There are 13 clinical trials
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.
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 ---
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).
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 ---
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 yearsDescription: 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 yearsDescription: 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 yearsThis 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.
Any eligible subject that receives at least one dose of the K27M/TT vaccine will be considered evaluable for clinical efficacy. --- K27M ---
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 monthsDescription: 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 monthsDescription: 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 monthsDescription: 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 monthsDescription: 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 monthsThis phase II trial studies how well dabrafenib with trametinib work after radiation therapy in treating patients with a type of genetic mutation (BRAF V600-mutant) and newly-diagnosed, high-grade glioma. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib with trametinib after radiation therapy may work better than treatments used in the past in helping to get rid of or shrinking tumors in patients with newly-diagnosed BRAF V600-mutant high-grade glioma.
- 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 BRAF NP_004324.2:p.V600X Glioblastoma H3 K27M Negative Malignant Glioma WHO Grade III Glioma Glioblastoma Glioma Astrocytoma Ganglioglioma PRIMARY OBJECTIVES: 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 ---
Anaplastic Astrocytoma Anaplastic Ganglioglioma Anaplastic Pleomorphic Xanthoastrocytoma BRAF NP_004324.2:p.V600X Glioblastoma H3 K27M Negative Malignant Glioma WHO Grade III Glioma Glioblastoma Glioma Astrocytoma Ganglioglioma PRIMARY OBJECTIVES: 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 --- --- 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 ---
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) 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 yearsDescription: 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.
Measure: Overall survival (OS) Time: From the date of diagnosis until death date of any cause or last follow up date, assessed up to 5 yearsDescription: 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 yearsThis 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.
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 Untreated Childhood Anaplastic Astrocytoma Untreated Childhood Anaplastic Oligoastrocytoma Untreated Childhood Glioblastoma Untreated Childhood Gliosarcoma Glioblastoma Glioma Astrocytoma Gliosarcoma Oligodendroglioma 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 ---
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 daysDescription: Adverse events will be graded using the NCI CTCAE version 4.0.
Measure: Incidence and grade of adverse events Time: Up to 4 yearsDescription: 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 8Description: Disease response will be reported descriptively.
Measure: Response rate (partial response, complete response, or stable disease) Time: Up to 4 yearsDescription: PFS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.
Measure: Progression-free survival (PFS) Time: Up to 4 yearsDescription: OS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.
Measure: Overall survival (OS) Time: Up to 4 yearsDescription: 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 8Pediatric 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
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 ---
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 treatmentDescription: 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 treatmentDescription: 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 28Description: 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 treatmentDescription: 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 treatmentDescription: 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 diagnosisDescription: 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 diagnosisThis 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.
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 ---
Archival tumor specimen: All subjects in all arms 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 ---
Description: Determination of recommended Phase 2 dose (RP2D) as a single agent or in combination with radiation
Measure: RP2D Time: 28 daysThis 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.
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 BRAF V600 Wild Type Glioblastoma H3 K27M Negative 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 ---
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 BRAF V600 Wild Type Glioblastoma H3 K27M Negative 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 --- --- 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 ---
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 yearsDescription: 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 yearsThis 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).
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 ---
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: 1yearDescription: 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: 2yearsDescription: The proportion of patients alive at 1 year for stratum A.
Measure: Overall Survival at 1Year Time: 1yearDescription: The proportion of patients alive at 2 years for stratum A.
Measure: Overall Survival at 2Years Time: 2yearsDescription: 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 DaysThe 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.
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 ---
Inclusion Criteria: 1. Patient must have glioma that is positive for the H3 K27M mutation (positive testing in CLIA laboratory) or have Grade III or IV glioma involving the thalamus, hypothalamus, brainstem, cerebellum, midbrain, or spinal cord. --- K27M ---
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.
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 ---
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 collectionsDescription: 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 collectionsDescription: 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 12The 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.
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 (any histology, including but not limited to glioblastoma, astrocytoma, and oligodendroglioma) in any tumor sample and presence of histone H3 K27M mutation by a CLIA-approved immunohistochemistry or DNA sequencing test on any glioma tumor sample. --- K27M ---
Description: Best overall response rate by RANO
Measure: Overall response rate Time: Through study completion, an average of 1 yearIn 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.
- 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 ---
Description: Primary feasibility endpoint is the number of individual toxicities and incidence of significant delays
Measure: Number of adverse events Time: 6 monthsDescription: 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 monthsDescription: 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