Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Nervous System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Lymphoma

Glioblastoma

Glioma

Sarcoma

Hodgkin Disease

Brain Neoplasms

Osteosarcoma

Wilms Tumor

Medulloblastoma

Diffuse Intrinsic Pontine Glioma

Neuroblastoma

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Ependymoma

Rhabdomyosarcoma

Sarcoma, Synovial

Desmoplastic Small Round Cell Tumor

Rhabdoid Tumor

Gliosarcoma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Neoplasms, Connective and Soft Tissue

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Myosarcoma

Lymphosarcoma

Soft Tissue Sarcoma

Hodgkin Lymphoma

Germ Cells Tumors

Wilms' Tumor

Ewing Sarcoma

Brain Tumor, Childhood

Synovial Sarcoma

Neuroepithelioma

Malignant Germ Cell Tumor

Gliomatosis Cerebri

IV dose of CLR 131, increased/decreased by dose level; single or fractionated dose

CLR 131

Jarrod Longcor

The study evaluates CLR 131 in children, adolescents, and young adults with relapsed or refractory malignant solid tumors and lymphoma and recurrent or refractory malignant brain tumors for which there are no standard treatment options with curative potential.

Even with standard, highly toxic multimodality therapies and salvage regimen, most pediatric patients with primary metastatic or relapsed solid tumors are confronted with a poor prognosis. For these patients there is currently no accepted successful treatment regimen. There is a need for new drugs, including targeted radiopharmaceuticals, preferably with cancer-specific uptake and broad applicability for these rare pediatric malignancies.

CLR 131 is a radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Cellectar Biosciences' novel cancer-targeted small-molecule compound (CLR1404) is radiolabeled with the isotope iodine-131 (I-131). CLR 131 has demonstrated tumor selective uptake across numerous adult and pediatric cancer cell types. Therapeutic efficacy has been demonstrated in various pediatric and adult-type cancer xenograft models, confirming the ability of CLR 131 to target tumors.

Based on the critical unmet medical need for effective agents with novel mechanisms of action in relapsed pediatric cancers and initial preclinical and clinical experience with radioiodinated CLR1404, Cellectar Biosciences has chosen to assess CLR 131 in a phase 1 pediatric trial.

Dose Escalation Study of CLR 131 in Children, Adolescents, and Young Adults With Relapsed or Refractory Malignant Tumors Including But Not Limited to Neuroblastoma, Rhabdomyosarcoma, Ewings Sarcoma, and Osteosarcoma

An Open-Label, Dose Escalation, Efficacy, and Safety Study of CLR 131 in Children, Adolescents, and Young Adults With Select Solid Tumors, Lymphoma, and Malignant Brain Tumors

DLT will be assessed by physical examination, vital signs, and laboratory values

Dose and regimen to be used in Phase 2 trials of CLR 131 in children, adolescents, and young adults

Response assessment per applicable criteria (e.g., Neuroblastoma Response Criteria (modified); RECIST 1.1; positron emission tomography response criteria in solid tumors (PERCIST); RANO)

Assessment via 131-I/CLR 131 SPECT/CT scans

Time from first infusion of CLR 131 until progression or recurrence of disease

Time from first infusion of CLR 131 until death due to any reason

Assessment of dosimetry via whole body planar imaging

Cellectar Biosciences, Inc.

Symptoms and General Pathology

Recurrence

Meningioma

Pinealoma

Astrocytoma

Oligodendroglioma

Choroid Plexus Neoplasms

Neoplasms, Vascular Tissue

Meningeal Neoplasms

Cerebral Ventricle Neoplasms

Pineocytoma

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Diffuse Astrocytoma

Pilocytic Astrocytoma

Pleomorphic Xanthoastrocytoma

Anaplastic Pleomorphic Xanthoastrocytoma

ONC206 is a member of the imipridone class of anti-cancer small molecules that share a unique tri-heterocyclic core chemical structure and target G protein-coupled receptors.

ONC206

Chris Tedesco

Marion Morrison, MD

Referrals

Kelly Mentges, RN

Mark Gilbert, MD

The primary objective of this Phase 1, open-label, dose-escalation, and exploratory study is to evaluate the safety and tolerability profile (establish the maximum-tolerated dose) and evaluate the occurrence of dose-limiting toxicities (DLTs) following single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms.

This is a Phase I, open-label, dose-escalation, and exploratory study of ONC206 in patients with recurrent, primary CNS neoplasms. All patients will be informed about the study and potential risks and required to provide written informed consent prior to undergoing study-related procedures.

There will be a total of 11 Dose Levels. Dose-escalation for Dose Levels 1 through 5 proceeded according to standard 3+3 design using a 28-day DLT window. The first cohort of 3 patients enrolled into the study received Dose Level 1 followed by increments as per the modified Fibonacci sequence. It is anticipated that approximately 46 patients will be enrolled in order to determine the MTD of ONC206.

For Dose Levels 1 through 5, a safety evaluation was conducted when 3 evaluable patients have completed 1 cycle (28 days) of therapy. After Protocol Amendment 6, all available PK data will also be considered for dose escalation decisions. Dose levels may be adjusted based on review of PK data but will not exceed maximum dose levels described in Table 6. Additionally, dose frequencies (e.g., once daily or 3 times daily) may be added and/or removed based on emerging PK data and concentration projections.

Prior to advancing/changing dose levels, a cohort summary must be completed and submitted to the sponsor Medical Monitor, for review and approval. Dose escalation for subsequent patients will proceed as follows:

* If no DLT is reported at a dose level, that dose level will be considered safe, and patient(s) will be enrolled at the next dose level. Toxicity information will continue to be evaluated from the time of the first protocol specific intervention, until 30 days from the last dose of study drug.
* If 1 patient in a cohort of 1 experiences a DLT, the dose level will be expanded to obtain an additional 2 evaluable patients.
* If 1 patient in a cohort at a dose level experiences a DLT, the dose level will be expanded to obtain an additional 3 evaluable patients.
* If 2 of 3 patients in a cohort at a dose level experience a DLT, that dose level will not be considered safe, no further dose escalation will take place, and the MTD will have been exceeded\*.
* If 1 patient experiences a DLT among the expanded cohort of evaluable patients, a cohort of 3 patients will be enrolled in the next higher dose level.
* If 2 or more patients experience a DLT among the expanded cohort of evaluable patients, that dose level will not be considered safe, no further dose escalation will take place, and the MTD will have been exceeded\*. The previous dose level at which ≤1 patients experienced a DLT will be declared the MTD.

  * When the MTD has been exceeded:

If less than 6 patients have been treated in the next lower dose level (the possible MTD level), additional patients will be entered into this dose level until there are 6 patients treated. If ≤1 of these 6 patients encountered DLT, then this dose level will be declared to be the MTD. If 2 or more of the 6 patients encounter DLT, then the MTD has been exceeded.

Given the experience with ONC201, it is possible a MTD may not be reached through the planned dose escalation cohorts. If the therapeutic target concentrations have been achieved in the dose escalation cohorts, and no DLT has been identified, then analysis of the safety and PK data will be evaluated by the Investigators and the Sponsor. Further dose levels may then be considered at higher intermittent dosing schedules and will be added by protocol amendment with review by the Institutional Review Board (IRB) before implementation.

Toxicities will be graded using the Common Terminology Criteria for Adverse Events Version 24.0 (CTCAE 24.0). If the CTCAE 24.0 does not apply to an adverse event, it will be graded as mild, moderate, or severe.

DLTs will be assessed during the first course of each cohort (28 days), and refers to a study drug related or possibly related event that meets 1 of the following criteria using the NCI CTCAE version 5.0:

* Grade 3 or higher non-hematologic toxicity.
* Grade 4 hematologic toxicity (ANC \<0.5 × 109/L and platelet count \<25 × 109/L). Lymphopenia is not considered a DLT. A confirmed DLT requires 2 consecutive measurements separated by 48 hours.
* Grade 3 neutropenia (ANC \<1.0 × 109/L) with elevated fever (\>101°F). A confirmed DLT requires 2 consecutive measurements.
* Grade 3 thrombocytopenia with clinically significant bleeding.
* Inability to receive the scheduled Cycle 2, Day 1 dose of study drug within 14 days due to study drug-related toxicity persisting from Cycle 1 or study drug-related toxicity newly encountered on Day 1 of Cycle 2.

Safety and tolerability will be monitored by assessing physical examinations including height (at Screening only) and weight, KPS, vital signs, ECG, laboratory assessments including hematology, chemistry, and coagulation, as well as collecting of the AEs at every visit.

Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms

A First-in-human Phase I Single-agent Dose-escalation, Food Effect and Dose Expansion Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms

MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.

MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in \>33% of participants. DLTs will be assessed in the first course of each cohort (28 days), and refer to a study drug-related or possibly related event that meets 1 of the following criteria defined in the subsequent Primary Outcome Measure using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE 5.0).

DLTs will be assessed in the first course of each cohort (28 days), and refer to a study drug-related or possibly related event that meets 1 of the following criteria using NCI CTCAE 5.0:

* Grade 3 or higher non-hematologic toxicity.
* Grade 4 hematologic toxicity (ANC \<0.5 × 109/L and platelet count \<25 × 109/L). Lymphopenia is not considered a DLT. A confirmed DLT requires 2 consecutive measurements separated by 48 hours.
* Grade 3 neutropenia (absolute neutrophil count \[ANC\] \<1.0 × 109/L) with elevated fever (\>101°F). A confirmed DLT requires 2 consecutive measurements.
* Grade 3 thrombocytopenia with clinically significant bleeding.
* Inability to receive the scheduled Cycle 2, Day 1 dose of study drug within 14 days due to study drug-related toxicity persisting from Cycle 1 or study drug-related toxicity newly encountered on Day 1 of Cycle 2.

National Institutes of Health (NIH)

Chimerix

Brain Stem Neoplasms

Infratentorial Neoplasms

Pharmaceutical Solutions

All Drugs and Chemicals

Antineoplastic Agents

Anticonvulsants

Central Nervous System Depressants

Psychotropic Drugs

Temozolomide

Valproic Acid

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

Neurotransmitter Agents

E.g. Valproat-neuraxpharm®, Valproat-neuraxpharm® Lösung, Ergenyl®, Ergenyl®-Lösung oder Orfiril® Saft (Valproic acid), \[10 mg/kg/d\] tablet oder juice, p.o., every day in parallel to simultaneous radiochemotherapy with cytostatic drug Temodal (Temozolomid): \[75 mg/m2/d\] during simultaneous radiochemotherapy (7 days a week, max. 49 days); \[150-200 mg/m2/d\] during consolidation therapy (for 5 days every 28 days, 12 cycles), tablets, p.o. (or powder for preparation of an intravenously applicable solution).

Valproic acid additionally to simultaneous radiochemotherapy with temozolomide

Temozolomide + Valproic Acid

Christof Kramm, Prof., MD

Udo Kontny, Prof. Dr.

Michael Frühwald, Prof.

Pablo Hernaiz-Driever, PD Dr.

Patrick Hundsdörfer, PD Dr.

Norbert Jorch, Dr.

Gabriele Calaminus, Dr.

Torsten Ebeling, Dr.

Arnulf Pekrun, Prof.

Georg Schwabe, PD Dr.

Dominik Schneider, Prof. Dr.

Ralf Knöfler, Prof. Dr.

Tanja Höll, Dr.

Axel Sauerbrey, Prof. Dr.

Markus Metzler, Prof.

Regina Wieland, Dr.

Martina Becker, Dr.

Charlotte Niemeyer, Prof.

Christine Mauz-Körholz, Prof. Dr.

Holger Lode, Prof.

Christof Kramm, Prof.

Toralf Bernig, Dr.

Uwe Kordes, Dr.

Annette Sander, Dr.

Olaf Witt, Prof. Dr.

Monika Streiter

Alfred Längler, Prof. Dr.

Norbert Graf, Prof.

Bernd Gruhn, Prof. Dr.

Alfred Leipold, Dr.

Michaela Nathrath, Prof.

Alexander Claviez, PD Dr.

Ümmügül Behr, Dr.

Thomas Imschweiler

Stefan Balzer, Dr.

Lars Fischer, Dr.

Thorsten Langer, Prof. Dr.

Antje Redlich, Dr.

Jörg Faber, Prof. Dr.

Matthias Dürken, PD Dr.

Bernhard Erdlenbruch, Prof.

Irene Teichert-von-Lüttichau, PD Dr.

Ronald Sträter, PD Dr.

Hermann Müller, Prof.

Marcus Jakob, Dr.

Harald Reinhard, PD Dr.

Aram Prokop, Dr. Dr.

Claudia Blattmann, PD Dr.

Martin Ebinger, PD Dr.

Klaus-Michael Debatin, Prof. Dr.

Matthias Eyrich, Prof. Dr.

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 effect of valproic acid which is traditionally used for treatment of seizure disorder, will be investigated. The aim of the trial will be to investigate whether this drug may increase the effects of radio- and chemotherapy, resulting in a better survival of the treated patients. Scientific studies provided evidence for anti-tumoral effects of valproic acid: the drug seems to be a so-called histondeacetylase inhibitor (HDAC inhibitor), controlling important genetic processes of tumor growth.

Studies in cell culture, animals and first clinical trials in adults as well provided evidence for efficacy of valproic acid 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.

The aim of the HIT-HGG-2013 trial will be to compare the effects of Valproic acid with data of the HIT-HGG-2007 trial (children and adolescents with same diseases, only treated with simultaneous temozolomide radiochemotherapy).

In the present study, it was originally planned to investigate the therapeutic efficiency and safety of valproic acid and the autophagy inhibitor chloroquine, both in addition to temozolomide therapy. Since distribution of Resochin junior (chloroquine phosphate) was terminated, recruitment of new patients was stopped on August 8, 2019. For continuation of the trial, the chloroquine arm was closed but the patients already recruited in this arm will be followed up.

Indication:

First-line treatment of high grade gliomas, diffuse intrinsic pontine glioma, and gliomatosis cerebri in paediatric patients \< 18 years of age.

Background:

Based on published preclinical and clinical results regarding the potential therapeutic benefit of adult and pediatric high grade glioma patients receiving the histone deacetylase (HDAC) inhibitor valproic acid (VPA; Barker et al. 2013; Wolff et al. 2008, 2011; Felix et al. 2011; Su et al. 2011; Rokes et al. 2010; Masoudi et al. 2008; Guthrie et al. 2013; Weller et al. 2011) in addition to radiochemotherapy, the present trial is aimed to investigate if the addition of VPA to radiochemo- and maintenance therapy with temozolomide (Stupp et al. 2005; Cohen et al. 2011a, b) provides a survival advantage in comparison to radiochemo- and maintenance therapy with temozolomide alone. Therapeutic efficiency of VPA will be evaluated by comparison with a historical patient control from the previous trial HIT-HGG-2007 with temozolomide radiochemo- and maintenance therapy alone. Besides therapeutic efficiencies as indicated by event-free survival (EFS) and overall survival (OS) treatment-related toxicities will also be analysed.

Therapy:

TMZ and VPA will be studied as investigational medicinal products in the present trial.

* Trial treatment will be performed as follows: Surgery with best possible extent of tumour resection
* Start as soon as diagnosis is confirmed with VPA 10 mg/kg/d in two daily doses preferencially as NONRETARDED FORMULA (e.g. Valproat-neuraxpharm®, Valproat-neuraxpharm® Lösung, Ergenyl®, Ergenyl®-Lösung or Orfiril® Saft; however, any VPA preparation including generic drugs is allowed; the use of a retarded formula might be helpful in some case as indicated below), increase by 10 mg/kg/d once per week up until recommended target Serum level of 75-100 μg/ml (520-694 μmol/L) is reached. If target serum levels cannot be reached with non-retarded formula and/or side effects occur which might be connected to VPA, change to a retarded formula may be helpful to obtain sufficient VPA serum levels and/or reduce side effects. If VPA target serum levels are still not reached and/or side effects occur even with a retarded VPA formula, please contact the HIT-HGG study office.

After start of VPA induction with simultaneous radiochemotherapy:

* Fractionated, locoregional radiotherapy, total dose 54-60 Gy
* Simultaneous chemotherapy with oral temozolomide, 7 days per week at 75 mg/m2/d, starting at day 1 for the entire period of radiotherapy (at maximum 49 days; oral temozolomide treatment may be started in single cases at maximum 7 days before radiotherapy if the 49 days treatment period still fully covers radiotherapy).
* Please, use temozolomide capsules (for oral application) and temozolomide powder (for preparation of an intravenously applicable solution). Any temozolomide preparation including generic drugs is allowed except for patients who are not able to swallow capsules and in whom the use of an intravenous solution is no Option only Temodal® capsules must be used to generate a temozolomide suspension as described in the Appendix A.11. Parents have to be advised how to prepare the Temodal® suspension at the trial site. PLEASE NOTE: Capsules of generic temozolomide drugs other than Temodal® MUST NOT be opened and used for generating temozolomide suspension.
* Maintenance therapy with daily VPA and temozolomide four weeks after simultaneous radiochemotherapy initiation of a 5 day-course of oral temozolomide \[150-200 mg/m2/d\], repeated every 28 days for in total 12 courses VPA treatment is performed until day 28 of the 12th course of temozolomide.
* Treatment doses may vary according to available medication formulations and sizes. Thus, deviances of +/- 15% of the recommended doses may be acceptable if not stated otherwise.The starting points of treatment may also vary in single cases. Thus, deviances of +/- 7 days of the recommended time periods to start treatment may be acceptable if not stated otherwise.

Primary end point : Event-free survival

Biometry (regarding the primary objectives):

1. Confirmatory statistical design:

   1. Difference between the treatment with additional VPA and the historic sample from the HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as a significant difference between VPA treatment and the historic sample. A directional interpretation will detect either a superiority of the VPA-treatment compared to the historic sample, or a superiority of the historic sample compared to the VPA Treatment sample.

   Statistical tests: adaptive Log-rank test / (conventional) Log-rank test

   Multiple Significance level α(overall) = 5% Power = 80% Assumed 6 months EFS-rates = 55% vs. 70%

   Multiple Testing: No Multiplicity Problem in this trial.
2. Estimated sample sizes:

About 167 recruitments at final analysis

Patient recruitment will be performed for 5,4 years. Individual follow-up (including study treatment) is required for this protocol for at least 1 year and 30 days after study entry. Long-term follow-up is strongly recommended and will be organised according to national guidelines and recommendations.

Financial support:

Deutsche Kinderkrebsstiftung, Bonn, Germany

International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013)

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)

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.

Deutsche Kinderkrebsstiftung

Hannover Medical School

University of Göttingen

Coordinating investigator

Other Dietary Supplements

Bevacizumab

Benzocaine

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Tannic Acid

radiation phase (week 1-6): daily valproic acid and radiation, for approximately 6 weeks post-radiation phase (week 7-10): valproic acid daily maintenance phase (starting week 11): daily valproic acid, and bevacizumab once every 2 weeks; to continue for a maximum duration of 2 years

Daily (pre-XRT, During XRT, Post-XRT and Maintenance Therapy) Started at 15 mg/kg/day divided into three doses a day as soon as patients have recovered from surgery but no later than the first day of XRT.

Dosage will be adjusted in increments of 5 mg/kg/day every 3-5 days to achieve and maintain trough concentrations between 85 and 115 mcg/ml

Valproic acid

All patients will receive bevacizumab (10 mg/kg iv) during the maintenance phase every two weeks for a maximum duration of therapy of 24 months.

Radiation therapy will start within 30 days of the definitive surgical procedure. Primary brain malignant gliomas will receive a total dose of between 54.0 and 59.4 Gy in 30-33 fractions over 6-7 weeks. Total dose will be 54.0 Gy for completely resected tumors and brainstem gliomas. The total dose will be 59.4 if the tumor is located in the brain but not the brainstem, and the tumor was incompletely resected. Primary spinal cord malignant gliomas will receive a total dose of between 50.4-54 Gy in 28-30 fractions over 5-6 weeks.

Radiation therapy

Jack Su, MD

Currently, there are few effective treatments for the following aggressive brain tumors: glioblastoma multiforme, anaplastic astrocytoma, gliomatosis cerebri, gliosarcoma, or brainstem glioma. Surgery and radiation can generally slow down these aggressive brain tumors, but in the majority of patients, these tumors will start growing again in 6-12 months. Adding chemotherapy drugs to surgery and radiation does not clearly improve the cure rate of children with malignant gliomas.

The investigators are conducting this study to see if the combination of valproic acid and bevacizumab (also known as AvastinTM) with surgery and radiation will shrink these brain tumors more effectively and improve the chance of cure.

With the exception of patients with diffuse intrinsic pontine glioma (DIPG), all patients should have the maximal surgical resection that can be safely performed prior to study entry. Submission of frozen tumor is strongly encouraged. After recovery from neurosurgery, all patients will start valproic acid (VPA) and radiation therapy.

VPA will be started at 15 mg/kg/day divided into three doses a day, ideally 48 hours prior to first day of radiation therapy, but no later than the first day of radiation therapy. Patients may also begin VPA sooner if they have post-operative seizures and require an anti-convulsant.

Radiation phase (week 1-6): Radiation therapy should begin within 30 days of definitive surgery or radiographic diagnosis, whichever is the later date. Date of surgery or radiographic diagnosis is considered day 1, and radiation should start no later than day 31. VPA will be continued daily without interruption during radiation therapy. VPA doses will be adjusted in increments of 5 mg/kg/day every 3-5 days to achieve and maintain trough concentrations between 85 to 115 mcg/ml. All patients will receive standard radiation therapy which will last approximately six week.

Post Radiation Phase (week 7-10): Patients will continue to receive VPA as previously dosed during radiation to maintain a trough concentration of 85-115 mcg/ml.

Maintenance Phase (starting week 11): Maintenance therapy will begin approximately 4 weeks after completion of radiation or week 11, whichever comes first.

Patients will continue VPA daily during maintenance therapy. All patients will start bevacizumab, 10 mg/kg intravenously every two weeks, at the start of maintenance therapy (week 11). Maintenance therapy will continue uninterrupted unless treatment related toxicities requires study drug interruption. In the absence of unacceptable toxicity or disease progression, patients will continue to receive protocol treatment for a maximum duration of two years (including the radiation phase).

Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma

A Phase 2 Study of Valproic Acid and Radiation, Followed by Maintenance Valproic Acid and Bevacizumab in Children With Newly Diagnosed High-grade Gliomas or Brainstem Gliomas

Results of this study has been published (Su JM, et al., Pediatr Blood Cancer 2020: 67:e28283). Additional de-identified information can be provided upon request.

To compare 1-year EFS for this trial versus historical series (ACNS0126 for high-grade gliomas; CCG-9941 for DIPG)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dose Escalation Study of CLR 131 in Children, Adolescents, and Young Adults With Relapsed or Refractory Malignant Tumors Including But Not Limited to Neuroblastoma, Rhabdomyosarcoma, Ewings Sarcoma, and Osteosarcoma	NCT03478462	Pediatric Solid... Pediatric Lymph... Pediatric Brain... DIPG Neuroblastoma Ewing Sarcoma Rhabdomyosarcom... Osteosarcoma	CLR 131	2 Years - 25 Years	Cellectar Biosciences, Inc.
Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms	NCT04541082	Central Nervous... Glioblastoma Gliosarcoma, Ad... Anaplastic Olig... Anaplastic Astr... Pilocytic Astro... Oligodendroglio... Gliomatosis Cer... Pleomorphic Xan... Anaplastic Pleo... Diffuse Midline... Ependymoma Ependymoma, Ana... Medulloblastoma Teratoid Rhabdo... Neuroectodermal... Neuroectodermal... Anaplastic Meni... Atypical Mening... Choroid Plexus ... Pineal Tumor Diffuse Astrocy... Glial Tumor	ONC206	18 Years -	Chimerix
International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013)	NCT03243461	Glioblastoma WH... Diffuse Midline... Anaplastic Astr... Diffuse Intrins... Gliomatosis Cer...	Temozolomide + ...	3 Years - 17 Years	University of Göttingen
Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma	NCT00879437	Glial Cell Tumo... Malignant Gliom... Glioblastoma Mu... Anaplastic Astr... Gliomatosis Cer... Gliosarcoma Brainstem Gliom... Diffuse Intrins...	Valproic acid Bevacizumab Radiation thera...	3 Years - 21 Years	Baylor College of Medicine
Prolonged Exposure to Doxorubicin in Patients With Glioblastoma Multiforme and Diffuse Intrinsic Pontine Glioma	NCT02758366	Glioblastoma (G... DIPG Brainstem Gliom... Diffuse Spinal ... Bilateral Thala... Gliomatosis Cer... Anaplastic Astr... Midline Diffuse...	Doxorubicin	3 Years - 30 Years	Meyer Children's Hospital IRCCS
Prolonged Exposure to Doxorubicin in Patients With Glioblastoma Multiforme and Diffuse Intrinsic Pontine Glioma	NCT02758366	Glioblastoma (G... DIPG Brainstem Gliom... Diffuse Spinal ... Bilateral Thala... Gliomatosis Cer... Anaplastic Astr... Midline Diffuse...	Doxorubicin	3 Years - 30 Years	Meyer Children's Hospital IRCCS

Spots Global Cancer Trial Database for gliomatosis cerebri