by conducting nimble, scientifically-rational, international trials to demonstrate the safety and feasibility of incorporating novel agents and therapeutic modalities into the most effective current regimens for children with newly-diagnosed high-risk brain tumors.
The COllaborative Network for NEuro-oncology Clinical Trials (CONNECT) conducts clinical trials in high-risk pediatric brain tumors (such as DIPG) to investigate combinations of novel drugs with traditional therapies. We seek to improve outcomes in the worst childhood brain tumors by combining innovative discoveries with “tried and true” therapy regimens through:
CONNECT member institutions lead the way in cutting edge research in the biology of high-risk pediatric brain tumors. By combining the considerable strengths in basic science and translational expertise among CONNECT’s international members, we can quickly translate basic science discoveries into novel therapies and new cures.
CONNECT is a global partnership of world-class childhood cancer centers and pediatric neuro-oncology experts. The international collaboration expands global access to novel, promising therapies for children and young adults with brain tumors, and improves scientific discovery through collaboration
In this research study, we want to learn about the safety of the study drugs, ribociclib and everolimus, when given together at different doses after radiation therapy. We also want to learn about the effects, if any, these drugs have on children and young adults with brain tumors.
We are asking people to be in this research study who have been diagnosed with a high grade glioma, their tumor has been screened for the Rb1 protein, and they have recently finished radiation therapy. If a patient has DIPG or a Bi-thalamic high grade glioma, they do not need to have the 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 that control how fast cells grow but in cancer cells these proteins no longer work correctly making tumor cells grow quickly. Both study drugs work in different ways to slow down the growth of tumor cells. The researchers think that if the study drugs are given together soon after radiation therapy, it may help improve the effect of the radiation in stopping or slowing down tumor growth.
The study drugs, ribociclib and everolimus, have been approved by the United States Food and Drug Administration (FDA). Ribociclib is approved to treat adults with breast cancer and everolimus is approved for use in adults and children who have other types of cancers. The combination of ribociclib and everolimus has not been tested in children or in people with brain tumors and is considered investigational.
In this research study the investigators want to learn more about the safety of the study drug, PTC596 has when taken during radiation. The investigators also want to learn about the effects, if any, these drugs have on children and young adults with brain tumors.
The investigators are asking people to be in this research study who have been diagnosed with a high grade glioma (HGG) including diffuse intrinsic pontine glioma (DIPG) to be in the research, because they have scheduled to have radiation to treat their cancer.
The study is divided into two parts. The goal of the first part is to find the dose of PTC596 that can be given with radiation without causing serious side effects. The purpose of this surgical study is to test the amount of a study drug that may be found in the tumor and blood when given prior to and during a planned surgery for removal of the recurrent tumor.
CONNECT1903: A Pilot Study of Larotectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion
SummaryIn this research study, we want to learn more about the effects of the study drug larotrectinib on children with brain tumors. We want to learn how well it works to shrink brain tumors when used alone or when given with standard chemotherapy or after radiation therapy.
The investigators are asking people to be in this research study who have been diagnosed with a high-grade glioma with a certain abnormal gene called NTRK. The investigators will evaluate the disease of the patients after they take the larotrectinib for 2 cycles. After taking the study drug for 2 cycles, the investigators will determine the next course of treatment. Patients will continue to receive either larotrectinib alone, larotrectinib with standard chemotherapy or larotrectinib alone after radiation therapy. The length of treatment depends on how well the patient is doing and which standard treatment the doctor thinks is best for them.
There is also a surgical cohort of the study where tumor samples and blood samples will be collected and sent to researchers to determine if larotrectinib is found in the tumor and how much is in the blood.
The purpose of this study is to learn about the effects of the study drug tocilizumab in patients with Adamantinomatous craniopharyngioma (ACP). We think this drug can benefit ACP patients who may or may not have undergone surgery or radiation as it may help shrink this type of brain tumor or slow its growth.
We are asking individuals to be in this research study if they have been diagnosed with ACP that has increased in size or is unable to be removed entirely by surgery.
Tocilizumab is a form of targeted immunosuppressive therapy and is given as a liquid through an intravenous (IV) infusion once every 2 weeks. The drug is approved by the United States Food and Drug administration (FDA) for a different disease in children.
In this research study, we want to find out if the study drug Lutathera is effective in treating different kinds of brain cancer. We also want to find the safest dose of this drug that does not cause serious side effects.
We are asking the participation of children and young adults who have been diagnosed with either a high-grade brain or spine tumor or a meningioma that expresses a specific protein called somatostatin receptor on its surface. This is confirmed with a special type of scan called a DOTATATE PET.
Lutathera is a form of targeted radiation therapy and is given by intravenous (IV) infusion once every 2 months. This drug is approved by the FDA (Food and Drug Administration) for the treatment of another type of cancer but it has not yet been approved for the treatment of brain/spine tumors.
The purpose of this study is to learn more about the effects of the study drug binimetinib in patients with Adamantinomatous craniopharyngioma (ACP). We think this drug can benefit ACP patients who may or may not have undergone surgery or radiation as it may help shrink this type of brain tumor or slow its growth. This is based on laboratory studies on cells grown in the lab from craniopharyngioma tumor tissue collected from patients at surgery.
We are asking individuals to be in this research study if they have been diagnosed with ACP that has increased in size or is unable to be removed entirely by surgery.
Binimetinib is a form of targeted chemotherapy and is given orally as a tablet twice a day. This drug is approved by the United States Food and Drug administration (FDA) to treat a different disease in children and adults.
The purpose of this phase 2 study is to see if a cancer vaccine (PEP-CMV) can help patients’ immune system fight against high-grade glioma and medulloblastoma. We think PEP-CMV, which is an immunotherapy given as an injection into the thigh, can benefit children by training their immune system to seek out and attack these tumors. This study is designed for patients with diffuse intrinsic pontine glioma (DIPG) or malignant glioma (WHO grade 3 or 4) who are newly diagnosed (within 6 weeks of finishing radiation) or patients with medulloblastoma whose tumor has come back at any point after having received radiation. Patients on this study receive a single, 5-day course of oral chemotherapy called temozolomide, which is deigned to condition the immune system, followed by PEP-CMV injections every 2 weeks for 3 vaccines, then monthly.
TarGeT is an innovative multi-arm clinical trial offering a precision medicine approach to treat children, adolescents, and young adults newly diagnosed with high-grade gliomas (HGGs), including DIPG. Detailed genetic sequencing using advanced technology will be performed on tumor tissue from all patients upfront, with return of results within 3 weeks. Patients will then be assigned to one of several unique molecularly-targeted treatment arms based on (and directly targeting) the genetic alterations identified in their tumor. Additionally, all patients with undergo upfront radiation. We will be investigating the effectiveness of molecularly-targeted treatments. Furthermore, in addition to studying the genetic alterations present in tumor tissue prior to treatment, we will collect blood samples as well as cerebrospinal fluid (CSF) and/or future tumor tissue (if a second surgery is performed) throughout the study. Genomic and immune profiling analyses will be performed on these specimens over time to identify biomarkers (“liquid biopsy” tools) that can predict early response or recurrence to treatment and improve the understanding of why some tumors become resistant to therapy.
TarGeT-SCR is the overarching screening protocol on which all patients must first enroll to confirm eligibility and be assigned to a targeted therapy arm based on their tumor's unique molecular profile. There are three different options by which patients can screen to allow as much flexibility as possible, including options to submit tissue for genetic sequencing or upload results of previously performed testing.
A high proportion of pediatric HGG and DIPG have alterations in the cell cycle or PI3K/mTOR pathways, which contribute to tumor cell growth, representing potential targets. Our team has recently studied the combination of two oral targeted drugs—ribociclib, a CDK4/6 inhibitor which blocks the cell cycle pathway and everolimus, an mTOR inhibitor which blocks the PI3K/mTOR pathway—which were shown to be safe when administered to children newly diagnosed with HGG and DIPG post-radiotherapy. In the TarGeT-A arm, we are specifically focusing on children and young adults with DIPG/DMG assigned to treatment with ribociclib and everolimus based on their tumor molecular profile on the phase II trial, through which effectiveness of the combination will be assessed. Patients will receive ribociclib orally days 1-21 and everolimus orally days 1-28 of 28-day cycles. In addition to studying the genetic alterations present in tumor tissue prior to treatment, we will collect blood samples as well as cerebrospinal fluid (CSF) and/or future tumor tissue (if a second surgery is performed) throughout the study. Genomic and immune profiling analyses will be performed on these specimens over time to identify biomarkers (“liquid biopsy” tools) that can predict early response or recurrence to the combination of ribociclib and everolimus and improve the understanding of why some tumors become resistant to therapy. We will also analyze imaging and patient- and parent-reported quality of life outcomes over time to develop minimally invasive predictors of treatment benefit.