Ribociclib and Everolimus for Glioblastoma Multiforme

All patients will receive ribociclib 400 mg and everolimus 2.5 mg (R2P2D) orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:

• Cohort 1: last ribociclib+everolimus dose 2 to 4 hours prior to craniotomy for tumor resection (n=8 patients)
• Cohort 2: last ribociclib+everolimus dose 8 to 10 hours prior to craniotomy for tumor resection (n=8 patients)
• Cohort 3: last ribociclib+everolimus dose 24 to 26 hours prior to craniotomy for tumor resection (n=8 patients) To assess the PK and PD endpoints listed above, blood, CSF and brain tumor tissue will be collected intraoperatively (enhancing and non-enhancing tumor tissue will be collected and analyzed separately). Additionally, blood samples will be obtained on Day 4 (the day before the surgery for Cohorts 1 & 2; 2 days before surgery for Cohort 3) at pre-dosing (trough level), 0.5, 1, 2, 4, 7 hours post dose. A pre-dosing (trough level) blood sample will also be obtained on Day 5.

Patients with tumors demonstrating favorable PK and PD will continue treatment with RP2D continuously in 28d cycles after surgery. This will constitute the Phase II component of the study. Patients will be treated until unacceptable toxicity is observed, or until disease progression as assessed by radiographic or clinical metrics. Preliminary rates of progression-free survival in patients with high-grade gliomas treated with ribociclib+everolimus will be measured through radiographic and clinical response metrics, specifically Response Assessment in Neuro-Oncology (RANO) criteria and investigator discretion. Overall survival in patients with high-grade gliomas treated with ribociclib+everolimus will be assessed by medical record review and survival follow up. Common Toxicity Criteria Adverse Event (CTC AE 4.03) will be utilized to review ribociclib+everolimus treatment effects in patients with brain tumors.

In Phase II portion, trough steady-state blood samples will be obtained on days 1, 8, 15, and 22 of each cycle prior to the administration of ribociclib+everolimus on that day. Note: ribociclib+everolimus will be administered in the clinics on the clinic visit days to ensure the collection of trough level samples.