Glioblastoma Multiforme
Conditions
Brief summary
The purpose of the protocol was to induce a novel radiochemotherapy with enzastaurin as first-line treatment regimen in glioblastoma: Participants with active, unmethylated MGMT promoter were treated with enzastaurin before, concomitant, and after radiotherapy to determine safety and PFS at 6 months (PFS-6) in phase II.
Interventions
DRUGEnzastaurin 500 milligram (mg) Once Daily (QD)
1125 mg loading dose D(-)7 then 500 mg QD, oral, daily until disease progression, given with and without radiotherapy treatment.
DRUGEnzastaurin 250 mg Twice Daily (BID)
1125 mg loading dose D(-)7 then 250 mg BID, oral, daily until disease progression, given with and without radiotherapy treatment.
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Present with newly diagnosed histologically proven supratentorial GBM. * Demonstration of an unmethylated MGMT-promotor * Participants must sign an informed consent document. Participants must be at least 18 years of age. * Estimated life expectancy of at least 12 weeks * Tumor tissue specimens (paraffin-embedded and/or frozen) from the GBM surgery or biopsy must be available for central pathology review and exploratory analysis of PKC-beta targets (for example, GSK3beta). * Disease evaluated by Gd-MRI (magnetic resonance imaging) within 72 hours postoperatively * Interval of greater than or equal to 2 and less than or equal to 4 weeks since surgery or biopsy * ECOG Performance Status of less than or equal to 2 * Adequate organ function including the following: * adequate bone marrow reserve: white blood cell (WBC) count greater than or equal to 3.0 X 109/L, absolute neutrophil count (ANC) greater than or equal to 1.5 X 109/L, platelet count greater than or equal to 75.0 X 109/L, and hemoglobin greater than or equal to 10.0 g/dL (greater than or equal to 6.2 mmol/L). * Hepatic: bilirubin less than or equal to 1.5 times the upper limit of normal (X ULN), alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) less than or equal to 2.5 X ULN, or less than or equal to 5 X ULN with liver metastases * Renal: serum creatinine less than or equal to 1.5 X ULN * Blood clotting: prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits * Participants must discontinue use of enzyme-inducing antiepileptic drugs (EIAEDs) greater than or equal to 14 days prior to study enrollment. The investigator may prescribe non-EIAEDs. Participants who must begin EIAED therapy while on study will be allowed to remain on study. * Clinically normal cardiac function without history of ischemic heart disease in the past 6 months and normal 12-lead electrocardiogram (ECG); no history of stroke
Exclusion criteria
* Have a prior malignancy (other than glioblastoma, or adequately treated carcinoma in situ of the cervix, or nonmelanoma skin cancer), unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence * Unable to undergo Gd MRI * Prior chemotherapy within the last 5 years * Prior chemotherapy for a brain tumor * Prior radiotherapy of the head * Are unable to discontinue use of carbamazepine, phenobarbital, and phenytoin * History of coagulation disorder associated with bleeding, or recurrent thrombotic events * Are receiving concurrent administration of anticoagulant therapy * Placement of Gliadel® wafer at surgery * Have a serious concomitant systemic disorder (for example, active infection including HIV, or cardiac disease) - participants who are pregnant, anticipate becoming pregnant within 6 months after study participation, or are currently breast-feeding * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Progression Free Survival at 6 Months (PFS-6) | Baseline to 6 months | PFS-6 is defined as the percentage of participants with PFS at 6 months from the date of diagnosis to the first date of objectively determined progressive disease (based on radiological assessment) or death from any cause. It is assumed that PFS follows an exponential distribution.Estimation using Kaplan-Meier technique. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Survival at 1 and 2 Years After Surgery | Baseline to 1 and 2 year | Overall survival (OS) time is defined as the time from the date of diagnosis to the date of death from any cause. For participants who are still alive at the time of analysis, survival time will be censored at the last contact date. OS rate at 1 year (respectively 2 years) is determined using the OS times. |
| Response Rate | Baseline to 30 months | Response rate is calculated as the number of participants with best response: complete response(CR: disappearance of all enhancing tumor on consecutive CT or magnetic resonance imaging (MRI) scans at least 1 month apart, off steroids, and neurologically stable or improved ) or partial response (PR:-50% reduction in size of enhancing tumor on consecutive CT or MRI scans at least 1 month apart, steroids stable or reduced, and neurologically stable or improved), divided by the number of participants treated, multiplied by 100. CR and PR were assessed according to the criteria defined by MacDonald et al. 1990. A CR or PR must be confirmed by a second assessment, performed ≥28 days after the first evidence of response. |
| Change in Neurologic Status as Measured by Mini Mental Status Questionnaire, Total Score | Baseline through Week 12 . | Mini Mental State Status questionnaire is 11 questions, total score can range from 0 to 30, with a higher score indicating better function and a negative change in baseline indicating decrease in cognitive function. |
Countries
Germany
Participant flow
Pre-assignment details
Completers were defined as participants who had failure event(progressive disease, death), or were off treatment or censored due to study completion. Participants completed follow-up after receiving 1 dose of study drug and a post dose efficacy evaluation.
Participants by arm
| Arm | Count |
|---|---|
| Enzastaurin Once Daily (QD) Enzastaurin given orally (PO) once daily (QD). 1125 mg loading dose D(-)7 then 500 mg PO,QD with concomitant radiotherapy. | 0 |
| Enzastaurin Twice Daily (BID) Enzastaurin 1125 mg loading dose D(-)7 then 250 mg twice daily (BID) PO. | 57 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Study Period 1 (Induction) | Adverse Event | 0 | 2 |
| Study Period 1 (Induction) | Death | 0 | 1 |
| Study Period 1 (Induction) | Progressive Disease | 0 | 1 |
Baseline characteristics
| Characteristic | Enzastaurin Twice Daily (BID) | Total | Enzastaurin Once Daily (QD) |
|---|---|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 11.29 | 55.6 years STANDARD_DEVIATION 11.29 | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 57 Participants | 57 Participants | — |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | — |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) White | 57 Participants | 57 Participants | — |
| Region of Enrollment Germany | 57 Participants | 57 Participants | 0 Participants |
| Sex: Female, Male Female | 21 Participants | 21 Participants | — |
| Sex: Female, Male Male | 36 Participants | 36 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 22 / 57 | 3 / 3 | 43 / 53 | 3 / 3 | 28 / 49 | 3 / 3 | 50 / 57 |
| serious Total, serious adverse events | 0 / 3 | 5 / 57 | 0 / 3 | 16 / 53 | 0 / 3 | 8 / 49 | 0 / 3 | 27 / 57 |
Outcome results
Primary
Percentage of Participants With Progression Free Survival at 6 Months (PFS-6)
PFS-6 is defined as the percentage of participants with PFS at 6 months from the date of diagnosis to the first date of objectively determined progressive disease (based on radiological assessment) or death from any cause. It is assumed that PFS follows an exponential distribution.Estimation using Kaplan-Meier technique.
Time frame: Baseline to 6 months
Population: All participants in BID arm who received at least one dose of study drug, BID, 4 participants were censored. Enzastaurin QD participants data not collected, as per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzastaurin Twice Daily (BID) | Percentage of Participants With Progression Free Survival at 6 Months (PFS-6) | 53.6 percentage of participants |
Secondary
Change in Neurologic Status as Measured by Mini Mental Status Questionnaire, Total Score
Mini Mental State Status questionnaire is 11 questions, total score can range from 0 to 30, with a higher score indicating better function and a negative change in baseline indicating decrease in cognitive function.
Time frame: Baseline through Week 12 .
Population: All participants in BID arm who received at least 1 dose of study drug and had evaluable data. Enzastaurin QD participants data not collected, as per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enzastaurin Twice Daily (BID) | Change in Neurologic Status as Measured by Mini Mental Status Questionnaire, Total Score | 28.3 units on a scale | Standard Deviation 4.86 |
Secondary
Percentage of Participants With Overall Survival at 1 and 2 Years After Surgery
Overall survival (OS) time is defined as the time from the date of diagnosis to the date of death from any cause. For participants who are still alive at the time of analysis, survival time will be censored at the last contact date. OS rate at 1 year (respectively 2 years) is determined using the OS times.
Time frame: Baseline to 1 and 2 year
Population: All participants in BID arm who received at least one dose of study drug, BID, 11 participants were censored. Enzastaurin QD participants data not collected, as per protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Enzastaurin Twice Daily (BID) | Percentage of Participants With Overall Survival at 1 and 2 Years After Surgery | 1 year | 63.0 percentage of participants |
| Enzastaurin Twice Daily (BID) | Percentage of Participants With Overall Survival at 1 and 2 Years After Surgery | 2 year | 27.0 percentage of participants |
Secondary
Response Rate
Response rate is calculated as the number of participants with best response: complete response(CR: disappearance of all enhancing tumor on consecutive CT or magnetic resonance imaging (MRI) scans at least 1 month apart, off steroids, and neurologically stable or improved ) or partial response (PR:-50% reduction in size of enhancing tumor on consecutive CT or MRI scans at least 1 month apart, steroids stable or reduced, and neurologically stable or improved), divided by the number of participants treated, multiplied by 100. CR and PR were assessed according to the criteria defined by MacDonald et al. 1990. A CR or PR must be confirmed by a second assessment, performed ≥28 days after the first evidence of response.
Time frame: Baseline to 30 months
Population: All participants in BID arm who received at least 1 dose of study drug. Enzastaurin QD participants data not collected, as per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzastaurin Twice Daily (BID) | Response Rate | 7.0 percentage of participants |