Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioblastoma

Glioma

Brain Neoplasms

Diffuse Intrinsic Pontine Glioma

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Brain Stem Neoplasms

Infratentorial Neoplasms

Anaplastic Astrocytoma

Neuroepithelioma

Leonie Mikael, PhD

Kathleen H Dorris, MD

Eugene M Hwang, MD

Ashley O Plant, MD

Susan C Chi, MD

David H Ashley, MD

Maryam Fouladi

Michael J Fisher, MD

Patricia Baxter, MD

Sarah Leary, MD

David Ziegler, MBBS

Tim Hassall, MBBS

Nick Gottardo, MBChB

Eric Bouffet, MD

Genevieve Legault, MD

Olaf Witt, MD

Jasper van der Lugt, MD, PhD

Darren Hargrave, MD

Maryam Fouladi, MD

Margot Lazow, MD

The goal of this study is to perform genetic sequencing on brain tumors from children, adolescents, and young adult patients who have been newly diagnosed with a high-grade glioma. This molecular profiling will decide if patients are eligible to participate in a subsequent treatment-based clinical trial based on the genetic alterations identified in their tumor.

A novel, molecularly-guided, multi-arm phase umbrella II trial is proposed in children, adolescents, and young adults with newly diagnosed HGG, including DIPG, in which we will (1) conduct comprehensive molecular screening of tumor tissue using a multi-omic approach (WES/WGS, gene fusion panels/RNASeq, DNA methylation microarray) across international CONNECT genomics cores with rapid return of clinical results, (2) stratify patients to biologically-targeted treatment arms, based on the tumor molecular profile and histopathology, and (3) perform longitudinal evaluation of peripheral blood, cerebrospinal fluid (CSF), and/or tumor tissue as well as advanced neuro-imaging to determine genomic, immune, and radiologic biomarkers predictive of response, recurrence, resistance, and toxicity.

Based on results of the above tumor molecular profiling and pathology-based confirmation of HGG diagnosis, eligible patients will be assigned to one of several biologically guided treatment arms on a phase II trial.

Approximately 400-450 patients will be enrolled on the screening protocol through which biospecimens (paired tumor DNA/RNA and normal comparator samples) will undergo extensive molecular profiling to assess eligibility to any of the therapeutic subprotocols of the phase II study.

Brain tumor samples with matched normal comparator (blood preferred alternatively, saliva or buccal swab)

Targeted Pediatric High-Grade Glioma Therapy

Molecularly-Guided Phase II Umbrella Trial for Children, Adolescents, and Young Adults Newly Diagnosed With High-Grade Glioma, Including Diffuse Intrinsic Pontine Glioma

Utilize molecular, clinical, and histopathologic data to assess eligibility for specific biologically-guided treatment subprotocols among pediatric, adolescent and young adult patients with newly diagnosed HGG, including DIPG.

Determine the percent of pediatric, adolescent, and young adult patients newly diagnosed with HGG, including DIPG, who undergo comprehensive molecular characterization across clinical molecular testing laboratories at CONNECT sites and begin treatment on a TarGeT treatment subprotocol within 10 calendar days of starting radiation therapy (RT) (if treatment involves an agent given concurrently with RT) or within 35 days of completion of RT (if treatment involves adjuvant maintenance therapy).

Increase knowledge of the genomic and immunologic landscape of newly-diagnosed pediatric and young adult HGGs, including DIPG, through comprehensive molecular characterization.

Determine the frequency and spectrum of germline cancer susceptibility mutations in children and young adults with HGG and DIPG and assess the feasibility of return of those results.

Prospectively collect tumor tissue from diagnostic biopsy/resection as well as baseline peripheral blood and cerebrospinal fluid (CSF) samples for the CONNECT biorepository to be used in correlative research for the present trial as well as future studies.

Nationwide Children's Hospital

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata B, C, or D).

Patients with DIPG, defined as a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO grade 2-4 glioma (e.g., diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altered diffuse midline glioma).

Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG.

Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation.

Ribociclib

Kathleen Dorris, MD

Eugene Hwang, MD

Ashley Plant, MD

Susan Chi, MD

David Ashley, MD

Peter de Blank, MD

The goal of this study is to determine the efficacy of the study drugs ribociclib and everolimus to treat pediatric and young adult patients newly diagnosed with a high-grade glioma (HGG), including DIPG, that have genetic changes in pathways (cell cycle, PI3K/mTOR) that these drugs target.

The main question the study aims to answer is whether the combination of ribociclib and everolimus can prolong the life of patients diagnosed with HGG, including DIPG.

This is a multicenter, international, phase II study of post-radiotherapy (RT) combination of ribociclib and everolimus to treat pediatric, adolescent, and young adult patients newly diagnosed with HGG and DIPG that harbor alterations of the cell cycle and/or PI3K/mTOR pathways to assess treatment efficacy (Part 2). The study will include a feasibility cohort (Part 1) to identify the dose of ribociclib PfOS (Powder for Oral Suspension) that is safe and tolerable in combination with everolimus. Efficacy for Part 2 study will be defined by progression-free survival (PFS; HGG \[stratum A\]) and Overall Survival (OS; DIPG \[stratum B\]), with key longitudinal biomarker correlatives. Outcomes among patients with primary thalamic, spinal cord, and/or secondary (radiation related) HGG (strata C) will be descriptively analyzed. Objective radiographic response rates and agent-specific toxicities will also be assessed, with a feasibility cohort to determine the recommended phase II dose (RP2D) of the combination of ribociclib and everolimus in patients with metastatic disease who received upfront craniospinal irradiation (stratum D).

Protocol therapy with the maintenance combination of ribociclib and everolimus must begin no later than 35 calendar days post-completion of RT. The earliest patients can begin protocol treatment is 28 calendar days post-completion of RT. Each cycle will be 28 days in duration and treatment can continue up to a total of 26 cycles. Ribociclib will be given orally once daily for 3 weeks (days 1-21), with one week off. Everolimus will be given orally daily continuously (days 1-28).

Study of Ribociclib and Everolimus in HGG and DIPG

PhaseII Study of Ribociclib and Everolimus Following Radiotherapy in Pediatric and Young Adult Patients Newly Diagnosed With HGG Including DIPG, Which Harbor Alterations of the Cell Cycle and/or PI3K/mTOR Pathways

To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG by estimating the distribution of PFS compared to molecularly-stratified and matched historical controls.

To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with DIPG by estimating the distribution of OS compared to molecularly-stratified and matched historical controls.

To identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of the combination of ribociclib and everolimus given to patients with metastatic HGG who have received craniospinal irradiation CSI.

Identify the safe dose of ribociclib powder for oral solution (PfOS) formulation in combination with everolimus that is feasible in pediatric patients with newly-diagnosed HGG, including DIPG, with cell cycle and/or PI3K/mTOR pathway alterations. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0 in the first 6-12 patients enrolled

Determine distribution of OS for pediatric and young adult patients newly-diagnosed with HGG which harbor cell cycle and/or PI3K/mTOR pathway alterations treated with post-RT ribociclib and everolimus.

Evaluate the radiographic objective response rate (ORR) defined as complete response (CR) + partial response (PR) in pediatric and young adult patients newly diagnosed with HGG treated with the combination of ribociclib and everolimus.

Evaluate the radiographic objective response rate (ORR) defined as complete response (CR) + partial response (PR) in pediatric and young adult patients newly diagnosed with DIPG treated with the combination of ribociclib and everolimus.

Assess and further characterize the safety and toxicity of post-RT combination of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG, including DIPG. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0.

Evaluate health-related quality of life outcomes of pediatric and young adult patients newly-diagnosed with HGG, including DIPG, treated with combination of ribociclib and everolimus, by patient and/or parent reporting at key timepoints in therapy using the patient reported outcomes measurement information system (PROMIS) survey.

Novartis

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphosarcoma

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Amino Acids

Carboplatin

Cyclophosphamide

Methotrexate

Vincristine

Cisplatin

Tyrosine

Lorlatinib administered as monotherapy by PO (per os) or NG (nasogastric) for two 28-day cycles at 115 mg/m2/day (or maximum 200mg/dose), after which disease evaluation by Magnetic Resonance Imaging (MRI) imaging will be performed.

Lorlatinib monotherapy x2 cycles followed by maintenance therapy with lorlatinib (115 mg/m2/day) and BABY-POG chemotherapy backbone (vincristine, cyclophosphamide, cisplatin) The BABYPOG chemotherapy backbone regimen will consist of six 12-week courses. Each course will consist of cycles A, A2 and B, which will be administered consecutively, in 28-day cycles for a total of 72 weeks

Lorlatinib monotherapy x2 cycles followed by maintenance therapy with lorlatinib (115 mg/m2/day) and HIT-SKK chemotherapy backbone (cyclophosphamide, vincristine, methotrexate, carboplatin, etposide) The recommended HIT-SKK chemotherapy backbone regimen consists of modular chemotherapy cycles, three courses of 4 blocks each (Element IIS, Element IIIS/1, Element IIIS/2, and Element IVS). Each element will be administered consecutively at 2-3-week intervals. Elements IIS and IVS cycles will be repeated twice thereafter. The entire length of treatment for HIT-SKK will be approximately 42 weeks.

Lorlatinib monotherapy x2 cycles followed by Radiation Therapy and continue lorlatnib maintenance monotherapy (115 mg/m2/day) 28 days post completion of RT for 12 cycles

Continue maintenance monotherapy for total 12 cycles

Lorlatinib

Continue lorlatinib with BABY-POG chemotherapy backbone for 72 weeks

Lorlatinib with chemotherapy1

Continue lorlatinib with HIT-SKK chemotherapy backbone for 42 weeks

Lorlatinib with chemotherapy 2

Continue lorlatinib monotherapy 28 days post completion of radiation therapy for 12 cycles

Lorlatinib post Radiation

Eugene Hwang

Susan Chi

Maryam Fouladi, MD, MSc

Sarah Leary

David Ziegler, MD

Tim Hassall, MD

Nicholas G Gottardo, MBChB

Eric Bouffet

Jasper van der Lugt

Hamza Gorsi, MD

The goal of this study is to determine the response of the study drug loratinib in treating children who are newly diagnosed high-grade glioma with a fusion in ALK or ROS1. It will also evaluate the safety of lorlatinib when given with chemotherapy or after radiation therapy.

This is a multi-institutional clinical trial of lorlatinib in children newly diagnosed with High Grade Glioma (HGG) harboring ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) or ALK (anaplastic lymphoma kinase) fusions. In this pilot study, investigators will assess the disease control rate (Continued Complete Response (CCR), Complete Response (CR), Partial Response (PR), and Stable Disease (SD)) of lorlatinib, and feasibility and safety of lorlatinib administration in combination with standard chemotherapy in children with newly diagnosed HGG with ROS or ALK fusions who receive 2 cycles of lorlatinib administered orally, once daily, at 115 mg/m2/day (or maximum of 200mg/dose) continuously. Secondary objectives include overall survival (OS) and progression free survival (PFS) lorlatinib as a single agent and in combination with standard chemotherapy used in children ≤ 48 months with HGG, or post focal radiotherapy in children \> 48 months of age. Children with HGG who have a CCR or CR after 2 cycles of therapy will continue to receive single agent lorlatinib for a total of 12xs 28-day cycles. Continuation of treatment beyond 12 cycles, and up to maximum 26 cycles, may be considered for patients on lorlatinib monotherapy if they are receiving clinical benefit from the study, at the discretion of the treating physician. Patients with PR or SD after 2 cycles of lorlatinib monotherapy will go on to receive lorlatinib either in combination with standard backbone chemotherapy (BABYPOG or HIT-SKK, investigator's choice) or post standard radiotherapy, based on the patient's age. Patients with PD after 2 cycles will be taken off protocol therapy.

Based on recent trials conducted in this patient population, investigators conservatively estimate that 1 child with newly diagnosed DIPG or HGG with either ROS1 or ALK fusion will be enrolled every 2 months on this study. Patients will start at the recommended phase 2 dose of 115 mg/m2/day, continuously for 28 days, and one dose de-de-escalations will be allowed. A maximum of 15 eligible patients will be enrolled, anticipated over 2.5 years.

Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion

A Pilot Study of Lorlatinib for Treatment of Children With Newly Diagnosed High-Grade Glioma With ROS-1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) or ALK (Anaplastic Lymphoma Kinase) Fusion

To assess the disease control rate (Complete Response \[CR\], Continued Complete Response \[CCR\], Partial Response \[PR\] and Stable Disease \[SD\]) of lorlatinib in young children with newly diagnosed high-grade glioma with ALK or ROS1 fusion after 2 cycles of lorlatinib monotherapy.

Assess and further characterize the safety and toxicity of lorlatinib in pediatric patients newly diagnosed with HGG with a fusion in ALK or ROS. This will be achieved by calculating the number of participants with, as well as frequency and severity of, lorlatinib-related Adverse Events as assessed by CTCAE v5.0

To assess the objective response rate (ORR) (Complete Response \[CR\] and Partial Response \[PR\]) of lorlatinib in children with newly diagnosed high-grade glioma with ALK or ROS1 fusion after 2 cycles of lorlatinib monotherapy.

To assess overall (OS) of children with high-grade gliomas treated with a lorlatinib-containing regimen at 1, 3 and 5 years and compare it to historical data from BABYPOG and HIT-SKK.

To assess progression-free survival (PFS) of children with high-grade gliomas treated with a lorlatinib-containing regimen at 1, 3 and 5 years and compare it to historical data from BABYPOG and HIT-SKK.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Targeted Pediatric High-Grade Glioma Therapy	NCT05839379	High Grade Glio... Diffuse Intrins... Anaplastic Astr... Glioblastoma Glioblastoma Mu... Diffuse Midline... Metastatic Brai... WHO Grade III G... WHO Grade IV Gl...		12 Months - 39 Years	Nationwide Children's Hospital
Study of Ribociclib and Everolimus in HGG and DIPG	NCT05843253	High Grade Glio... Diffuse Intrins... Anaplastic Astr... Glioblastoma Glioblastoma Mu... Diffuse Midline... Metastatic Brai... WHO Grade III G... WHO Grade IV Gl...	Ribociclib Everolimus	12 Months - 39 Years	Nationwide Children's Hospital
Lorlatinib for Newly-Diagnosed High-Grade Glioma With ROS or ALK Fusion	NCT06333899	High Grade Glio... Diffuse Intrins... Anaplastic Astr... Infant Type Hem... Glioblastoma Glioblastoma Mu... WHO Grade III G... WHO Grade IV Gl... Diffuse Midline...	Lorlatinib Lorlatinib with... Lorlatinib with... Lorlatinib post...	1 Year - 21 Years	Nationwide Children's Hospital

Spots Global Cancer Trial Database for who grade iv glioma