Neoplasms

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Everolimus

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Immunologic Factors

Ribociclib administered orally; daily on days 1-21 each 28 day cycle; dose calculation age dependent (\>21 yrs of age 300mg daily (DIPG only); \</=21 yrs of age 120 mg/m2/day) Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; dose calculation age dependent (\>21yrs 2.5mg/day (DIPG only); \</=21yr 1.2 mg/m2/day) BSA \>/=0.75m2

Ribociclib administered orally; daily on days 1-21 each 28 day cycle; 170 mg/m2/day Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; 1.2 mg/m2/day BSA \>/=0.45m2

Ribociclib administered orally; daily on days 1-21 each 28 day cycle; 170 mg/m2/day Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; 1.5 mg/m2/day BSA \>/=0.45m2

Ribociclib administered orally; daily on days 1-21 each 28 day cycle; 300mg daily Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; 2.5mg/day

ribociclib

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.

The goals of this study are:

* Find the safest dose of ribociclib and everolimus that can be given together after radiation.
* Learn the side effects (both good and bad) the study drugs have on the body and tumor.
* Measure the levels of study drug in the blood over time.
* Study the changes in the endocrine system that may be caused by the tumor, surgery or radiation.

This is a phase I study to determine: 1) the MTD and/or the recommended phase II dose (RP2D) of ribociclib and everolimus which can be safely administered during maintenance therapy for up to 24 courses following completion of radiation therapy with newly diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG, 2) characterization of the pharmacokinetic profile of ribociclib and everolimus as combination maintenance therapy following completion of radiation therapy with newly diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG.

Patients with RB+ tumors and non-biopsied DIPG will receive standard radiation therapy prior to enrollment followed by ribociclib and everolimus as maintenance therapy. Upon completion of radiation therapy, a 2 - 4 week break will occur and then ribociclib will be given orally daily for 21 days followed by a 7 day break every 28 days at 70% of the adult RP2D (300 mg) in combination with everolimus at 80% of the adult RP2D (2.5 mg) given orally once daily continuously for up to 24 courses. One course is equivalent to 28 days. Due to dosing concerns with the limited dosing capsules (50 mg and 200 mg are only available), dose escalations will have BSA restrictions to accommodate for variations from target doses and BSA adjusted actual dose. Two intra-patient dose-de-escalations will be allowed if dose limiting toxicities arise and may continue study treatment for up to 24 courses in the absence of disease progression or unacceptable toxicity.

A Study of Ribociclib and Everolimus Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)

A Phase I Study of Ribociclib and Everolimus Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)

IPD would only be shared following publication of the study.

Number of individual toxicities and incidence of significant delays

number of dose limiting toxicities experienced at each dose level

Plasma concentration of ribociclib and everolimus over time

Overall survival is defined as the time from diagnosis to death.

the assessment of true vs. pseudoprogression will be based on the tumor measurements from subsequent scans

Novartis

Children's Hospital Medical Center, Cincinnati

Ribociclib administered orally; daily on days 1-21 each 28 day cycle; dose calculation age dependent (\>21 yrs of age 600mg daily (DIPG); \<21 yrs of age 350 mg/m2/day)

Ribociclib

Mariko DeWire, MD

In this research study the investigators want to learn more about the effects, both good and bad, when the study drug Ribociclib is given after radiation therapy.

The investigators are asking people to be in this research study that have been newly diagnosed with a high grade glioma, and the tumor has been screened for the Rb1 protein, and have recently finished radiation therapy. Patients with a DIPG or a Bi-thalamic high grade glioma do not need to have tumor tissue screened for the Rb1 protein but do need to have finished radiation therapy.

Tumor cells grow and divide quickly. In normal cells, there are proteins called cyclin-dependent kinases (CDK 4 and 6) that control cell division. Another protein Rb1 also controls cell division and works to stop cells from dividing so they do not become cancer cells. But in cancer, the CDK 4 and 6 proteins are out of control making the cells divide and grow quickly. The study drug, ribociclib stops the CDK 4 and 6 proteins. When the CDK 4 and 6 proteins are stopped, the normal Rb1 protein can now work to slow cell growth. For patients with HGG, to be in this study tumor tissue must have a normal Rb1 protein. The researchers think that if the study drug is given soon after radiation therapy, it may help improve the effect of the radiation in stopping the tumor from growing.

The study drug, Ribociclib is considered investigational as it has not yet been approved by the United States Food and Drug Administration. The study drug has been tested in children and adults with cancer in prior research studies.

Ribociclib has shown an acceptable toxicity profile in adults and pediatrics. Available data suggests that over 70% of DIPG patient have an intact RB and 90% HGG patients have expression of RB, therefore CDK4/6 inhibition is a suitable target. Given the dismal prognosis for children with DIPG and HGG, it is appropriate to evaluate the long term feasibility and early efficacy of Ribociclib following radiation therapy in patients with RB+ tumors. The aim of the upfront biopsy molecular studies proposed is to identify subgroups of patients who will benefit from the use of checkpoint inhibitors in the setting of intact RB pathway. This study will play a major role in moving the field of DIPG/HGG research forward as the investigators intend to reveal feasibility of upfront stereotactic biopsy and specific pathway directed therapy following radiation therapy with the ultimate goal to add additional targeted therapy in combination with Ribociclib resulting in improving the outcome for patients diagnosed with these fatal tumors.

The current proposal will be a novel pediatric study to obtain biopsy in DIPG prior to therapy and administer molecularly targeted therapy following radiation therapy in children with newly diagnosed DIPG and HGG. In this study, the investigators will assess the assess long-term feasibility and early efficacy of Ribociclib administered daily for 3 weeks and off one week every 28 days following radiation therapy for at least 6 courses and up to 12 courses in patients with newly-diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG. Moreover, the investigators will approach this devastating disease with a multi-disciplinary team and evaluate the quality of life and functional outcome resulting in effective interventions.

A Phase I/II Study of Ribociclib,a CDK4/6 Inhibitor, Following Radiation Therapy

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

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

Adverse events grades 1 and 2 that are at least possibly related to ribociclib and all adverse events grades 3 and higher regardless of attribution during study treatment were recorded for the purposes of safety monitoring.

There were no serious adverse events attributable to study treatment.

Diffuse Intrinsic Pontine Glioma and High Grade Glioma

Ribociclib administered orally; daily on days 1-21 each 28 day cycle; dose calculation age dependent (\>21 yrs of age 600mg daily (DIPG); \<21 yrs of age 350 mg/m2/day)

Baseline characteristics data are collected irrespective of Arm/Group and cannot be reported separately.

Diffuse Instrinsic Pontine Glioma and Diffuse Midline Glioma

One enrolled participant was ineligible for study treatment and removed from trial therefore deemed inevaluable.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Demographics for participants are combined for enrolled participants stratified by diagnosis. Intervention was identical for all diagnoses.

Renee Doughman

Ribociclib administered orally; daily on days 1-21 each 28 day cycle; dose calculation age dependent (\>21 yrs of age 600mg daily (DIPG); \<21 yrs of age 350 mg/m2/day)

Ribociclib

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Ribociclib and Everolimus Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)	NCT03355794	Diffuse Intrins... Malignant Gliom... High Grade Glio... Bithalamic High... Brainstem Gliom... Glioblastoma Anaplastic Astr...	ribociclib Everolimus	12 Months - 30 Years	Children's Hospital Medical Center, Cincinnati
A Phase I/II Study of Ribociclib,a CDK4/6 Inhibitor, Following Radiation Therapy	NCT02607124	High Grade Glio... Diffuse Intrins... Bithalamic High...	Ribociclib	12 Months - 30 Years	Children's Hospital Medical Center, Cincinnati

Spots Global Cancer Trial Database for bithalamic high grade glioma