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)
Overview
- Phase
- Phase 1
- Status
- Terminated
- Enrollment
- 11
- Locations
- 1
- Primary Endpoint
- Number of Adverse Events
Overview
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.
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 12 Months to 30 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
- •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.
Exclusion Criteria
- •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
Arms & Interventions
RB+ 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)
Intervention: Ribociclib (Drug)
Non-Biopsied Diffuse Instrinsic Pontine 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)
Intervention: Ribociclib (Drug)
Outcomes
Primary Outcomes
Number of Adverse Events
Time Frame: 6 months
Primary feasibility endpoint is the number of individual toxicities and incidence of significant delays
Number of Patients Alive at One Year
Time Frame: 1 year
Secondary Outcomes
No secondary outcomes reported