A Phase 0/I Study of Ribociclib (LEE011) in Combination With Everolimus in Preoperative Recurrent High-Grade Glioma Patients Scheduled for Resection

Inclusion Criteria

• Prior resection of histologically-diagnosed WHO Grade III or IV glioma. A. Glioma patients who have progressed on or following standard (Stupp regimen) therapy, which included maximal surgical resection, temozolomide, and fractionated radiotherapy.
• Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-enhanced MRI.
• Subjects must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per RANO criteria.
• For gliomas, archival tissue must demonstrate: (a) RB positivity (≥20%) on immunohistochemistry OR no RB mutations on next-generation sequencing (NGS), (b) Chromosomal loss of CDKN2A/B/C OR CDK4/6 or CCND1/2 amplification on array CGH, (c) mTOR+: PTEN loss OR PIK3C2B or AKT3 amplification on aCGH OR mutations for PIK3CA or PIK3R1, or mTOR or PTEN mutations using rhAMP analysis or pS6 positivity on immunohistochemistry (≥10% for pS6). If mutations within the mTOR/PI3K pathways cannot be accurately detected due to poor tissue quality the enrollment criteria will be determined using RB and pS6 positivity.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Appendix 1)
• Patients ≥ 18 years of age
• Ability to understand and the willingness to sign a written informed consent document. (personally or by the legally authorized representative, if applicable).
• Patient has voluntarily agreed to participate by giving written informed consent.(personally or by the legally authorized representative, 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.)

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
• Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or patient has had a hysterectomy.
• Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility):

The following laboratory criteria have been met:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (recommended)
• Hemoglobin (Hgb) ≥ 9.0 g/dL
• Platelets ≥ 100 x 109/L
• Potassium, total calcium (corrected for serum albumin), magnesium, sodium, and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication.
• INR ≤1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug)
• Serum creatinine 38.5°C
• Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)
• Known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air)
• Active, bleeding diathesis
• Patients with known hypersensitivity to any of the excipients of ribociclib or mTOR inhibitors (sirolimus or everolimus), including peanut, soy and lactose
• Patients with a clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.
• Prior therapy with ribociclib or any CDK4/6 inhibitor (e.g. palbociclib, abemaciclib), or with everolimus
• Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to starting study drug, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion) and/or in whom ≥25% of the bone marrow (El