Ribociclib (LEE011) in Preoperative Glioma and Meningioma Patients
900 mg/d is the maximally tolerated dose (MTD), as determined in a recent Novartis-sponsored Phase I study for advanced solid tumor patients. The recommended dose expansion and Phase 2 is 600mg/d for 3 weeks on and 1 week off. Due to drug pharmacokinetics, the MTD (900mg) dose will be used for pre-surgical dosing in order to maximize the opportunity to identify relevant tumor pharmacokinetic and pharmacodynamics endpoints.
To assess the PK, PD, and PG endpoints listed above, CSF and brain tumor tissue will be collected intraoperatively (for gliomas, enhancing and non-enhancing tumor tissue will be collected and analyzed separately). Additionally, blood samples will be obtained at 0.5, 1, 2, 4, 6, 8, and 24 hours after the final ribociclib dose is administered.
Patients with tumors demonstrating positive PK, PD, and PG effects will continue treatment with ribociclib (21 days on, 7 days off) 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 and high-grade meningiomas treated with ribociclib 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 and high-grade meningiomas treated with ribociclib will be assessed by medical record review and survival follow up. Common Toxicity Criteria Adverse Event (CTC AE 4.0) will be utilized to review ribociclib treatment effects in patients with brain tumors. The trough plasma samples of ribociclib will be collected at pre-dosing on each clinical visit day (e.g., days 1, 22, 43, 64…) prior to the administration of ceritinib on that day. Ribociclib will be administered in the clinics on the clinic visit days to ensure the collection of trough level samples.