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 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: CONNECT1701_LEE/RAD17T-MD-1604
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Diffuse Intrinsic Pontine Glioma; Malignant Glioma of Brain; High Grade Glioma; Bithalamic High Grade Glioma; Brainstem Glioma; Glioblastoma; Anaplastic Astrocytoma

Keywords

DIPG; High Grade Glioma; ribociclib; everolimus

Outcome Measures

Primary Outcomes (3)

• Number of adverse events

  Number of individual toxicities and incidence of significant delays

  6 months

• Estimate the maximum tolerated dose and/or recommended phase 2 dose of ribociclib combined with everolimus

  number of dose limiting toxicities experienced at each dose level

  28 days

• Pharmacokinetics of combination of ribociclib and everolimus

  Plasma concentration of ribociclib and everolimus over time

  7 days

Secondary Outcomes (3)

• Time from diagnosis to death - overall survival

  48 months

• Number of patients with observed pseudoprogression

  12 months

• Whole exome sequencing to explore biology of DIPG and HGG tumors

  24 months

Study Arms (4)

Dose level 1 (starting dose level) (participants </= 21yrs)

EXPERIMENTAL

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

Drug: ribociclib; Drug: Everolimus

Dose level 2 (participants </= 21yrs)

EXPERIMENTAL

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

Drug: ribociclib; Drug: Everolimus

Dose level 3 (participants </= 21yrs)

EXPERIMENTAL

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

Drug: ribociclib; Drug: Everolimus

Dose level 1 (DIPG participants > 21yrs)

EXPERIMENTAL

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

Drug: ribociclib; Drug: Everolimus

Interventions

ribociclib DRUG

Oral capsule or liquid formula

Also known as: Kisqali

Dose level 1 (DIPG participants > 21yrs); Dose level 1 (starting dose level) (participants </= 21yrs); Dose level 2 (participants </= 21yrs); Dose level 3 (participants </= 21yrs)

Everolimus DRUG

Oral tablets or dispersible tablets

Also known as: Afinitor

Dose level 1 (DIPG participants > 21yrs); Dose level 1 (starting dose level) (participants </= 21yrs); Dose level 2 (participants </= 21yrs); Dose level 3 (participants </= 21yrs)

Eligibility Criteria

• Age: 12 Months - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age Patients must be ≥ 12 months of age and ≤ 30 years of age at the time of study entry for patients diagnosed with DIPG.
• Patients must be ≥ 12 months of age and ≤ 21 years of age at the time of study entry for patients diagnosed with HGG.
• BSA restrictions for patients ≤ 21 years of age at the time of study entry
• Patients enrolled on dose level -1 must have BSA≥0.55m2
• Patients enrolled on dose level 0\* must have BSA≥0.75m2
• Patients enrolled on dose level 0 must have BSA≥0.55m2
• Patients enrolled on dose level 1 must have BSA≥0.75m2
• Patients enrolled on dose level 2 and 3 must have BSA≥ 0.45m2
• RB status Screening for RB applies to all patients with pre-trial tumor tissue except for patients diagnosed with DIPG and bi-thalamic tumors who do not have available tissue.
• RB testing must be evaluated centrally at CCHMC prior to enrollment or report from CLIA certified lab must be reviewed centrally at CCHMC.
• Tumor
• Diffuse Intrinsic Pontine Glioma (DIPG):
• Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined on neuroimaging as tumors with a pontine epicenter and diffuse intrinsic involvement of the pons, are eligible without histologic confirmation.
• Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to have + RB and be the following according to the 2016 World Health Organization Classification of Tumors of the Central Nervous System proved to be high grade gliomas (such as anaplastic astrocytoma, glioblastoma, H3K27-mutant diffuse midline glioma or diffuse astrocytoma) Or histologically-confirmed malignant glioma WHO II-IV "other than above".
• Note: Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma with or without anaplasia, gangliogliomas, or other mixed gliomas without anaplasia are not eligible.

You may not qualify if:

• Concurrent Illness Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results.
• Inability to Participate Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
• Received a radiosensitizer, craniospinal irradiation therapy, investigational agent or any additional adjuvant therapy during radiation therapy.
• Received prior therapy with CDK4/6 inhibitor and/or mTOR inhibitor.
• Seizures Patients who are currently receiving enzyme inducing anti-epileptic drugs that are known strong inducers or inhibitors of CYP3A4/5 (EIAEDs). Patients with a history of seizures and maintained on an anti-epileptic drug that is not a strong inducers or inhibitor of CYP3A4/5 are eligible.
• Patient has a known hypersensitivity to ribociclib or any of its excipients as described below:
• The capsules contain only the drug substance without any excipients.
• The film-coated tablets consist of drug substance and compendial quality colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, magnesium stearate and microcrystalline cellulose. The film-coating is a mix of compendial quality iron oxides, lecithin, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum. Patients allergic to peanut and soy are not permiteed to take the film-coated tablet formulation.
• The oral solution consists of ribociclib succinate in water with an orange flavoring agent and common excipients such as preservatives, sweetener and pH modifier
• Clinically significant active cardiac disease, uncontrolled heart disease and/or history of cardiac dysfunction including any of the following;
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Documented cardiomyopathy
• Patient has a Left Ventricular Ejection Fraction (LVEF) \<50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
• History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead
• Novartis: collaborator

Study Sites (7)

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

MeSH Terms

Conditions

Diffuse Intrinsic Pontine Glioma; Glioma; Glioblastoma; Astrocytoma

Interventions

ribociclib; Everolimus

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2017
• First Posted: November 28, 2017
• Study Start: November 14, 2017
• Primary Completion: July 31, 2020
• Study Completion: July 31, 2022
• Last Updated: January 13, 2023

Record last verified: 2023-01

Locations

US (7)