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)

This is a phase I study to determine: 1) the MTD and/or the recommended phase II dose (RP2D)
of ribociclib and everolimus which can be safely administered during maintenance therapy for
up to 24 courses following completion of radiation therapy with newly diagnosed non-biopsied
DIPG and RB+ biopsied DIPG and HGG, 2) characterization of the pharmacokinetic profile of
ribociclib and everolimus as combination maintenance therapy following completion of
radiation therapy with newly diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG.

Patients with RB+ tumors and non-biopsied DIPG will receive standard radiation therapy prior
to enrollment followed by ribociclib and everolimus as maintenance therapy. Upon completion
of radiation therapy, a 2 - 4 week break will occur and then ribociclib will be given orally
daily for 21 days followed by a 7 day break every 28 days at 70% of the adult RP2D (300 mg)
in combination with everolimus at 80% of the adult RP2D (2.5 mg) given orally once daily
continuously for up to 24 courses. One course is equivalent to 28 days. Due to dosing
concerns with the limited dosing capsules (50 mg and 200 mg are only available), dose
escalations will have BSA restrictions to accommodate for variations from target doses and
BSA adjusted actual dose. Two intra-patient dose-de-escalations will be allowed if dose
limiting toxicities arise and may continue study treatment for up to 24 courses in the
absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- 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.

- BSA restrictions for patients ≤ 21 years of age at the time of study entry

- Patients enrolled on dose level -1 must have BSA≥0.55m2

- Patients enrolled on dose level 0* must have BSA≥0.75m2

- Patients enrolled on dose level 0 must have BSA≥0.55m2

- Patients enrolled on dose level 1 must have BSA≥0.75m2

- Patients enrolled on dose level 2 and 3 must have BSA≥ 0.45m2

- RB status Screening for RB applies to all patients with pre-trial tumor tissue except
for patients diagnosed with DIPG and bi-thalamic tumors who do not have available
tissue.

RB testing must be evaluated centrally at CCHMC prior to enrollment or report from CLIA
certified lab must be reviewed centrally 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 proved to be high grade gliomas
(such as anaplastic astrocytoma, glioblastoma, H3K27-mutant diffuse midline glioma or
diffuse astrocytoma) Or histologically-confirmed malignant glioma WHO II-IV "other than
above".

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. 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.

Patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not eligible.

- MRI of spine must be performed prior to enrollment if the treating physician suspects
disseminated disease as a baseline evaluation. If leptomeningeal disease develops post
radiation therapy and prior to enrollment, patients may be considered eligible if
craniospinal irradiation was not received prior to enrollment.

- 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 (focal to disease) and/or steroids (dexamethasone with goal to wean
dexamethasone throughout protocol therapy).

- 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 have begun 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

- All patients must have recovered from all acute RT-related toxicities to ≤ grade 2
prior to initiating the use of ribociclib and everolimus.

- 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 Women of child-bearing potential are defined as all women
physiologically capable of becoming pregnant, unless they are using highly effective
methods of contraception throughout the study and for 8 weeks after study drug
discontinuation.

- 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.

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, 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.