Ribociclib and Everolimus Following Radiotherapy in Patients with High-Grade Glioma, and Diffuse Intrinsic Pontine Glioma, Harboring Cell Cycle and/or PI3K/mTOR Pathway Genetic Changes (A TarGeT Treatment Trial)

Inclusion Criteria

• CRITERIA TO ENROLL ON TarGeT-SCR (CENTRAL MOLECULAR AND HISTOPATHOLOGICAL SCREENING):
• Age: * Patients must be ≥12 months and ≤39 years of age at the time of enrollment on TarGeT-SCR * For the Part 1 Initial Feasibility Cohort only: patients must be <21 years of age at the time of enrollment onto TarGeT-A protocol
• Patients must have a body surface area (BSA) ≥ 0.45m^2
• Patients with newly-diagnosed HGG, including DIPG are eligible. All patients must have tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR: * For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse World Health Organization (WHO) grade 2-4 glioma * All other HGGs must be WHO grade 3 or 4
• There are no disease status requirements for enrollment * Measurable disease is not required. Patients without measurable disease are eligible * Metastatic/disseminated or multifocal disease or gliomatosis cerebri: Patients with metastatic or multifocal disease or gliomatosis cerebri who received upfront CSI are eligible as part of a feasibility cohort (Part 2: Stratum D) * Primary spinal tumor: Patients with a primary spinal HGG are eligible * Secondary/radiation-related HGG: Patients with secondary, radiation-related HGG are eligible
• TarGeT-A Part 1: Initial Feasibility Study for the combination of ribociclib PfOS formulation with everolimus: Enrollment on this cohort will be limited to patients aged <21 years with primary intracranial localized HGG and DIPG
• TarGeT-A Part 2: Phase 2 Study: * Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata C-D) * Stratum B: Patients with DIPG * Stratum C: Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG * Stratum D: Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received CSI
• CRITERIA FOR ASSIGNMENT TO TarGeT-A:
• Presence of at least one relevant actionable somatic alteration, detailed here: * Pathogenic alterations presumed to cause activation of cell cycle: ** Amplification of CDK4 or CDK6 ** Deletion of CDKN2A, CDKN2B, or CDKN2C ** Amplification of CCND1 or CCND2 * Pathogenic alterations presumed to cause activation of the PI3K/mTOR pathway: ** Deletion or mutation of PTEN ** Mutation or amplification of PIK3CA ** Mutation of PIK3R1 * Patients with evidence of homozygous (biallelic) RB1 loss by sequencing are excluded from this treatment protocol (TarGeT-A) * Patients whose tumors harbor other alterations suspected to activate the cell cycle and/or PI3K/mTOR pathway could potentially also be eligible, but only following consensus recommendation by the international multidisciplinary molecular screening committee
• Karnofsky ≥ 50% for patients > 16 years of age and 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 for HGG: * Surgery, radiation, and/or dexamethasone are permissible. Temozolomide administered concurrently with radiotherapy is permissible, but discouraged. No other prior anticancer therapy for HGG will be allowed * Radiation therapy requirements: Patients must have received photon or proton radiation therapy (RT) * Timing between diagnosis and start of RT: Patients must have started RT within 31 calendar days of initial diagnosis (defined as the date of diagnostic biopsy or resection; if a patient underwent two upfront surgeries [e.g., biopsy then resection or debulking], this is the date of the second surgery) * Radiotherapy, delivered via photon or proton beam, must have been administered a standard dose including (54 Gy in 30 fractions for DIPG, 59.4 Gy in 33 fractions or 54-60 Gy in 30 fractions for other HGG), 45 Gy-50.4 Gy for primary spinal disease, and/or 36 Gy-39.6 Gy craniospinal for patients with spinal or leptomeningeal metastatic disease with supplemental boost to 45-54 Gy for metastasis within the thecal sac and 54 Gy-60 Gy for intracranial metastasis). Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the sponsor-investigator to confirm eligibility prior to study enrollment * Patients must enroll and start treatment on TarGeT-A no later than 35 calendar days post-completion of RT. The earliest patients can begin protocol treatment is 28 calendar days post-completion of RT
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (must be performed within 7 days prior to enrollment unless otherwise indicated)
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (must be performed within 7 days prior to enrollment unless otherwise indicated)
• Hemoglobin > 8 g/dL (may be transfused) (must be performed within 7 days prior to enrollment unless otherwise indicated)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2 OR serum creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment unless otherwise indicated): * 1 to < 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female) * 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female) * 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female) * 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female) * 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: Maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female) * The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the center for disease control [CDC])
• Total bilirubin must be ≤ 1.5 times institutional upper limit of normal for age (must be performed within 7 days prior to enrollment unless otherwise indicated)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) ≤ 3 times institutional upper limit of normal (must be performed within 7 days prior to enrollment unless otherwise indicated)
• Serum albumin ≥ 2g/dL (must be performed within 7 days prior to enrollment unless otherwise indicated)
• Left Ventricular Ejection fraction of ≥ 50% by echocardiogram
• Corrected QT Interval (QTc) ≤ 450 msec (by Bazett formula)
• Patients with seizure disorder may be enrolled if well-controlled on anticonvulsants that is not a strong inducer or inhibitor of CYP3A4/5
• No evidence of dyspnea at rest, and a pulse oximetry >94% on room air if there is clinical indication for determination
• Patients must be able to take both ribociclib and everolimus by mouth. Administration via nasogastric (NG)/nasojejunal (NJ)/gastrostomy (G)-tube is not allowed
• All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
• Male and female patients of childbearing potential must be willing to use a highly effective contraception method

Exclusion Criteria

• Pregnant or breast-feeding women will not be entered on this study due to known potential risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use at least one highly effective method of contraception, plus a barrier method of contraception (eg, condom), while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy. * Not engaging in sexual activity for the total duration of the drug treatment is acceptable; however, periodic abstinence, the rhythm method and the withdrawal method are not acceptable. A highly effective contraception method is defined as one that results in a low failure rate (<1% per year) when used consistently and correctly. The following are considered highly effective contraception methods: ** Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation ** Progesterone-only hormonal contraception associated with inhibition of ovulation ** Intra Uterine Device (IUD) ** Intra Uterine hormone releasing system ** Bilateral tubal occlusion ** Vasectomized partner ** Sexual abstinence (avoiding having heterosexual intercourse) * The following contraceptive measures are NOT considered effective ** Progesterone-only hormonal contraception (birth control pill) that that does NOT stop ovulation ** Male or female condom with or without spermicide ** Cap, diaphragm or sponge with spermicide * Hormonal contraception may be susceptible to interaction with the Investigational Medicinal Product, which may reduce the efficacy of the contraception method * Contraception methods that in the context of this guidance are considered to have low user dependency * Vasectomised partner is a highly effective birth control method, provided that the partner is the sole sexual partner of the woman considered to be of childbearing potential and that the vasectomised partner has received medical assessment of the surgical success * In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject * A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) are also considered acceptable, but not highly effective, birth control methods
• Concomitant Medications * Corticosteroids: Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported * Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible * Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible, with the exception of temozolomide given concurrently with RT only * Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants that are strong inducers or inhibitors of CYP3A4/5 are not eligible * Strong CYP3A4/5 inducers or inhibitors: Patients who are receiving strong inducers or inhibitors of CYP3A4/5 within 14 days of enrollment are not eligible * Patients who are receiving medications known to prolong QTc interval are not eligible * Anticoagulants: patients who are receiving therapeutic anticoagulation are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible
• Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible
• Patients with prior or ongoing clinically significant medical or psychiatric condition that, in the investigator’s opinion, could affect the safety of the subject, or could impair the assessment of study results are not eligible