Phase 1/2 Study of Enzastaurin in Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma (GS) Patients

Study Overview
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Brief Summary
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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.

Official Title
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Phase 1/2 Study of Enzastaurin Plus Temozolomide During and Following Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

Conditions
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Glioblastoma, Glioblastoma Multiforme, Gliosarcoma

Intervention / Treatment
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* Drug: enzastaurin
* Drug: temozolomide
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>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. | Drug: enzastaurin<br>* 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<br>* Other names: LY317615;Drug: temozolomide<br>* 75 milligrams per meter squared (mg/m^2), oral, daily, 6 weeks then 200 mg/m^2, oral, daily, twelve 28 day cycles<br>Radiation: radiation therapy<br>* 1.8-2.0 Gy x 30 fractions, 5 days/week, for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Until MTD can be determined (up to 12 cycles, 28 days per cycle) | 
| 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. | Baseline to death from any cause (Up to 48 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every cycle (up to 12 cycles, 28 days per cycle) | 
| 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. | Baseline, Cycle 2, end of study (up to 12 cycles, 28 days per cycle) | 
| 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. | Baseline, following radiation, every other cycle (up to 12 cycles, 28 days per cycle) | 
| 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. | Every cycle (28 days per cycle) | 
| 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. | Each radiologic assessment (up to 12 cycles, 28 days per cycle) | 
| 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. | Baseline to measured progressive disease (up to 12 cycles, 28 days per cycle) | 
| 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. | Every cycle (up to 12 cycles, 28 days per cycle) | 
| 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. | Every cycle (up to 12 cycles, 28 days per cycle) | 
| 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 (%). | Cycle 1 Day 22, Cycle 2 Day 5, 28 days per Cycle | 
| 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 (%). | 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 |