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

Completed · Early Phase 1

Conditions studied: Glioblastoma Multiforme, Glioma of Brain

In brief

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

Key facts

Study ID

NCT03834740

Run by

St. Joseph's Hospital and Medical Center, Phoenix

People needed

27

Starts

2019-01-19

Expected to finish

2022-02-18

Last updated by the study team

2025-05-30

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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
• 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)

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)
• 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).

Where it is running

• Chandler Regional Medical Center — Chandler, Arizona, United States
• St. Joseph's Hospital and Medical Center — Phoenix, Arizona, United States
• HonorHealth Scottsdale Osborn Medical Center — Scottsdale, Arizona, United States

Full record on ClinicalTrials.gov

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