Enzastaurin Before and Concomitant With Radiation, Followed by Enzastaurin in Participants With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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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.

Official Title
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Enzastaurin Before and Concomitant With Radiation Therapy, Followed by Enzastaurin Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma Without Methylation of the Promoter Gene of MGMT Enzyme - a Phase II Study

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Enzastaurin 500 milligram (mg) Once Daily (QD)
* Drug: Enzastaurin 250 mg Twice Daily (BID)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzastaurin Once Daily (QD)<br>Enzastaurin given orally (PO) once daily (QD). 1125 mg loading dose D(-)7 then 500 mg PO,QD with concomitant radiotherapy. | Drug: Enzastaurin 500 milligram (mg) Once Daily (QD)<br>* 1125 mg loading dose D(-)7 then 500 mg QD, oral, daily until disease progression, given with and without radiotherapy treatment.<br>* Other names: LY317615;|
| Experimental: Enzastaurin Twice Daily (BID)<br>Enzastaurin 1125 mg loading dose D(-)7 then 250 mg twice daily (BID) PO, with concomitant radiotherapy. | Drug: Enzastaurin 250 mg Twice Daily (BID)<br>* 1125 mg loading dose D(-)7 then 250 mg BID, oral, daily until disease progression, given with and without radiotherapy treatment.<br>* Other names: LY317615;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 1 and 2 year | 
| 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. | Baseline to 30 months | 
| 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. | Baseline through Week 12 . |