Ribociclib (LEE011) in Preoperative Glioma and Meningioma Patients

Inclusion Criteria

• One prior resection of histologically-diagnosed World Health Organization (WHO)Grade III or IV glioma, or WHO grade II or III meningioma.

• MRI evidence of disease recurrence

• For gliomas, archival tissue must demonstrate: (a) RB positivity onimmunohistochemistry OR no RB mutations on next-gen sequencing (NGS), (b) Chromosome 9p21.3 deletion on FISH OR CDKN2A/B/C loss on array CGH OR CDK4/6 or CCND1/2amplification on array CGH.

• For meningiomas, archival tissue much demonstrate (a) RB positivity onimmunohistochemistry OR no RB mutations on next-gen sequencing (NGS).

• Eastern Cooperative Oncology Group (ECOG) performance status ≤2

• Patients ≥ 18 years of age

• Ability to understand and the willingness to sign a written informed consentdocument (personally or by the legally authorized representative, if applicable).

• Patient has voluntarily agreed to participate by giving written informed consent (personally or via legally-authorized representative(s), and assent if applicable).

(Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.)

• Patients must have recovered from all toxicities related to prior anticancertherapies to ≤ grade 2 (CTCAE v 4.03), provided that concomitant medication is givenprior to initiation of treatment with ribociclib. Exception to this criterion:patients with any grade of alopecia are allowed to enter the treatment.

• The following laboratory criteria have been met:

• Absolute neutrophil count (ANC) ≥1.5 x 109/L

• Hemoglobin (Hgb) ≥ 9 g/dL

• Platelets ≥100 x 10^9/L

• Potassium, total calcium (corrected for serum albumin), magnesium, and sodiumwithin normal limits for the institution or corrected to within normal limitswith supplements before first dose of study medication.

• INR ≤1.5

• Serum creatinine < 1.5 mg/dL or creatinine clearance ≥ 50 mL/min

• In the absence of liver metastases, alanine aminotransferase (ALT) andaspartate aminotransferase (AST) < 2.5 x ULN.

• Serum total bilirubin < ULN, or < 3.0 x ULN in patients with well-documentedGilbert's syndrome.

• Patient with available standard 12-lead ECG with the following parameters atscreening (defined as the mean of the ECGs):

• QTcF interval at screening < 450 msec (using Fridericia's correction)

• Resting heartrate 50-90 bpm

• Must be able to swallow ribociclib capsules/tablets

• If patient is receiving tamoxifen or toremifene, a washout period of 5 half-livesprior to enrollment is required

Exclusion Criteria:

• Archival tissue not available for research use.

• Archival tumor not Rb-positive status

• No prior radiotherapy

• Co-morbid condition(s) that, at the opinion of the investigator, prevent safesurgical treatment

• Active infection or fever > 38.5°C

• Patients with known hypersensitivity to any of the excipients of ribociclib

• Patients with known hypersensitivity to peanut, soy or lactose

• Prior therapy with ribociclib.

• Patient has a concurrent malignancy or malignancy within 3 years prior to startingstudy drug, with the exception of adequately treated, basal or squamous cellcarcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.

• Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of the study drugs (e.g., ulcerative diseases, uncontrollednausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

• History of HIV infection (testing not mandatory).

• Other concurrent severe and/or uncontrolled medical condition that would, in theinvestigator's judgment, cause unacceptable safety risks, contraindicate patientparticipation in the clinical study or compromise compliance with the protocol.

• Clinically significant, uncontrolled heart disease and/or cardiac repolarizationabnormalities.

• History of acute coronary syndromes (including myocardial infarction, unstableangina, coronary artery bypass grafting, coronary angioplasty, or stenting) orsymptomatic pericarditis within 6 months prior to screening

• History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV)

• Documented cardiomyopathy

• Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gatedacquisition (MUGA) scan or echocardiogram (ECHO) at screening

• Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia),complete left bundle branch block, high-grade AV block (e.g. bifascicularblock, Mobitz type II and third-degree AV block)

• Long QT syndrome or family history of idiopathic sudden death or congenitallong QT syndrome, or any of the following:

• Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia orhypomagnesemia, history of cardiac failure, or history of clinicallysignificant/symptomatic bradycardia.

• Concomitant use of medication(s) with a known risk to prolong the QT intervaland/or known to cause Torsades de Pointe that cannot be discontinued (within 5half-lives or 7 days prior to starting study drug) or replaced by safealternative medication

• Inability to determine the QT interval on screening (QTcF, using Fridericia'scorrection)

• Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening

• Currently receiving any of the following medications and cannot be discontinued 7days prior to starting study drug:

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

• That have a narrow therapeutic window and are predominantly metabolized throughCYP3A4/5

• Herbal preparations/medications, dietary supplements known as strong inhibitorsor inducers of CYP3A4 or those with a known risk of QT prolongation. (Does notinclude Ca, Mg, Vit D or KCl supplements).

• Currently receiving warfarin or other coumarin-derived anticoagulant for treatment,prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH)or fondaparinux is allowed.

• Participation in a prior investigational study within 30 days prior to enrollment orwithin 5 half-lives of the investigational product, whichever is longer.

• Major surgery within 14 days prior to starting study drug or has not recovered frommajor side effects (tumor biopsy is not considered as major surgery).

• Has not recovered from all toxicities related to prior anticancer therapies toNCI-CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with grade 1taxane-induced neuropathy, any grade of alopecia, amenorrhea or other toxicities notconsidered a safety risk for the patient as per investigator's discretion, areallowed to enter the study.).

• Child-Pugh score B or C.

• History of non-compliance to medical regimen.

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of afemale after conception and until the termination of gestation, confirmed by apositive hCG laboratory test.]

• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionduring dosing and for 3 months after the last dose of study treatment. Highlyeffective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy) or tubal ligation at least six weeks before taking studytreatment. In case of oophorectomy alone, only when the reproductive status ofthe woman has been confirmed by follow up hormone level assessment.

• Male sterilization (at least 6 months prior to screening) with the appropriatepost-vasectomy documentation of the absence of sperm in the ejaculate. Forfemale subjects on the study the vasectomized male partner should be the solepartner for that subject.

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS), orother forms of hormonal contraception that have comparable efficacy (failurerate <1%), for example hormone vaginal ring or transdermal hormonecontraception.

• In case of use of oral contraception, women should have been stable on the samepill for a minimum of 3 months before taking study treatment.

• Note: Oral contraceptives are allowed but should be used in conjunction with abarrier method of contraception due to unknown effect of drug-drug interaction.

• Women are considered post-menopausal and not of child bearing potential if they havehad 12 months of natural (spontaneous) amenorrhea with an appropriate clinicalprofile (e.g. age appropriate history of vasomotor symptoms) or have had surgicalbilateral oophorectomy (with or without hysterectomy) or tubal ligation at least sixweeks ago. In the case of oophorectomy alone, only when the reproductive status ofthe woman has been confirmed by follow up hormone level assessment is she considerednot of child bearing potential.

• Sexually active males unless they use a condom during intercourse while taking drugand for 21 days after stopping treatment and should not father a child in thisperiod. A condom is required to be used also by vasectomized men in order to preventdelivery of the drug via seminal fluid.