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)

Patients with diffuse intrinsic brain stem glioma (DIPG) can be enrolled without the need for available tumor tissue for RB protein status confirmation. If DIPG or bi-thalamic patients have been biopsied and if available tissue, RB status will be tested. These must be RB+ to be eligible for enrollment.

Bi-thalamic tumors, biopsied and noted to have intact RB are eligible. Bi-thalamic tumors that are not biopsied will be eligible to enroll on the DIPG non-biopsied arm. 107

High-grade Glioma (HGG):

Patients with newly-diagnosed non-brainstem high-grade glioma (HGG) are eligible. Patients must have had histologically verified high-grade glioma such as anaplastic astrocytoma, glioblastoma, H3 K27 mutant diffuse midline glioma etc. Or histologically-confirmed non-brain stem malignant high grade glioma WHO III-IV "other than above".

AND RB+ noted on immunohistochemistry.

Patients with primary spinal cord tumors are eligible. Patients with multi-focal disease within the cerebrum are eligible.

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

* Long QT syndrome or known 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 for 7 days prior to starting study drug(s) or replaced by safe alternative medication.

* Hypertension defined below:

Patients 1-12 years of age (pediatric) with blood pressure that is ≥ 95th percentile for age, height and gender at the time of enrollment

Patients who are ≥ 13 years of age (adolescents) with a blood pressure that is ≥130/80 mm of Hg at the time of enrollment.

\* Note: If a BP reading prior to enrollment does not meet parameters, blood pressure should be rechecked and documented to be within eligibility range prior to patient enrollment.

Inability to determine the QTc interval on the ECG (i.e.: unreadable or not interpretable) or QTc ≥ 450 msec as determined by screening ECG.

Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drugs ribociclib and everolimus

* Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges

* Strong and moderate inhibitors or inducers of CYP3A4/5

* Substrates of CYP3A4/5 with a narrow therapeutic index

* Other investigational and anti-neoplastic therapies, including chemotherapy, immunotherapy, target therapy, biological response modifiers

* 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 (except for vitamins) including, but not limited to: St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. Patients should stop using all herbal medications and dietary supplements at least 7 days prior to first dose of study treatment.

Bleeding Disorder 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 as long as patient has adequate coagulation defined as: aPTT INR≤1.5 x upper limit of normal.

Patient has a history of non-compliance to medical regimen.

Known need for major surgery within 14 days of the first dose of ribociclib and everolimus. Gastrostomy, insertion of a G tube, Ventriculo-peritoneal shunt, endoscopic ventriculostomy and central venous access are NOT considered major surgery.

What this study is about