Early-Phase Study to Assess Inhibitor Ribociclib in Patients With Recurrent Glioblastoma or Anaplastic Glioma
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|ClinicalTrials.gov Identifier: NCT02345824|
Recruitment Status : Active, not recruiting
First Posted : January 26, 2015
Last Update Posted : June 7, 2018
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma Glioma||Drug: Ribociclib||Phase 1|
Preliminary evaluation of efficacy and determination of the ribociclib safety profile in patients with brain tumors will be studied. All patients will be treated with ribociclib (600 mg/day) for 8-21 days before surgical resection of the recurrent tumor. Rb status of the recurrent tumor will be determined by immunohistochemistry within 2 weeks after surgery. Patients with Rb-positive tumors will continue treatment with ribociclib (21 days on, 7 days off) after surgery. Patients will be treated until unacceptable toxicity is observed, or until disease progression as assessed by radiographic or clinical metrics. We will determine whether molecular markers associated with changes induced by ribociclib treatment in tumors (matching initial vs. recurrent tumors) correlate with progression-free survival.
Approximately 20% of patients with recurrent high-grade glioma will undergo surgical resection of their tumor typically at the time of first recurrence. These patients will be eligible for this study. An extra 10 mL of blood will be collected during a routine clinical procedure prior to initiation of ribociclib treatment (i.e., baseline blood sample), separated into plasma and buffy coat fractions, and frozen for pharmacokinetic (PK) analysis. Patients will be treated with ribociclib for 8-21 days prior to surgery to identify drug effects on tumor cells, and to determine drug PK. The last presurgical dose of ribociclib will be administered on the day of surgery at 4-8 hours prior to surgery to allow sufficient time for the drug to enter tumor cells, inhibit CDK4/6, and modulate downstream effectors. Blood will be acquired within 1 hour before surgery (as close to the time of surgery as possible). Blood will be separated into plasma and buffy coat fractions, and frozen. During surgery, samples of brain tumor core and infiltrating brain tumor will be acquired. Tissue samples will be frozen or fixed in paraffin embedded blocks and histology for PK and molecular analyses.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||3 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Early-Phase Study to Assess Tumor Pharmacokinetics and Efficacy of the CDK4/6 Inhibitor Ribociclib (LEE011) in Patients With Recurrent Glioblastoma or Anaplastic Glioma|
|Study Start Date :||March 2016|
|Estimated Primary Completion Date :||September 2019|
|Estimated Study Completion Date :||January 2020|
Experimental: Ribociclib (LEE011) Treatment
Patients will be treated with ribociclib (LEE011) (recommended phase 2 dose of 600 mg/day) for 8-21 days prior to surgery. For preliminary evaluation of efficacy and toxicity, patients with Rb-positive tumors will resume treatment with ribociclib at 14-28 days post-surgery on a schedule of 21 days on, 7 days off in a 28-day cycle. Patients will be treated until unacceptable toxicity is observed, or until disease progression as assessed by radiographic or clinical metrics.
Other Name: LEE011
- Inhibition of CDK4/CDK6 Signaling Pathway in Cell Proliferation [ Time Frame: an expected average of 1 year to allow laboratory quality assessment of tumor proliferation ]Levels of phospho-Rb in tumor cells, the fraction of Ki67-positive tumor cells, and the fraction of TUNEL-positive tumor cells in primary (baseline) vs. recurrent (post-LEE011) tumor samples will be assessed via laboratory practices as a means of studying Inhibition of CDK4/CDK6 Signaling Pathway in Cell Proliferation.
- Ribociclib Concentration in Tissues [ Time Frame: 1 Day Collection as the time of initial surgery ]
Concentrations of ribociclib will be gathered from tumor core and infiltrating tumor tissue which is gathered at the time of initial surgery for the removal of the patients tumor.
This will be completed to assess whether ribociclib treatment induces changes in brain tumor cell fate (proliferation, apoptosis, senescence) and E2F activation. Biomarkers will be compared in ribociclib-treated recurrent tumors vs. matching baseline tumors vs. archived recurrent tumors from other patients.
Laboratory will assess the frequencies of Rb mutations and loss in primary and recurrent brain tumors.
- Ribociclib Concentration in Plasma [ Time Frame: time of Pharmacokinetic draws ]
Concentrations of ribociclib in blood plasma will be gathered through pharmacokinetic draws at specified time points throughout study participation and will be used to assist in the assessment of whether ribociclib treatment induces changes in brain tumor cell fate (proliferation, apoptosis, senescence) and E2F activation. Biomarkers will be compared in ribociclib-treated recurrent tumors vs. matching baseline tumors vs. archived recurrent tumors from other patients.
To determine the frequencies of Rb mutations and loss in primary and recurrent brain tumors.
- Tumor Progression [ Time Frame: Over 1 year, which is expected average length of participation per patient ]Preliminary rates of progression-free survival in patients with high-grade gliomas treated with ribociclib will be measured through radiographic and clinical response metrics, specifically Response Assessment in Neuro-Oncology (RANO) criteria and investigator discretion.
- Survival Outcomes [ Time Frame: Over 1 year, which is expected average length of participation per patient ]Overall survival in patients with high-grade gliomas treated with ribociclib will be assessed by medical record review and survival follow up.
- Ribociclib Safety Profile [ Time Frame: 30 days post last dose of LEE011 per patient ]Common Toxicity Criteria Adverse Event (CTCAE 4.0) will be utilized to review ribociclib treatment effects in patients with brain tumors.
- Identifying Treatment Induced Changes in Oncogenic Pathways [ Time Frame: Over 1 year, which is expected average length of participation per patient ]To identify treatment-induced changes in compensatory oncogenic pathways that may promote drug resistance, through the use of reverse-phase protein array analysis of tumor samples.
- Ribociclib Concentrations in Cerebrospinal Fluid (CSF) [ Time Frame: 1 Day Collection as the time of initial surgery ]Cerebrospinal Fluid (CSF) obtained at the time of surgery and processed to assess the amount of ribociclib concentrations
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02345824
|United States, Virginia|
|University of Virginia Health System|
|Charlottesville, Virginia, United States, 22908|
|Principal Investigator:||Camilo Fadul, MD||University of Virginia|