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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
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Camilo E. Fadul, MD, University of Virginia

Brief Summary:
This is a single-institution, open-label, early-phase study to assess the ability of ribociclib (LEE011) to inhibit CDK4/CDK6/Rb/E2F signaling and cell proliferation/viability in core and infiltrating tumor tissues obtained from patients with recurrent glioblastoma or anaplastic glioma compared to the baseline/primary pathologic tumor specimen. Abundant preclinical evidence indicates that Rb-deficient cancer cells are resistant to CDK4/6 inhibition and ongoing trials with CDK4/6 inhibitors exclude patients with Rb-deficient tumors. The investigators will evaluate 10 patients with Rb-positive glioblastoma or anaplastic glioma in this study. Given that a minority of glioblastomas ha Rb loss the investigators anticipate enrolling a maximum of 20 patients, to meet our goal of 10 patients with Rb-positive tumors.

Condition or disease Intervention/treatment Phase
Glioblastoma Glioma Drug: Ribociclib Phase 1

Detailed Description:

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)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

Drug Information available for: Ribociclib

Arm Intervention/treatment
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.
Drug: Ribociclib
CDK4/6 INHIBITOR
Other Name: LEE011




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.


  2. 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.


  3. 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.

  4. 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.

  5. 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.


Other Outcome Measures:
  1. 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.

  2. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Written informed consent must be obtained prior to any screening procedures
  • Patients age 18-85 are eligible for study participation
  • History of grade III or IV glioma (GBM or AG) with archived FFPE and/or frozen tumor tissue available
  • Patient must be a candidate for surgical resection of recurrent high-grade glioma
  • Karnofsky Performance Scale score ≥ 70.
  • Life expectancy of 4 months or longer.
  • Received at least 1 prior systemic therapy for glioma.
  • A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy (including cytotoxic and biological therapies and major surgery) and enrollment, to allow the effects of prior therapy to have abated
  • Patients must have adequate organ function
  • For continued ribociclib treatment after surgery, immunohistochemical (IHC) confirmation of Rb expression in ≥50% of malignant tumors cells in at least 1 tumor specimen is

Exclusion criteria:

  • Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of ribociclib such as patients with a history of GI surgery which may result in intestinal blind loops and patients with clinically significant gastroparesis, unresolved nausea, vomiting, or diarrhea of CTCAE grade > 1
  • Impaired cardiac function or clinically significant cardiac diseases
  • Patients who are currently receiving treatment (within 5 days prior to starting study drug) with agents that are metabolized predominantly through CYP3A4 and that have a narrow therapeutic window. Agents including vitamins, supplements, and herbal supplements that are either (i) metabolized solely through CYP3A4/5, CYP1A2 or BSEP and have a narrow therapeutic window or (ii) are strong inhibitors of CYP3A4/5, CYP1A2 or BSEP. Agents that are known strong inducers or inhibitors CYP3A4 are prohibited. Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and for 7 days before the first dose.
  • Patients with concurrent severe and/or uncontrolled concurrent medical conditions that the investigator believes could compromise participation in the study (e.g., uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection)
  • Pregnant or 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 (> 5 mIU/mL).
  • Women of childbearing potential, defined as all women physically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception must be used by both sexes (female patients and their male partners) during study treatment and for 30 days after the last dose of study medication
  • Fertile males must be willing to use contraception. Fertile males must use condom with spermicide (double barrier method). Effective contraception, as defined above, must be used by both sexes (male patients and their female partners) during study treatment and for 30 days after the last dose of study medication. A condom is required to be used by vasectomized men in order to prevent delivery of the study drug via seminal fluid.
  • Patients unwilling or unable to comply with the protocol
  • Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not mandatory)

Information from the National Library of Medicine

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


Locations
United States, Virginia
University of Virginia Health System
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
University of Virginia
Novartis Pharmaceuticals
Investigators
Principal Investigator: Camilo Fadul, MD University of Virginia

Responsible Party: Camilo E. Fadul, MD, Professor, University of Virginia
ClinicalTrials.gov Identifier: NCT02345824     History of Changes
Other Study ID Numbers: D13223
18729 ( Other Identifier: IRB )
First Posted: January 26, 2015    Key Record Dates
Last Update Posted: June 7, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Camilo E. Fadul, MD, University of Virginia:
CDK4/6 Inhibitor
LEE011
Recurrent Glioblastoma
Anaplastic Glioma
Ribociclib

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue