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

NCT03834740 | Completed Early Phase 1 Results DMC FDA Drug

• 1 other identifier: 18-500-311-70-38
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 3

Brief Summary

In the proposed trial, patients will be administered ribociclib+everolimus prior to surgical resection of their tumor. Recurrent GBM patients will be randomized into one of the three time-interval cohorts for the first two dose levels. In the lead-in dose escalation study, the first six subjects (lead-in) will receive ribociclib 400 mg and everolimus 2.5 mg orally-administered in 5 daily doses with the last dose. If one or less patient experiences DLT among the 6 patients, this regimen with ribociclib 400 mg and everolimus 2.5mg will be considered safe and we will continue with the dose escalation phase of the study up to Level 3. Four dose escalation levels: Level 0: ribociclib 400mg and everolimus 2.5 Level 1: ribociclib 600mg and everolimus 2.5mg Level 2: ribociclib 600mg and everolimus 5mg Level 3: ribociclib 600mg and everolimus 10mg

Conditions

Glioblastoma Multiforme; Glioma of Brain

Keywords

recurrent GBM; brain tumor; GBM; glioma

Outcome Measures

Primary Outcomes (7)

• Maximum Tolerated Dose (MTD)

  Highest dose of each drug that did not cause a DLT in \>17% of participants

  From the date of the first dose given until the second documented DLT, assessed up to 24 months

• Pharmacokinetic Analysis - Total Ribociclib Concentration

  Total ribociclib concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis

  0-24 hours after the last dose

• Pharmacokinetic Analysis - Unbound Ribociclib Concentration

  Unbound ribociclib concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis

  0-24 hours after the last dose

• Pharmacokinetic Analysis - Total Everolimus Concentration

  Total everolimus concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis

  0-24 hours after the last dose

• Pharmacokinetic Analysis - Unbound Everolimus Concentration

  Unbound everolimus concentrations in non-enhancing and contrast-enhancing tumor tissue samples using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method and equilibrium dialysis

  0-24 hours after the last dose

• % Change of pRB+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue

  The percentage change of pRB positive cells in resected post-treatment recurrent GBM tumor tissue compared to baseline (archival primary GBM tumor tissue collected at screening). A positive PD effect is defined as \>30% decrease in pRB+ cells.

  Baseline, Intraoperatively

• % Change of pS6+ Cells in Resected Post-Treatment rGMB Tissue vs Baseline Tissue

  The percentage change of pS6 positive cells in resected post-treatment recurrent GBM tumor tissue compared to baseline (archival primary GBM tumor tissue collected at screening). A positive PD effect is defined as \>30% decrease in pS6+ cells.

  Baseline, Intraoperatively

Secondary Outcomes (3)

• Median Progression-Free Survival (PFS) in Phase 2 Participants

  From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

• Median Overall Survival (OS) in Phase 2 Participants

  From date of surgery to date of death from any cause, assessed up to 60 months

• Median Concentration of Trough Plasma Concentrations of Total Ribociclib and Total Everolimus in Phase 2 Participants

  From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Study Arms (3)

Cohort 1: last dose 1 to 3 hours prior to resection

EXPERIMENTAL

Three to fourteen patients will receive ribociclib and everolimus 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 1 to 3 hours prior to craniotomy for tumor resection

Drug: Ribociclib; Drug: Everolimus

Cohort 2: last dose 7 to 9 hours prior to resection

EXPERIMENTAL

Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection: • Cohort 2: last ribociclib+everolimus dose 7 to 9 hours prior to craniotomy for tumor resection

Drug: Ribociclib; Drug: Everolimus

Cohort 3: last dose 23 to 25 hours prior to resection

EXPERIMENTAL

Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection: • Cohort 3: last ribociclib+everolimus dose 23 to 25 hours prior to craniotomy for tumor resection

Drug: Ribociclib; Drug: Everolimus

Interventions

Ribociclib DRUG

Ribociclib administered orally in 5 daily doses prior to resection

Cohort 1: last dose 1 to 3 hours prior to resection; Cohort 2: last dose 7 to 9 hours prior to resection; Cohort 3: last dose 23 to 25 hours prior to resection

Everolimus DRUG

Everolimus administered orally in 5 daily doses prior to resection

Cohort 1: last dose 1 to 3 hours prior to resection; Cohort 2: last dose 7 to 9 hours prior to resection; Cohort 3: last dose 23 to 25 hours prior to resection

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Patients eligible must not meet any of the following criteria:
• Archival tissue is not available for research use or there is not a sufficient quantity available to confirm eligibility.
• Archival tumor is not Rb-positive status and mTOR-positive status
• Patient has not received prior radiotherapy
• Co-morbid condition(s) that, at the opinion of the investigator, prevent safe surgical treatment
• Active infection or fever \> 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 (Ellis, 1961) was irradiated
• Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

Sponsors & Collaborators

• St. Joseph's Hospital and Medical Center, Phoenix: lead
• Ivy Brain Tumor Center: collaborator
• Barrow Neurological Institute: collaborator

Study Sites (3)

Chandler Regional Medical Center

Chandler, Arizona, 85224, United States

Location

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

Location

HonorHealth Scottsdale Osborn Medical Center

Scottsdale, Arizona, 85251, United States

Location

Related Publications (2)

• Johnson KC, Tien AC, Jiang J, McNamara J, Chang YW, Montgomery C, DeSantis A, Elena-Sanchez L, Fujita Y, Kim S, Spitzer A, Gabriel P, Flynn WF, Courtois ET, Hong A, Harmon J, Umemura Y, Tovmasyan A, Li J, Mehta S, Verhaak RGW, Sanai N. Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma. Neuro Oncol. 2025 Nov 8:noaf257. doi: 10.1093/neuonc/noaf257. Online ahead of print.

  PMID: 41206763 DERIVED

• Johnson KC, Tien AC, Jiang J, McNamara J, Chang YW, Montgomery C, DeSantis A, Elena-Sanchez L, Fujita Y, Kim S, Spitzer A, Gabriel P, Flynn WF, Courtois ET, Hong A, Harmon J, Umemura Y, Tovmasyan A, Li J, Mehta S, Verhaak R, Sanai N. Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of combined CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma. medRxiv [Preprint]. 2024 Jun 7:2024.06.07.24308439. doi: 10.1101/2024.06.07.24308439.

  PMID: 38883740 DERIVED

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms; Glioma

Interventions

ribociclib; Everolimus

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Nader Sanai
• Organization: Ivy Brain Tumor Center

research@ivybraintumorcenter.org

602-406-8605

Study Officials

• Nader Sanai, MD

  Deputy Director of the Ivy Brain Tumor Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2019
• First Posted: February 8, 2019
• Study Start: January 19, 2019
• Primary Completion: February 18, 2022
• Study Completion: February 18, 2022
• Last Updated: May 30, 2025
• Results First Posted: May 30, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)