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High Grade GliomaPhase 1/2NCT02607124

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

A Phase 1/2 study testing Ribociclib in people with High Grade Glioma and Diffuse Intrinsic Pontine Glioma, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 12 months to 30 years
What is being tested?
Ribociclib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
1 siteUnited States
Study dates
Apr 2016to Aug 2018
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 months to 30 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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.
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  • 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)
  • Patients must have had histologically verified the following according to the 2016 World Health Organization classification of tumors of the central nervous system: anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS), glioblastoma multiforme (IDH mutant, IDH wildtype, or NOS), diffuse astrocytoma (IDH mutant, IDH wildtype or NOS)
  • AND RB positive noted on immunohistochemistry.
  • Patients with primary spinal cord tumors are eligible. Patients with multi-focal disease within the cerebrum are eligible.
  • Patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not eligible.
  • Performance Status
  • Karnofsky > 50 % for patients >16 years of age or Lansky > 50 for patients < 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • Prior Therapy
  • Patients must have not received any prior therapy other than surgery, radiation and/or steroids.
  • Radiation therapy requirements
  • Patients diagnosed with DIPG: any variances in the radiotherapy dose within 10% of the current standard dose (54 Gy) will be discussed with the Sponsor-Investigator to confirm eligibility prior to study enrollment
  • Patients diagnosed with HGG: any variances in the radiotherapy dose within 10% of the current standard dose (59.4 Gy) will be discussed with the Sponsor-Investigator to confirm eligibility prior to study enrollment.
  • Patients diagnosed with primary spinal tumors any variances in the radiotherapy dose within 10% of the current standard dose (54 Gy) will be discussed with the Sponsor-Investigator to confirm eligibility prior to study enrollment.
  • Timing of Radiation - radiation therapy must begin no later than 30 days after the date of radiographic diagnosis or definitive surgery, whichever is the later date.
  • Organ Function
  • Patients must have normal organ and marrow function documented within 7 days of study enrollment as defined below:
  • Absolute neutrophil count ≥ 1000mm3
  • Platelets ≥ 75,000/mm3 (unsupported for 7 days)
  • Hemoglobin ≥ 9g/dl (unsupported) for 7 days
  • Total bilirubin ≤ 3 times upper limit of normal (ULN) for age
  • ALT (SGPT) ≤ 2.5 X ULN for age
  • Albumin ≥ 2 g/dl
  • Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73m2 or serum creatinine based on age/gender.
  • Pregnancy Status Female patients of childbearing potential, must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test.
  • Pregnancy Prevention Patients of childbearing or child fathering potential must use a highly effective method of contraception throughout the study while taking the drug and for 21 days after stopping treatment
  • Female patients with infants must agree not to breastfeed their infants while on this study.
  • Informed Consent Signed informed consent according to institutional guidelines must be obtained. Assent, when appropriate, will be obtained according to institutional guidelines.

Who cannot join

  • 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.
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  • 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
  • Hypertension defined below:
  • Patients 2-17 years of age must have a blood pressure that is ≤ 95th percentile for age, height and gender at the time of enrollment.
  • Patients who are ≥ 18 years of age must have a systolic blood pressure that is > 160 or diastolic < 90 mm of Hg at the time of enrollment
  • Note: If a BP reading prior to enrollment is above the 95th percentile for age, height and gender, it is to be rechecked and documented to be ≤ 95th percentile for age, height and gender prior to patient enrollment.
  • Inability to determine the QTcF interval on the ECG (i.e. unreadable or not interpretable) or QTcF > 450 msec (using Fridericia's correction). All as determined by screening ECG (using the mean QTcF of triplicate ECGs)
  • Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug Ribociclib:
  • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pomelos, star-fruit, and Seville oranges
  • Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
  • Medications that have a known risk to prolong the QT interval or induce Torsades de Pointes
  • Herbal preparations/medications, dietary supplements.
  • Patient is currently receiving warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed
  • Patient has a history of non-compliance to medical regimen.
  • Known need for major surgery within 14 days of the first dose of Ribociclib. Gastrostomy, insertion of a G tube, Ventriculo-peritoneal shunt, endoscopic ventriculostomy and central venous access are NOT considered major surgery.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

Other trials in United States

About this study

Official title: 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)

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.

Read more

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.

Read the detailed description

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.

Being tested
Ribociclib
Keywords
DIPG
Medical subject headings
Glioma, Diffuse Intrinsic Pontine Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RibociclibDrug

    Also called LEE011

Study groups in NCT02607124
Study groupRoleWhat they receive
RB+ High Grade GliomaExperimentalRibociclib 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)
Receives: Drug: Ribociclib
Non-Biopsied Diffuse Instrinsic Pontine GliomaExperimentalRibociclib 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)
Receives: Drug: Ribociclib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Adverse Events

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

    Measured: 6 months

  2. Number of Patients Alive at One Year

    Measured: 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Nov 2015 (estimated)
  2. Study startApr 2016
  3. Primary completionMay 2018
  4. Study completionAug 2018

Why it stopped: A competing trial was opened for patient population with combination of ribociclib and everolimus.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02607124
Sponsor's protocol ID
CLEE011XUS17T
Status last verified
Oct 2020
First submitted
16 Nov 2015
Last updated
5 Nov 2020
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 33034839

  • 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.

    PubMed 32354716

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Ribociclib in people with High Grade Glioma and Diffuse Intrinsic Pontine Glioma, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 41 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 5 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Adverse Events (time frame: 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02607124, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2020; AzTrials last refreshed its copy on 2 Nov 2026.

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