2 RET FAN1 GABRD ASCL1 RAF1 RUNX1 GDNF APC GDNF MSH3 BRAF BMPR1A KRAS BRD4 KEAP1 DICER1 MLH1 MSH2 C11ORF95 PMS2 MLH3 GPC3 TP53 PTPN11 MYO1H PIK3CA NBN RELA CHEK2 SETBP1 PHOX2B KCNAB2 MAPRE2 IFNG RB1 RPS20 PHOX2B FLI1 NF1 PMS1 RB1 CHEK2 EDN3 PALB2 APC TP53 MSH2 SKI NBN ERBB2 APC NF2