GlioblastomaPhase 1NCT02345824
Early-Phase Study to Assess Inhibitor Ribociclib in Patients With Recurrent Glioblastoma or Anaplastic Glioma
A Phase 1 study testing Ribociclib in people with Glioblastoma and Glioma, run by University of Virginia at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 85 years
- Conditions the study is for
- Glioblastoma, Glioma
- What is being tested?
- Ribociclib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2016to Jan 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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
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- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Virginia Health System
Charlottesville, Virginia, 22908
About this study
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
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.
Read the 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.
- Conditions
- Glioblastoma, Glioma
- Being tested
- Ribociclib
- Keywords
- CDK4/6 Inhibitor, LEE011, Recurrent Glioblastoma, Anaplastic Glioma, Ribociclib
- Medical subject headings
- Glioblastoma, Glioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RibociclibDrug
Also called LEE011
CDK4/6 INHIBITOR
| Study group | Role | What they receive |
|---|---|---|
| Ribociclib (LEE011) Treatment | Experimental | 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. Receives: Drug: Ribociclib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Inhibition of CDK4/CDK6 Signaling Pathway in Cell 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.
Measured: an expected average of 1 year to allow laboratory quality assessment of tumor proliferation
Secondary outcomes (5)
Ribociclib Concentration in Tissues
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.
Measured: 1 Day Collection as the time of initial surgery
Ribociclib Concentration in Plasma
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.
Measured: time of Pharmacokinetic draws
Tumor Progression
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.
Measured: Over 1 year, which is expected average length of participation per patient
Survival Outcomes
Overall survival in patients with high-grade gliomas treated with ribociclib will be assessed by medical record review and survival follow up.
Measured: Over 1 year, which is expected average length of participation per patient
Ribociclib Safety Profile
Common Toxicity Criteria Adverse Event (CTCAE 4.0) will be utilized to review ribociclib treatment effects in patients with brain tumors.
Measured: 30 days post last dose of LEE011 per patient
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jan 2015 (estimated)
- Study startMar 2016
- Primary completionSep 2019 (estimated)
- Study completionJan 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for GlioblastomaStudies of the same condition, open and under way.
- More trials run by University of VirginiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Virginia
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Responsible party
- Principal investigator, Camilo E. Fadul, MD, University of Virginia
- Investigators
- Camilo Fadul, MD, Principal investigator, University of Virginia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02345824
- Sponsor's protocol ID
- D13223
- Other IDs
- 18729
- Status last verified
- Jun 2018
- First submitted
- 2 Jan 2015
- Last updated
- 7 Jun 2018
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Miller TW, Traphagen NA, Li J, Lewis LD, Lopes B, Asthagiri A, Loomba J, De Jong J, Schiff D, Patel SH, Purow BW, Fadul CE. Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma. J Neurooncol. 2019 Sep;144(3):563-572. doi: 10.1007/s11060-019-03258-0. Epub 2019 Aug 9.
PubMed 31399936
Study at a glance
From the registry record, last updated by the sponsor on 7 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02345824
- Acronym / sponsor ID
- D13223
- Conditions
- Glioblastoma, Glioma
- Keywords
- CDK4/6 Inhibitor, LEE011, Recurrent Glioblastoma, Anaplastic Glioma, Ribociclib
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 3 participants (actual)
- Lead sponsor
- University of VirginiaUniversity, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Study start
- Mar 2016
- Primary completion
- Sep 2019 (estimated)
- Study completion
- Jan 2020 (estimated)
- First posted
- 26 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Ribociclib (LEE011) Treatment | Experimental | Drug: RibociclibPatients 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. |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (9 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RibociclibAlso: LEE011CDK4/6 INHIBITOR | Drug | Ribociclib (LEE011) Treatment |
Primary outcome
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.
5 secondary outcomes
Ribociclib Concentration in Tissues
Time frame: 1 Day Collection as the time of initial surgery
Ribociclib Concentration in Plasma
Time frame: time of Pharmacokinetic draws
Tumor Progression
Time frame: Over 1 year, which is expected average length of participation per patient
Survival Outcomes
Time frame: Over 1 year, which is expected average length of participation per patient
Ribociclib Safety Profile
Time frame: 30 days post last dose of LEE011 per patient
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jun 2018.
- Derived from this study: PubMed 31399936Miller TW, Traphagen NA, Li J, Lewis LD, Lopes B, Asthagiri A, Loomba J, De Jong J, Schiff D, Patel SH, Purow BW, Fadul CE. Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma. J Neurooncol. 2019 Sep;144(3):563-572. doi: 10.1007/s11060-019-03258-0. Epub 2019 Aug 9.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Camilo Fadul, MD principal investigator
University of Virginia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ribociclib in people with Glioblastoma and Glioma, run by University of Virginia at 1 site 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 10 inclusion and 9 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: status not confirmed, as of the sponsor's last update on 7 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
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?
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). 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 NCT02345824, which also lists 1 linked publication.
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 7 Jun 2018.