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

NCT02607124 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: CLEE011XUS17T
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

High Grade Glioma; Diffuse Intrinsic Pontine Glioma; Bithalamic High Grade Glioma

Keywords

DIPG

Outcome Measures

Primary Outcomes (2)

• Number of Adverse Events

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

  6 months

• Number of Patients Alive at One Year

  1 year

Study Arms (2)

RB+ High Grade Glioma

EXPERIMENTAL

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)

Drug: Ribociclib

Non-Biopsied Diffuse Instrinsic Pontine Glioma

EXPERIMENTAL

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)

Drug: Ribociclib

Interventions

Ribociclib DRUG

Also known as: LEE011

Non-Biopsied Diffuse Instrinsic Pontine Glioma; RB+ High Grade Glioma

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.
• RB status
• Diagnostic stereotactic biopsy: Patients diagnosed with DIPG may choose to have a stereotactic biopsy prior to starting radiation therapy.
• Toxicities related to biopsy must have resolved prior to proceeding with radiation therapy.
• Screening for Rb applies to all patients with available tissue except for patients diagnosed with DIPG and bi-thalamic tumors.
• If resection occurred at an outside institution, eligibility and treatment MRI evaluations in addition to Rb testing must be completed 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: an anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS), glioblastoma (IDH mutant, IDH wildtype or NOS), diffuse midline glioma, H3 K27M mutant or H3 K27M negative, diffuse astrocytoma (IDH mutant, IDH wildtype or NOS).
• Note: Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma with or without anaplasia, gangliogliomas, or other mixed gliomas without anaplasia are not eligible.
• Patients with diffuse intrinsic brain stem glioma (DIPG) can be enrolled without the need for available tumor tissue for RB protein status confirmation.
• Bi-thalamic tumors, biopsied and noted to have intact RB. Bi-thalamic tumors that are not biopsied will be eligible to enroll on the DIPG/bi-thalamic non-biopsied arm.
• High-grade Glioma (HGG)

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 or any additional adjuvant therapy during radiation therapy.
• Patients with disseminated disease to the spine are not eligible, and MRI of spine must be performed prior to enrollment if the treating physician suspects disseminated disease.
• 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.
• 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
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
• Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
• Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication

Sponsors & Collaborators

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

Study Sites (1)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (2)

• DeWire M, Fuller C, Hummel TR, Chow LML, Salloum R, de Blank P, Pater L, Lawson S, Zhu X, Dexheimer P, Carle AC, Kumar SS, Drissi R, Stevenson CB, Lane A, Breneman J, Witte D, Jones BV, Leach JL, Fouladi M. A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). J Neurooncol. 2020 Sep;149(3):511-522. doi: 10.1007/s11060-020-03641-2. Epub 2020 Oct 9.

  PMID: 33034839 DERIVED

• Gilligan LA, DeWire-Schottmiller MD, Fouladi M, DeBlank P, Leach JL. Tumor Response Assessment in Diffuse Intrinsic Pontine Glioma: Comparison of Semiautomated Volumetric, Semiautomated Linear, and Manual Linear Tumor Measurement Strategies. AJNR Am J Neuroradiol. 2020 May;41(5):866-873. doi: 10.3174/ajnr.A6555. Epub 2020 Apr 30.

  PMID: 32354716 DERIVED

MeSH Terms

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma

Interventions

ribociclib

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

Results Point of Contact

• Title: Renee Doughman
• Organization: Cincinnati Childrens Hosptial Medical Center

renee.doughman@cchmc.org

513-636-1699

Study Officials

• Mariko DeWire, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

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 16, 2015
• First Posted: November 17, 2015
• Study Start: April 1, 2016
• Primary Completion: May 1, 2018
• Study Completion: August 1, 2018
• Last Updated: November 5, 2020
• Results First Posted: November 5, 2020

Record last verified: 2020-10

Locations

US (1)