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)
Condition: Diffuse Intrinsic Pontine Glioma; Malignant Glioma of Brain; High Grade Glioma; Bithalamic High Grade Glioma; Brainstem Glioma; Glioblastoma; Anaplastic Astrocytoma
MeSH terms: Glioblastoma; Glioma; Astrocytoma; Diffuse Intrinsic Pontine Glioma
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): ribociclib; Everolimus
Intervention type(s): Drug; Drug
Intervention description(s): Oral capsule or liquid formula; Oral tablets or dispersible tablets
Other intervention name(s): Kisqali; Afinitor
Intervention MeSH terms: Everolimus
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: DIPG; High Grade Glioma; ribociclib; everolimus