Back to resultsPhase 1/2 Study of Enzastaurin in Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma (GS) Patients
Primary Purpose
Glioblastoma, Glioblastoma Multiforme, Gliosarcoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
enzastaurin
temozolomide
radiation therapy
Sponsored by
About this trial
This is an interventional treatment trial for Glioblastoma
Eligibility Criteria
Inclusion Criteria:
- Patients must have a histologically confirmed diagnosis of intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS).
- Biopsy or resection must have been performed no more than 5 weeks prior to treatment.
- An MRI or CT scan must be obtained within 14 days prior to treatment.
- Patients must not have received prior drug therapy for brain tumors.
- Patients must have adequate organ function demonstrated by lab tests within 14 days prior to treatment.
Exclusion Criteria:
- Patients will be excluded if unable to swallow tablets.
- Patients will be excluded if unable to discontinue use of enzyme inducing antiepileptic drugs or have been off of these agents less than 2 weeks prior to treatment (i.e. phenytoin (Dilantin®), carbamazepine, etc.).
- Patients will be excluded if have active infection.
- Patients will be excluded if have a significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.
- Patients will be excluded if they have concurrent therapy with an anticoagulant. If the patient requires anticoagulant therapy after starting treatment, the patient may remain on study but should be monitored carefully.
Sites / Locations
- For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559), Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
A
Arm Description
The Phase 1 consisted of the dose escalation of enzastaurin in 2 cohorts of up to 6 patients to assess maximum tolerated dose (MTD). Cohort 1 = radiotherapy/enzastaurin 250 mg per day/temozolomide 75 mg/m^2 therapy. The 6 initial cohort patients were clinically evaluated for dose-limiting toxicities (DLT). If no more than 1 of 6 patients experienced a DLT or tumor progression, patients continued 1 complete adjuvant enzastaurin/temozolomide 28-day cycle. If there was no significant toxicity after the first adjuvant cycle, participants received subsequent adjuvant enzastaurin/temozolomide cycles. If no more than 1 of the 6 initial cohort participants treated at 250 mg of enzastaurin experienced a DLT during radiotherapy and the first adjuvant cycle, up to 6 more participants could be entered at 500 mg of enzastaurin. The Phase 2, using the MTD determined in the Phase 1 (250 mg), evaluated the combination's safety and measured OS.
Outcomes
Primary Outcome Measures
Phase 1- Determination of the Maximum Tolerated Dose (MTD) of Enzastaurin
Phase 1- dose escalation of enzastaurin in 2 cohorts up to 6 participants each in order to assess MTD. After radiation/enzastaurin 250 mg per day/temozolomide 75 mg/m^2 therapy, if no more than 1 of 6 patients experienced a dose-limiting toxicity (DLT) or tumor progression, participants completed one 28-day cycle. If no significant toxicity after the first cycle, participants received subsequent cycles. If no more than 1 of the 6 patients treated at 250 mg of enzastaurin experienced a DLT, up to 6 more patients could be entered at escalated dose cohort of enzastaurin (500 mg).
Phase 1 and Phase 2 - Overall Survival (OS)
OS is the time from surgical diagnosis to the date of death from any cause. For participants who were alive, OS was censored at the last contact.
Secondary Outcome Measures
Phase 1 - Number of Participants With Adverse Events (AEs)
Summaries of serious AEs (SAEs) and all other non-serious AEs are located in the Reported Adverse Event Module.
Phase 1 and 2: Association Between Biomarkers and Clinical Outcome
Phosphorylated-S6 (pS6) ribosomal protein is a biomarker that's being investigated as a potential marker for clinical outcome using 2211 or 2215 antibody to pS6. Reported here are the hazard ratios and 95% confidence intervals (CIs) for participants for whom an pS6 immunohistochemistry (IHC) score was available. The IHC assays were scored using a 0 to +3 scoring system (no positive staining was scored 0; at least 25% immunoreactivity of cells was scored +1; 26% to 75% was scored +2; and 76% or greater was scored +3). Hazard ratio (HR) > 1 indicates worse outcome for that IHC score.
Phase 1 - Response Rate With Macdonald Criteria
Response categories: complete response (CR): disappearance of all enhancing tumor on consecutive magnetic resonance imaging (MRI) scans at least 1 month apart, off steroids, and neurologically stable or improved. Partial response (PR): 50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, and neurologically stable or improved. Progressive disease (PD): >25% increase in size of enhancing tumor or any new tumor on MRI scans, or neurologically worse, and steroids stable or increased. Stable disease (SD): all other situations.
Phase 2 - Number of Participants With Adverse Events (AEs)
Summaries of serious AEs (SAEs) and all other non-serious AEs are located in the Reported Adverse Event Module.
Number of Participants Undergoing Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy (MRI/MRS) for Clinical Evaluation at Baseline
Number of patients having MRI/MRS for clinical evaluation with baseline assessment.
Phase 1 and 2 - Progression-Free Survival (PFS)
PFS was defined as the time from date of first dose to the first observation of disease progression, or death due to any cause.
Functional Assessment of Cancer Therapy - Brain (FACT-Br)
Total FACT-Br score includes physical well-being, social/family well-being, emotional well-being, functional well-being and additional concerns related to brain tumors. The score ranges 0 to 200, with a higher score representing better quality of life.
M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT)
General and brain tumor-specific symptoms each assessed on a scale of 0 to 10, with a higher score representing higher symptom burden. The 4 symptom scales reported as changing over the course of the study are listed here.
Phase 1- Pharmacokinetics (PK): Maximum Observed Drug Concentration During 1 Dosing Interval at Steady State (Cmax,ss) for Enzastaurin, LY326020, and Total Analyte (Enzastaurin + LY326020) When Enzastaurin Administered With or Without Temozolomide
Cmax,ss was calculated using concentration versus time data of enzastaurin, LY326020, and Total Analyte (enzastaurin + LY326020) when 250 mg or 500 mg enzastaurin was administered alone or with 75 mg/m^2 temozolomide. Data are reported as Geometric Mean and Geometric Coefficient of Variation (%).
Phase 1 and 2- Pharmacokinetics: Area Under the Concentration-Time Curve During 1 Dosing Interval at Steady State (AUCτ,ss) for Enzastaurin, LY326020 and Total Analyte (Enzastaurin + LY326020) When Enzastaurin Administered With or Without Temozolomide
AUCτ,ss was calculated using concentration versus time data of enzastaurin, LY326020, and total analyte (enzastaurin + LY326020). Data are reported as Geometric Mean and Geometric Coefficient of Variation (%).
Full Information
NCT ID
NCT00402116
First Posted
November 17, 2006
Last Updated
July 23, 2020
Sponsor
Eli Lilly and Company
Collaborators
University of California, San Francisco
1. Study Identification
Unique Protocol Identification Number
NCT00402116
Brief Title
Phase 1/2 Study of Enzastaurin in Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma (GS) Patients
Official Title
Phase 1/2 Study of Enzastaurin Plus Temozolomide During and Following Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma
Study Type
Interventional
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
September 2006 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
December 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eli Lilly and Company
Collaborators
University of California, San Francisco
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
There will be 2 phases in this study. Patients will either be enrolled to the first phase or to the second phase, depending upon when they enroll into the study.
The first phase of this study is done to evaluate the safety of enzastaurin in patients. This is done by gradually increasing the dose of the drug in small groups of patients and watching closely for side effects.
In the second phase of the study, the dose determined to be safe will be used with temozolomide during and following radiation therapy to see if the combination can help patients with brain tumors live longer.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Glioblastoma Multiforme, Gliosarcoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
72 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Experimental
Arm Description
The Phase 1 consisted of the dose escalation of enzastaurin in 2 cohorts of up to 6 patients to assess maximum tolerated dose (MTD). Cohort 1 = radiotherapy/enzastaurin 250 mg per day/temozolomide 75 mg/m^2 therapy. The 6 initial cohort patients were clinically evaluated for dose-limiting toxicities (DLT). If no more than 1 of 6 patients experienced a DLT or tumor progression, patients continued 1 complete adjuvant enzastaurin/temozolomide 28-day cycle. If there was no significant toxicity after the first adjuvant cycle, participants received subsequent adjuvant enzastaurin/temozolomide cycles. If no more than 1 of the 6 initial cohort participants treated at 250 mg of enzastaurin experienced a DLT during radiotherapy and the first adjuvant cycle, up to 6 more participants could be entered at 500 mg of enzastaurin. The Phase 2, using the MTD determined in the Phase 1 (250 mg), evaluated the combination's safety and measured OS.
Intervention Type
Drug
Intervention Name(s)
enzastaurin
Other Intervention Name(s)
LY317615
Intervention Description
Phase 1 - 250 mg Cohort 1 with one dose escalation allowed to 500 mg for Cohort 2, oral, daily, 6 weeks then twelve 28 day cycles
Phase 2 - Phase 1 established dose, oral, daily, 6 weeks then twelve 28 day cycles
Intervention Type
Drug
Intervention Name(s)
temozolomide
Intervention Description
75 milligrams per meter squared (mg/m^2), oral, daily, 6 weeks then 200 mg/m^2, oral, daily, twelve 28 day cycles
Intervention Type
Radiation
Intervention Name(s)
radiation therapy
Intervention Description
1.8-2.0 Gy x 30 fractions, 5 days/week, for 6 weeks
Primary Outcome Measure Information:
Title
Phase 1- Determination of the Maximum Tolerated Dose (MTD) of Enzastaurin
Description
Phase 1- dose escalation of enzastaurin in 2 cohorts up to 6 participants each in order to assess MTD. After radiation/enzastaurin 250 mg per day/temozolomide 75 mg/m^2 therapy, if no more than 1 of 6 patients experienced a dose-limiting toxicity (DLT) or tumor progression, participants completed one 28-day cycle. If no significant toxicity after the first cycle, participants received subsequent cycles. If no more than 1 of the 6 patients treated at 250 mg of enzastaurin experienced a DLT, up to 6 more patients could be entered at escalated dose cohort of enzastaurin (500 mg).
Time Frame
Until MTD can be determined (up to 12 cycles, 28 days per cycle)
Title
Phase 1 and Phase 2 - Overall Survival (OS)
Description
OS is the time from surgical diagnosis to the date of death from any cause. For participants who were alive, OS was censored at the last contact.
Time Frame
Baseline to death from any cause (Up to 48 weeks)
Secondary Outcome Measure Information:
Title
Phase 1 - Number of Participants With Adverse Events (AEs)
Description
Summaries of serious AEs (SAEs) and all other non-serious AEs are located in the Reported Adverse Event Module.
Time Frame
Every cycle (up to 12 cycles, 28 days per cycle)
Title
Phase 1 and 2: Association Between Biomarkers and Clinical Outcome
Description
Phosphorylated-S6 (pS6) ribosomal protein is a biomarker that's being investigated as a potential marker for clinical outcome using 2211 or 2215 antibody to pS6. Reported here are the hazard ratios and 95% confidence intervals (CIs) for participants for whom an pS6 immunohistochemistry (IHC) score was available. The IHC assays were scored using a 0 to +3 scoring system (no positive staining was scored 0; at least 25% immunoreactivity of cells was scored +1; 26% to 75% was scored +2; and 76% or greater was scored +3). Hazard ratio (HR) > 1 indicates worse outcome for that IHC score.
Time Frame
Baseline, Cycle 2, end of study (up to 12 cycles, 28 days per cycle)
Title
Phase 1 - Response Rate With Macdonald Criteria
Description
Response categories: complete response (CR): disappearance of all enhancing tumor on consecutive magnetic resonance imaging (MRI) scans at least 1 month apart, off steroids, and neurologically stable or improved. Partial response (PR): 50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, and neurologically stable or improved. Progressive disease (PD): >25% increase in size of enhancing tumor or any new tumor on MRI scans, or neurologically worse, and steroids stable or increased. Stable disease (SD): all other situations.
Time Frame
Baseline, following radiation, every other cycle (up to 12 cycles, 28 days per cycle)
Title
Phase 2 - Number of Participants With Adverse Events (AEs)
Description
Summaries of serious AEs (SAEs) and all other non-serious AEs are located in the Reported Adverse Event Module.
Time Frame
Every cycle (28 days per cycle)
Title
Number of Participants Undergoing Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy (MRI/MRS) for Clinical Evaluation at Baseline
Description
Number of patients having MRI/MRS for clinical evaluation with baseline assessment.
Time Frame
Each radiologic assessment (up to 12 cycles, 28 days per cycle)
Title
Phase 1 and 2 - Progression-Free Survival (PFS)
Description
PFS was defined as the time from date of first dose to the first observation of disease progression, or death due to any cause.
Time Frame
Baseline to measured progressive disease (up to 12 cycles, 28 days per cycle)
Title
Functional Assessment of Cancer Therapy - Brain (FACT-Br)
Description
Total FACT-Br score includes physical well-being, social/family well-being, emotional well-being, functional well-being and additional concerns related to brain tumors. The score ranges 0 to 200, with a higher score representing better quality of life.
Time Frame
Every cycle (up to 12 cycles, 28 days per cycle)
Title
M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT)
Description
General and brain tumor-specific symptoms each assessed on a scale of 0 to 10, with a higher score representing higher symptom burden. The 4 symptom scales reported as changing over the course of the study are listed here.
Time Frame
Every cycle (up to 12 cycles, 28 days per cycle)
Title
Phase 1- Pharmacokinetics (PK): Maximum Observed Drug Concentration During 1 Dosing Interval at Steady State (Cmax,ss) for Enzastaurin, LY326020, and Total Analyte (Enzastaurin + LY326020) When Enzastaurin Administered With or Without Temozolomide
Description
Cmax,ss was calculated using concentration versus time data of enzastaurin, LY326020, and Total Analyte (enzastaurin + LY326020) when 250 mg or 500 mg enzastaurin was administered alone or with 75 mg/m^2 temozolomide. Data are reported as Geometric Mean and Geometric Coefficient of Variation (%).
Time Frame
Cycle 1 Day 22, Cycle 2 Day 5, 28 days per Cycle
Title
Phase 1 and 2- Pharmacokinetics: Area Under the Concentration-Time Curve During 1 Dosing Interval at Steady State (AUCτ,ss) for Enzastaurin, LY326020 and Total Analyte (Enzastaurin + LY326020) When Enzastaurin Administered With or Without Temozolomide
Description
AUCτ,ss was calculated using concentration versus time data of enzastaurin, LY326020, and total analyte (enzastaurin + LY326020). Data are reported as Geometric Mean and Geometric Coefficient of Variation (%).
Time Frame
Phase 1, Cycle 1 Day 22, Cycle 2 Day 5 of a 28 day Cycle; Phase 2, Cycle 1 Day 22 of a 28 day Cycle
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients must have a histologically confirmed diagnosis of intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS).
Biopsy or resection must have been performed no more than 5 weeks prior to treatment.
An MRI or CT scan must be obtained within 14 days prior to treatment.
Patients must not have received prior drug therapy for brain tumors.
Patients must have adequate organ function demonstrated by lab tests within 14 days prior to treatment.
Exclusion Criteria:
Patients will be excluded if unable to swallow tablets.
Patients will be excluded if unable to discontinue use of enzyme inducing antiepileptic drugs or have been off of these agents less than 2 weeks prior to treatment (i.e. phenytoin (Dilantin®), carbamazepine, etc.).
Patients will be excluded if have active infection.
Patients will be excluded if have a significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.
Patients will be excluded if they have concurrent therapy with an anticoagulant. If the patient requires anticoagulant therapy after starting treatment, the patient may remain on study but should be monitored carefully.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Organizational Affiliation
Eli Lilly and Company
Official's Role
Study Director
Facility Information:
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559), Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician
City
San Francisco
State/Province
California
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Phase 1/2 Study of Enzastaurin in Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma (GS) Patients
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