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

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• Glioblastoma 1,920
• Gliosarcoma 238

Glioblastoma

1,920 studies on the registry are indexed under Glioblastoma; 450 are open to participants now.

This study's enrollment of 72 is above the median of 36 across 1,618 interventional studies indexed under Glioblastoma.

Lead sponsor

Eli Lilly and Company is the lead sponsor of 2,048 studies on the registry; 140 are open to participants now.

Of its 521 completed or terminated interventional studies of FDA-regulated products, 341 (65%) have results posted.

Study arms

• Experimental
  A

  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 · Drug: temozolomide · Radiation: radiation therapy

Interventions

• Drugenzastaurin

  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

  Also known as: LY317615

• Drugtemozolomide

  75 milligrams per meter squared (mg/m\^2), oral, daily, 6 weeks then 200 mg/m\^2, oral, daily, twelve 28 day cycles

• Radiationradiation therapy

  1.8-2.0 Gy x 30 fractions, 5 days/week, for 6 weeks

Primary outcomes

1. 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).

   Time frame: Until MTD can be determined (up to 12 cycles, 28 days per cycle)

2. 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.

   Time frame: Baseline to death from any cause (Up to 48 weeks)

Secondary outcomes

1. 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.

   Time frame: Every cycle (up to 12 cycles, 28 days per cycle)

2. 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.

   Time frame: Baseline, Cycle 2, end of study (up to 12 cycles, 28 days per cycle)

3. 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.

   Time frame: Baseline, following radiation, every other cycle (up to 12 cycles, 28 days per cycle)

4. 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.

   Time frame: Every cycle (28 days per cycle)

5. 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.

   Time frame: Each radiologic assessment (up to 12 cycles, 28 days per cycle)

6. 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.

   Time frame: Baseline to measured progressive disease (up to 12 cycles, 28 days per cycle)

7. 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.

   Time frame: Every cycle (up to 12 cycles, 28 days per cycle)

8. 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.

   Time frame: Every cycle (up to 12 cycles, 28 days per cycle)

9. 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 (%).

   Time frame: Cycle 1 Day 22, Cycle 2 Day 5, 28 days per Cycle

10. 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 (%).

    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

Baseline characteristics