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Glioblastoma MultiformeEarly Phase 1NCT03834740

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

A Early Phase 1 study testing Ribociclib and Everolimus in people with Glioblastoma Multiforme and Glioma of Brain, run by St. Joseph's Hospital and Medical Center, Phoenix at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Glioblastoma Multiforme, Glioma of Brain
What is being tested?
Ribociclib and Everolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
27 participants
Where
3 sitesUnited States
Study dates
19 Jan 2019to 18 Feb 2022
Phase
Early Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 26Show fewer
  • 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 < 1.5 mg/dL
  • Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min.
  • In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN.
  • Serum total bilirubin <ULN, or < 3.0 x ULN in patients with well-documented Gilbert's syndrome.
  • Serum cholesterol < 300 mg/dL or < 7.75 mmol/L AND triclycerides < 2.5 x ULN (NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.)
  • QTcF interval at screening < 450 msec [using Fridericia's correction (formula = QT/(RR)0.33)]
  • Resting heart rate 50-90 bpm (may be repeated up to 2x)
  • Must be able to swallow ribociclib and everolimus capsules/tablets

Who cannot join

  • 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
Show all 51Show fewer
  • 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)
  • Patient has a known history of HIV infection (seropositivity; testing not mandatory)
  • Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
  • Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy as indicated by the medical history. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina pectoris, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening.
  • History of documented congestive heart failure (New York Heart Association functional classification III-IV).
  • Documented cardiomyopathy
  • Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (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. bifascicular block, Mobitz type II and third-degree AV block).
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
  • Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
  • Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication
  • Inability to determine the QT interval on screening (QTcF, using Fridericia's correction)
  • Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening (may be repeated up to 2x).
  • Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug (see Appendix 2 for details):
  • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, pomegranates or pomegranate juice and Seville oranges
  • That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
  • Herbal preparations/medications, dietary supplements known as strong inhibitors or inducers of CYP3A4 or those with a known risk of QT prolongation. (Does not include Ca, Mg, Vit D or KCl supplements)
  • Known strong inhibitors or inducers of P-gp
  • Patients taking ACE inhibitors
  • Patient is 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 or within 5 half-lives of the investigational product, whichever is longer
  • Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery)
  • Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 Grade ≤2 (Exception to this criterion: patients with any grade of alopecia and amenorrhea are allowed to enter the study)
  • Patient with a Child-Pugh score B or C
  • Patient has a history of non-compliance to medical regimen or inability to grant consent
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.]
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unwilling to use highly effective methods of contraception during dosing and for 3 months after the last dose of study treatment. Highly effective contraception methods include:
  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  • Male sterilization (at least 6 months prior to screening) with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. For female subjects on the study the vasectomized male partner should be the sole partner for that subject
  • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
  • In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment
  • Note: Oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
  • Sexually active males unwilling to use a condom during intercourse while taking drug and for 21 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Chandler Regional Medical Center

    Chandler, Arizona, 85224

  • St. Joseph's Hospital and Medical Center

    Phoenix, Arizona, 85013

  • HonorHealth Scottsdale Osborn Medical Center

    Scottsdale, Arizona, 85251

Other trials in United States

About this study

Official title: A Phase 0/I Study of Ribociclib (LEE011) in Combination With Everolimus in Preoperative Rb-Intact Recurrent High-Grade Glioma Patients Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration

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.

Read more

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

Being tested
Ribociclib, Everolimus
Keywords
recurrent GBM, brain tumor, GBM, glioma
Medical subject headings
Glioblastoma, Brain Neoplasms, Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RibociclibDrug

    Ribociclib administered orally in 5 daily doses prior to resection

  • EverolimusDrug

    Everolimus administered orally in 5 daily doses prior to resection

Study groups in NCT03834740
Study groupRoleWhat they receive
Cohort 1: last dose 1 to 3 hours prior to resectionExperimentalThree 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
Receives: Drug: Ribociclib; Drug: Everolimus
Cohort 2: last dose 7 to 9 hours prior to resectionExperimentalThree 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
Receives: Drug: Ribociclib; Drug: Everolimus
Cohort 3: last dose 23 to 25 hours prior to resectionExperimentalThree 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
Receives: Drug: Ribociclib; Drug: Everolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (MTD)

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

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

  2. 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

    Measured: 0-24 hours after the last dose

  3. 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

    Measured: 0-24 hours after the last dose

  4. 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

    Measured: 0-24 hours after the last dose

  5. 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

    Measured: 0-24 hours after the last dose

  6. % 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.

    Measured: Baseline, Intraoperatively

  7. % 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.

    Measured: Baseline, Intraoperatively

Secondary outcomes (3)

  1. 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

    Measured: 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

  2. Median Overall Survival (OS) in Phase 2 Participants

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

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

  3. 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

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Feb 2019
  2. Study start19 Jan 2019
  3. Primary completion18 Feb 2022
  4. Study completion18 Feb 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
27 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03834740
Sponsor's protocol ID
18-500-311-70-38
Status last verified
May 2025
First submitted
30 Jan 2019
Last updated
30 May 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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. 2026 Mar 1;28(3):659-671. doi: 10.1093/neuonc/noaf257.

    PubMed 41206763

  • 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.

    PubMed 38883740

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Ribociclib and Everolimus in people with Glioblastoma Multiforme and Glioma of Brain, run by St. Joseph's Hospital and Medical Center, Phoenix at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 51 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 May 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) (time frame: From the date of the first dose given until the second documented DLT, assessed up to 24 months). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03834740, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 May 2025.

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